Published in the Bulletin of Experimental Treatments for AIDS January 1998 issue, by the San Francisco AIDS Foundation.

January 1998 Table of Contents

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Selected Highlights from Recent Conferences

Harvey S. Bartnof, MD

This article presents highlights from 3 recent conferences. The 35th annual meeting of the Infectious Disease Society of America (IDSA) was held in San Francisco, September 13-16, 1997. The 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) took place in Toronto, Ontario, September 28-October 1, 1997. Finally, the 6th European Conference on Clinical Aspects and Treatment of HIV Infection (ECCATHI) was held in Hamburg, Germany, October 11-15, 1997. Highlights cover anti-HIV therapies, new drug combinations and treatments for opportunistic infections. See also "Conference Highlights on Non-Nucleoside Reverse Transcriptase Inhibitors."

• Therapies for HIV/AIDS
• HIV Viral Load
• Double Protease Inhibitor Combinations
• New Therapies and Combinations
• Updated Trial Results
• HIV Therapy for Infants and Children
• Opportunistic Infections, Cancers and Other Conditions
• Infants and Children
• Epidemiology
• Miscellaneous

Therapies for HIV/AIDS

Can Prophylactic Antibiotics be Stopped after Response to HAART?

In the Netherlands, 50 patients stopped their Pneumocystis carinii pneumonia (PCP) prophylaxis (antibiotics taken to prevent the disease) after their CD4 cell counts rose in response to highly active antiretroviral therapy (HAART) while they were enrolled in an open, non-randomized study.

• Trimethoprim-sulfamethoxazole (TMP-SMX; Septra, Bactrim) use was discontinued after CD4 cell counts increased to greater than 200 CD4 cells/mm³ for more than 1 month
• 45 patients were taking primary PCP prophylaxis
• 5 were taking secondary prophylaxis (to prevent a second case of PCP)
• Follow-up CD4 cell counts and HIV viral load testing was done every 3 months after PCP prophylaxis was stopped
• If CD4 cell count decreased to below 200 CD4 cells/mm³, PCP prophylaxis was restarted
• 80% had undetectable viral load at the time prophylaxis was stopped; none of the other 20% had a viral load greater than 15,000 copies/mL
• 22% had not taken other anti-HIV therapy prior to HAART; the other 78% had taken other antiretrovirals prior to starting HAART
• Mean lowest CD4 cell count of the 50 patients was 89 CD4 cells/mm³; 77 cells/mm³ in the 5 patients taking PCP as secondary prophylaxis
• Mean CD4 cell count when TMP-SMX was stopped was 370 cells/mm³; 346 cells/mm³ in the secondary prophylaxis group
• Interim results showed no PCP after a median of 3.9 months (mean 6.4 months; range 0.4-30.5 months) of follow-up
• Mean follow-up time in secondary prophylaxis group was only 2.6 months
• None of 50 patients had to restart PCP prophylaxis
• Before stopping prophylaxis, some physicians would prefer to require that:
  • CD4 cell count greater be than 200 CD4 cells/mm³ for 3-6 months and
  • CD4 percentage increase to greater than 20% and
  • Viral load be undetectable HIV viral load for 3-6 months; and
  • PCP prophylaxis be restarted if CD4 cell count decreases below 200 cells/mm³ or if HIV viral load increases to greater than 10,000 copies/mL
• This study will continue for 2 years
• The authors conclude that the follow-up duration is too short to make any recommendations.

Before stopping any medication, always discuss the issue with your physician. Before HAART, 5% of all PCP cases occurred in HIV positive patients with a CD4 cell count greater than 200 cells/mm³. However, many had high HIV RNA viral loads (see also BETA, September 1997, page 52).

Schneider MME and others. Discontinuation of Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients with an increase of their CD4 cell counts (> 200 mm³), due to aggressive antiretroviral therapy. ICAAC. Abstract LB-11.

Thompson MA and others. Viral load and risk of specific opportunistic infections in patients with CD4 counts<300 cells/mm³ enrolled in CPCRA 036. IDSA. Abstract 555.

Patients Stop CMV after HAART

Eighteen patients in 2 studies agreed to stop their secondary cytomegalovirus (CMV) prophylaxis after responding to HAART. None developed CMV retinitis reactivation or progression

Study 1

• University of California at San Diego; study of 11 patients
• Median CD4 cell count when HAART started was 54 cells/mm³
• Median HIV viral load was 4.34 log copies/mL
• Median CD4 cell count when prophylaxis stopped was 172 cells/mm³
• Median HIV RNA viral load when prophylaxis stopped was 4.82 log copies/mL (only 2 had undetectable viral loads)
• CMV prophylaxis was stopped after a mean of 56 weeks
• After prophylaxis stopped, retinal photographs were taken every 2 weeks
• After a median of 161 days of being off CMV prophylaxis, none of the 11 patients had retinitis progression or reactivation
• Authors recommended larger studies to assess the safety of stopping CMV prophylaxis when HIV viral load is incompletely suppressed
• Authors concluded that lack of CMV progression suggests that HAART restored CMV-specific immunity even in patients without complete suppression of HIV viral load.

Saag M, Director AIDS Outpatient Clinic, University of Alabama,at Practical Management of HIV Disease in the Era of Resistance satellite symposium at 35^th IDSA.

Study 2

• University Germans Hospital in Spain, study of 7 patients
• Median CD4 cell count at time of CMV diagnosis was 35 cells/mm³
• Median HIV viral load at time of CMV diagnosis was 5.1 log copies/mL
• Requirements for stopping CMV prophylaxis after response to HAART:
  • CD4 cell count has increased to greater than 150 cells/mm³ and
  • HIV RNA viral load has become undetectable and
  • Qualitative PCR test for CMV has become negative and
  • Patients agree to frequent eye examinations (weekly for first 3 months then every 2 weeks)
• Secondary CMV prophylaxis was stopped after a mean of 3.5 months
• None relapsed after a median 9 months of follow-up (range of 9-12)
• After 9 months, median CD4 cell count was 300 cells/mm³.

Peter Ruane, MD, and colleagues from Tower Infectious Disease Medical Associates, suggested that routine eye examinations for CMV may not be necessary in patients whose lowest CD4 cell counts were less than 50 cells/mm³ and whose counts have increased significantly as a result of HAART. His medical group followed 503 HIV positive patients in 1996. Of the total, 285 patients had CD4 cell counts less than 50 cells/mm³ between 1994-1996. After HAART was initiated, those 285 patients had a mean maximum CD4 cell count of 127 cells/mm³. No new case of CMV disease has occurred from 1996 through May 1997, compared with 51 new cases of CMV disease in 1994. HIV RNA viral load changes were not stated in the abstract.

Most CMV retinitis progression occurs within 2-3 months after starting HAART, but other opportunistic infections have occurred later. PCP occurred after a mean of 110 days, Mycobacterium avium complex (MAC) disease in a mean of 64 days and tuberculosis (TB) in a mean of 72 days, according to Christian Michelet, MD, from the Hopital Pontchaillou in Rennes, France. According to Marc Jouan, MD, from the Hospital Pitié-Salpetrière in Paris, France, most disseminated MAC infections that occur within 3 months of starting HAART are in those who:

• still have a low CD4 cell count
• still have a high HIV viral load or
• are not adherent to drug regimens.

Casado JL and others. Evolution of cytomegalovirus retinitis in AIDS patients after protease inhibitors introduction. ICAAC. Abstract I-35.

Jouan M and others. Decreased incidence of disseminated MAC infection in 689 AIDS patients receiving antiretroviral treatment with protease inhibitors. ICAAC. Abstract I-30.

Michelet C and others. Opportunistic infection occurred under protease inhibitors in HIV patients. ICAAC. Abstract I-29.

Ruane P and others. Impact of new antiretroviral therapies on CMV disease, incidence and costs. ICAAC.

Abstract N-20.

Torriani FJ and others. Lack of progression after discontinuation of maintenance therapy for cytomegalovirus retinitis in AIDS patients responding to highly active antiretroviral therapy (HAART).

ICAAC. Abstract I-33.

Tural C and others. Long lasting remission of cytomegalovirus retinitis without maintenance therapy in HIVplus patients. ICAAC. Abstract I-36.

HAART Cocktails Do Not Fix Everything

According to several presentations, even when CD4 cell counts increase significantly and HIV viral loads become undetectable, people may still experience a variety of symptoms and opportunistic conditions.

• Wasting (weight loss) continued in approximately 25% who responded to HAART (described in later section)
• Hepatitis C viral loads did not change much in many patients coinfected with HIV and HCV (described in later section)
• Progressive multifocal leukoencephalopathy (PML) brain disease developed in a person with AIDS several months after excellent response to HAART including an undetectable HIV viral load (described in later section)
• Culturable, live HIV was detected in memory CD4 cells from all of 18 adherent patients who responded to HAART for up to 30 months as demonstrated by undetectable HIV RNA viral load and increased CD4 cell counts (Siciliano study)
• Use of 4-drug HAART cocktail for 1 year (including 2 protease inhibitors) did not preclude finding HIV RNA in lymph tissues of 4 of 6 patients who had undetectable blood HIV RNA viral load less than 50 copies/mL after 6 months (Aaron Diamond Center study)
• CD4/CD8 cell count ratios did not always return to normal after 1 year of 4-drug HAART, even if the cocktail effectively decreased HIV viral load to undetectable levels and increased CD4 cell counts significantly (Aaron Diamond Center study)
• Naive CD4 cells (cells that respond to new infectious agents) did not return to normal after 1 year of 4-drug HAART including double protease inhibitors, even if the cocktail is otherwise highly effective (Aaron Diamond Center study).

Berger D and others. Measurement of body weight and body cell mass in patients receiving highly active antiretroviral therapy (HAART). ICAAC. Abstract I-26.

Brosgart C and others. Cidofovir therapy for progressive multifocal leukoencephalopathy in two AIDS patients. ICAAC. Abstract I-5.

Mauss S and others. Influence of HIV protease inhibitors on hepatitis C viral load in individuals with HIV and HCV coinfection. ICAAC. Abstract H-26.

Pastor A and others. Hepatitis C virus and HIV viral load in co-infected patients undergoing anti-HIV-retroviral therapy. ICAAC. Abstract I-163.

Ribeiro AT and others. Correlation between body weight and plasma viral load in HIV patients treated by a protease inhibitor. ICAAC. Abstract I-27.

Rutschmann OT and others. Impact of HIV protease inhibitors on HCV viremia. ICAAC. Abstract I-165.

Siciliano R. Latent reservoir of HIV. ICAAC. Abstract S-36.

Talal A and others. Saquinavir in combination with AZT/3TC and ritonavir: a conventional BID regimen. ICAAC. Abstract I-208.

Can Indinavir be Taken Every 12 Hours at a Higher Dose?

Study 1

• Pilot study with 87 patients (20% women) in Baltimore and Nashville evaluated indinavir (Crixivan) 1,000 mg or 1,200 mg every 12 hours, combined with AZT/3TC, compared to standard indinavir 800 mg every 8 hours plus AZT/3TC
• Study required no prior 3TC or protease inhibitor use, HIV RNA viral load greater than 10,000 copies/mL and CD4 cell count between 150-500 cells/mm³.
• Mean baseline CD4 cell count was 264-294 cells/mm³; viral load was 4.58-4.78 log copies/mL
• Interim results after 20 weeks in a small numbers of patients showed that CD4 cell count increased by 60 cells/mm³ in each twice-daily group and by 100 cells/mm³ in the 3-times daily group
• Viral load became undetectable (limit of detection 500 copies) in 75% of each twice-daily group and 50% of standard dosing group, with almost identical results using an ultrasensitive viral load test with a limit of detection 50 copies/mL
• Interim adverse events included nausea and vomiting in 54-56% of all 3 groups; serious adverse events were experienced by 13% in 1,200 mg indinavir group (no increase in kidney stones), 0% in 1,000 mg group and 3% in standard dose group
• 20% discontinued participation in 1,200 mg group, 14% in 1,000 mg group and 34% in standard dose group
• Limitations of the interim report: small number of patients reaching 20 weeks; trough (lowest) levels of indinavir were not measured in the twice-daily group

Study 2

• Prospective study of 29 patients (31% women) in Barcelona, Spain
• 43% had no prior HIV therapy
• Indinavir at 1,200 mg plus d4T/3TC, each every 12 hours was "most common regimen" (used by 65%)
• Baseline CD4 cell count and HIV viral load were not stated in abstract
• After 3 months, viral load was undetectable (limit of detection 200 copies) in 83% (24 of 29); CD4 cell count changes and median viral load decreases were not stated in abstract
• 4 of 23 participants (17%) had stomach or intestinal problems causing 1 to withdraw from therapy and another to change back to indinavir at 800 mg every 8 hours; 1 of 23 (4%) developed a kidney stone
• Indinavir drug trough levels prior to a dose were not stated in abstract

The authors concluded that their preliminary data showed that a twice daily regimen of indinavir 1,200 mg in combination was as well tolerated as the standard regimen of 800 mg every 8 hours, leading to similar antiviral efficacy.

Mallolas J and others. Efficacy and tolerance of indinavir twice daily. Abstract 225, 35th IDSA

Nguyen B-Y and others. A pilot, multicenter, open-label, randomized study to compare the safety and activity of indinavir sulfate administered every 8 hours versus every 12 hours in combination with zidovudine and lamivudine. ICAAC. Abstract I-91.

Pilot Study of Nelfinavir Taken Twice Daily

• Ongoing study of 10 patients with no prior HIV therapy
• 1,250 mg nelfinavir plus d4T/3TC taken twice daily
• At entry, participants were treatment-naive and had CD4 cell counts greater than or equal to 100 cells/mm³ and HIV RNA viral loads greater than or equal to 15,000 copies/mL
• Mean baseline CD4 cell count was 340 cells/mm³ and mean HIV viral load was 162,537 copies/mL
• Interim results at 16 weeks for 9 patients (1 of the 10 was lost to follow-up) were presented
• Mean CD4 cell count was increase 75 cells/mm³
• Viral load became undetectable (limit of detection of detection 400 copies) in 100%
• No serious adverse events were reported; 4 of 9 reported transient, moderate diarrhea and 3 of 9 reported nausea
• All 9 were adherent with drug regimen
• Nelfinavir drug level before the second dose was not reported in abstract
• A large trial in 24 European centers using this regimen is currently underway.

Sension M and others. An open-label study to assess the safety and efficacy of BID dosing of Viracept (nelfinavir mesylate) combined with stavudine (d4T) plus lamivudine (3TC) in HIV-infected treatment-naive patients. ECCATHI.

Once Daily ddI

Five abstracts were presented on studies of ddI (Videx) taken once daily in combination with d4T and in some cases a protease inhibitor. The long intracellular half-life (time for half of an original amount to be metabolized) of ddI permits once daily dosing at 300-400 mg.

Study 1 (Petrak)

• Ongoing 12-month, open-label study of 50 HIV positive North American patients (15% women)
• Prior nucleoside analog therapy was permitted. but no prior protease inhibitor therapy allowed
• Study permitted participants with a CD4 cell count of 200 cells/mm³ or less and HIV RNA viral load of 10,000 copies/mL or greater
• Baseline median CD4 cell count was 95 cells/mm³; baseline viral load was 25,090 copies/mL
• ddI 400 mg once daily was taken with 20 mL of double strength antacid such as Mylanta plus d4T 40 mg every 12 hours plus indinavir 800 mg every 8 hours
• Patients were instructed to take indinavir and d4T first, wait 1 hour, then take ddI with Mylanta, then allow one-half hour before eating
• Interim results after 6 months in 22 of 27 adherent patients (including 4 women) were presented
• Median increase in CD4 cell count was 164 cells/mm³
• By 4 weeks, viral load decreased a median of 1.7 log copies/mL
• Viral load was undetectable (limit of detection 500 copies) in 94% of participants
• 56% of patients who failed prior AZT/3TC achieved undetectable viral load after 1 month
• 2 patients had stomach or intestinal pain which resolved; 2 had peripheral neuropathy (medications were discontinued); 3 had a recurrence of herpes simplex or varicella zoster (shingles); 1 was hospitalized for heat stroke unrelated to therapy
• Authors concluded that this triple combination including once daily ddI was well-tolerated and led to significant improvements in surrogate markers

Study 2 (Reynes)

• Pilot study of 52 patients in France with no prior HIV therapy and a baseline CD4 cell count of 100-500 cells/mm³
• Regimen was once daily ddI 300 mg plus d4T 40 mg every 12 hours (if weight was less than 60 kg, ddI dose was 200 mg and d4T dose was 30 mg)
• Mean baseline CD4 cell count was 330 cells/mm³ and mean HIV RNA viral load (using Quantiplex 2.0 test) was 4.5 log copies/mL
• After 24 weeks mean CD4 cell count increase was 139 cells/mm³
• Mean HIV RNA viral load decreased 1.48 log copies/mL
• 62% achieved undetectable viral load
• 14% (7 of 52) discontinued therapy by 24 weeks; 4% had peripheral neuropathy, 2% had low platelet cell count, 2% had psychiatric disturbance; 6% were poorly adherence or were lost to follow-up
• Authors concluded that regimen was safe, had potent immunologic effects and was acceptable to participants

Study 3 (Martinez)

• Prospective study of 80 patients (22% women) in Barcelona, Spain, with no prior HIV therapy
• Mean baseline CD4 cell count was 178 cells/mm³ and mean viral load was 4.9 log copies/mL
• 2 regimens were used: once daily ddI plus twice daily d4T with or without saquinavir, and once daily ddI plus indinavir plus either AZT or d4T
• After 3 months in 23 patients mean viral load decrease was 1.9 log copies/mL
• Viral load was undetectable (limit of detection 200 copies) in 10 of 23 (43%), all of whom were taking a protease inhibitor
• Mean CD4 cell count increase was 86 cells/mm³
• 9% experienced gastrointestinal distress, half of whom withdrew from study
• Authors concluded that once daily ddI should be further studied

In addition to the 3 above studies, a University of Texas study (Keiser) used ddI monotherapy in 16 patients. Twice daily and once daily use led to similar 8-week HIV viral load reductions. A London study (Khaksar) looked at ddI as part of 2-3 drug regimen in 38 patients (treatment duration was not stated in abstract). Finally, a study in Paris (Kirstetter) used a regimen of ddI/d4T for 6 months in 14 patients. Five experienced virologic failure and 2 experienced neuropathy.

Keiser P and others. An open label, pilot study of the efficacy and tolerability of once daily versus twice-daily ddI. IDSA. Abstract 210.

Khaksar S and others. Once daily didanosine antiretroviral therapy for HIV disease (London). ECCATHI. Abstract 449.

Kirstetter M and others. Combination of once daily administration of didanosine and stavudine in naive patients. A pilot study. ECCATHI. Abstract 365.

Martinez E and others. Safety and efficacy of once-daily dosing of didanosine (Barcelona). IDSA.Abstract 211.

Petrak R and others. A study to evaluate the clinical and virologic efficacy of a Crixivan, ddI and d4T combination. ICAAC. Abstract 215.

Reynes J and others. Stadi pilot study: once daily administration of didanosine in combination with stavudine in antiretroviral naive patients. ICAAC. Abstract I-128a. Also ECCATHI. Abstract 253.

Is HAART Effective for Everyone?

Several reports at ICAAC suggested that HAART is not effective for all HIV positive people, and that the degree of success may be more limited than initially anticipated. However, if treatment guidelines are followed and patients are adherent with drug regimens, results are good.

Response to HAART at SFGH

• Retrospective chart review of 196 patients at San Francisco General Hospital (SFGH) with 3 or more clinic visits between March 1996 and March 1997
• Participants started and maintained indinavir or ritonavir therapy for 24 weeks or longer, and received at least 2 viral load tests during that time
• HAART success was defined as having undetectable results on their 2 most recent viral load tests (limit of detection 500 copies/mL). Failure was defined as detectable viral load on the 2 most recent tests
• Median baseline CD4 cell count was 129 cells/mm³ and HIV viral load was 4.67 log copies/mL
• After 6 months, 47% (64 of 137) had undetectable viral load ("durable and potent response") while 53% failed therapy
• Viral load was undetectable in 58-69% of patients who adhered to drug regimen
• Viral load was undetectable in 10-20% of patients who did not adhere to regimen
• Viral load undetectable in 85% if nucleoside analog drugs were started or changed when indinavir or ritonavir was started and if patient adherent to regimen
• In multivariate analysis, drug failure was 4 times more likely if baseline viral load was greater than 100,000 copies/mL, 4 times more likely if baseline CD4 cell count was less than 200 cells/mm³, 14 times more likely if there was no change in nucleoside analogs when ritonavir or indinavir was started, and 15 times more likely if a patient was not adherent.

