Published in the Bulletin of Experimental Treatments for AIDS December 1996 issue, by the San Francisco AIDS Foundation.

December 1996 Table of Contents

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Research Notes

by Harvey S. Bartnof, MD, and Henry E. Chang

This edition of Research Notes is divided into 3 sections:

• Part I. Selected Highlights from the 36th Annual ICAAC Conference (Bartnof)
• Part II. Highlights from the Third International Congress on Drug Therapy in HIV Infection (Chang)
• Part III. Research Highlights from the medical literature (Bartnof).

Part 1: Selected Highlights from the 36th Annual ICAAC

The 36th annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in New Orleans, LA, on September 15-18, 1996. ICAAC is the annual meeting of the American Society for Microbiology. There were approximately 12,000 attendees, including over 5,000 from outside the U.S. Over 1,700 abstracts were presented, including over 300 related to HIV/AIDS.

HIV Therapies

DMP-266 plus Indinavir is a Very Effective Combination

• HIV viral load decreased by 3.2 log copies/mL after 14 weeks
• DMP-266 decreased indinavir level by one-third

In a late-breaker session, the results of treating HIV positive individuals with DMP-266 alone or in combination with indinavir (Crixivan) were presented. DMP-266 is a non-nucleoside reverse transcriptase inhibitor (NNRTI) in the same class as the recently FDA-approved drug nevirapine (Viramune). Indinavir is a protease inhibitor.

Sixteen patients were enrolled in the double-blind, placebo-controlled pilot study. Several research institutions were involved, including San Francisco General Hospital-University of California at San Francisco. Enrollment criteria included CD4 counts between 200 and 500 cells/mm³ and an HIV RNA viral load greater than 20,000 copies/mL. The mean baseline CD4 count was 221 cells/mm³, while the mean baseline viral load was 131,825 copies/mL. Thirteen (81%) of the participants had received prior antiretroviral therapy and 1 (6%) had prior therapy with a protease inhibitor. Eighty-one percent were male and 56% were Caucasian.

Eleven patients were randomized to receive 2 weeks of DMP-266, 200 mg daily, while the other 5 were given placebo. After 2 weeks, open-label indinavir, 800 mg every 8 hours, was given to all enrollees.

After 2 weeks of monotherapy with DMP-266, the mean HIV viral load decreased by 1.58 log copies/mL, while the mean CD4 count increased by 96 cells/mm³. No significant changes occurred after 2 weeks among the placebo patients. After 14 weeks of treatment, the combination arm had a mean viral load reduction of 3.2 log copies/mL. Indinavir monotherapy results were not reported; however, historically patients on indinavir monotherapy have not demonstrated the same magnitude of viral load reduction. After 14 weeks of therapy, 55% (6 of 11) of combination therapy patients had HIV viral loads below 400 copies/mL, compared to only 20% (1 of 5) of the indinavir monotherapy patients. Mean increases of greater than 100 CD4 cells/mm³ were observed in both arms after 14 weeks of treatment.

In the combination therapy group, DMP-266 caused a 37% decrease in the blood level of indinavir, whereas indinavir did not cause a change in the blood level of DMP-266. The authors suggest that indinavir levels may need to be increased in future trials with DMP-266 in order to prevent indinavir resistance due to subtherapeutic drug levels.

The treatments were well tolerated. A total of 69%, representing patients in both groups, reported adverse events. The most common symptoms were headache, dizziness, rash and diarrhea. All symptoms were rated as mild or moderate. No enrollee stopped therapy due to adverse effects.

In this small study, the promising combination of DMP-266 plus indinavir was able to achieve one of the largest reductions in HIV viral load ever reported. Future studies with the combination are planned.

Mayers D and others. A double-blind pilot study to evaluate the antiviral activity, tolerability and pharmacokinetics of DMP-266 alone and in combination with indinavir. 36th ICAAC. Late-breaker abstract and presentation LB8a.