The current IAS-USA and DHHS HIV treatment guidelines (see BETA, June 1997) that recommend starting or changing regimens with at least 2-3 anti-HIV drugs had not yet been published when this data was being collected (through March 1997). It is likely that the overall success of HAART would be more successful if the study were repeated today. It is quite possible that many of the "failures" in this study that had low but detectable viral loads will remain free of disease without clinical progression for many years. The results underscore the importance of adherence to drug regimens and the need to change or add at least 2 new drugs when making a therapeutic intervention.

Deeks S and others. Incidence and predictors of virologic failure to indinavir or/and ritonavir in an urban health clinic. ICAAC. Abstract LB-2.

Low Undetectable Viral Load Rates in Clinical Practice

• California Clinical Trials Group study of 97 patients
• Mean baseline CD4 cell count was 140 cells/mm³ and mean viral load 4.8 log copies/mL
• At baseline 48 of 97 (49%) were taking triple HIV therapy including a protease inhibitor
• After 6 months, viral load was undetectable (limit of detection 400 copies) in 15 of 44 (34%)
• Authors concluded that the reason for low rate of undetectable viral load may be due to extensive prior HIV therapy, non-adherence or drug resistance.

Haubrich R and others. Low rate of maximal suppression of HIV-1 RNA in a trial of RNA monitoring in clinical practice. ICAAC. Abstract I-128b.

Some HIV Positive Homeless Can Adhere to HAART Regimens

• 86% of 91 San Francisco homeless patients continued in the study for 6 months; 67% were injection drug users
• Patients received a median 6 health care provider visits annually
• 19% were prescribed HAART
• A mean of 4.4 doses of HAART per week were not taken
• 33% of those taking HAART missed more than 10% of prescribed doses.

Bangsberg D and others. Protease inhibitors in HIV-infected homeless and marginally housed adults. ICAAC. Abstract I-180.

HIV Viral Load

Viral Load Change May Not be Due to Anti-HIV Therapy

• Increase or decrease of 0.7 log copies/mL (5-fold) may be due to a combination of measurement error, test assay variability and/or biological variation in HIV RNA measurements
• Guidelines that define a 0.5 log change as significant may be too low.

Bartlett JA and others. What rises or reductions in HIV-1 RNA are clinically significant? ICAAC. Abstract I-135.

Viral Load and Influenza Vaccine

• Study of 29 patients (7% women)
• An inverse relationship was seen between blood plasma viral load and antibody response to vaccine; the higher the viral load, the less the immune system responds to influenza vaccine
• 6 of 8 (75%) of those with viral load less than 4 log copies/mL, 6 of 12 (50%) of those with viral load between 4-5 log, and 1 of 9 (11%) of those with viral load greater than 5 log had a significant (4-fold or greater) increases in influenza antibody levels
• A significant, direct relationship between CD4 cell count and vaccine response was seen
• 1 of 12 (8%) of those with CD4 cell counts less than 100 cells/mm³ and 12 of 17 (71%) of those with CD4 cell counts greater than 100 cells/mm³ had a significant increase in influenza antibodies
• No correlation was seen between HIV therapy status or age and influenza antibody increases due to vaccine
• The authors concludes that either high viral load or low CD4 cell count are associated with a markedly impaired immune response to influenza vaccine
• Delaying vaccine until after a therapeutic response to HAART has occurred may allow for improved antibody responses.
• In a second study assessing response to influenza vaccine, 75% of 16 HIV positive patients with a baseline CD4 cell count of 200 cells/mm³ or greater had a significant antibody response.

Fuller JD and others. High viral load is associated with decreased antibody response to influenza vaccination. IDSA. Abstract 187.

Reboli AC and others. The serologic response and late effects on viral load and CD4 count of influenza vaccination in HIV-infected patients with CD4 counts 200 cells/mm³. IDSA. Abstract 516.

Duration of Viral Load Suppression Correlates with Lowest Viral Load Level

• In the INCAS trials, a median of 154 days of viral load suppression was achieved for those whose lowest viral load measurement was less than 20 copies/mL, compared to a median of 7 days of viral load suppression for those whose lowest viral load level did not reach 20 copies/mL.
• Baseline viral load did not statistically correlate with duration of suppression in a multivariate analysis (see next report for different results).

Raboud JM and others. Predictors of duration of plasma viral load suppression. ICAAC. Abstract A-14.

Baseline Viral Load Predicts Likelihood and Durability of Undetectable Viral Load

• 1,076 patients from 6 clinical trials treated with AZT/3TC were studied for up to 52 weeks
• Mean baseline CD4 cell count was 202 cells/mm³ and mean viral load was 63,095 copies/mL
• 512 patients had no prior anti-HIV therapy and 564 had prior therapy
• Results at 48 weeks were highly significant in the group with no prior anti-HIV therapy
• 72% had undetectable viral load (limit of detection 400 copies/mL) if baseline viral load less than 5,000 cop/mL
• 32% had undetectable viral load if baseline viral load was 5,001-20,000 copies/mL
• 17% had undetectable viral load if baseline viral load was 20,001-50,000 copies/mL
• 14% had undetectable viral load if baseline viral load was 50,001-200,000 copies/mL
• 0% had undetectable viral load if baseline viral load was greater than 200,001 copies/mL
• Results were similarly significant for the group with prior HIV therapies, but with lower overall rates of sustained undetectable viral load
• Baseline CD4 cell count was not predictive of sustained viral load reductions
• The authors concluded that potent combinations of HIV therapy should be used when the baseline HIV viral load is greater than 5,000 copies/mL to increase the chance of sustained viral load suppression.

Opravil M and others. Baseline HIV RNA determines the durability of RNA suppression during AZT/3TC treatment. ICAAC. Abstract I-130.

AIDS Progression Uncommon When Viral Load is Suppressed to Less than 5,000 Copies/mL

• 1,448 patients from 6 controlled trials taking AZT/3TC
• 195 (13%) progressed to AIDS within 1 year
• 188 of 195 (96%) progressors experienced treatment failure (viral load greater than 5,000 copies/mL)
• 7 of 195 (4%) of progressors had viral load less than 5,000 copies/mL
• Of 323 patients with viral load less than 5,000 copies/mL, only 7 (2%) progressed (2 developed lymphoma, 1 developed CMV retinitis, 2 deaths unrelated to HIV/AIDS and 2 demonstrated a viral load increase shortly after progression
• The authors concluded that the viral load level required to prevent disease progression may be higher than the level required to delay the development of drug resistance; however, the latter would eventually lead to a higher viral load and disease progression.

Staszewski S and others. Progression to AIDS very rare when HIV-1 RNA below 5,000 copies/mL. ICAAC. Abstract I-129.

Higher CD4 Cell Increase from HAART Occurs if Baseline CD8 Cell Count is Low

• Low baseline HIV viral load also predicts lesser increase in CD4 cell count
• The authors concluded that another mechanism for CD4 cell count depletion must be occurring other than direct HIV viral destruction.

Keita-Perse O and others. Does viral load at initiation of tritherapy influence the increase of CD4 T-cell count? ICAAC. Abstract A-18.

Indinavir Non-Responders Have Lower Blood Levels of Drug than Responders

• Responders were defined as those with undetectable HIV viral load (less than 500 copies/mL)
• Blood levels of drug may vary considerably even in adherent patients
• 1 non-responding, adherent patient had adequate indinavir blood levels only 58% of the time
• 1 study with triple therapy with indinavir/nevirapine/3TC found that a significant decrease in blood viral load correlated with subtherapeutic levels of indinavir, even with therapeutic levels of nevirapine
• Some authors conclude that measuring indinavir blood levels may be helpful in understanding failure of anti-HIV therapy and in monitoring patients.

Acosta EP and others. Indinavir pharmacokinetics and relationships between exposure and antiviral effect. ICAAC. Abstract A-15.

Burger DM and others. Therapeutic drug monitoring of the HIV protease inhibitor indinavir. ICAAC. Abstract A-19.

Harris M and others. Virologic response to indinavir/nevirapine/3TC correlates with indinavir trough concentrations. ICAAC. Abstract I-173.

Harris M and others. Cumulative antiviral effect (CAVE): a valuable tool to assess the impact of antiretroviral therapy. ECCATHI. Abstract 412.

Rectal HIV Viral Load Measurements Do Not Always Correlate with Blood Plasma Levels

• Small study of 10 subjects with 40 visits and samples
• 15% had detectable rectal viral load when plasma viral load was undetectable
• 9% had at least 0.5 log copies/mL higher viral load in rectum than in blood plasma
• Results also support the concept of differing viral load and response to antiretroviral therapy in various body compartments.
• Authors caution that results may have public health implications regarding anal sex.

Celum CL and others. HIV viral load in rectal mucosa and plasma: implications for pathogenesis studies and transmission. IDSA. Abstract 195.

Benefits from HAART

Several reports documented continued declining AIDS illnesses, hospitalizations and deaths in developed countries due to HAART. Various studies showed decreases in the rates of CMV disease including retinitis, MAC, tuberculosis, toxoplasmosis (brain infection), microsporidiosis, cryptosporidiosis, PML, cryptococcal meningitis (infection of brain coverings) and oral candidiasis (including fluconazole-resistant candidiasis). HAART also:

• Completely cleared severe AIDS dementia in a 38-year-old woman with AIDS taking indinavir/AZT/3TC
• Caused a remission of diarrhea due to microsporidiosis in 15 patients.
• Improved survival from PML in 29 patients from Germany (survival greater than 500 days with HAART compared to a survival of only 123 days with combination nucleoside therapy or 127 days if anti-HIV therapy was stopped after PML was diagnosed.
• Led to a partial restoration of lymph gland architecture in 2 people with AIDS, including reformation of lymphoid follicles, regrowth of B-lymphocytes and reappearance of T-cells
• Led to increases in total white cells, platelet cells (necessary for normal blood clotting) and hemoglobin
• Reversed the abnormal decrease in neutrophil (white blood cell) adhesion caused by HIV
• Improved CD8 lymphocyte counts.

Albrecht H and others. Highly active antiretroviral therapy (HAART) significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. ICAAC. Abstract I-34. Also IDSA. Abstract 512.

Baril L and others. The impact of highly active antiretroviral therapy on the incidence of CMV disease in AIDS patients. ICAAC. Abstract I-31.

Bermudes RA and others. The effect of initiating protease inhibitor therapy on hospitalization rates and quality of life in HIVplus patients. ICAAC. Abstract I-182.

Conejero JM and others. Reduction in progression to AIDS and death since the introduction of protease inhibitors. ICAAC. Abstract I-181.

Duval X and others. HIV protease inhibitors decrease the risk of cytomegalovirus disease in HIV-infected patients with CMV viremia. ICAAC. Abstract I-37.

Feinberg M and others. Histologic changes associated with 4-drug combination therapy in antiretroviral naive HIV-infected persons. IDSA. Abstract 772.

Gendelman HE and others. HIV-1 dementia: a metabolic encephalopathy abrogated by Highly Active AntiRetroviral Therapy (HAART). IDSA. Abstract 550.

Goguel J and others. Remission of AIDS-associated intestinal microsporidiosis with combined antiretroviral therapy. ICAAC. Abstract I-32.

Hood S and others. Decreasing incidence of oropharyngeal candidiasis in an HIV cohort following the introduction of proteinase inhibitors. ICAAC. Abstract I-28.

Jouan M and others. Decreased incidence of disseminated MAC infection in 689 AIDS patients receiving antiretroviral treatment with protease inhibitors. ICAAC. Abstract I-30

Le Moing V and others. Decrease of intestinal cryptosporidiosis prevalence in HIV-infected patients concomitant to diffusion of protease inhibitors. ICAAC. Abstract I-38.

Martins MD and others. Declining rates of symptomatic oropharyngeal candidiasis carriage of Candida albicans and fluconazole resistance in HIV patients. IDSA. Abstract 138.

Michelet C and others. Opportunistic infection occurred under protease inhibitors in HIV patients. ICAAC. Abstract I-29.

Moore D and others. Reversal of abnormalities of neutrophil adhesion molecule expression in HIV infection following protease inhibitor therapy. ICAAC. Abstract I-74.

Moore RD and others. Effectiveness of combination antiretroviral therapy in clinical practice. ICAAC. Abstract I-176.

O’Donovan C and others. The impact of protease inhibitors on HIV infected patients. ICAAC. Abstract I-177.

Palella F and others. Declining morbidity and mortality in an ambulatory HIV-infected population. ICAAC. Abstract I-17.

Perez-Elias MJ and others. Indinavir and ritonavir effectiveness in HIV patients with a CD4 count below 50 cells/mL and more than a year of previous nucleoside analogue treatment. A specialized outpatient clinic experience. ICAAC. Abstract I-178.

Rosenberg E and others. Vigorous HIV-1 specific CD4plus T cell responses correlate with control of viremia. IDSA. Abstract 767.

Double Protease Inhibitor Combinations

Ritonavir plus Indinavir is a Promising Regimen

Twice daily ritonavir plus indinavir, 400 mg of each, is a promising regimen.

• Combination of ritonair plus indinavir, 400 mg each twice daily, leads to lower peak levels and 3-6- fold higher trough levels of indinavir than standard dose indinavir (800 mg every 8 hours)
• Indinavir exposure ("area under curve") is similar to that of standard monotherapy dose
• Indinavir half-life increased from 2 to 5.8 hours
• No effect seen on levels of ritonavir, when compared to standard dose
• Adherence is likely to be higher with twice-daily versus 3-times-daily dosing of indinavir.

Hsu A and others. Evaluation of potential ritonavir and indinavir combination BID regimens. ICAAC. Abstract A-57.

Nelfinavir plus Saquinavir is an Effective Combination

Study 1 (SPICE study)

• Study of 157 patients (10% women) in randomized open-label 48-week study
• Participants used 2-4 drugs; 54% had no previous HIV therapy
• Entry viral load was greater than or equal to 5,000 copies/mL
• 54% were treatment-naive; all were able to start at least 1 new nucleoside analog drug
• 4 regimens were used: nelfinavir 750 mg every 8 hours plus saquinavir soft-gel 800 mg every 8 hours with or without 2 nucleoside analogs; 2 nucleoside analogs with nelfinavir or saquinavir soft-gel capsule (11% of treatment-experienced patients in nucleoside analog groups started 2 new nucleoside analogs)
• Mean baseline CD4 cell count was 307 cells/mm³ and mean HIV viral load was 4.8 log copies/mL

• At 16 weeks in 133 patients, mean CD4 cell count increase 90-110 cells/mm³ mean decrease in viral load using a test with a limit of detection of 400 copies was 1.6-1.9 log (1.9 log in 4-drug group); mean decrease in viral load using a test with a limit of detection of 50 copies was 2.0-2.6 log (2.6 log in 4-drug group)
• Viral load became undetectable (limit of detection 400 copies) in 84% in 4-drug group, in greater than 90% of 4-drug group participants with no prior HIV therapy, in 76% of the saquinavir plus 2 nucleoside analog group, in 57% of the nelfinavir play saquinavir group, and in 50% of the nelfinavir plus saquinavir group)
• Viral load became undetectable (limit of detection 50 cop) in 57% of saquinavir plus 2 nucleoside analog group, in 49% of the 4-drug group, in 32% of the nelfinavir plus 2 nucleoside analog group, and in 28% of the nelfinavir plus saquinavir group
• Side effects experienced inlcuded diarrhea (19-46%), nausea (8-19%), abdominal pain (2-8%), vomitting (2-8%), fatigue (0-6%), weakness (0-8%), joint aches (2-8%)
• 6-15% of each group discontinued or crossed-over into another group
• Study is continuing to 48 weeks
• The authors concluded that a 4-drug combination including nelfinavir plus saquinavir-soft gel shows a potent initial viral load suppression and is reasonably well tolerated

Study 2 (Ottawa, Ontario)

• 14 patients (7% women) in open-label study for 12 months
• Participants used 2-4 drugs; no previous protease inhibitor use
• Nelfinavir used at standard dose of 750 mg every 8 hours plus saquinavir soft-gel capsule at reduced dose of 800 mg every 8 hours with or without 1 or 2 nucleoside analog drugs (AZT or 3TC or d4T)
• Entry criteria included a CD4 cell count of 25-500 cells/mm³ and an HIV viral load greater than 20,000 copies/mL. Participants had no previous protease inhibitor therapy, were on a stable nucleoside analog regimen or had a "washout period"
• Median baseline CD4 cell count was 327 cells/mm³ and mean viral load was 39,917 copies/mL. 11 of 14 had taken prior nucleoside drugs while 3 had not
• After 11 months (in 10 patients), viral load became undetectable (limit of detection 500 copies/mL) in 90%
• Median viral load decreased by 2.1 log copies/mL
• Median CD4 cell count increased by 175 cells/mm³
• After 20-35 weeks (in 12 patients), the common nelfinavir mutation D30N was not detected, and the common saquinavir mutations L90M or G48V were found in 4 of 13 and was associated with an increase in HIV viral load
• Side effects were moderate and included diarrhea in 43% (83% of these were found to have intestinal parasites), headaches (21%), rectal gas (14%), and heartburn, abdominal pain, abdominal cramps, weakness and pain in legs (7% each)
• No serious treatment-related side effects and no clinically significant abnormal laboratory abnormalities were found.

Kravcik S and others. Protease gene mutations and long-term follow-up of HIV-infected patients treated with Viracept (nelfinavir mesylate) plus saquinavir-soft gel capsule. ICAAC. Abstract I-191

Posniak A and others. NV15436 study of protease inhibitors in combination in Europe (SPICE); (saquinavir [soft gel] plus nelfinavir). ECCATHI. Abstract and oral presentation 209.

Ritonavir plus Saquinavir Leads to Undetectable Viral Load in Cerebrospinal Fluid

Study 1

• Open-label, randomized study of 141 patients no protease inhibitor drug use and nucleoside analog use discontinued, at several North American locations; cerebrospinal fluid (CSF) data was available for 13 patients
• Participants received ritonavir plus saquinavir, 400-600 mg each twice daily or 400 mg of each 3 times daily, for 60 weeks; nucleoside analog drugs were discontinued at the start of therapy
• Median baseline CD4 cell count was 264 cells/mm³ and viral load was 57,000 copies/mL in the 13 patients in CSF substudy
• After 48-60 weeks, blood plasma viral load was undetectable in 90% of 109 patients after 48 weeks of follow-up
• CSF viral load was undetectable (limit of detection 400 copies) in 12 of 13 (92%); 13th patient (with drug doses 600 mg each) had CSF viral load of 650 copies/mL and plasma level less than 200 copies/mL
• Of 109 patients completing 48 weeks, the fewest discontinuations due to drug adverse events was in the 400 mg-400 mg group
• Drug levels in CSF are still being evaluated; CSF white cell count data were not presented
• The authors concluded that for HIV positive patients without protease inhibitor experience, the double protease combination of ritonavir plus saquinavir, 400 mg each every 12 hours, is the best tolerated. It leads to significant rates of undetectable viral load within 1 year in both blood plasma and CSF

Study 2

• A case report from London described the detection of a CSF viral load of 13,800 copies/mL and a plasma viral load of 1,800 copies/mL in a patient taking ritonavir plus saquinavir for at least 2 weeks. The patient did not have meningitis.
• The authors concluded that a combination of 2 protease inhibitors alone may not provide sufficient antiviral effect in the brain to prevent HIV dementia. They continued that the CSF may "function as a sanctuary site and source of drug-resistant escape mutations."
• While the plasma viral load was reasonably low, the patient may not have been taking therapy long enough to achieve undetectable levels in either body compartment.

Farthing C and others. Cerebrospinal fluid (CSF) and plasma HIV RNA suppression with ritonavir-saquinavir in protease inhibitor naive patients. ICAAC. Abstract LB-3.

Moyle GJ and others. Pharmacokinetics of saquinavir at steady state in CSF and plasma: correlation between plasma and CSF viral load in patients on saquinavir containing regimens. ICAAC. Abstract 235.