Update on Ritonavir/Saquinavir Combination

• 12-week HIV RNA viral load reduction of 3.0 log copies/mL
• 12-week CD4 count increase of 113 cells/mm³
• Ritonavir dose 600 mg twice daily; saquinavir dose 400 mg twice daily
• Twice-daily dose better tolerated than 3-times-daily dose

A combinination of the protease inhibitors ritonavir (Norvir) and saquinavir (Invirase) had previously been reported to be a very promising regimen, due to the increased blood levels of saquinavir that can be achieved in a rat model (see BETA December 1995, page 27). However, the optimal doses of the drugs when used in combination had been unknown. Results after 6 weeks of combination therapy were reported at the XI International Conference on AIDS (see BETA September 1996, page 27). Interim results after 12 weeks were reported at ICAAC by Cal Cohen, MD.

The trial was a multicenter, randomized, open-label study of 35 patients. Entry criteria for HIV positive people included baseline CD4 counts between 100 and 500 cells/mm³, no previous exposure to protease inhibitors and discontinuation of therapy with reverse transcriptase inhibitors. Results for the 35 patients treated for 12 weeks (the longest period) were presented. Baseline CD4 counts were in the high 200s cells/mm³, while baseline HIV viral load levels ranged from 4.3 to 4.7 log copies/mL. The patients received 600 mg of ritonavir twice daily and 400 mg of saquinavir twice daily.

After 12 weeks, the mean HIV viral load reduction was 3.06 log copies/mL, with a mean CD4 count increase of 113 cells/mm³. Approximately 75% had undetectable HIV viral loads (using a test with a limit of detection of 400 copies/mL). A second group of 35 patients receiving 400 mg saquinavir twice daily and 400 mg of ritonavir twice daily achieved a viral load reduction of 2.74 log copies/mL and a CD4 count increase of 91 cells/mm³ after 12 weeks.

Six-week follow-up data were also presented for 65 patients randomized to either 400 mg of each drug 3 times daily or 600 mg of each drug twice daily. After 6 weeks, those 2 arms had viral load reductions of 2.1 and 2.2 log copies/mL, respectively, and CD4 count increases of 74 cells/mm³ and 88 cells/mm³, respectively.

Nine patients discontinued therapy due to side effects: 2 from each arm of the 12-week groups, 5 from the 3-times-daily arm and none from the 600 mg dose arm. Most side effects were described as mild, and included those previously described for one or the other of these agents, including nausea, diarrhea, fatigue and numbness around the mouth.

The authors indicate that a twice-daily combination regimen of ritonavir plus saquinavir may be better tolerated than a 3-times-daily regimen. Additional follow-up of these patients is appropriate before any recommendations can be established for this combination.

BETA: page 27. December 1995.

BETA: page 27. September 1996.

Cohen C and others. Ritonavir/saquinavir combination treatment in HIV-infected patients. 36th ICAAC. Late-breaker abstract and presentation LB7b.

Interleukin 2 plus Indinavir Increases CD4 Cell Counts

• Sustained increase of 200-250 cells/mm³ in 1-year trial of 36 patients
• Stable to slight decrease in HIV viral load

The classic hallmark of AIDS has been the progressive decline in the CD4 T-lymphocyte count. Previously, interleukin 2 (IL-2, T-cell growth factor, brand name Proleukin) has been shown to increase CD4 cell counts when given intravenously or subcutaneously (see BETA, June 1995, pages 47-48 and BETA, September 1996, page 30). Many of these studies were able to show an increase in CD4 counts primarily when the baseline CD4 cell count was not too low, in the range of 500 cells/mm³. Researchers from the National Institutes of Allergy and Infectious Diseases (NIAID) reported on the ability of IL-2 to increase the CD4 count even when starting with lower baseline levels, in the 150-200 cells/mm³ range. The IL-2 was given intravenously along with oral indinavir. The lead author of this open-label study was Judith Falloon, MD.

A total of 36 patients with baseline CD4 counts less than 300 cells/mm³ (or less than 20% of total T-cells) were randomized to one of 3 arms:

1) IL-2 infusions, up to 12 million international units (IU) daily, continuously for 5 days every 8 weeks, plus 600 mg of indinavir 4 times daily throughout the study;

2) IL-2 infusions as in arm 1 above, plus indinavir 4 times daily for 10 days, coinciding with the IL-2 infusions; or

3) indinavir alone, in the same doses as in arm 1, with no IL-2.

All 36 participants had prior trial exposure to IL-2 plus AZT (Retrovir) or related drugs. The participants either had not responded to IL-2 previously or were in a control arm and had decreasing CD4 counts. After 14 weeks in the current trial, all enrollees were allowed to supplement their regimens with other antiretrovirals. Also, those in arm 2 were allowed to take indinavir continuously after week 14. Those in arm 3 were allowed to add IL-2 to their regimen after week 14.

At the 50-week mark, 8 of 12 patients in each arm were still taking IL-2. Participants in all 3 arms sustained significant increases in CD4 cell counts. Mean changes in CD4 counts from baseline to week 50 were an increase from 205 cells/mm³ to 464 cells/mm³ in arm 1, an increase from 191 cells/mm³ to 415 cells/mm³ in arm 2 and an increase from 144 cells/mm³ to 376 cells/mm³ in arm 3. Mean changes in plasma viral load from baseline to week 50 were a decrease from 4.9 to 4.6 log copies/mL in arm 1, a decrease from 5.0 to 4.8 log copies/mL in arm 2 and a decrease from 5.1 to 4.7 log copies/mL in arm 3.

No participants died during the study and no new opportunistic infections occurred. One patient from arm 3 who did not opt to take IL-2 developed AIDS dementia.

Therapy was well tolerated. No new side effects were observed with either IL-2 or indinavir. IL-2 caused mild-to-moderate flu-like symptoms, while indinavir was associated with kidney stone pain (if inadequately hydrated) and an asymptomatic increase in blood levels of bilirubin, a product of red blood cell breakdown.

The results indicate that one year of IL-2 infusions, 5 days every 2 months, plus oral indinavir can lead to significant increases in CD4 counts, even when starting with low baseline CD4 levels of 150-200 cells/mm³. Increases ranged from 200 to 250 cells/mm³. The CD4 count increases are associated with HIV viral loads that remain stable or decrease somewhat. The authors state that their findings will be useful in designing a Phase III trial. HIV-infected persons or their healthcare providers interested in NIAID clinical trials using IL-2 can call 800-AIDS-NIH.

BETA: pages 47-48. June 1995.

BETA: page 30. September 1996.

Falloon J and others. Indinavir and interleukin-2 in HIV: one year follow-up. 36th ICAAC. Abstract and poster presentation I108.

CAESAR Trial Documents Benefits of Adding 3TC

• Data Safety and Monitoring Board ends trial early due to significant benefits
• HIV disease progression and death rates reduced by 53%

Julio Montaner, MD, from St. Paul's Hospital in Vancouver, BC, presented preliminary results of the CAESAR trial of combination anti-HIV therapies. The 52-week study demonstrated decreased rates of AIDS progression and death by adding 3TC (Epivir) with or without loviride, an experimental NNRTI drug, to existing reverse transcriptase inhibitor (RTI) monotherapy or combination therapy. An independent Data Safety and Monitoring Board ended the trial early due to disease progression rates in the drug arm that were approximately 50% of those in the placebo arm. Progression was defined as a new AIDS diagnosis or death. There was no significant difference in disease progression rates when comparing the addition of 3TC to the addition of 3TC plus loviride; however, the trial lacked enough statistical power to detect such a difference.

A total of 1,892 patients were recruited from 14 countries. Baseline CD4 counts were 25-250 cells/mm³ (median 131 cells/mm³); HIV viral load levels were not reported. The trial was double-blind and randomized. At entry, participants were taking either AZT monotherapy, AZT plus ddI (Videx), or AZT plus ddC (Hivid). The AZT monotherapy group comprised 62% of enrollees. All participants were randomized to add to their existing RTI therapy either 3TC, 3TC plus loviride, or placebo.

Disease progression occurred in 9% of the 3TC arm, 8% of the 3TC/loviride arm and 17% of the placebo arm. Death occurred in 2.4% of the 3TC arm, 2.7% of the 3TC/loviride arm and 4.6% of the placebo arm. For the two 3TC-containing arms, this represents a 53% decrease in disease progression and a 54% decreased risk of death. Both of these findings were highly statistically significant. A subset of 322 patients in the 3TC-containing arms were analyzed and found to have decreases in HIV viral load and increases in CD4 cell counts.