4-Drug Combination Twice Daily Leads to 100% Undetectable Viral Load

• All participants had never taken protease inhibitor drugs or 3TC, 80% had never taken any antiretroviral drugs at all.
• 12 patients at Aaron Diamond Center in New York City with early to chronic HIV infection; 80% had never taken any anti-HIV therapy and 100% had never taken protease inhibitors or 3TC; duration of HIV infection ranged from 90 days to 8 years
• Regimen consisted of ritonavir 400 mg every 12 hours (after 21 days, increased to 500 mg for 7 days and then to 600 mg) plus saquinavir 400 mg every 12 hours (after 42 days, saquinavir increased to 600 mg every 12 hours) plus AZT 300 mg every 12 hours (later changed to d4T every 12 hours in 3 patients) plus 3TC 150 mg every 12 hours. AZT/3TC were added on study day 14
• Mean baseline CD4 cell count was 385 cells/mm³ and mean HIV viral load was 5.3 log copies/mL
• At 48 weeks in 10 patients, the median CD4 cell count increase was 86 cells/mm³
• At 16 weeks, median viral load decrease was 3.7 log copies/mL
• At 24 weeks, 100% of patients (10 of 10) had undetectable viral load (limit of detection 50 copies); at 48 weeks, 100% of patients (9 of 9) had undetectable viral load (limit of detection 25 copies)
• At 48 weeks, 7 of 10 had negative lymphoid tissue (lymph node, tonsil or intestinal lymph tissue) cultures for HIV even after CD8 cells were removed in vitro
• At 48 weeks, 4 of 4 patients tested had negative CSF HIV cultures
• 2 of 6 tonsil lymph tissue did have multispliced HIV RNA consistent with RNA of regulatory genes not RNA-associated with active HIV reproduction
• 2 patients withdrew from study due to increased liver enzymes (1 had grade 4, life threatening elevation; 1 of those 2 was replaced in the study)
• Gastrointestinal side effects including nausea and diarrhea were common, leading to the withdrawal of 1 patient
• 2 patients changed from AZT to d4T due to nausea
• The authors concluded that this 4 drug regimen including double protease inhibitor therapy leads to a quick, significant and persistently undetectable reduction of HIV viral load in 100% of patients who can tolerate the drugs.

Talal A and others. Saquinavir in combination with AZT/3TC and ritonavir: a conventional BID regimen. ICAAC.Abstract I-208.

Ritonavir plus Saquinavir Added to AZT plus 3TC (4 Drugs Twice Daily)

• Pilot phase II open-label study of 16 patients in France (ANRS 069 study)
• Regimen included ritonavir 600 mg plus saquinavir 400 mg, every 12 hours
• At entry, patients had been taking AZT/3TC for greater than 3 months (no previous protease inhibitors) and had a CD4 cell count less than 200 cells/mm³ and HIV viral load greater than 20,000 copies/mL
• Mean baseline CD4 cell count was 103 cells/mm³ and mean HIV viral load was 4.86 log copies/mL; mean prior antiretroviral therapy was 49 months (i.e., extensive prior nucleoside treatment)
• After 24 weeks, mean CD4 cell count increase was 93 cells/mm³
• Median viral load decrease was 3.0 log copies/mL
• Viral load became undetectable (limit of detection 200 copies) in 62% (10 of 16)
• Side effects included elevated blood triglycerides (94%), diarrhea (69%), numbness around the mouth (31%), hot flushes (25%), taste impairment (25%) and increased liver enzymes (19%)
• 56% (9 of 16) had ritonavir dose reductions due to adverse events (6 patients reduced to 500 mg twice daily and 3 patients to 400 mg twice daily)
• The authors concluded that ritonavir plus saquinavir added to a regimen of AZT/3TC in patients without prior protease inhibitor experience leads to impressive surrogate marker data.

Michelet C and others. Safety and efficacy of a combination of ritonavir and saquinavir added to AZT plus 3TC in HIV-infected patients. ICAAC. Abstract I-202.

4-Drug Therapy in People with Advanced AIDS

• 58 patients were included in observational study for 48 weeks; 69% had prior protease inhibitor therapy and 90% had prior therapy with nucleoside analog drugs
• Median baseline CD4 cell count was 175 cells/mm³ and HIV viral load was 5.0 log copies/mL
• 69% had prior protease inhibitor experience and 90% had prior therapy with nucleoside analogs
• Regimen consisted of ritonavir plus saquinavir plus 3TC plus either AZT or d4T
• After a mean follow-up of 25 weeks, the maximal CD4 cell count increase was 141 cells/mm³
• Maximal viral load reduction was 2.2 log copies/mL
• Viral load was undetectable in 63%
• Therapy failed in 41%, defined as failure to achieve undetectable viral load
• Patients without prior protease inhibitor therapy were more likely to respond to quadruple therapy (55%) than patients with protease inhibitor experience (40%)
• Side effects were similar to those already reported for the drugs, including diarrhea (36%), nausea (12%) and rash (2%)
• 10% stopped treatment due to adverse events.

Kaufmann G and others. Efficacy of a 4-drug combination therapy including 2 protease inhibitors in patients with advanced HIV-1 illness. ICAAC. Abstract I-200.

Ritonavir plus Saquinavir plus 2 Nucleoside Analogs in Treatment-Experienced Patients

• Retrospective analysis of all 58 patients in Vancouver taking ritonavir 600 mg plus saquinavir 600 mg, both every 12 hours for 2 months or longer, plus currently prescribed nucleoside analog drugs
• 38% had prior protease inhibitor therapy and most had prior nucleoside analog therapy
• Median baseline CD4 cell count was 130 cells/mm³ and HIV viral load was 4.8 log copies/mL
• After a median 5.4 months, median CD4 cell count increase was 80 cells/mm³
• Median viral load decrease was 1.85 log copies/mL
• Viral load became undetectable (limit of detection 500 copies) in 49%
• Those with no prior protease inhibitor therapy were 4.5 times more likely to achieve undetectable viral load than those with prior protease inhibitor experience
• Adverse drug events included nausea, vomiting and diarrhea (41% each) and insomnia and rash (3% each)
• 12% discontinued therapy, including 5% due to nausea, vomiting or diarrhea and 3% due to increasing HIV viral load (3% lost to death unrelated to therapy)
• The authors concluded that ritonavir plus saquinavir is effective in suppressing HIV viral load in patients previously treated with nucleoside analog drugs, although prior protease inhibitor therapy limits these benefits markedly
• Surrogate marker benefits may have been even better if one or more of baseline nucleoside analog drugs had been changed.

Rhone SA and others. The antiviral effect of ritonavir and saquinavir among HIV infected adults: preliminary results from a community based study. ICAAC. Abstract I-207.

Drugs Combinations After Failing Nelfinavir

Study 1 (St. Paul, MN)

• 19 patients rolled over from studies 506 (11 patients), 511 (1 patient) and 525 (7 patients)
• Regimen consisted of ritonavir 400 mg plus saquinavir 400 mg plus d4T 40 mg plus 3TC 150 mg, all taken every 12 hours
• Mean baseline CD4 cell count was 109-226 cells/mm³ and mean viral load was 60,948-233,667 copies/mL
• Nelfinavir had been used for a mean of 30-41 weeks
• At baseline, 13 of 16 (81%) had D30N resistance mutations (associated with nelfinavir resistance), 2 of 16 (13%) had L90M mutation (saquinavir resistance), 7 of 11 (64%) had M184V mutation (3TC resistance) and 8 of 11 (73%) had other nucleoside analog drug resistance mutations
• At week 16 in 7 patients from studies 506 and 511, mean CD4 cell count increase was 80 cells/mm³ , mean viral load decrease was 1.4 log copies/mL, and viral load was undetectable (limit of detection 500 copies) in 6 of 7, though viral load level increased after week 8; at week 24, viral load was undetectable in 5 of 7 (71%)
• At 16 weeks in 4 patients from Study 525, mean viral load decrease was 0.6 log copies/mL and viral load was undetectable in 43%

Study 2 (New York City)

• Open-label pilot retrospective study of 12 patients
• Nelfinavir had been taken for 3 months or longer (median 11 months) with a loss of HIV viral "containment"
• Participants were switched to ritonavir/saquinavir plus 1-2 nucleoside analogs or to indinavir plus 2 nucleoside analogs (AZT/3TC or d4T/ddI)
• Median baseline CD4 cell count at time of switch was 289 cells/mm³ and viral load was 4.5 log copies/mL
• After 8 weeks, the median viral load reduction was 0.46 log (0.55 log if switch was to ritonavir/saquinavir regimen, 0.21 log if switch was to indinavir regimen)
• Viral load was undetectable in 3 of 12 (25%) (2 in the indinavir group and 1 in the ritonavir/saquinavir group)
• 3 viral load response patterns were noted after 8 weeks: durable response (3 of 12), transient response (4 of 12) and no response (5 of 12)
• The authors concluded that in patients without prior protease inhibitor experience who are failing nelfinavir combination therapy, a switch to a new single or double protease inhibitor 3- or 4-drug combination leads to a smaller than expected reduction in HIV viral load or none at all. However, a minority do reach an undetectable viral load in the short run. Drug resistance correlation might help predict those who will respond.

Henry K and others. Experience with a ritonavir/saquinavir based regimen for the treatment of HIV-infection in subjects developing increased viral loads while receiving nelfinavir. ICAAC. Abstract I-204.

Sampson MS and others (presentation by Barr M). Viral load changes in nelfinavir treated patients switched to a second protease inhibitor after loss of viral suppression. ICAAC. Abstract LB-5.

Ritonavir plus Saquinavir after Failing Indinavir or Other Protease Inhibitors

Study 1 (San Francisco)

• Open-label study with 19 patients (5% women)
• Regimen included ritonavir 400 mg plus saquinavir 400 mg, both every 12 hours and nucleoside analog drug modification if possible (6 of 19 had brief prior ritonavir experience; mean prior nucleoside analog therapy was 53 months)
• Median baseline CD4 cell count was 169 cells/mm³ and HIV viral load was 4.5 log copies/mL
• 11 of 19 (58%) had their nucleoside analog therapy changed at the time of the switch to ritonavir/saquinavir, mostly from AZT/3TC to d4T/3TC
• Viral load became undetectable (limit of detection 500 copies) in 7 of 19 at week 4, in 3 of 19 at week 12 and in 2 of 15 (13%) at week 24
• 9 of 12 who failed on therapy developed L90M saquinavir resistance mutation, compared to durable responders who did not develop the mutation
• The authors concluded that a ritonavir/saquinavir-containing 4-drug combination in patients who failed prior indinavir therapy lead to a potent but transient decrease in HIV viral load.

Study 2 (Spain)

• Study of 11 patients who had failed indinavir monotherapy (4) or different combination therapies (7)
• Regimen included ritonavir 400 mg plus saquinavir every 12 hours
• Mean baseline CD4 cell count 50 of cells/mm³ and HIV viral load of 4.9 log copies/mL
• Results for 8 of 11 patients who completed 24 weeks showed a ean CD4 cell count increase of 60 cells/mm³ and a mean viral load decreases of 1.3 log copies/mL
• 2 of 8 had the saquinavir resistance mutations L90M and G48V at baseline; saquinavir resistance mutations were present in 2 of 3 non-responders
• The authors concluded that patients who have failed indinavir therapy who did not have saquinavir mutations may be more likely to respond to ritonavir plus saquinavir

Study 3 (Albany, NY)

• Retrospective evaluation of 33 patients
• 23 of 33 had previously taken indinavir, 11 of 33 had taken ritonavir and 5 of 33 had taken saquinavir (some had taken more than 1 protease inhibitor); all had previously used nucleoside analog drugs
• Median baseline CD4 cell count was 61 cells/mm³ and HIV viral load was 197,273 copies/mL
• Results after 5 weeks in 33 patients showed a median CD4 cell count increase of 28 cells/mm³ and median decrease in viral load of 97,764 copies/mL to 99,509 copies/mL (percentage undetectable was not in abstract)
• Results after 22 weeks in 11 patients showed median CD4 cell count increase of 47 cells/mm³ and median decrease in viral load of 80,689 copies/mL (from 116,090 to 35,401) (percentage undetectable was not in abstract)
• 15 patients discontinued double protease inhibitor therapy due to drug toxicity (20%), elevated or increased HIV viral load (40%) or both (40%)
• No data were presented regarding type of prior protease inhibitor therapy and outcome, and no data was given on baseline resistance mutations
• The authors concluded that ritonavir plus saquinavir is of limited value in people with AIDS who have extensive previous treatment

Deeks S and others. Virologic effect of ritonavir plus saquinavir in subjects who have failed indinavir. ICAAC. Abstract I-205.

Piliero P and others. A retrospective evaluation of the combination of ritonavir and saquinavir in protease inhibitor experienced patients. IDSA. Abstract 230.

Puig T and others. Usefulness of ritonavir and saquinavir combination therapy for HIV-advanced patients failing on indinavir. ICAAC. Abstract I-201.

Ritonavir plus Saquinavir plus d4T is a Good Combination

• Open-label phase II study of approximately 60 patients (5% women) from Switzerland
• Regimen consisted of ritonavir 400-600 mg every 12 hours plus saquinavir 600 mg every 12 hours plus d4T 30-40 mg every 12 hours
• Entry criteria included a CD4 cell count less than 250 cells/mm³, HIV viral load greater than or equal to 10,000 copies/mL (subsequently increased to greater than 25,000 copies/mL), no or stable nucleoside analog therapy for 2 months or longer and no prior d4T or protease inhibitor therapy
• Mean baseline CD4 cell count 84 was cells/mm³ and HIV viral load was 5.2 log copies/mL
• After 9 weeks in 49 patients, mean CD4 cell count increase was 102 cells/mm³ and mean HIV viral load decrease was 2.5 log copies/mL
• Viral load became undetectable (limit of detection 500 copies) in 67% (33 of 49)
• 7 patients discontinued before week 9
• Side effects included fatigue (2), MAC infection (1), increased liver enzymes (1); 1 patient discontinued due to a kidney infection, and 2 patient discontinued by request
• Ritonavir levels were found to be therapeutic in 15 of 16 patients in which levels were measured, with corresponding 10-100-fold elevated levels of saquinavir; all 15 had significant viral load reductions and CD4 cell count increases.

Battegay M and others. A pilot study of saquinavir in combination with ritonavir and d4T in patients with advanced HIV disease. ICAAC. Abstract I-203.

Vernazza PL and others. Virologic assessment of a 9-week phase II combination study of saquinavir, ritonavir and d4T. ICAAC. Abstract I-209.

Ritonavir Added to Prolonged Saquinavir Monotherapy

• Mutation at codon 90 may predict a poor response
• Lack of mutations l90M or G48V indicated a more favorable response
• Study included 12 patients previously treated with saquinavir monotherapy for median 4.9 years
• New regimen included ritonavir 500 mg plus saquinavir 400 mg, each twice daily
• Median baseline CD4 cell count was 250 cells/mm³ and HIV viral load was 4.8 log copies/mL
• After 16 weeks in 11 patients, the median increase in CD4 cell count was 30 cells/mm³ and viral load decreased by 0.03 log copies/mL
• Results yielded 3 patterns, based on saquinavir mutations

* If no saquinavir mutations were present at baseline (3 of 11 patients), median increase in CD4 cell count was 80 cells/mm³ and viral load decrease was 2.0 log copies/mL

* If saquinavir mutation L90M was present at baseline (7 of 11 patients), median increase in CD4 cell count was 20 cells/mm³ and viral load increase was 0.22 log copies/mL (these patients did have a transient viral load decrease response at week 2)

* If both saquinavir mutations L90M and G48V were present at baseline (1 patient), CD4 cell count decreased by 50 cells/mm³ and viral load increased by 0.21 log copies/mL (no viral load response was seen, even initially)

• Mutation at codon 90 may predict a poor response
• Lack of mutations L90M and G48V indicates a more favorable response
• The authors concluded that a lack of saquinavir mutations may indicate a favorable response to combined double protease inhibitor therapy with ritonavir plus saquinavir
• Although this study is small, the results add more evidence for the benefits of drug resistance testing, particularly regarding which drugs to exclude from a regimen due to the presence of resistance mutations.

Pym AS and others. Presence of mutation at codon 90 may predict response to ritonavir-saquinavir combination therapy in HIV infected patients pre-treated with saquinavir monotherapy. ICAAC. Abstract I-193.

Ritonavir plus Saquinavir in Protease Inhibitor-Experienced Patients

• Open-label prospective study of 54 patients from St. Vincent’s Hospital in New York City
• Ritonavir was added to saquinavir-containing regimen, or saquinavir was added to ritonavir-containing regimen, or ritonavir plus saquinavir were added after a failing indiavir-containing combination was stopped
• Reason for changing of therapy was clinical failure (7%), virologic failure (increasing HIV viral load in 52%) or intolerance of drug (34% due to gastrointestinal symptoms)
• Mean baseline CD4 cell count was 166 cells/mm³ and HIV viral load was 4.65 log copies/mL
• At 12 weeks, mean viral load reduction was 0.55 log copies/mL (all 3 groups), 1.0 log (in ritonavir added group), 0.11 log (in saquinavir added group), and 0.34 log (in ritonavir and saquinavir added group)
• A greater than 0.5 log reduction in viral load was achieved by 29% (in ritonavir added group), 4% (in saquinavir added group) and 10% (in ritonavir and saquinavir added group)
• Results underscore the need to change 2 or more drugs when a patient is failing a regimen (although some patients in this study changed due to drug intolerance)
• Patients experienced with protease inhibitors in combination are less likely to respond to other protease inhibitor(s) in combination.

Sampson M and others. Ritonavir-saquinavir combination treatment in protease inhibitor experienced patients with advanced HIV disease. ICAAC. Abstract I-104.

Ritonavir plus Saquinavir After Failing Indinavir or Ritonavir Combinations

• Open-label prospective study in France of 24 patients (25% women)
• Reason for changing therapy was virologic failure (87%) or drug intolerance (12%)
• Prior protease inhibitors used were indinavir (75%) and ritonavir (25%), for a mean 7.3 months; prior nucleoside analog therapy duration was a mean 43 months
• Regimen included ritonavir 400-600 mg twice daily and saquinavir 400-600 mg twice daily
• Mean baseline CD4 cell count 107 was cells/mm³ and HIV viral load 5.06 log copies/mL
• After 4 months, mean CD4 cell count increase was 35 cells/mm3 and mean viral load decrease 0.45 log copies/mL
• Viral load undetectable (limit of detection 500 copies) 2 of 19 (11%)
• Adverse events include gastrointestinal distress (13%) and elevated liver enzymes (4%)
• The authors concludes that there is a lack of efficacy in ritonavir plus saquinavir combination in patients who have failed or are intolerant to either a ritonavir or an indinavir combination, with a limited but transient decrease in HIV viral load and an insignificant increase in CD4 cell count.

Batisse D and others. Efficacy and safety of ritonavir and saquinavir in combination in protease inhibitors-experienced patients. ICAAC. Abstract I-206.

ABT-378 plus Ritonavir

• ABT-378 (an experimental protease inhibitor from Abbott Laboratories) plus ritonavir is the most potent double protease inhibitor combination to date
• ABT-378 is 10 times more potent than ritonavir in vitro
• A single dose each of ABT-378 400 mg plus ritonavir 50 mg leads to a concentration of ABT-378 that is 32 times higher than the IC50 (concentration that inhibits 50% of HIV) in vivo 12 hours after dosing
• Single dose co-administration was well tolerated without serious side effects
• Blood concentrations of ABT-378 was not affected by food
• ABT-378 has low levels of cross-resistance with either indinavir or saquinavir.

Lal R and others. Single-dose pharmacokinetics of ABT-378 in combination with ritonavir. ICAAC. Abstract I-194.

Sun E. Targetting the flexible pit second-generation HIV protease inhibitors. IDSA. Abstract S60.

PNU-140690 plus Ritonavir is Effective

• PNU is an experimental non-peptide protease inhibitor
• In vitro synergy (enhanced effect of combining 2 drugs) was demonstrated for ritonavir-resistant HIV isolates.

Chong K and others. In vitro combination of HIV-1 protease inhibitor PNU-140690 with ritonavir against ritonavir sensitive and resistant clinical isolates. ICAAC. Abstract I-197.