The report adds to our understanding of the benefits of adding 3TC to RTI therapy using AZT with or without ddI or ddC. Whether the addition of loviride with 3TC provides any additional benefit remains to be determined. Further analyses of subgroups within the trial may lead to new findings.

Montaner J and others. CAESAR: confirmation of the clinical benefit of 3TC (Epivir) in HIV-1 disease, preliminary results. 36th ICAAC. Late-breaker abstract and presentation LB6.

Staszewski S and others. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. Journal of the American Medical Association 276(2): 111-117. July 10, 1996.

AZT Monotherapy Outdated for Children with HIV

• Either ddI alone or ddI plus AZT is more effective than AZT alone
• Significantly more children in the AZT monotherapy arm experienced HIV disease progression, death or drug toxicity when compared to either ddI monotherapy or ddI plus AZT arms
• 839 children were enrolled for 18-42 months

Englund JA and others. Results of ACTG 152, a randomized comparative trial of zidovudine (ZDV), didanosine (ddI), and ZDV/ddI combination therapy in symptomatic HIV-infected children. 36th ICAAC. Abstract and oral presentation I150.

HIV Viral Load

Injection Drug Users Have Lower HIV Viral Loads than Gay/Bisexual Men

Researchers from Johns Hopkins School of Medicine have determined that viral load measurements may not be comparable across different behavioral risk groups. Until the XI International Conference on AIDS in Vancouver, most viral load reports were from studies of gay/bisexual men. Reports on other risk groups were presented in Vancouver (see BETA, September 1996, page 7) and in the literature since then. A new finding presented at ICAAC suggests that injection drug users (IDU) have lower HIV viral loads than gay/bisexual men, even after adjusting for multiple variables. Moreover, recent injectors appear to have significantly lower viral loads than IDU who have not recently injected.

The researchers analyzed HIV viral load measurements from 547 participants from the Baltimore arm of the Multicenter AIDS Cohort Study (MACS), comprised of gay/bisexual men, and the ALIVE study of men and women IDU. Even after adjusting for variables including CD4 count, race, age, gender and HIV therapy, viral loads were significantly lower among the 299 IDU than among the 248 gay/bisexual men (8 infectious units per million [IUPM] peripheral blood mononuclear cells versus 12 IUPM, respectively). IDU who had injected within the previous 6 months had significantly lower viral loads than those who had not injected within the previous 6 months (8 versus 12 IUPM, respectively). Frequency of injection was unrelated to viral load. Since most of the IDU injected both heroin and cocaine, it was difficult to assess any differences in effects from the 2 drugs.

The significance of these findings is unknown. Will the IDU with lower viral loads progress more slowly than otherwise comparable gay/bisexual men? Or will the IDU with lower viral loads experience faster progression? Future analysis may reveal the answer. BETA: page 7. September 1996.

Farzadegan H and others. Injection drug use is associated with lower HIV viral load. 36th ICAAC. Abstract and poster presentation I57.

Kaposi's Sarcoma

Saliva May Be Transmission Route of KSHV

• Research group isolates KSHV from saliva of KaposiÕs sarcoma patients
• Results directly conflict with earlier research

Researchers from the University of Washington School of Medicine have proposed that Kaposi's sarcoma-associated herpes virus (KSHV), also called human herpesvirus type 8, may be transmitted by saliva. Kaposi's sarcoma (KS) is the most common tumor among AIDS patients. It occurs much more commonly among HIV positive men whose risk behavior was sexual contact with other men. This fact led to the hypothesis that KS might be caused, in part, by a sexually transmitted infection or co-factor. The newly described herpesvirus has been linked to KS because it has been detected in the vast majority of KS lesions and in the B-lymphocytes of individuals with KS.

David M. Koelle, MD, and colleagues examined the saliva of 7 gay/bisexual men with KS or prior KS. Using a polymerase chain reaction (PCR) test to detect KSHV DNA in saliva samples, 6 of 7 tests were positive. Some samples had very high levels of KSHV, up to 1 million copies/mL of saliva. The researchers detected KSHV in both salivary fluid and salivary cells. They determined that some of the KSHV was infectious, since they were able to infect cultured cells in vitro using the saliva samples.