KNI-272 Double Protease Combinations Studied in Rats

• Combining the experimental protease inhibitor KNI-272 and indinavir leads to a 6-fold increase of KNI-272 and a 2.6-fold increase of indinavir
• Combining KNI-272 and ritonavir leads to a 21-fold increase of KNI-272 (effect on ritonavir was not stated)
• KNI-272 plus saquinavir does not lead to a change in KNI-272 level (effect on saquinavir was not stated)
• All data are "area under the curve" concentration measurements.

Sato H and others. Altered pharmacokinetics of KNI-272 when co-administered with other protease inhibitors. ECCATHI. Abstract 334.

Nelfinavir After Previous Protease Inhibitor Failure

Study 1 (San Diego)

• After failing or not tolerating an indinavir- or ritonavir-containing regimen, a nelfinavir-containing combination was tried as alternate therapy
• 23 patients were in nelfinavir expanded access program after a median 29 days
• 92% had failed prior protease inhibitor therapy, while 8% were intolerant
• Median baseline CD4 cell count was 37 cells/mm³ and HIV viral load 5 log copies/mL
• After 1 month, the median CD4 cell count increase was 25 cells/mm³ (some decreased while others increased) and median viral load increase was 0.05 log copies/mL (some increased while others decreased)
• 52% had discordant CD4 and viral load responses, e.g., an increase in one and a decrease in the other
• Genotypic resistance mutations were not reported in the abstract
• No changes in quality of life measurements
• No apparent benefits in short term follow-up after 1 month

Study 2 (Denver, CO)

• After failing or not tolerating indinavir-, ritonavir-, or saquinavir-containing combinations, patients were given a nelfinavir-combination
• 16 patients were in nelfinavir expanded access program after 1 month
• The percentage failing versus not tolerating protease inhibitors was not stated
• Mean baseline CD4 cell count was 62 cells/mm³ (viral load not stated in abstract)
• 9 of 16 (56%) were still taking nelfinavir after a mean of 109 days
• All had a greater than 0.3 log copies/mL decrease in HIV viral load
• 8 of those 9 had a mean viral load decrease greater than 0.7 log copes/mL and a CD4 cell count increase of 28 cells/mm³
• 6 of those 8 were taking triple therapy, while 2 of the 8 were taking double therapy
• 7 of 16 (43%) no longer taking nelfinavir after taking the drug for a mean 78 days
• 4 of those 7 stopped nelfinavir due to failure to respond or HIV progression; 2 stopped due to adverse events
• A greater than 0.7 log copies/mL decrease in HIV viral load occurred among 7 patients taking nelfinavir-triple combination therapy compared to a 0.1 log copies/mL increase in HIV viral load among the 7 patients taking nelfinavir double combinations
• Nelfinavir genotypic resistance mutations were not reported in the abstract
• Adverse drug reaction occurred in 75%, most commonly diarrhea
• The authors conclude that nelfinavir-containing triple combinations may provide benefits to some patients who have failed or are intolerant to other protease inhibitor combinations

The results of the Denver study differ from those of the San Diego study, although the Denver report did not indicate in their abstract baseline viral load nor the percentages of patients failing versus intolerant to prior protease inhibitors. Also, the Denver patients who responded may have been those who were intolerant to (rather than failing) previous protease inhibitors and who had not developed protease inhibitor cross-resistance mutations.

Ballard C and others. Early CD4, viral load, and quality of life response to salvage treatment with nelfinavir: the UCSD Owen Clinic nelfinavir expanded access experience. ICAAC. Abstract I-192.

McNicholl IR and others. A descriptive report on 16 protease inhibitor experienced HIV positive patients receiving nelfinavir. ICAAC. Abstract I-196.

New Therapies and Combinations

4-Drug Combination Restores Lymph Nodes

• 7 patients at the National Institute of Allergy and Infectious Diseases (NIAID)
• Indinavir 1,000 mg every 8 hours plus nevirapine (Viramune) plus AZT/3TC; 3 of 7 subsequently changed from AZT to d4T
• Lymph node biopsies were done at baseline and 2 months after starting 4-drug therapy
• Baseline CD4 cell count less than 300 (3 patients) or greater than 500 cells/mm³ (4 patients); HIV viral load at baseline was not stated
• Viral load decreases after 4 months ranged from 1.5 to 3.5 log copies/mL; rate of decline in viral load was reported to be faster than in earlier reports on 3-drug HAART
• One woman had baseline viral load greater than 6 log copies/mL and CD4 cell count of 7 cells/mm³ and had taken no prior HIV therapies. Her baseline lymph node architecture on biopsy showed complete destruction. After 2 months, lymphoid follicles and germinal centers in lymph node were partially re-established, with reappearance of T and B lymphocytes. Her viral load decreased to less than 500 copies/mL and her CD4 cell count increased to more than 50 cells/mm³
• 3 other lymph node biopsies from other patients showed less dramatic changes
• Authors concluded that in HIV positive patients without prior HIV therapy who had severe lymph tissue disruption, HAART with 4 drugs (including 3 different HIV drug classes) achieved a partial restoration of lymph node architecture.

Feinberg M and others. Histologic changes associated with 4-drug combination therapy in antiretroviral naive HIV-infected persons. IDSA. Abstract 772.

Soft-Gel Saquinavir as Effective as Other Protease Inhibitors

Study 1 (NV15182)

• Open-label study of 442 HIV positive patients (10% women) who added soft-gel saquinavir (Fortovase) 1,200 mg every 8 hours to their anti-HIV drug regimen; less than 25% had prior therapy with protease inhibitors

• Mean baseline CD4 cell count was 227 cells/mm³ and HIV RNA viral load was 4.14 log copies/mL
• 96% had prior antiretroviral therapy for a mean of 3.9 years; 95% had prior experience with 2 or more reverse transcriptase inhibitors; 73% had taken 3TC, 65% AZT, 32% d4T, 12% ddC and 12% ddI.
• After 24 weeks, 43% had undetectable HIV viral load (limit of detection 400 copies/mL) including 75% of those who never took reverse transcriptase inhibitors before and 28% of those who had taken protease inhibitors before
• CD4 cell count increased an average of 80 cells/mm³, or by more than 200 cells/mm³ in those who had not previously taken HIV drugs
• 8% withdrew early due to adverse events related to Fortovase, including diarrhea (19%), nausea (10%), abdominal discomfort (9%), acid sensation (dyspepsia, 8%), gas (6%), headache (6%), fatigue (5%), vomiting (3%), abdominal pain (2%) and a marked increase in liver enzymes (2-3%); 1 hemophiliac patient had a stroke but was able to restart Fortovase and 1 patient was hospitalized to due severe diarrhea.

Study 2 (SUN Study)

• 42 patients in a 24-week open-label study, including an option to extend therapy to 48 weeks
• Fortovase 1,200 mg every 8 hours plus AZT 300 mg and 3TC 150 mg each every 12 hours
• Entry criteria required no prior HIV therapies; no chronic hepatitis B or C; CD4 cell count greater than 100 cells/mm³ and HIV RNA viral load greater than 10,000 copies/mL
• Mean baseline CD4 cell count was 419 cells/mm³ and viral load was 4.8 log (63,759) copies/mL.
• At week 16 in 26 patients, viral load was undetectable in 81% (limit of detection 400 copies/mL)
• Viral load was undetectable in 35% (limit of detection of Ultra-Direct PCR test 20 copies/mL)

• Mean viral load decreased 2.9 log copies/mL
• Mean CD4 cell count increased 170 cells/mm³

• Adverse events occurring in more than 5% of participants were nausea, vomiting, diarrhea and headaches

• 1 patient developed grade III (severe) elevation of liver enzymes at week 4 that resolved when therapy was stopped; another had grade IV (life-threatening) elevation of liver enzymes associated with acute hepatitis A viral infection
• 16 of 42 (38%) patients were not included in analysis; 6 were lost to follow-up, 4 refused treatment, 3 were non-adherent, 2 withdrew due to side effects and 1 missed the 16 week evaluation
• Authors concluded that triple combination therapy including Fortovase was effective and well-tolerated.

Study 3 (CHEESE study)

• 45 patients (13% women) enrolled in a 48-week randomized, open-label pilot study
• Fortovase 1,200 mg every 8 hours plus AZT 200 mg every 8 hours plus 3TC 150 mg every 12 hours, or indinavir 800 mg every 8 hours plus AZT/3TC (same doses)
• Entry criteria included prior AZT therapy for less than 12 months, but no prior protease inhibitor or 3TC experience; CD4 cell count less than 500 cells/mm³ and/or HIV viral load greater than 10,000 copies/mL and/or CDC classification B or C (symptomatic) HIV disease
• Mean baseline CD4 cell count was 296-310 cells/mm³ and viral load was 4.9 log copies/mL
• At week 12 (66% of 44 patients reached 12 weeks), viral load was undetectable (limit of detection 2.6 log copies/ml) in 100% (both groups)
• Significant 75 cells/mm³ CD4 cell count increase was seen in Fortovase group; CD4 cell count in indinavir group showed little change
• Side effects from Fortovase included diarrhea (29%), heartburn (10%), nausea (10%), headache (5%) and abdominal pain (5%); kidney stones occurred in 5% of indinavir group
• Authors concluded from interim data that Fortovase was as effective as indinavir when either was combined with AZT/3TC in terms of viral load suppression and CD4 cell count increases.

Borleffs JCC and others. Saquinavir soft-gelatine capsules versus indinavir as part of AZT and 3TC containing triple therapy. IDSA Abstract 219, ICAAC Abstract I-92 and ECCATHI Abstract 353.

Farthing C and others. Soft-gel capsule saquinavir in combination with AZT and 3TC in antiretroviral-naive HIV-1 infected patients. IDSA. Abstract 220.

Gill MJ and others. Safety of saquinavir soft-gelatin capsule in combination with other antiretroviral agents: multicenter study NV15182: 24-week analysis.

Sension M and others. Saquinavir soft-gel capsule in combination with AZT and 3TC in treatment-naive patients. ICAAC. Abstract I-190.

Soft-Gel Saquinavir plus 2 Nucleoside Analogs Normalized CD8 Counts

• Open-label trial of 23 patients; 17 were nucleoside analog-experienced and 6 were nucleoside analog-naive; all were protease inhibitor-naive; study ran for 8-24 weeks
• Mean baseline CD4 cell count was 316 cells/mm³ and viral load was 38,000 copies/mL
• At week 8, 74% had undetectable viral load undetectable; at week 24 CD4 cell count increased to 424 cells/mm³
• CD8 cell percentage significantly decreased from 61% to 53% at 8 weeks
• This is first protease inhibitor to demonstrate a return to a more normalized CD8 cell count (ritonavir and indinavir each increase CD8 cell counts).

Tsoukas C and others. Impact of saquinavir soft-gel capsules plus 2 reverse transcriptase inhibitors on reversing HIV induced immune dysregulation. ICAAC. Abstract I-73.

Indinavir/d4T plus 3TC or ddI as Effective as Indinavir/AZT/3TC

• 200 patients enrolled in 2 studies (START I and START II); 50% enrolled to date; patients had no prior HIV therapy
• Mean baseline CD4 cell count was 396-459 cells/mm3 and HIV viral load was 26,893-47,234 log copies/mL
• At 24 weeks in 47 patients, mean viral load reduction was 1.5-2 log copies/mL
• Viral load was undetectable (limit of detection 500 copies) in more than 75% of all groups (by 12 weeks)
• Viral load was undetectable in greater than 90% in both d4T-containing groups (indinavir/d4T/3TC and indinavir/d4T/ddI)
• "Minor" gastrointestinal side effects occurred in group receiving AZT.

Eron JJ. Current data on triple-drug therapy. Guidelines in Action Satellite symposium (Roche Pharmaceuticals) prior to ICAAC.

Gulick R and others. A 15-site, open-label, randomized, comparative study of stavudine + lamivudine + indinavir verses zidovudine + lamivudine + indinavir in treatment naive HIV-infected patients. ECCATHI. Abstract 433.

Knechten H and others. Combination therapy with stavudine (d4T), lamivudine (3TC) and indinavir in antiretroviral-naive and experienced HIV infected patients. ICAAC. Abstract I-107.

Murphy R and others. A 15-site, open-label, randomized, comparative study of stavudine + didanosine + indinavir versus zidovudine + lamivudine + indinavir in treatment naive HIV-infected patients. ECCATHI. Abstract 434.

1592 More Potent than AZT or 3TC

• The experimental nucleoside analog 1592 (abacavir) is more potent than AZT or 3TC against resting HIV-infected blood mononuclear cells in vitro.

Saavedra J and others. Comparative antiviral effect of zidovudine, lamivudine and 1592U89 on latently-infected cells. ICAAC. Abstract I-59.

MKC-442 Shows Benefits

• MKC-442 is a nucleoside analog drug that functions as a non-nucleoside reverse transcriptase inhibitor
• Drug showed benefit in Phase IB trials at a dose of 500 mg every 12 hours
• Side effects include headache, loose stools, rash and an anticipated increase in liver enzymes due to interaction with P450 enzyme system
• Only 1 of 6 patients stopped taking the drug, due to rash
• Half-life of 6-8 hours (time for half of an original dose to be metabolized).

Moxham CP and others. Preliminary efficacy and safety of MKC-442 in HIV-infected patients. ICAAC. Abstract I-61.

Saquinavir Combination Decreases AIDS and Death by 50%

Study 1 (SV 14604)

• Phase III trial of 3,485 patients; prior AZT therapy for 16 weeks or less was permitted; follow-up lasted 13-17 months
• 4 regimens were studied: hard-gel saquinavir (Invirase) plus AZT/ddC, Invirase/AZT, AZT/ddC, and AZT alone
• 8% experienced disease progression or death in the group receiving the triple combination compared to 15% in the AZT/ddC group and 12% in the Invirase/AZT group
• The triple therapy group had significantly larger CD4 cell count increases and HIV viral load decreases than the AZT/ddC group (actual numbers were not presented)
• This was the first study to demonstrate significant clinical benefit from Invirase/AZT/ddC when compared to double nucleoside analog therapy (AZT/ddC) in drug-naive patients

Study 2 (NV14256)

• 940 patients had prior AZT therapy for 16 weeks or longer and were followed-up for a median of 17 months
• 3 regimens were studied: Invirase/ddC, Invirase monotherapy and ddC monotherapy
• After a median 17 months, the Invirase/ddC group and the ddC monotherapy group each demonstrated a 38% decrease in HIV disease progression that correlated with a 2-fold increase in CD4 cell count and 3-fold decrease in HIV viral load.

Clumeck N and others. Changes in HIV-1 RNA from saquinavir use as predictors of risk of AIDS/death. ICAAC. Abstract LB-4.

Hughes MD and others. Changes in HIV-1 RNA from saquinavir use as predictors of risk of AIDS/death. ICAAC. Abstract I-133.

Hydroxyurea plus ddI plus d4T

• Study of 10 patients for 8 weeks using hydroxyurea (Hydrea)
• Significant increases in CD4 naive cells and insignificant increases in CD8 naive cells were recorded.
• Significant increase in CD4 cell count (baseline 206 cells/mm³; increase of 43 cells/mm³) for 10 patients and decrease in HIV viral load by 1.9 log copies/mL for 8 of 10 patients were reported (baseline viral load not stated).

Nokta MA and others. Partial immune restoration of HIV-infected patients on aggressive antiretroviral therapy (ddI, d4T and hydroxyurea). ICAAC. Abstract I-77.

Hydroxyurea and ddI

• Hydroxyurea substantially decreases the concentration of ddI necessary to inhibit HIV growth in vitro

Rana KZ and others. Reduction of the IC50 of didanosine by hydroxyurea against HIV. ICAAC. Abstract I-124.

Fusion Inhibitor T-20 Shows Benefits in Phase I/II Trials

• T-20 inhibited gp41 (HIV membrane protein) in mononuclear cells
• Open-label, dose-escalation study enrolled 16 HIV positive patients, either without or with previous HIV therapy (off drugs for 15 days).
• Entry criteria were a CD4 cell count greater than or equal to 100 cells/mm³ and HIV viral load greater than or equal to 10,000 copies/mL
• T-20 rapid intravenous (IV) infusion was given once on day 1, then no drug on days 2-3, then IV every 12 hours on days 4-14 (dose 3 mg, 10 mg, 30 mg or 100 mg); evaluation on day 14 (4 patients at each dose level)
• At 100 mg dosage, mean CD4 cell count increase was 52 cells/mm³ (lesser increase or decrease in lower dose groups)
• Mean viral load decrease was 1.5 log copies/mL (lesser decreases in lower dose groups)
• Viral load was undetectable (limit of detection 500 copies) in 100% (4 of 4 patients)
• All 4 of these patients had increased appetites
• No changes in blood cell counts or chemistries were recorded
• Fever from other causes was reported by 2 patients in the lower dose groups
• Authors concluded that short-term administration of T-20 fusion inhibitor was well-tolerated, safe and showed benefits on surrogate markers.

Saag M and others. A short-term assessment of the safety, pharmacokinetics and antiviral activity of T-20, an inhibitor of gp41 membrane fusion. IDSA. Abstract 771.

PNU-140690 Results Reported

• Phase I study of 60 patients
• Drug is a second generation non-peptide protease inhibitor, tested as a single dose
• Mild-to-moderate side effects included nausea, vomiting and diarrhea
• Blood levels 8 hours after 1 dose of 500 mg or greater suggest that this drug would have potent activity against HIV
• In vitro activity was demonstrated against HIV strains with resistance to nucleoside analog drugs and FDA-approved peptide protease inhibitors.

Borin M and others. Single-dose safety, tolerance, and pharmacokinetics of PNU-140690, a new HIV protease inhibitor, in healthy volunteers.

Thaisrivongs S and others. PNU-140690, a novel nonpeptidic inhibitor of the HIV protease. ECCATHI. Abstract 332.

AR177 Studies Showed No Adverse Effects

• AR177 (Zintevir) showed no adverse effects after 2 weeks in study of 16 patients
• Drug is a guanosine analog inhibitor of HIV integrase.

Wallace T and others. Single- and multiple-dose pharmacokinetics of AR177, an anti-HIV oligonucleotide, in humans. ICAAC. Abstract I-70.

PD173606 Effective When Protease Inhibitor Resistance Mutations are Present

• In vitro efficacy was demonstrated when protease inhibitor resistance mutations V32, V82 and I84 were present (these are common resistance mutations for ritonavir and indinavir)
• PD173606 is a non-peptide protease inhibitor unlike currently marketed drugs.

Sharmeen L and others. Antiviral activity of PD173606, PD177298, PD178390 and PD178392: non-peptidic HIV-1 protease inhibitors. ICAAC. Abstract I-64.

Tummino PJ and others. Biochemical characterization of dihydropyrone HIV-1 protease inhibitors with a novel resistance profile. ICAAC. Abstract I-62.

CXCR4 Receptor Antagonist AMD3100 Demonstrates Anti-HIV Effects in vitro

• No benefits against macrophage-tropic strains that use CCR5 receptor (see BETA, March 1997, page 22)
• AMD3100 is a bicyclam that has efficacy in nanomolar (extremely low concentration, 10^-9) range against both HIV-1 and HIV-2 (West African isolates).

Este JA and others. Inhibition of HIV-1 replication by the bicyclam AMD3100, a CXCR4 antagonist. ICAAC. Abstract I-66.

Kuritzkes DR. Pitting new drugs against HIV: advances in antiretroviral chemotherapy. IDSA. Abstract S59.

New Class of Anti-HIV Drugs Identified

• New class of inhibitors of HIV nuclear translocation
• CNI-H0294 has activity against HIV-infected macrophages in vitro.

Ussery MA and others. Antiviral activity in macrophages of CNI-H0294, a specific inhibitor of the nuclear translocation of the HIV-1 genome. ICAAC. Abstract I-65.

HIV Therapies Side Effects And Drug Interactions

"Buffalo Hump" Due to Indinavir

• Noticeable swelling due to fatty tissue deposits ("buffalo hump") in the middle of the upper back below the base of the neck in 3 gay/bisexual male patients (average age 47 years) seen at 1 infectious disease practice in Los Angeles
• Poster showed anonymous photographs revealing a 6x2.75 inch (15x7 cm) swelling on 1 patient’s back
• Swelling prevents patients from lying on their backs and has caused cosmetic concerns
• Patients complained of having to hold their necks in an "uncomfortable position while awake"
• Magnetic resonance imaging (MRI) scans revealed tissue with the same density as fat without a capsule
• Baseline CD4 cell count was less than 50 cells/mm³ in 2 of 3 patients; the other patient had a baseline count of less than 200 cells/mm³
• All 3 had extensive prior therapy with nucleoside reverse transcriptase inhibitor drugs
• For 2 patients, swelling occurred 6-7 months after starting triple therapy with indinavir, while the third was aware of a prior swelling that rapidly increased 2 months after starting the cocktail
• When the "humps" were noticed, the mean total weight gain was 4 pounds
• None appeared "cushingoid" (a particular body shape associated with excess hormonal production in the adrenal glands above each kidney) and serum cortisol levels were normal
• 1 patient is scheduled for surgery to remove the excess tissue; a second is considering the same surgery.

Ruane PJ. Atypical accumulations of fatty tissue. ICAAC. Abstract I-185.

Hypoglycemia Due to Protease Inhibitors

Studies indicate that symptomatic hyperglycemia (high blood sugar) due to protease inhibitors is more common than initially reported. A retrospective chart review from Newark showed that 5.7% (6 of 105) of patients taking protease inhibitors developed diabetes symptoms.

• Risk is increased if there is a family history of diabetes
• 2 patients required insulin injections; 2 required oral hypoglycemia pills; 2 controlled their symptoms with diet; 1 of 6 required hospitalization for nonketotic hyperosmolar state (severe diabetes complication) and protease inhibitor therapy was discontinued
• Symptoms occurred in 3 Caucasians, 2 African-Americans and 1 Hispanic
• Symptoms occurred within a mean of 3 months (range 2-4 months) after starting protease inhibitor therapy
• Of the remaining 94 patients 28 (30%) had blood glucose levels greater than 126 mg/dl and 8 (9%) had levels greater than 150 mg/dl during protease inhibitor therapy, all without symptoms of elevated blood sugar (note these levels were all increased when compared with glucose levels before protease inhibitor therapy)
• Authors concluded that protease inhibitor therapy was associated with impaired glucose homeostasis in a significant proportion of patients and overt symptomatic diabetes in a minority.

Dever LL and others. Hyperglycemia associated with protease inhibitors in HIV-infected patients. ICAAC. Abstract LB-8.

Hypersensitivity Reactions due to Protease Inhibitors

• 6% (22 of 384) patients from Italy had allergic reactions
• Skin was red with flat-raised bumps (maculopapular rash) or hives
• 10 patients were taking indinavir; the onset of bumps occurred a mean of 21 days after starting drug
• 11 patients were taking ritonavir; onset of bumps occurred a mean 16 days after starting drug
• 1 patient was taking saquinavir (onset time not stated)
• Skin reaction resolved in 73% (16 of 22) after protease inhibitors were discontinued
• 68% (15 of 22) were also taking a sulfa antibiotic (a common cause of rashes in HIV/AIDS patients); all 22 were taking several drugs
• 2 patients each who were taking ritonavir or indinavir had rash resolution when the sulfa drug was discontinued and the protease inhibitor was maintained; none of those 4 had had a prior rash from sulfa drugs, despite having taken the drug for many months
• Rash due to protease inhibitors appears more common than rash due to nucleoside analogs
• Protease inhibitor inhibition of the cytochrome P450 liver pathway may lead to an alteration in sulfa metabolism, thus allowing sulfa toxicity to induce rash in some patients. Those not taking sulfa antibiotics may develop a true "allergic" reactions to protease inhibitors.

Quirino TR and others. Treatment with protease inhibitors in HIV-infected patients: are hypersensitivity reactions more common? ICAAC. Abstract I-186.

Indinavir Kidney Stones More Common than in Initial Reports

• 6.9% (12 of 174) patients in 1 study developed kidney stones a mean of 4 months after starting indinavir (Chicago study)
• 8 of 12 continued indinavir and 5 of 12 developed a second kidney stone
• 12% of 158 in second study developed kidney stones a median of 5.6 months after starting drug (German study)
• An additional 11% had kidney pain without any stones seen by sonogram (an ultrasound test)
• Kidney function (as measured by creatinine levels) was abnormally and significantly higher (median 1.3 mg/dl) at the time stones occurred, compared with baseline levels 2 weeks before
• No other factors were associated with stone development (age, gender, CD4 cell count, concurrent medications) (see also BETA September 1997, page 45).

Mauss S and others. Increased incidence of nephrolithiasis and flank pain in HIV seropositive individuals treated with indinavir. ICAAC. Abstract I-184.

Polyak B and others. The clinical incidence of nephrolithiasis in HIV-positive patients receiving indinavir. ICAAC. Abstract I-183.

Liver Failure and Death Associated with Triple Therapy

• Case report on an overweight patient with several potential causes of liver disease
• Causes were not stated for preexisting enlarged liver and abnormal elevation of liver enzymes
• AZT/ddC led to even higher liver enzyme levels and fatty changes on liver biopsy; drugs were then stopped
• CMV disease was treated with ganciclovir (Cytovene)
• AZT/3TC/saquinavir was instituted; saquinavir caused very high blood levels of cholesterol and lipids (fats)
• AZT was replace with d4T
• 3TC/saquinavir was stopped and ddI/indinavir started due to CD4 cell count of 5 cells/mm³ and HIV RNA viral load of 1,120,000 copies/mL
• 7 other medications being taken at that time were ganciclovir, dapsone (PCP prophylaxis), pyrimethamine (for toxoplasmosis), fluconazole (for candidiasis), azithromycin (for MAC), omeprazole (stomach acid blocker) and fluoxetine (anti-depressant)
• 11 weeks after indinavir/ddI was added, the patient became jaundiced, progressed to liver failure and subsequently died
• Autopsy liver findings revealed severe fatty changes, without acute infection
• Hepatitis B and C viral status was not stated
• Liver toxicity in this patient may have been due to obesity preexisting liver disease, high cholesterol and lipids, prior AZT/ddC liver toxicity, possible current ddI liver toxicity (these last 3 drugs have been reported to cause fatty liver and rarely liver failure and death) and treatment with 10 different medications
• If d4T and indinavir were co-factors in this patient’s liver failure, those findings would indicate a new side effect of those drugs.

Barry C and others. Fatal acute hepatic failure due to triple therapy. ICAAC. Abstract I-187.

Low Blood Counts Possibly due to Indinavir

• Case report from France of a woman with severe anemia (low red cell count) and low platelets (necessary for normal blood clotting)
• Woman was taking indinavir in addition to ddI, pyrimethamine (toxoplasmosis prophylaxis), clindamycin and folinic acid
• She had taken anti-toxoplasmosis medications for years without problems; symptoms and abnormal blood counts were found 3 months after starting indinavir
• Other laboratory abnormalities were elevated bilirubin (a common side effect of indinavir) and extreme elevation of lactate dehydrogenase (LDH, a cellular enzyme)
• No infectious cause or autoimmune cause of abnormalities was found
• Patient required blood transfusions and indinavir discontinuation
• 4 weeks later, there were normal red cell measurements (no anemia), improved bilirubin and much improved LDH levels; at this time, anti-HIV therapy was d4T/3TC.

Lacoste D and others. Anemia and thrombocytopenia, adverse events due to indinavir therapy? ECCATHI. Abstract 734.

In vivo Ritonavir Leads to 35% Decrease in Methadone Blood Levels

• Smaller decreases have been seen with other marketed protease inhibitors
• Methadone doses will likely need to be increased if ritonavir also taken
• Study contradicts findings of in vitro interactions.

Guibert A and others. In vitro effect of HIV protease inhibitors on methadone metabolism. ICAAC. Abstract A-58.

Avoiding Alprazolam May Not Be Necessary When Taking Ritonavir

• In vivo results of single dose alprazolam (Xanax) 1 mg led to unexpected finding of a 12% decrease in alprazolam concentration ("area under the curve"), compared to alprazolam monotherapy
• Slight increase in patient-rated sedation compared to alprazolam monotherapy
• Psychomotor testing revealed mild decrease in efficiency
• Authors concluded that warnings not to take alprazolam and ritonavir together were unwarranted and that a dose reduction of alprazolam was unnecessary when taking ritonavir
• Prolonged sedation may still occur
• Interactions with other drugs that are recommended not to be taken with ritonavir are being clinically evaluated.

Frye R and others. Effect of ritonavir on the pharmacokinetics and pharmacodynamics of alprazolam. ICAAC. Abstract A-59.

141W94 and Ketoconazole

• 141W94 and ketoconazole (Nizoral) co-administration led to insignificant increases in both drugs after a single dose of each
• 1,200 mg 141W94 plus 400 mg ketoconazole were studied
• Dose adjustment during co-administration was not necessary
• Concentration ("area under the curve") was increased by 32% (for 141W94) and 44% (for ketoconazole).

Polk RE and others. Pharmacokinetic (PK) interactions between ketoconazole and the HIV protease inhibitor 141W94 after single-dose administration to normal volunteers. ICAAC. Abstract A-61.

141W94 and 1592

• 141W94 and 1592 (abacavir) showed little to no drug interactions
• 141W94 dose of 900 mg every 12 hours; 1592 dose of 300 mg every 12 hours.

McDowell JA and others (presented by Sadler BM). Evaluation of potential pharmacokinetic (PK) drug interaction between 141W94 and 1592U89 in HIV positive patients. ICAAC. Abstract A-62.

141W94 and KNI-272 Inhibit Liver Enzymes

• The experimental protease inhibitors 141W94 and KNI-272 both inhibit the liver enzyme CYP3A4 to the same degree as indinavir and nelfinavir
• The list of drugs to avoid with either 141W94 or KNI-272 will likely be similar to those for indinavir and nelfinavir.

Sato H and others. Altered pharmacokinetics of KNI-272 when co-administered with other protease inhibitors. ECCATHI. Abstract 334.

Wooley J and others. Cytochrome P-450 isozyme induction, inhibition and metabolism studies with the protease inhibitor, 141W94. ICAAC. Abstract A-60.

Crivat M and others. Pharmacokinetic of saquinavir and study of intestinal function in HIV patients. ICAAC. Abstract A-9.

Drug Resistance and HIV Mutations

Researchers and many practitioners are using HIV drug resistance tests to help determine which drugs may and may not be effective in individual patients. However the tests have limitations.

• Line Probe Assay for mutations in reverse transcriptase enzyme can measure both qualitative and quantitative mutations
• Rapid HIV-1 drug resistance and susceptibility phenotype test from ViroLogic Inc was described
• GeneChip test measures genotypes of HIV protease and reverse transcriptase
• Resistance mutations indicate drugs that are less likely to be helpful
• Uncommon HIV resistant strains may not always be measured
• Antivirogram test system found a correlation between genotypic and phenotypic HIV resistance in the AVANTI 1 study.
• 3TC (Epivir) resistance was documented in 2 newly infected HIV positive patients
• Several reports in the double protease inhibitor section above include updated information regarding HIV mutations and resistance.

Conway B and others. Antiretroviral therapy of primary HIV infection. ICAAC. Abstract I-82.

Hurt MH and others. High sensitivity method for HIV-1 genotyping using the GeneChip HIV PRT assay (Affymetrix Inc.). ICAAC. Abstract I-109.

Parkin N and others. The use of a rapid phenotypic HIV-1 drug resistance and susceptibility assay in analyzing the emergence of drug-resistant virus during triple combination therapy (ViroLogic Inc). ICAAC. Abstract LB-1.

Pauwels R and others. Correlation between genotypic and phenotypic resistance data in AVANTI. ICAAC. Abstract I-112.

Puig T and others. Usefulness of ritonavir and saquinavir combination therapy for HIV-advanced patients failing on indinavir. ICAAC. Abstract I-201.

Pym AS and others. Presence of mutation at codon 90 may predict response to ritonavir-saquinavir combination therapy in HIV infected patients pre-treated with saquinavir monotherapy. ICAAC. Abstract I-193.

Schuurman R and others. Semi-quantitative determination of nucleoside analogue resistance mutations using the HIV-1 RT LiPA on longitudinal patient samples. ICAAC. Abstract I-81.

Adefovir Monotherapy

• Clinical resistance to adefovir dipivoxil (Preveon) monotherapy is uncommon after 12 months
• Phase II study of 25 patients
• Presence of 1 or more of 4 in vitro genotypic mutations in reverse transcriptase enzyme was not associated with clinical resistance up to 1 year
• HIV viral load reductions were maintained despite the development of adefovir genotypic mutations in 33% of patients.

Mulato AS and others. Genotypic characterization of HIV-1 variants isolated from AIDS patients after prolonged therapy with adefovir dipivoxil (bis-POM PMEA). ICAAC. Abstract I-114.

Nelfinavir plus Saquinavir Does Not Lead to Common Nelfinavir Mutation

• 13 patients were analyzed after 20-35 weeks of double protease therapy with nelfinavir and soft-gel saquinavir (Fortovase); 8 were also taking 1 or 2 nucleoside analog drugs (AZT and/or 3TC and/or d4T)
• The common nelfinavir mutation D30N was not detected
• The common saquinavir mutations L90M or G48V were found in 4 of 13, and were associated with increases in HIV viral load.

Kravcik S and others. Protease gene mutations and long-term follow-up of HIV-infected patients treated with Viracept (nelfinavir mesylate) plus saquinavir-soft gel capsule. ICAAC. Abstract I-191.

Adefovir Active against Several HIV-Resistant Strains

• In vitro data demonstrated adefovir activity against resistance mutations associated with AZT, ddI, ddC and 3TC
• Drug was even active against multi-drug resistant Q151M strain of HIV
• Clinical resistance to adefovir was uncommon after 12 months of therapy, even though in vitro mutations appeared in 28% (8 of 29).

Mulato AS and others. Genotypic characterization of HIV-1 variants isolated from AIDS patients after prolonged therapy with adefovir dipivoxil (bis-POM PMEA, Preveon). ICAAC. Abstract I-114.

PMPA Effective against Drug-Resistant HIV Strains in vitro

• Phosphomethoxypropyl adenine (PMPA) was even effective against multi-drug resistant Q151M strain of HIV
• Main resistance mutation to PMPA is K65R that showed cross-resistance to ddC, ddI, 3TC and adefovir in vitro
• Phase I clinical trials of PMPA are completed (see also BETA, December 1995, pages 50-51).

Cherrington JM and others. In vitro selection and characterization of HIV-1 variants with reduced susceptibility to PMPA. ICAAC. Abstract I-113.

Updated Trial Results

Indinavir Triple Therapy may be Less Effective in AZT-Naive Patients

• Even though 80% of participants in Merck's 035 trial (AZT-experienced patients) had undetectable HIV viral load (limit of detection 400 copies/mL) after 2 years, only 60% of AVANTI 2 trial (AZT-naive patients) had undetectable viral load (limit of detection 500 copies/mL) after 1 year.

Study 1 (AVANTI 2)

• 100 anti-HIV drug-naive patients randomized to AZT/3TC with or without indinavir
• Entry CD4 cell counts between 150-500 cells/mm³
• Mean baseline CD4 cell count 270-280 cells/mm³ and viral load 4.5-4.7 log copies/mL
• After 1 year, viral load was undetectable (limit of detection 500 copies) in 60% in indinavir/AZT/3TC arm compared to 18% in AZT/3TC arm; using ultra-sensitive test (limit of detection 20 copies), undetectable rates were 45% and 1%, respectively.
• CD4 cell count increased by 125 cells/mm³ in triple therapy arm compared to 71 cells/mm³ in AZT/3TC arm
• Adverse events included nausea (48% in both arms), muscle inflammation (10-20%) and increased bilirubin (4-16%)

Study 2 (Merck 035 extension)

• 97 HIV positive patients with 6 months of prior AZT therapy
• Double-blind, randomized to AZT/3TC with or without indinavir, or indinavir monotherapy; after 6 months, all patients were given open-label triple therapy with all 3 drugs
• Entry criteria were CD4 cell count between 50-400 cells/mm³ and viral load of 20,000 or greater log copies/mL
• Mean baseline CD4 cell count was 144 cells/mm³ and viral load was 43,190 log copies/mL
• After 2 years, viral load was undetectable (limit of detection 500 copies) in 80% of the initial triple therapy group, compared to 40% in initial indinavir monotherapy group and 30% in initial AZT/3TC group; using ultrasensitive viral load test (limit of detection 50 copies), viral load was undetectable in 65%, less than 40% and less than 25% in the 3 groups, respectively
• CD4 cell count increased by 230 cells/mm³ in the initial triple therapy group (was still increasing in second year of therapy), compared to an increase of 100 cells/mm³ in the initial indinavir monotherapy group and 95 cells/mm³ in initial AZT/3TC group
• 15% of the initial triple therapy group withdrew from the study, compared with 35% of initial indinavir monotherapy group and 45% of initial AZT/3TC group
• Triple therapy with indinavir/AZT/3TC had continued benefits up to 2 years. Delayed sequential triple therapy did not lead to the same degree of benefits. The resulting differences when comparing these 2 studies are likely due to the fact that the Merck study selected for those who could tolerate AZT.

Gerstoft J and others. AVANTI 2, a randomized, double blind, comparative trial to evaluate the efficacy, safety and tolerance of combination antiretroviral regimens for the treatment of HIV-1 infection: AZT/3TC vs AZT/3TC/indinavir in antiretroviral naive. ICAAC. Abstract I-87.

Gulick R and others. Indinavir, zidovudine (ZDV) and lamivudine (3TC): concurrent or sequential therapy in ZDV-experienced patients. ICAAC. Abstract I-89.

Nelfinavir/AZT/3TC Effective up to 1 Year

• Study 511 enrolled 297 patients, all without prior anti-HIV therapy
• Regimens included AZT/3TC with or without nelfinavir 750 or 500 mg every 8 hours; AZT/3TC group added nelfinavir from months 6-12
• Baseline mean CD4 cell count was 283/mm³ and HIV viral load was 4.9 log copies/mL
• In 750 mg dose group, 80% had undetectable viral load (limit of detection 500 copies/mL) at 1 year and CD4 cell counts increased by 180 cells/mm³
• Higher response rate and more durable response was seen if baseline viral load was less than 50,000 copies/mL, with 90% still responding at 12 months
• In the group taking nelfinavir 500 mg every 8 hours plus AZT/3TC, CD4 cell increases were the same as for the nelfinavir 750 mg group, but only 60% achieved a viral load less than 500 copies/mL
• In the AZT/3TC double therapy group in which nelfinavir was added from months 6-12, CD4 cell counts increased by 130 cells/mm³, but only 55% achieved an undetectable viral load
• Adverse events included diarrhea (12%), nausea (7%), abdominal pain (4%), rash (4%) and flatulence (2%); diarrhea responded to over-the-counter anti-diarrheal medication.

Saag M and others. Durable effect of Viracept (nelfinavir mesylate) in triple combination therapy. ICAAC. Abstract I-101.

Saag M and others. Long-term virological and immunological effect of the HIV protease inhibitor Viracept (nelfinavir mesylate) in combination with zidovudine and lamivudine. IDSA. Abstract 221.

HIV Therapy for Infants and Children

Protease Inhibitor Combinations More Effective for Children than Nucleoside Analog Therapy

Study 1 (Pediatric ACTG 338)

• Children were given ritonavir combination with 1-2 nucleoside analog drugs (d4T or AZT plus 3TC); children had had prior therapy with nucleoside analog drugs
• 162 patients were aged 2-17 years
• Median baseline CD4 cell count was 628-644 cells/mm³ (these levels are quite low for HIV positive infants and children) and HIV viral load was 4.3-4.4 log copies/mL
• Interim results at 12 weeks indicate improvements in surrogate markers
• Median increase in CD4 cell counts was seen in both ritonavir groups compared to a return to baseline in AZT/3TC group
• Median viral load decrease was 1.7-1.8 log in ritonavir-containing groups and 0.33 log in AZT/3TC group
• Viral load was undetectable (limit of detection 400 copies) in 57-61% of ritonavir groups, compared to 14% of AZT/3TC group
• Percentage of patients with undetectable viral load increased as baseline viral load decreased
• Adverse events affected 16-21% in ritonavir groups compared to 5% in AZT/3TC group (mostly nausea and vomiting); the taste of the ritonavir suspension was also problematic
• 57% were still on full ritonavir dose (based on weight) after 12 weeks; 10% were off ritonavir permanently due to intolerance or side effects

Study 2 (New York City)

• 32 HIV positive children, retrospective chart review
• 16 patients taking protease inhibitor-containing combination therapy for 6 months or longer, compared to 16 controls treated with nucleoside analog therapy
• Protease inhibitor combinations were more effective than double nucleoside analog therapy in decreasing HIV viral load
• Protease inhibitor combinations cause a reversal of the pathogenic syncytium-inducing (SI) phenotype HIV strain to the more benign non-syncytium inducing (NSI) strain
• SI to NSI conversion correlated with increasing CD4 cell counts
• Nucleoside analog combination therapy did not cause any children with SI phenotype to revert to NSI phenotype
• First report of protease inhibitor therapy reversing SI to NSI phenotype

Dobroszycke J and others. The effects of HAART in a group of HIV-1 infected infants. IDSA. Abstract 492.