The authors state that their findings indicate that KSHV replication occurs in the mouth, and that finding the virus in saliva is "consistent with...a possible role for saliva in the person-to-person transmission of KSHV infection." They comment that KSHV is very similar to another type of herpesvirus, Epstein-Barr virus (EBV), which is transmitted by the salivary route. EBV is the cause of mononucleosis (the "kissing disease" of young adulthood) and of HIV-related oral hairy leukoplakia. The authors caution that, "It may be prudent to avoid contact with potentially infectious body substances, including saliva, until additional information is available."

The results directly conflict with those of Jay A. Levy, MD, from the University of California at San Francisco (UCSF), whose lab did not detect KSHV in saliva samples of men with AIDS-KS in 1995. In addition, it is possible that there are natural inhibitors to KSHV present in the saliva of uninfected but exposed individuals, similar to natural salivary inhibitors of HIV. Animal models could be used to help predict the transmissibility of KSHV by saliva. Lastly, researchers at the Centers for Disease Control and Prevention (CDC) have detected KSHV in the semen of 91% of 33 HIV positive gay men, which correlated with the future development of KS lesions (see BETA, September 1995, page 30 and BETA, March 1996, page 16). Finally, it should be emphasized that the presence of an infectious agent in a bodily fluid does not necessarily mean that that fluid is the route of transmission for the agent. The final answer about the mechanism of transmission for KSHV awaits further research.

BETA: page 30. September 1995.

BETA: page 16. March 1996.

Koelle D and others. Detection of Kaposi's sarcoma-associated herpesvirus in saliva of human immunodeficiency virus infected individuals with and without Kaposi's sarcoma. 36th ICAAC. Abstract and oral presentation H84.

Cryptococcosis

Liposomal Amphotericin B is Effective

• Lower doses of liposomal (enclosed in fat globules) amphotericin B (AmBisome) are as effective as higher doses of non-liposomal amphotericin B
• 4 mg/kg dose of liposomal amphotericin B is better than 7 mg/kg dose of regular amphotericin B
• Lower rate of kidney toxicity with liposomal formulation
• Liposomal formulation kills Cryptococcus neoformans in cerebrospinal fluid sooner (14 days vs more than 21 days for non-liposomal amphotericin B)
• Study of 28 patients in the Netherlands

Leenders ACA and others. A randomized trial of liposomal amphotericin B (AmBisome) 4 mg/kg versus amphotericin B 7 mg/kg for cryptococcal meningitis in HIV-infected patients. 36th ICAAC. Abstract and oral presentation LM35.

Cryptosporidiosis

Nitazoxanide Shows Efficacy for Cryptosporidial Diarrhea

• Cryptosporidium cysts cleared or nearly cleared from stool in 33% of patients
• Daily bowel movements decreased by half or more in 18% of patients
• Diarrhea completely resolved in another 18%
• Medication well tolerated; skin rash in 6%

Diarrhea due to Cryptosporidium parvum is one of the most difficult to treat opportunistic infections associated with AIDS. Encouraging results of a few therapies were presented at the Vancouver AIDS conference in July (see BETA, September 1996, page 34). A report from Mexico described very impressive results using nitazoxanide (NTZ). A more sobering yet promising report on NTZ was presented at ICAAC. The authors included Lawrence Davis, MD, Rosemary Soave, MD, from New York Hospital-Cornell Medical Center, and Jeffrey Fessel, MD, from Kaiser Foundation Research Institute in San Francisco. The trial was an open-label Phase I/II study.

Thirty patients with AIDS-related cryptosporidial diarrhea were enrolled and received daily NTZ for 4 weeks. The daily doses were either 500 mg, 1,000 mg, 1,500 mg or 2,000 mg. Those who had persistent diarrhea received an additional 4 weeks of treatment using the 2,000 mg daily dose.