Essajee S and others. CD4 and viral phenotypic responses of HIV-1 infected children to antiretroviral therapy with and without protease inhibitors. ICAAC. Abstract I-122.

Yogev R and others (Oral presentation by Nachman S). Virologic efficacy of ZDV+3TC vs. d4T+ritonavir vs. ZDV+3TC+ritonavir in stable antiretroviral experienced HIV-infected children (Pediatric ACTG Trial 338). ICAAC. Abstract LB-6.

AZT/3TC Better than ddI Monotherapy

• Pediatric ACTG study 300 of children with symptomatic infection
• Blinded and randomized trial enrolled 615 children with median follow-up of 9.5 months
• Results included significantly fewer AIDS-related events, decreased disease progression and deaths, decreased HIV viral loads, better weight gain
• Particularly good for those children less than 3 years of age
• Results somewhat in conflict with pediatric ACTG 152 study.

McKinney RE for PACTG 300. Pediatrics ACTG trial 300: clinical efficacy of ZDV/3TC vs. ddI vs. ZDV/ddI in symptomatic, HIV infected children. IDSA. Abstract 768.

Opportunistic Infections, Cancers and other Conditions

Candidiasis

Amphotericin B for Oral Candidiasis

• Amphotericin B oral solution (Fungizone) shows some benefits for oral candidiasis resistant to fluconazole (Diflucan)
• 1 teaspoon (5 mL of 100 mg/mL) 4 times daily for 2-4 weeks was given, followed by maintenance therapy
• 60 patients (22% women) participated in this AIDS Clinical Trials Group (ACTG) open label study
• Results indicated a 45% response rate with an 8% toxicity rate, including nausea, vomiting and diarrhea.

Zingman B and others. Amphotericin B oral suspension for fluconazole-resistant oral candidiasis in HIV-infected patients. ICAAC Abstract I-152.

Fluconazole plus Terbinafine for Candidiasis

• Combination of fluconazole plus terbinafine shows synergy against fluconazole-resistant Candida species in Vitro
• Species included Candida albicans, glabrata, krusei and tropicalis.

Ryder NS and others. Synergy between terbinafine and fluconazole against azole- and multidrug-resistant Candida isolates. ICAAC Abstract E-70.

Voriconazole for Candidiasis

• Voriconazole shows greater activity than either fluconazole or itraconazole against Candida in vitro
• Many fluconazole-resistant isolates are also resistant to voriconazole
• Voriconazloe also has activity against cryptococcus, including fluconazole-resistant strains.

Chin N-X and others. In vitro antifungal activity of voriconazole alone and in combination with flucytosine against Candida species and other pathogenic fungi. ICAAC Abstract E-84.

Clancy CJ and others. In vitro activity of voriconazole against yeasts and comparison with fluconazole. ICAAC Abstract E-88.

Marco F and others. In vitro activities of voriconazole (UK-109,496) and four other antifungal agents against 400 clinical isolates of Candida spp. ICAAC Abstract E-82.

Nelson PW and others. Activity of voriconazole vs. Candida: effects of incubation time, Candida species, and fluconazole susceptibility. ICAAC Abstract E-87.

Coccidioidomycosis

Sordaricin Derivatives for Coccidiomycosis

• Experimental sordaricin derivatives are equal to or better than fluconazole against Coccidioidomycosis, a fungal blood infection caused by Coccidiodes immitis
• Mouse model

Clemons KV and others. Efficacy of sordaricin derivatives GM193663, GM211676 or GM237354 in a murine model of systemic coccidioidomycosis. ICAAC Abstract F-62.

Cryptococcal Meningitis

High Cerebrospinal Fluid Pressure Very Common in AIDS-Related Cryptococcal Meningitis

• 27% have opening spinal canal pressures greater than 350 mm mercury
• Response is good with repeated cerebrospinal fluid (CSF) drainage to lower the pressure
• Sudy done pre-HAART

Graybill JR and others. Cerebrospinal fluid (CSF) hypertension in patients with AIDS and cryptococcal meningitis. ICAAC Abstract I-153.

Nimodipine Decreases High CSF Pressures in Rats

• Experimental meningitis model in rats (pneumococcal meningitis)
• May have applicability to high CSF pressures that occur in crytococcal meningitis

Paul R and others. Effect of nimodipine in experimental pneumococcal meningitis. ICAAC Abstract B-74.

Cytomegalovirus

Ganciclovir for CMV

• Ganciclovir eye implant plus oral ganciclovir is significantly more effective than implant alone in decreasing cytomegalovirus (CMV) retinitis progression and new CMV disease
• Decreased rate of developing Kaposi’s sarcoma (KS) occurred
• 377 patients with CMV disease in 1 eye studied
• Randomized, partially placebo-controlled trial occurred
• 3 groups: ganciclovir implant plus oral ganciclovir 1500 mg every 8 hours; ganciclovir implant plus oral placebo; or intravenous ganciclovir alone
• Endpoint: biopsy-proven CMV disease outside the eye; new CMV disease in the opposite eye; or CMV progression in the affected eye (latter 2 groups were confirmed by photographs) occurred
• After 6 months, either new CMV in opposite eye or biopsy-proven CMV disease exclusive of the eye occurred in 18% of the intravenous ganciclovir group, 22% in the implant and oral ganciclovir group, and 38% in the implant and placebo group (statistically significant difference)
• CMV progression in the initially affected eye was significantly delayed by the addition of oral ganciclovir
• Oral ganciclovir also significantly reduced the incidence of new AIDS conditions, particularly Kaposi’s sarcoma (KS), and the number of new hospitalizations
• Survival was insignificantly extended in the implant plus oral ganciclovir group, compared to the intravenous or intramuscular injection placebo group: median survival rates were 568, 426, and 388 days, respectively
• In a subgroup also receiving protease inhibitors, the rate of new CMV disease was equally low in all 3 groups
• Adverse events were similar in the 3 groups, except for low white cell counts (neutropenia) in the oral ganciclovir groups, and sepsis (life-threatening low blood pressure due to bacterial infection of the blood) in the intravenous ganciclovir group
• Authors concluded that without protease inhibitor therapy, 4.5 grams of oral ganciclovir daily plus a ganciclovir implant significantly delayed both the progression of CMV eye disease and the rate of new CMV disease and reduced the rate of KS.

Martin D and others. Combined oral ganciclovir (GCV) and intravitreal ganciclovir implant for treatment of patients with cytomegalovirus retinitis: a randomized, controlled study. ICAAC Abstract LB-9.

Presence of CMV DNA in Eye Fluid Correlates with CMV Disease

• If fluid was positive, CMV disease was active in the eye
• If aqueous humor (fluid in front part of eyeball) produced a negative CMV DNA test, CMV disease was healed or was not present in that eye
• Study required a small needle inserted into the eye to collect fluid.

Spector SA. CMV disease in patients with AIDS: pathogenesis, natural history and future directions in treatment and prevention. ICAAC Abstract S76.

CMV Viral Load

• Baseline blood CMV viral load correlates with 2.5-fold increased mortality
• Also correlated with a 3.4-fold increased risk for retinitis
• Compared to baseline CMV negative PCR (polymerase chain reaction), with hierarchical increased risk for mortality and retinitis with increasing CMV viral load
• Syntex 1654 (Roche) Oral Ganciclovir Group of 619 patients without HAART was studied.

Spector SA and others. Impact of oral ganciclovir on plasma cytomegalovirus DNA and development of CMV disease in advanced AIDS. ICAAC Abstract I-232.

Spector SA. CMV disease in patients with AIDS: pathogenesis, natural history and future directions in treatment and prevention. IDSA Abstract S76.

CMV Pre-Emptive Treatment for High CMV Viral Loads

• AIDS patients with CD4 cell count less than 50 cells/mm³ and without clinical retinitis studied
• Dose was 3 or 6 grams oral ganciclovir daily
• Quantitative polymerase chain reaction (PCR) CMV viral loads decreased from 4.3 to 2.0 log copies/mL within 24 days on the 3 gram daily dose
• HIV positive patients with high CMV viral loads represented a group most likely to benefit from ganciclovir therapy before retinitis developed.

Grzywacz M and others. Response of asymptomatic CMV viremia to oral ganciclovir 3g/day or 6g/day. ICAAC Abstract H-58.

Experimental CMV Vaccine Safe and Produces Neutralizing

• 168 healthy HIV negative adults; 64% women
• Either 3 or 4 doses of vaccine were given.

Marshall GS and others. Safety and immunogenicity of CMV gB/MF59 vaccine in healthy seronegative adults. ICAAC Abstract H-80.

Hepatitis

Hepatitis A Can Be Fatal in HIV Positive Persons

• Hepatitis A vaccine is recommended for HIV positive persons, particularly if they are already antibody-positive for either hepatitis B or C (see BETA September 1997, page 49).

Dieterich D. Improving the Management of HIV Disease: Cases from the Clinic Conference sponsored by International AIDS Society-USA; San Francisco, October 4, 1997.

3TC for Hepatitis B

• 3TC reduces hepatitis B hivur (HBV) DNA when added to AZT-containing anti-HIV therapies in patients infected with HIV and HBV
• Analysis of CAESAR trial subset of 1,574 patients revealed 119 (8%) who were positive for hepatitis B surface antigen (HBsAg) at baseline, indicating that they were contagious for hepatitis B
• Of those who were HBsAg positive at baseline, 83 (70%) had detectable HBV DNA (Roche Amplicor PCR, limit of detection 400 copies/mL)
• Significantly greater proportion of people in 3TC (Epivir)-containing groups achieved undetectable HBV DNA levels than in placebo group
• Placebo (maintaining AZT-containing therapy): 18% undetectable vs. 3TC added to AZT-containing therapy: 48% undetectable vs. 3TC/loviride added to AZT-containing regimen: 31% undetectable
• Of those who were hepatitis e antigen (e Ag) positive at baseline (64 of 119 or 54% of those who were HBsAg positive at baseline), significantly more of the 3TC-containing groups became e Ag negative (placebo 10% vs. 3TC 19% vs. 3TC plus loviride 27%)
• No significant improvements in ALT (alanine aminotransferase, liver enzyme) occurred in 3TC-containing groups
• Placebo group had worsened elevation with an increase of 3.0 international units (IU) vs. 3TC group (increase of 0.6 IU vs. decrease of 5.1 IU in 3TC/loviride group)
• An insignificant trend towards slower disease progression occurred in the HBsAg patients who received 3TC, when compared to placebo
• Specific correlations of hepatitis marker improvements with HIV marker improvements were not stated in the abstract
• Study terminated early by data safety monitoring board because of significant decrease in progression of HIV disease in 3TC-containing groups (see BETA fill-in)

Cooper D and others. Effect of lamivudine on hepatitis B/HIV co-infected patients from the CAESAR study. ICAAC Abstract H-31.

Oral Lobucavir Decreases Hepatitis B Viral Load

• Phase I/II randomized, double-blind, placebo-controlled trial ran for 28 days
• 22 patients including 3 who were co-infected with HIV and HBV were studied
• Patients were baseline positive for hepatitis surface antigen for at least 6 months; baseline liver enzymes were less than 5 times the upper limit of normal (abnormal but not grossly abnormal)
• Lobucavir dose 200 mg either twice daily or 4 times daily was given
• Lobucavir had activity against HIV, HBV and several herpesviruses including cytomegalovirus (CMV retinitis), herpes simplex virus (lip fever blisters and genital herpes) and varicella-zoster virus (shingles)
• Results indicated a significant decrease in HBV DNA after 4 weeks of treatment; however, 4 weeks after therapy was discontinued, HBV viral loads returned to baseline in all but one lobucavir patient
• After 4 weeks of lobucavir, HBV DNA decreased by a mean 2.7 log copies/mL, compared with a 0.05 log decrease in the placebo group
• Four patients in lobucavir group (2 in each dose group) had HBV DNA levels that became undetectable
• 7 of 17 (41%) patients in the lobucavir group had sharp increases in liver enzymes (greater than 5 times the upper limits of normal) compared to 1 of 5 (20%) of placebo patients
• Lobucavir was well-tolerated with infrequent adverse events when compared to placebo groups
• Further studies were thought to be warranted.

Sherman M and others. Lobucavir treatment for chronic hepatitis B infection: a placebo-controlled phase 1/2 study. ICAAC Abstract H-32.

BMS-200475 Effective for Chronic Hepatitis B in a Woodchuck Model

• Human safety study of 1 dose of BMS-200475, an oral nucleoside analog, reported in 6 healthy volunteers
• Drug was well-tolerated with 31% reporting mild drowsiness, dizziness and headache; all symptoms were reversible
• There were no effects on blood cells or chemistries or on electrocardiogram (heart test)
• Further testing was indicated.

Grasela DM and others. BMS-200475: single oral dose.

Medina I and others. Maintenance therapy with BMS-200475 in the woodchuck model of chronic hepatitis B infection. ICAAC Abstract H-10.

Famciclovir plus Interferon Alpha for Hepatitis B

• Famciclovir plus interferon alpha was beneficial for hepatitis B infection in 5 HIV negative persons

Marques AR and others. Combination therapy with famciclovir and interferon for the treatment of chronic hepatitis B. ICAAC Abstract H-35.

Triple Drug HAART Decreases HIV but Usually not HCV Viral Load

Study 1 (Germany)

• Therapy for 18 patients for 12 weeks included either indinavir or saquinavir hard gel plus nucleoside analog drugs
• Significant reductions in HIV viral load in "most" without significant reductions in HCV viral load occurred.

Study 2 (Switzerland)

• HAART (ritonavir, indinavir or ritonavir-saquinavir, each with nucleoside analogs) were taken by 19 patients (16% women) for 32 weeks
• Significant reductions in HIV viral load with increased CD4 cell counts and insignificantly increased CD8 cell counts, yet no change in HCV viral load occurred
• There was a significant but transient increase in both HCV viral load and liver enzymes at 8 weeks, possibly due to the increase in CD8 cell counts.

Study 3 (Virginia)

• Retrospective review of 26 patients treated with HAART for 6 months
• Only 50% (13 of 26) of patients achieved significant reductions in HIV viral load
• Only 2 of 13 achieved significant reductions in HCV viral load that was associated with a greater than 10-fold increase in CD4 percentage.

Mauss S and others. Influence of HIV protease inhibitors on hepatitis C viral load in individuals with HIV and HCV coinfection. ICAAC Abstract H-26.

Pastor A and others. Hepatitis C virus and HIV viral load in co-infected patients undergoing anti-HIV-retroviral therapy. ICAAC Abstract I-163.

Rutschmann OT and others. Impact of HIV protease inhibitors on HCV viremia. ICAAC Abstract I-165.

Interferon-alpha 2b Benefits Some Patients with Both HIV and HCV

Study 1 (Germany)

• 17 patients, all negative for hepatitis B surface antigen (no active infection with hepatitis B) and no CDC-defined AIDS, participated
• Patients were not taking anti-HIV therapy
• Interferon alpha-2b, 5 million international units (MIU) was injected 3 times weekly for 6-12 months, decreased to 3 MIU 3 times weekly, if possible; no HIV therapy was given
• 8 of 17 (47%) patients responded with a complete remission of hepatitis C, including normalized liver enzymes and undetectable HCV RNA viral load
• Patients were taking anti-HIV nucleoside analog drug(s)
• Sustained, complete remission for 6 months or longer occurred in 5 of 8 (5 of 17 or 29%)
• Complete responders had significantly higher baseline CD4 cell counts (median 525 cells/mm³) than non-responders (245 cells/mm³)
• Responders were more likely to have hepatitis C genotype 3 than genotype 1 (a majority of HCV infections in U.S. are with genotype 1)
• Neither baseline HCV viral loads nor liver enzyme tests distinguished responders from non-responders
• Alpha interferon-2b was well-tolerated for more than 4 months in all but 1 patient
• No severe toxicity from alpha interferon was observed
• HIV viral load levels not mentioned in presentation or abstract

Study 2 (France)

• 22 patients (9% women) with documented hepatitis C by liver biopsy and elevated HCV RNA viral load participated in an open-label study; there were no other causes of chronic hepatitis; they had no prior HIV therapies or interferon therapy; and none had HIV symptoms except possibly oral candidiasis.
• Interferon-alpha 6 MIU was injected 3 times weekly for 6 months, then 3 MIU 3 times weekly for months 7-12
• Co-administration of AZT 250 mg was given twice daily and/or ddI at the standard dose
• 19 patients completed the study
• After 6 months, liver enzymes normalized in only 37%; after 12 months in 33%
• After 12 months, HCV RNA viral load was undetectable (by Chiron bDNA test with a limit of detection of 200,000 copies/mL) in only 12%
• Median baseline HCV viral load 15 x 10³ copies/mL decreased significantly to 0.75 x 10³ copies/mL by 6 months, then increased for a not significant total reduction of 5.7 x 10³ copies/mL by 12 months (then on the lower dose interferon-alpha)
• 3 patients discontinued the study by 1st month (the second patient preferred to discontinue while the third developed Mycobacterium avium infection)
• CD4 cell count insignificantly increased
• Total HIV RNA viral load reduction by month 12 was insignificant
• Combination of alpha interferon plus AZT and/or ddI lead to a sustained HCV virologic response in only a minority of co-infected patients; a liver enzyme (biochemical) response may have occurred in the same or larger minority of patients.

Dupon M and others. Serum hepatitis C virus RNA levels in patients coinfected with human immunodeficiency virus during combination therapy with recombinant interferon-alpha 2b and nucleoside analogues. ICAAC Abstract I-166.

Mauss A and others. Success of treatment of chronic hepatitis C with interferon alpha in patients infected with HIV 1 influenced by CD4+ cell count. ICAAC Abstract I-164.

HIV/HCV Co-Infection and T-Cell Counts

• Co-infection with HIV and HCV causes chronic active hepatitis and cirrhosis significantly less often when CD4 and CD8 T-cell counts are low
• This was a retrospective study of 51 patients who had a liver biopsy
• Authors concluded that liver inflammation due to HCV was dependent on immune status. Liver inflammation was associated with a better, though not normal immune status as measured by CD4 and CD8 cell counts
• Potentially confounding factors: neither HCV nor HIV viral load results were analyzed or presented.

Roger PM and others. Influence of HIV infection on chronic hepatitis C: support for immune-mediated pathogenesis of hepatitis C virus infection. ICAAC Abstract I-167.

HIV/HCV Co-Infection Significantly Accelerates HIV Disease Progression

• Study in France of 238 patients.

Piroth L and others. Does hepatitis C virus (HCV) coinfection accelerate clinical and biological evolution of HIV infected patients? ICAAC Abstract H-36.

HIV/HCV Co-infection Significantly Accelerates Hepatits C Progression

• 160 injection drug users in France with chronic hepatitis C infection
• Either HIV infection or alcohol consumption significantly increased risk of death.

Di Martino V and others. Detrimental influence of HIV infection on the outcome of chronic hepatitis C: a multivariate analysis. ICAAC Abstract H-37.

HIV/HCV Co-Infection and Liver Enzyme/Viral Load Levels

• Co-infection with HIV and HCV causes significantly higher abnormal liver enzyme test results and insignificantly higher HIV viral loads
• Case-control retrospective study of 50 patients in Pennsylvania
• Comparison group was HIV positive, HCV negative
• Potentially cofounding variables: hepatitis B status was not mentioned during the presentation nor in the abstract

Gupta A and others. Relationship between hepatitis C virus viral load and HIV viral load: a case control study. ICAAC Abstract I-162.

Hepatitis C Outbreak in Texas Traced to Criminal Tampering

• Tampering with intravenous narcotics by a scrub nurse who was HCV positive.
• Transmission was due to a lapse in narcotic control, not a lapse in infection control
• IV fentanyl citrate was the narcotic involved at an ambulatory surgery center.

Sehulster L and others. Hepatitis C outbreak linked to narcotic tampering in an ambulatory surgical center. ICAAC Abstract J-28.

HGV Rates in HIV Positive Persons Reveal Variations in Data

Studies 1 and 2 (Strasbourg, France; Baltimore, MD)

• HGV genome (RNA) was common among 151 HIV positive patients from Strasbourg, France (37%) and among 2,452 emergency patients in Baltimore, Maryland (10%) including 10% who were HIV positive
• Higher rates occurred among men (39%) than women (35%) in France, but were equivalent in Baltimore men and women (9-10%)
• Higher rates occurred among gay/bisexual men (49%) than heterosexual men (27%) in Strasbourg, while heterosexuals from Baltimore had a 10% infection rate (gay/bisexual rate not stated in abstract).
• Higher rate among injection drug users than transfusion patients occurred in Strasbourg (38% and 25%, respectively) and Baltimore (15% and 8%, respectively)
• Prevalence of HGV decreased with increasing age in Strasbourg compared to a predominance in the 15-34 year age group in Baltimore
• No relationship was found between HGV RNA and immune status by CD4 cell count (HIV viral load not mentioned) in Strasbourg
• No relationship was found between coinfection with hepatitis C virus in Strasbourg

Study 3 (Nice, France)

• 100 consecutive HIV positive patients (18% women) were tested for HGV
• Results revealed 31% were HGV antibody positive, including 36% of gay/bisexual men, 35% of injection drug users, and 29% of heterosexually-acquired HIV: there was no difference in rate by HIV transmission group
• Only 8% of a "healthy" HIV-negative control group was HGV antibody positive
• Only 4% of 100 had detectable HGV RNA, indicating most HIV positive patients had controlled or cleared their HGV infection and were not HGV viremic

Study 4 (Cleveland)

• 23% (44 of 196) of random stored blood samples from HIV positive patients with a CD4 cell count less than 200 cells/mm³ were positive for hepatitis G RNA, as measured by RT-PCR (reverse transcriptase-polymerase chain reaction) testing
• Gay/bisexual men were 61% less likely to be positive than other HIV risk group members
• Hepatitis G RNA positivity was not associated with increased liver function tests
• Those who were positive for hepatitis G RNA were 7 times more likely to be positive for hepatitis B surface antigen (an indicator of contagious state of hepatitis B)
• Hepatitis C antibody positivity was not associated with hepatitis G RNA positivity

Durant J and others. Detection of hepatitis G virus and anti-HGV in HIV-infected patients. ICAAC Abstract I-168.

Kelen GD and others. Hepatitis GB virus-C (GBV-C) in an emergency department population. ICAAC Abstract H-39.

Rey D and others. Detection of hepatitis G virus genome in HIV-infected patients and hemodialysis HIV-negative patients. ICAAC Abstract H-28.

Woolley I and others. Hepatitis G is common in AIDS patients but is not associated with abnormal liver function tests or other clinical syndromes. IDSA Abstract 514.

Herpes Simplex Virus

Genital Herpes in People with HIV

• HIV positive persons with more severe genital herpes episodes have significantly lower number of herpes simplex virus (HSV)-specific CD8 cytotoxic cell precursors (1 in 170,000) than HIV positive persons with mild recurrences (1 in 26,000)
• This was the first study to demonstrate an association between severity of genital herpes and HSV-specific CD8 cell precursors

Posavad CM and others. Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8+ cytotoxic T lymphocyte responses. ICAAC Abstract H-71.

Histoplasmosis

Sordaricin Derivatives for Histoplasmosis

• Experimental sordaricin derivatives better than fluconazole in a mouse model of histoplasmosis.

Najvar LK and others. New sordaricin antifungal drugs active in murine histoplasmosis. ICAAC Abstract F-63.

Kaposi’s Sarcoma

Topical Retinoic Acid Gel Effective for Individual KS Lesions

• Data safety monitoring board stopped the phase III trial early due to significant benefits
• This was a randomized, double-blind, placebo-controlled, 12-week study of 0.1% 9-cis-retinoic acid (Panretin) applied twice daily to KS lesions in AIDS patients
• In an interim analysis of 82 patients, 42% of drug group (36 patients) achieved complete or partial response (reduction in size or number of KS lesions), compared to 7% of patients using placebo gel (46 patients)
• All enrolled patients had the option to receive active drug after 1st 12 weeks, up to 9 additional months
• A second phase III trial must be completed (or also interrupted early due to significant response) before for FDA drug application process could be initiated; expanded access in the interim would be appropriate
• An oral formulation of retinoic acid is also being tested for AIDS-KS, as well as for non-HIV breast, ovarian, prostate and blood (leukemia) cancer (see also BETA, March 1997, page 45).

International Panretin topical gel trial demonstrates positive results in Kaposi’s sarcoma: study stopped per protocol at interim analysis of results. (ICAAC Press release) Allergan Ligand Retinoid Therapeutics, Inc.

Elevated Nerve Growth Factor Levels in People with KS

• Significantly elevated levels of nerve growth factor detected in blood serum of AIDS patients with Kaposi's sarcoma (KS) as compared to people with AIDS without KS and who were uninfected with Kaposi’s sarcoma-associated herpesvirus (KSHV) and to HIV negative controls
• Nerve growth factor may be a co-factor in the development of KS and the maintenance of KSHV

Pica F and others. Association between high levels of nerve growth factor and seropositivity to KSHV/HHV8 in HIV patients with Kaposi’s sarcoma. ICAAC Abstract H-120.

Microsporidiosis

Albendazole and Fumagillin Each Beneficial for Microsporidial Diarrhea

• Studies ANRS 035 and 054
• Albendazole 400 mg twice daily for 3 weeks cleared infection and diarrhea due to Encephalitozoon intestinalis in 8 French patients, although it recurred in 60% without secondary prophylaxis (pre-HAART)
• Oral fumagillin 20-60 mg daily for 1-2 weeks cleared infection and diarrhea due to Enterocytozoon bieneusi in 28 French patients, although side effects included low blood platelet counts (reversible), low white cell counts (neutropenia), rash and abdominal pain (pre-HAART).

Molina J-M and others. Albendazole for treatment and prophylaxis of microsporidiosis due to Encephalitozoon intestinalis in patients with AIDS. ICAAC Abstract I-148.

Molina J-M and others. A dose-escalation study of oral fumagillin for the treatment of Enterocytozoon bieneusi infections in patients with AIDS. ICAAC Abstract I-149.

Animal Model for Microsporidiosis Identified

• Rhesus monkeys with simian immunodeficiency virus infection were commonly infected with Enterocytozoon bieneusi
• Microsporidia was the most common infectious cause of diarrhea in AIDS patients in the pre-HAART era.

Anderson DC and others. Naturally-acquired Enterocytozoon bieneusi (Microsporidia) hepatobiliary infection in rhesus monkeys with simian immunodeficiency virus (SIV): a possible animal model of disease. ICAAC Abstract K-120b.

Epidemic Outbreak of Microsporidiosis among AIDS Patients in France in 1995

• Transmission to 65 patients was likely linked to the water supply

Cotte L and others. Outbreak of intestinal microsporidiosis in HIV-infected patients in relation with town water distribution system. ICAAC Abstract I-147.

Risk factors for HIV-related Microsporidiosis Identified in France and New Orleans

• Swimming in a pool and gay/bisexual male contact suggested transmission via fecal-oral route, including waterborne and specific person-to-person contamination (France)
• Occasional consumption of well water and occasional or frequent contact with either sea-water fish or fresh-water fish (but not eating fish or crustaceans) was statistically associated with microsporidial diarrhea (New Orleans).

Dascomb K and others. Environmental exposures associated with microsporidiosis in HIV-infected patients. IDSA Abstract 523.

Hutin Y and others. Risk factors for intestinal microsporidiosis in patients infected with HIV. ICAAC Abstract I-150.

Mycobacterium avium Complex (MAC)

Once Daily Clarithromycin as Effective as Rifabutin as Primary Prophylaxis for MAC

• Retrospective study from University of Buffalo, New York (pre-HAART)
• 131 patients with at least 1 CD4 cell count less than 100 cells/mm³ were observed for at least 90 days, received at least 30 days of prophylaxis, and had surveillance blood cultures for MAC
• Endpoints were development of MAC, death, started on HAART, or lost to follow-up
• 56 patients were on clarithromycin (Biaxin) 500 mg; 29 were on rifabutin (Mycobutin) 300 mg; and 46 took no prophylaxis
• 95% were taking PCP prophylaxis and 98% were taking anti-HIV therapy (non-HAART)
• 17% developed MAC, with clarithromycin group or rifabutin group significantly superior (78% decreased risk of MAC for either drug), compared to the no prophylaxis group
• Clarithromycin was significantly better than no prophylaxis in preventing death, but not better than rifabutin
• Authors concluded that once daily clarithromycin was as effective as rifabutin in preventing MAC blood infection and improving survival in persons with HIV and CD4 cell count less than 100 cells/mm³. Added benefits would be lower cost and once daily dosing.

Hewitt RG and others. Once daily, reduced dose clarithromycin for the prevention of Mycobacterium avium complex bacteremia (MAC) in HIV + patients prior to the use of HIV-1 protease inhibitors. ICAAC Abstract I-223.

Patients with Multidrug-resistant MAC Respond to Liposomal Amikacin

• In vitro drug sensitivities were not reported in abstract
• Past studies showed no benefits for non-liposomal amikacin
• In a separate study of 8 HIV positive volunteers, the half-life (amount of time for half of an original amount to be metabolized) of liposomal amikacin (MiKasome) was greater than 80 hours
• Possible dosing of 1-2 times weekly was provided
• MiKasome available by request from NeXstar Pharmaceuticals for this purpose.

Fielding RM and others. A multiple dose phase 1 safety and pharmacokinetic study of low-clearance liposomal amikacin (MiKasome) in HIV seropositive individuals. IDSA Abstract 716.

Fielding RM and others. Liposomal amikacin (MiKasome) steady-state pharmacokinetics: increased antibiotic exposure and residence with decreased frequency of administration (in dogs). ICAAC Abstract A-120b.

Nelson MR and others. Liposomal amikacin (MiKasome) in the treatment of HIV related mycobacterial disease. ICAAC Abstract A-91b.

Clarithromycin Reduces Opportunistic Infections and Increases Survival

• Results independent of baseline CD4 cell count or disseminated MAC infection
• MAC Prophylaxis Study Group.

Notario G and others. Clarithromycin survival benefit due to reduction in the rate of all opportunistic infections. ICAAC Abstract I-213.

Grapefruit Juice and Clarithromycin

• Grapefruit juice does not increase blood concentrations of clarithromycin.

Cheng K and others. Effect of grapefruit juice on clarithromycin pharmacokinetics. ICAAC Abstract A-119.

Clarithromycin plus Interleukin-12 More Effective than Either Alone in Mouse MAC Model

• Combination led to lower mycobacterial counts in liver and spleen.

Bermudez LE and others. Combination of clarithromycin and interleukin-12 for the treatment of disseminated Mycobacterium avium complex infection in mice. ICAAC Abstract B-37.

KRM-1648 Shows Anti-MAC Benefits In Vitro

• KRM-1648 (Benzoxazinorifamycin) was more effective than either clarithromycin or rifabutin for MAC prophylaxis in mouse model
• Biapenem also showed anti-MAC activity in vitro.

Aralar PA and others. The antimycobacterial activity of the carbapenems, biapenem, imipenem, meropenem, panipenem and BO2727 against Mycobacterium avium complex (MAC). ICAAC Abstract E-165.

Saito H and others. Chemoprophylaxis against Mycobacterium avium complex infection induced in mice. ICAAC Abstract F-34.

Tomioka H and others. Antimicrobial activities of KRM-1648 and clarithromycin against M. avium complex replicating in alveolar pneumocyte cell line A549. ICAAC Abstract F-33.

Ketolides HMR3647 and HMR3004 Effective in Mouse MAC Model

• Authors concluded that ketolides may be useful alone or in combination as therapy for and prophylaxis against disseminated MAC in humans.

Wu M and others. Efficacy of 2 ketolides, HMR3004 and HMR3647, in treatment of disseminated M. avium (MAC) disease in beige mice. ICAAC Abstract F-261.

Ethambutol Blood Levels

• Ethambutol blood levels maximized when given on an empty stomach

Peloquin CA and others. Effect of food and antacids on the pharmacokinetics of ethambutol and pyrazinamide. ICAAC Abstract A-3.

Rifabutin Interactions with Fluconazole Deemed Insignificant

• Co-administration may be possible with careful monitoring.

Gatti G and others. Population pharmacokinetic analysis of rifabutin in HIV-infected patients. ICAAC Abstract A-10.

MAC From Spa

• Married heterosexual HIV negative couple acquire MAC lung infection from uncleaned spa
• DNA sequencing indicated identical MAC strains from each person’s lung infection, their home spa water, and their home shower
• Spa was uncleaned for 8 months
• Was the first case of spa-associated MAC infection with identical environmental and clinical genes
• Spa water may represent a source of MAC for HIV positive persons as well.

Bodnar UR and others. Pulmonary Mycobacterium avium complex infection associated with spa use. ICAAC Abstract K-117.

Pneumocystis Carinii Pneumonia (PCP)

Atovaquone Suspension Effective for PCP Prophylaxis

• Phase III study of 476 patients (Protocol 213 Study Team)
• Daily dose of 750 mg or 1,500 mg of atovaquone (Mepron) suspension was given
• Was equivalent to monthly aerosolized pentamidine
• Rash was more common in atovaquone group (42%) than pentamidine group (25%)
• Bronchospasm (breathing tube muscle constriction with wheezing sounds) was more common in pentamidine group (10%) than atovaquone group (3%)
• Other side effects were equivalent.

Chan C and others. Prophylaxis of Pneumocystis carinii pneumonia-a comparison of Mepron suspension with aerosolized pentamidine. IDSA Abstract 518.

Atovaquone Suspension Efficacy Equals Dapsone for PCP Prophylaxis

• Randomized trial recruited 1,057 AIDS patients (12% women); pre-HAART
• Studies CPCRA 034 and ACTG 277
• Entry criteria were a history of intolerance to trimethoprim-sulfamethoxazole (TMP-SMX) and any 1 of the following: prior PCP or CD4 cell count less than 200 cells/mm³ or CD4 cell percentage less than 15%
• Daily atovaquone suspension 1,500 mg or dapsone 100 mg, with switch to other drug if intolerant or failure (i.e., developed PCP), was given
• If in dapsone group and positive blood test for toxoplasmosis occurred, pyrimethamine was added (16%) to help prevent toxoplasmosis
• Median baseline CD4 cell count was 60 cells/mm³; 28% had prior PCP; 52% were already taking dapsone; 16% were injection drug users
• After 604 days, no significant difference occurred in any of the following: developing PCP (15-18 PCP cases per 100 person-years); developing toxoplasmosis (2-3 cases per 100 person-years); death; or discontinuation rate due to adverse events
• Side effect profile was significantly different and associated with discontinuation:
• Stomach-intestinal symptoms (diarrhea, vomiting, cramping) were significantly higher in atovaquone
• Rash and anemia were both significantly higher in dapsone group
• Significantly higher discontinuation rate occurred for those taking dapsone at baseline than those not taking it at baseline
• Authors concluded that for HIV positive patients intolerant to TMP-SMX who were taking dapsone, they should continue dapsone; for those not on dapsone, atovaquone would be a better initial choice (possible statistical bias due to high baseline dapsone therapy).

El-Sadr W and others. Atovaquone versus dapsone in the prevention of P. carinii pneumonia in patients intolerant to trimethoprim and/or sulfamethoxazole. IDSA Abstract 769.

Daily Double Strength TMP-SMX

• Daily TMP-SMX double-strength not significantly better than 3 times weekly in preventing PCP
• CPCRA study. Largest PCP prophylaxis study to date with 2,625 patients (pre-HAART); 16% were women, 44% were African-American, 15% were Latino, and 34% were injection users
• Daily dose was significantly better for secondary prophylaxis (preventing 2nd episode PCP)
• Daily dose led to significantly lower rates of bacterial pneumonia
• Daily dose had significantly higher rates of adverse events.

El-Sadr W and others. Daily versus thrice weekly trimethoprim-sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia (PCP)(CPCRA). ICAAC Abstract I-146.

New TMP-SMX Desensitization Protocol

• New recipe for desensitization to TMP-SMX allows three-quaters of patients to continue therapy safely
• TMP-SMX was most effective for PCP prevention; it was also very inexpensive; rash and/or fever occurred among approximately 45% of HIV positive individuals
• Was a randomized, double-blind study
• Inclusion criteria were HIV positive individuals with prior rash or fever due to TMP-SMX
• Exclusion criteria were TMP-SMX fever of 103.3° Fahrenheit or higher; bronchospasm (constriction of breathing tubes often with wheezing sounds); urticaria ("hives"); or Stevens Johnson syndrome (life threatening shedding of all skin)
• 153 patients were randomized to either 6-day incremental dose escalation of TMP-S suspension (liquid) ending with single strength dose tablet daily or rechallenged with single-strength TMP-SMX tablet daily
• All patients were started on anti-histamine therapy 1 day prior to starting TMP-SMX for the study and continued throughout the re-introduction period
• After 6 months, 79% of dose escalation group were able to maintain 6 months of daily single-strength TMP-SMX with a tolerable skin rash rate of 14%
• 56% of the rechallenged group were able to maintain 6 months of daily single-strength TMP-SMX with a tolerable skin rash rate of 18%.
• Authors concluded that 6-day dose escalation method for reintroducing TMP-SMX for HIV positive patients with prior treatment-limiting rash or fever was significantly more successful in maintaining subjects on single-strength TMP-SMX daily for 6 months than direct reintroduction. Moreover, even direct reintroduction allowed for 56% to continue therapy for 6 months.

Leoung G and others (presentation by Stanford J). A randomized, double-blind trial of TMP/SMX dose escalation vs. direct rechallenge in HIV + persons at risk for PCP and with prior treatment-limiting rash or fever. ICAAC Abstract LB-10.

Atovaquone Suspension May Be Taken with Nutritional Supplement High in Fat

• Sustecal Plus with 28 grams fat was used
• Similar absorption as with a high fat (22 grams) breakfast occurred
• Blood levels were too low when taken without food.

Freeman CD and others. Atovaquone suspension bioavailability with food and enteral nutrition. ICAAC Abstract A-1.

Sordaricin Derivative for PCP

• Sordaricin derivative GM 237354 shows benefits in rat PCP model

Dei-Cas E and others. A new antimicrobial molecule (GM 237354) highly active against Pneumocystis carinii: in vivo studies and ultrastructural data. ICAAC Abstract F-65.

Herreros E and others. Anti-pneumocystis activity of GM 237354 in vitro and in vivo. ICAAC Abstract F-64.

DN3 27-1 Effective as Prophylaxis against PCP in Mouse and Rat Model

• Authors recommended that the drug advance to phase I testing in humans.

Bartlett MS and others. The 8-aminoquinolone DN3 27-1 was effective for prophylaxis against Pneumocystis carinii in mice and rats. ICAAC Abstract F-174.

Progressive Multifocal Leukoencephalopathy (PML)

Patients with PML Despite HAART Respond to IV Cidofovir

• 1 patient did not fully respond to HAART, the other did, yet both subsequently developed PML 4 and 9 months after HAART started
• PML symptoms: both were unable to walk and required full-time care
• 1 patient had a brain biopsy with a positive DNA hybridization test for PML; both had MRI scan changes suggesting PML
• Standard dose cidofovir (Vistide) started within 2-4 weeks of PML symptoms (weekly for 2 weeks, then every 2 weeks)
• After 2 months of cidofovir, both patients were walking and living on their own
• MRI scans revealed stable or improved PML lesions
• Both patients were stable 7 and 9 months each after starting cidofovir
• Cidofovir had activity against other polyomaviruses (PML is caused by the polyomavirus JC, the initials of the first patient described with the disease).