The report analyzed 22 patients who completed at least 4 weeks of treatment with NTZ. A reduction in the frequency of daily bowel movements occurred in 15 of 22 (68%). This occurred in 2 of 6 in the 500 mg dosage group, 7 of 7 in the 1,000 mg group, 4 of 6 in the 1,500 mg group and 2 of 3 in the 2,000 mg group. A 50% or more reduction in daily bowel movements occurred in 4 of 22 (18%), while 3 of 22 (14%) had a 25-50% reduction in daily bowel movements. Diarrhea resolved in 4 of 22 (18%). The drug was well tolerated, with only 2 enrollees experiencing a skin rash.

The authors conclude that NTZ has efficacy against cryptosporidial diarrhea. They state that future studies are warranted with longer treatment times and possibly higher dosages, greater than 2,000 mg daily. NTZ is available by expanded access through Unimed Pharmaceuticals. This report, in addition to those from the Vancouver conference, represents a very promising advance in the treatment for this severe opportunistic infection.

BETA: page 34. September 1996.

Davis LJ and others. Nitazoxanide for AIDS-related cryptosporidial diarrhea: an open-label safety, efficacy and pharmacokinetic study. 36th ICAAC. Abstract and poster presentation LM50.

Berberine May Alleviate Diarrhea due to Microsporidium and Cryptosporidium

Berberine is an alkaloid derived from the bark and roots of several types of plants. It has been used in India, China and Japan to treat various types of conditions in HIV negative individuals, including diarrhea due to parasites or bacteria. Some of its benefit may derive from its ability to block fluid secretion into the intestines. It is very poorly absorbed from the intestinal tract, greatly reducing side effects. Researchers from the Medical College of Pennsylvania have shown that berberine can inhibit the in vitro growth of Microsporidia, a common cause of diarrhea in AIDS patients. It may also have some efficacy against other parasites, including Cryptosporidium parvum.

McDevitt JT and others. Berberine: a candidate for the treatment of diarrhea in AIDS patients. 36th ICAAC. Abstract and poster F175.

GM-CSF plus Paromomycin for Cryptosporidial Diarrhea

• 2 cases from Milan, Italy, had no prior response to paromomycin (Humatin) alone
• Granulocyte macrophage colony-stimulating factor (GM-CSF, Leukine) 300 micrograms given daily along with paromomycin 4.3 grams daily and AZT 500 mg daily
• Diarrhea stopped after 2 days, but returned when GM-CSF was stopped
• 1 patient "cured" of Cryptosporidium parvum 7 months after treatment with GM-CSF/paromomycin and AZT
• 1 patient had continued recurrences of diarrhea when GM-CSF was stopped due to Cryptosporidium parvum in the gall bladder bile ducts.

Capetti A and others. Can rHuGM-CSF help in treating drug-resistant cryptosporidiosis in AIDS? 36th ICAAC. Abstract and oral presentation G33.

Cytomegalovirus

New Drug 1263W94 Effective against Ganciclovir-Resistant Cytomegalovirus In Vitro

• 1263W94 also effective against some cidofovir-resistant cytomegalovirus in vitro

Researchers from Glaxo Wellcome and the University of Michigan have reported that 1263W94, an investigational oral drug, shows significant activity against cytomegalovirus (CMV), a cause of blindness in people with AIDS. In vitro studies indicate that 1263W94 has greater activity against CMV than ganciclovir (Cytovene), foscarnet (Foscavir), cidofovir (Vistide) or lobucavir. Ganciclovir and/or foscarnet are the first-line agents for CMV treatment. The new drug shows activity against CMV strains that are resistant to either ganciclovir or cidofovir. The agent does not block the action of AZT, ddI, ddC or nevirapine. Phase I/II clinical trials using 1263W94 are currently underway.

Biron KK and others. Antiviral activity and mechanism of action of 1263W94, a benzimidazole riboside inhibitor of human cytomegalovirus. 36th ICAAC. Abstract and oral presentation H85.