Brosgart C and others. Cidofovir therapy for progressive multifocal leukoencephalopathy in two AIDS patients. ICAAC Abstract I-5.

Salmonellosis

Outbreak of Salmonella Saphra Traced to Mexican Cantaloupe

• Salmonella can cause bloody diarrhea and life-threatening typhoid fever among both HIV positive and negative persons
• 23 cases occurred in California from March-April, 1997
• All were immunocompromised, very young (6 years or younger) or elderly (65 years or older); 5 were hospitalized
• Compared to controls, cases were 15 times more likely to have eaten cantaloupe in the week before onset of symptoms and were 12 times more likely to have eaten precut cantaloupe (both statistically significant)
• Origin was traced to 1 U.S. distributor importing cantaloupes from 1 region of Mexican
• To prevent Salmonella infection, authors recommended that cantaloupes should be scrubbed in running water before they are sliced.

Mohle-Boetani JC and others. Outbreak of Salmonella saphra, California, 1997. IDSA Abstract 279.

S.F. Bay Area Pet Store Reptiles Carry Salmonella

• 21% of 821 pet reptiles for sale were cultured and 101 were culture positive but did not show symptoms; 59% of San Francisco Bay Area pet store reptiles carry Salmonella in stools
• Reptiles consisted of turtles, iguanas, snakes and other lizards (no difference by type)
• 10% of Salmonella isolates were resistant to 1 or more antibiotics
• 15 pet stores in San Francisco and Alameda counties had infected reptiles
• "Practice Safe Rhex" poster was displayed and included warning to always wash one’s hands after handling reptiles.

Mermin JH and others. Reptile-associated Salmonella in the San Francisco Bay Area. ICAAC Abstract 309.

Sinusitis

Nasal Spray plus Antibiotic Better than Antibiotic Alone for Sinusitis

• Sinusitis affects 20-68% of HIV positive persons
• Study was a placebo-controlled trial of 49 patients, follow-up 42 weeks-1 year
• Fluticasone 0.05% (Flonase, 1 puff in each nostril every 12 hours for 3 weeks) plus cefuroxime axetil (Ceftin, 250 mg orally every 12 hours for 3 weeks) was given
• Results: 39 of 49 (80%) were cured or showed clinical improvement
• 24 of 39 (61%) in steroid and antibiotic group, compared to 15 of 39 (38%) of placebo and antibiotic group (significance not stated, but probably significant), had sinusitis
• There were significantly fewer sinus symptoms at the completion of therapy in steroid and antibiotic group, compared to placebo and antibiotic group
• 43% recurrence rate existed in a mean 10 weeks after therapy, with no reported difference between the 2 groups.

Small C and others. Treatment of sinusitis in HIV+ patients. IDSA Abstract 541.

Streptococcal Pneumonia

HIV Positive Individuals Lose Effect from Pneumococcal Vaccine after 5 Years

• Revaccinating after 5 years increased protective pneumococcal antibodies
• Blood levels of protective antibodies might need to be measured periodically or periodic revaccination should be considered
• CD4 cell counts and HIV RNA viral load correlates were not stated in abstract
• Pneumococcal revaccination every 5-10 years was a common practice for organ transplant recipients who, like HIV positive individuals, were also at high risk for pneumococcal disease.

Tasker SA and others. Pneumococcal reimmunization in HIV-1 infected patients. ICAAC Abstract I-45.

Streptococcus Pneumonia Drug Resistance in San Francisco AIDS Patients

• 24% were resistant to trimethoprim-sulfamethoxazole (Bactrim, Septra, Cotrim)
• 9% were resistant to penicillin
• Resistance rates were much lower in non-AIDS isolates
• 584 cases of invasive pnuemococcal disease were found among AIDS patients from October 1, 1994, to December 31, 1996.

Nuorti P and others. Population-based surveillance for drug-resistant Streptococcus pneumoniae in San Francisco, California. IDSA Abstract 292.

Multidrug-Resistant Pneumonia Outbreak in New York City

• Outbreak of multidrug-resistant streptoccal pneumonia reported from long-term care AIDS facility in New York City from April 1995 to January 1996
• There were 7 cases in 64 AIDS patients; 2 were fatal
• 6 of 64 (11%) were AIDS residents, but no staff were carriers (no symptoms) of streptococcal pneumonia
• Pneumococcal vaccine was highly effective in preventing disease but not carriage state
• Previous rifabutin protective against disease and carriage existed
• Authors agreed with IDSA/CDC guidelines that the pneumococcal vaccine should be given to all HIV positive persons.

Kornblum J and others. Outbreak of multi-drug resistant Streptococcus pneumoniae (MDRSP) at a long-term care facility for persons with AIDS. ICAAC Abstract C-52.

Toxoplasmosis

PCR Blood Test for Toxoplasmosis

• PCR blood test in HIV positive persons is 100% specific, but not very sensitive in diagnosing brain toxoplasmosis
• A negative test virtually excludes a diagnosis of toxoplasmosis.

Franzen C and others. Limited value of the polymerase chain reaction for the detection of Toxoplasma gondii in blood from HIV-infected persons. ICAAC Abstract D-76.

Ketolides HMR3647 and HMR3004 Effective in Toxoplasmosis Mouse Model

• Authors concluded that ketolides may be useful alone or in combination for toxoplasmosis in humans

Araujo F and others. Ketolides are active against Toxoplasma gondii. ICAAC Abstract F-251.

Tuberculosis

Outbreak of Tuberculosis Due to Highly Contagious Strain

• Extensive transmission was documented among HIV negative persons, including those with limited, casual exposure (Fort Collins, Colorado)
• 337 of 461 (73%) contacts had positive TB skin tests; 86 had documented prior negative tests.

Shinnick TM and others. Characteristics of a hypertransmissible strain of Mycobacterium tuberculosis. ICAAC Abstract B-31.

3-month Short Course Double Therapy Effective as Primary Prophylaxis

• Prospective, comparative, randomized, open study of 113 HIV positive patients in Spain
• PPD (purified protein derivative) TB skin test positive or PPD negative, yet anergic (abnormal no reaction to any skin test indicating decreased immunity) HIV positive patients were studied
• Isoniazid (INH) 300 mg daily plus rifampin 600 mg daily for 3 months was given compared to standard prophylaxis of INH 300 mg daily for 1 year
• Mean follow-up was 6 months (3 months in short course group and 8 months in standard group)
• Efficacy was similar in each group (TB occurred in 3 standard therapy group and in 1 short course group; for adherent patients: only 1 case TB occurred in standard group)
• Significantly less hepatitis and fewer adverse events occurred in short course therapy group; insignificantly fewer patient withdrawals in short course group occurred
• Larger study was indicated before a change in recommendation be initiated. This may be difficult to do as more HIV positive patients are placed on HAART.

Geijo P and others. A prospective, multicenter, open trial of 3-month rifampin plus isoniazid regimen versus 12-month isoniazid regimen for prevention of tuberculosis in HIV patients. ICAAC Abstract I-212.

KRM-1648 Effective for Most Rifampin-Resistant TB Strains

Arvind M and others. Comparative in vitro activities of rifamycin analogs against rifampin-sensitive and rifampin-resistant Mycobacterium tuberculosis. ICAAC Abstract F-36.

Once Weekly Rifapentine Effective in Mouse TB Model

• Rifapentine was taken for 8 weeks as part of a 4-drug regimen that also included isoniazid, pyrazinamide, and streptomycin
• For first 2 weeks, daily streptomycin was also required
• Patients were HIV negative

Grosset J and others. Once-weekly rifapentine-containing combined regimens for treatment of tuberculosis in mice. ICAAC Abstract B-36.

Multidrug-Resistant TB

• Multidrug-resistant TB present on every continent and probably every country throughout the world.

Associated Press, quoting Michael Iseman, M.D., TB Chief at the National Jewish Medical and Research Center in Denver, Colorado; San Francisco Chronicle, October 23, 1997, p A2.

Drug-Resistant TB in San Diego County

• 22% of 331 patients with pulmonary TB from San Diego County, CA have strains that are resistant to 1 or more standard TB drugs
• HIV infection status not stated in abstract
• Occurred from February 1995 through May 1996.

Peter CR and others. Drug-resistant pulmonary tuberculosis in the Baja California-San Diego county border population. ICAAC Abstract E-162.

Wasting and Malabsorption

Growth Hormone and Weight Gain

• During treatment for acute opportunistic infections (OI), a 2-week course of growth hormone reverses protein loss and leads to larger weight gain
• 20 men with acute Pneumocystis carinii pneumonia (PCP) or bacterial or cytomegalovirus (CMV) stomach or intestinal infections participated
• The men received recombinant human growth hormone (HGH, Serostim) 6 mg or placebo subcutaneously for 14 days, nutrition counseling and high-energy oral supplements
• Both HGH and placebo groups were treated with standard OI antibiotics
• Baseline and 15-day measurements were done by DEXA (dual-energy X-ray absorptiometry)
• Fat-free mass (muscle) increased significantly by 2.2 kg in HGH group compared to 0.8 kg gain in placebo group
• Body weight increased insignificantly by 2.0 kg in HGH group compared to 0.6 kg gain in placebo group
• There were no reported differences in adverse events or in response to antibiotics for OI.

Paton N and others. Growth hormone therapy during acute opportunistic infections in AIDS has a protein-sparing effect. ICAAC Abstract I-22.

Helicobacter pylori Infection Linked to Malabsorption

• Helicobacter pylori infection linked to a loss of stomach acid and malabsorption of anti-HIV drugs and food
• 37% of 99 randomly selected HIV positive patients in Buffalo, New York
• Heliobacter pylori was the bacterial cause of intestinal ulcers in both HIV positive and negative persons and was treatable with oral antibiotics

Shelton MJ and others. Helicobacter pylori serology, not ethnic group, is primary determinant of gastric pH in HIV (+) subjects. ICAAC Abstract I-160.

Weight Loss Occurs in 25% of People Taking HAART for 4 Months

Study 1 (France)

• 9 patients (20 women) [French study] all taking PI combination for 4 months
• Mean weight gain of 5 pounds occurred in all patients; all but 1 patient had a decrease in HIV viral load
• 25% had a mean weight loss of 7 pounds
• No correlation was found between HIV body weight changes and viral load changes

Study 2 (U.S.)

• 54 patients (2 women) taking HAART combinations with a protease inhibitor (PI, 47) or a non-nucleoside reverse transcriptase inhibitor (7) for 115 days (6-14 weeks) 15-45% of patients taking HAART had a decrease in body cell mass
• No relationship between changes in either weight or body cell mass with HIV viral load changes from HAART was found
• 9 of 13 (67%) gained body cell mass despite an increase in viral load
• 8 of 27 (30%) lost body cell mass despite a decrease in viral load
• No specific trends emerged regarding a relationship between weight or body cell mass change and androgen (male hormone) therapy (69%), either testosterone patch or injection or oxandrolone (Oxandrin) pills
• Authors concluded that diagnosis and treatment of wasting is independent of treatment for HIV with HAART
• Additional follow-up may reveal higher rates of lean body mass increases from HAART.

Berger D and others. Measurement of body weight and body cell mass in patients receiving highly active antiretroviral therapy (HAART) ICAAC Abstract I-26.

Ribeiro AT and others. Correlation between body weight and plasma viral load in HIV patients treated by a protease inhibitor. ICAAC Abstract I-27.

Oxandrolone Shows Continued Benefits for up to 1 Year

• 20 men, 1 woman with wasting syndrome were given a dose of 10 mg oral oxandrolone (Oxandrin) every 12 hours
• Significant mean body cell mass increase of 11.8 pounds and body weight increase of 20.1 pounds over baseline after 1 year (8 patients) occurred
• Non-significant mean increase of ideal body weight from 88.9% to 104.7% and increase in body fat of 4.9 pounds occurred
• No adverse events were reported
• Possible benefits from supplemental glutamine 20 grams daily for 1st month (IDSA abstract from Providence, Rhode Island) might exist
• Potential confounding factors with concomitant protease inhibitor therapy were not discussed.

Fisher A and others. Effects of oxandrolone and L-glutamine on body weight, body cell mass, and body fat in patients with HIV infection-preliminary analysis. IDSA Abstract 548.

Poles MA and others. Oxandrolone as a treatment for HIV-associated weight loss: a 1-year follow-up. ICAAC Abstract I-69.

Megestrol Acetate Leads to Weight Gain

• 2 different doses of megestrol acetate (Megace) lead to insignificantly different weight gains
• Randomized trial of 52 patients treated daily for 8 weeks with either 320 mg or 480 mg megestrol
• Results revealed a mean 3.34 kg weight gain in the 320 mg group compared to a mean 2.36 kg weight gain in the 480 mg group
• Both doses led to increases in body fat and muscle
• Body compartment changes were not measured by BIA (bio-impedence analysis) or DEXA (dual-energy X-ray absorptiometry).

Polo R and others. Comparison of 2 different doses of megestrol acetate in HIV-infected patients affected with weight loss. ICAAC Abstract I-24.

Infants and Children

Glutathione Levels in HIV Positive Children

• Naturally-occurring antioxidant glutathione significantly decreased in HIV positive children
• These were the first studies to document the deficiency in HIV positive children not taking HAART
• Glutathione was significantly correlated with growth failure, high HIV viral loads and low CD4 cell counts.
• See BETA, June 1997, pages 48-49 for information about glutathione levels in adult HIV positive and AIDS patients.

Rodriguez JF and others. Glutathione levels in HIV-infected children. ICAAC Abstract G-69.

Rodriguez J and others. Glutathione levels in HIV (+) and HIV (-) Puerto Rican pediatric patients. IDSA Abstract 494.

HIV Positive Children Have Weaker Responses to Hemophilus Vaccination

• Significant correllation existed with lower B-lymphocyte (antibody producing cell) counts
• It was not associated with high HIV viral loads, although the study had only 15 patients
• Additional booster doses led to improved antibody levels
• The children were aged 4-13 years.

Choudhury S and others. Immunogenicity of Hemophilus influenza type b (Hib) vaccine in human immunodeficiency virus patients. ICAAC Abstract G-104.

Many HIV Positive Children at Risk for Tetanus Even if Vaccinated

• Abnormal decline in tetanus antibodies was documented
• 25% of children given additional tetanus booster did not respond
• Lack of response was associated with low B-cell counts and somewhat with HIV viral load
• The children were aged 6-12 years
• Authors recommended monitoring tetanus antibodies in HIV positive children and administering boosters if low.

Choudhury S and others. Significant waning of antibody to tetanus toxoid in human immunodeficiency virus patients. ICAAC Abstract G-110.

Epidemiology

Knowledge of HIV Status

• At least 66% of HIV positive persons in the U.S. know their HIV status
• This consists of a minimum of 500,000 out of 750,000 HIV positive persons
• Those tested only at anonymous test sites were excluded from analysis.

Sweeney PA and others. A minimum estimate of the number of living HIV infected persons confidentially tested in the United States. ICAAC Abstract I-16.

HIV Acquisition Documented in Incarcerated Brazilians

• Issue of availability of condoms and clean needle works for prisoners, in addition to widespread HIV education in prisons, was stressed.

Diaz RS and others. Estimation of HIV-1 incidence among inmates in a Brazilian prison using a detuned EIA testing strategy. ICAAC Abstract I-20.

8,500 People Worldwide Infected with HIV Daily in 1997

• 3,000 (35%) women daily
• 1,000 (12%) children daily under age 15
• 3,750 (44%) daily who are 15-25 years of age
• 7,650 (90%) people in developing countries who have little chance of access to potent HIV drugs
• India is now the country with the largest number of HIV positive persons at 4 million; half of Bombay sex workers are HIV positive
• 40% of pregnant women in Harare, Zimbabwe are HIV positive
• 10,000 orphans in Brazil because their mothers have died of AIDS; 34,000 children in Brazil have mothers with AIDS and 137,000 children in Brazil have mothers who are HIV positive
• Because of HIV-AIDS, life expectancy at birth has declined in Kenya, Uganda, Zimbabwe and several other countries
• Northern Thailand has seen a significant increase in TB rates
• In 1996, 1.5 million people died from AIDS, representing 25% of all AIDS deaths since the pandemic began
• AIDS is now tied for the second leading infectious cause of death in the world (tied with malaria worldwide deaths, most of those are HIV negative). The number 1 infectious cause of death worldwide is tuberculosis with 3 million deaths annually, most are HIV negative.

Piot P. Global epidemiology of HIV infection. ICAAC Oral presentation S-33.

Miscellaneous

HIV Antibody Test Turns Positive 12 Months after Accidental Needlestick

• Health worker at San Francisco General Hospital (SFGH)
• Hepatitis C virus (HCV) was transmitted from same exposure, with increased liver enzymes 3 weeks after injury
• Current SFGH policy is to test health care workers for 2 years after simultaneous occupational exposure to both HIV and HCV
• This was the 2nd documented case of simultaneous occupational transmission of HCV and HIV, with a delayed positive blood test for the latter.

Beekmann SE and others. Combination post-exposure prophylaxis (PEP). A prospective study of HIV-exposed health care workers. IDSA Abstract 481.

Increased Gonorrhea Rates in Gay/Bisexual Men in U.S.

• U.S. gonorrhea rates in gay/bisexual men increased 400% from 1988-1996
• Surveys done of West coast U.S. public and military sexually transmitted disease clinic patients
• Proportion of urethral (penile) gonorrhea cases among gay/bisexual men increased from 6.4% to 25.2%
• San Francisco’s 1996 rate in gay and bisexual men was 55%; Seattle was 37%
• Rates in the U.S. among gay/bisexual men doubled from 4.0% to 8.7%
• Gay and bisexual men with urethral gonorrhea were significantly more likely to be Caucasian (59%) than heterosexual men with urethral gonorrhea (8%)
• Total number of urethral gonorrhea cases in 28 clinics was 44,776
• Still, total gonorrhea rates in U.S. declined during the same period
• Gonorrhea is a documented STD co-factor that increases HIV transmission
• Urethral gonorrhea transmission indicated unsafe sexual practices that increase the risk of HIV and hepatitis B transmission
• Locations included Albuquerque, Atlanta, Baltimore, Birmingham, Chicago, Cincinnati, Cleveland, Denver, Fort Lewis (Washington), Honolulu, Kansas City, Long Beach, Minneapolis, Nassau County, New Orleans, Orange County, Philadelphia, Phoenix, Portland, St. Louis, San Francisco, San Diego, San Antonio, Seattle and West Palm Beach.

Fox KK and others. Changing epidemiology of gonorrhea: findings from a sentinel system. IDSA Abstract 298.

Semen HIV Viral Load

• Semen HIV viral loads significantly lower in non-transmitting HIV positive heterosexual men, compared to HIV positive heterosexual men who have transmitted HIV to their female partners
• Blood HIV viral loads and immune profiles were similar in the two groups
• Group consisted of 15 heterosexual couples from France, an HIV positive man and an HIV negative woman
• No HIV negative woman was positive for CCR5 mutant 32 allele
• Blood and genital HIV viral loads were not necessarily parallel.

Dalod M and others. Virological and immunological characteristics of couples serodifferent for human immunodeficiency virus serostatus. ICAAC Abstract I-42.

Washing Lettuce Reduces Bacterial Contamination

• Washing individually separated lettuce leaves with water was significantly more effective in removing bacteria from core leaves than washing intact, cored lettuce heads
• Study was prompted by life-threatening diarrheal outbreak of E. Coli 0157:H7 traced to lettuce at a Toronto hospital.

Davidson RJ and others. Does washing lettuce reduce the risk of food-borne enteric disease? It’s only the tip of the iceberg. ICAAC Abstract J-209.

Oral Ivermectin for Scabies

• Single oral dose of ivermectin is an effective therapy for scabies
• This therapy avoids 2 nighttime applications of standard prescription topical cream spaced 1 week apart
• It was not FDA-approved for this indication
• More than 1 dose may be needed for Norwegian scabies, which occur more commonly in people with HIV/AIDS.

Freedman DO. Diagnosis of parasitic eosinophilia, Infectious Disease Review course, Satellite Symposium for 35th IDSA.

Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee at the San Francisco AIDS Foundation since 1987.

Page last updated 05 February 1998