Monoclonal CMV Antibody Therapy Not Effective for Retinitis

• Treatment causes twice the mortality of placebo for relapsing retinitis

Results of the multicenter Monoclonal Antibody CMV Retinitis Trial were presented by Doug Dieterich, MD, from New York University School of Medicine, on behalf of the Studies of Ocular Complications of AIDS Research Group. The Phase II/III randomized, placebo-controlled study evaluated the efficacy and safety of MSL-109 (Protovir), a human monoclonal antibody given intravenously for CMV retinitis. A total of 209 enrollees with either newly diagnosed or relapsing retinitis were enrolled. A 60 mg dose of MSL-109 or placebo was given intravenously every 2 weeks.

Eye photographs were evaluated by non-treating physicians. Progression of retinitis occurred in a mean 65 days in the MSL-109 group and a mean 66 days in the placebo group, a difference that was not significant. There was a statistically significant difference in mortality in the trial, limited to those enrollees with relapsing retinitis. The death rate in the treatment arm was twice that in the placebo arm. However, there were no differences in death rates in those with newly diagnosed retinitis when comparing MSL-109 to placebo. The reasons for the excess mortality are unknown.

The monoclonal CMV antibody MSL-109 is not effective in the treatment of HIV-associated CMV retinitis. The higher death rate due to the drug probably precludes future trials.

Dieterich D. Monoclonal antibody CMV retinitis trial: preliminary results. 36th ICAAC. Late-breaker abstract and presentation LB8b.

Pneumocystis carinii Pneumonia

Tests of Mouth/Throat Samples Identify 3 out of 4 Pneumocystis carinii Lung Infections

• PCR test used
• Experimental test may avoid the need for 75% of bronchoscopy tests currently used to diagnose Pneumocystis carinii pneumonia

Researchers from Hvidovre Hospital in Copenhagen, Denmark, have found that a new PCR test of fluids used to wash out the mouth and throat was able to detect Pneumocystis carinii organisms 72% of the times that the organism was detected in lung fluids. The lung fluids were obtained by bronchoscopy, the insertion of a flexible tube into the bronchial airway while the patient is sedated. The study included 25 patients being evaluated for possible Pneumocystis carinii pneumonia (PCP). When the new test was used on mouth/throat washings of HIV negative hospital staff controls, none were positive, indicating a high specificity.

Testing of more samples would be the next step. In addition, a comparison with the sputum induction technique for collecting fluid samples would be quite useful. Sputum induction involves inhaling a salty mist to stimulate coughing up phlegm. Using washings from the mouth and throat would be a much less invasive, less expensive and more comfortable way to diagnose PCP.

Lundgren B and others. Evaluation of PCR technique for diagnosing Pneumocystis carinii pneumonia in HIV positive patients using oropharyngeal washings. 36th ICAAC. Abstract and poster D72.

Toxoplasmosis

Trovafloxacin Effective against Toxoplasmosis in Mouse Model

There is a clear need for new non-toxic therapies for life-threatening toxoplasmosis encephalitis (brain infection) in people with AIDS, especially pregnant HIV positive women. Researchers from the Palo Alto Medical Foundation Research Institute have determined that trovafloxacin, a quinolone antibiotic, was 100% effective in treating mice with acute toxoplasmosis. Moreover, no significant toxicity was found. The authors suggest that trovafloxacin may be useful in treating toxoplasmosis in humans.

Khan AA and others. Trovafloxacin is active against Toxoplasma gondii. 36th ICAAC. Abstract and poster E74.

Progression and Survival

Decreased Survival for AIDS Patients in Managed Care

• Decreased survival when compared with traditional "fee-for-service" patients
• Quality of life measurements not reported

Researchers from the Multicenter AIDS Cohort Study (MACS) have reported a shorter survival time after an AIDS diagnosis for those patients who are enrolled in managed care organizations (MCO). Those in MCO were compared to those with traditional indemnity insurance coverage, also called "fee-for-service" (FFS).

A total of 947 HIV-infected men from MACS were enrolled in the study. They were evaluated for survival times from October 1991 through March 1995. For those who were HIV positive at study entry, there were no differences in survival times when comparing insurance type -- MCO vs FFS -- after adjusting for disease stage and demographic variables (e.g., age). However, for the 335 who had AIDS at entry or developed AIDS during the study, median survival was 17 months for those in MCO and 30 months for those using FFS. After statistically controlling for demographic variables and the severity of AIDS conditions, there was still a 58% higher death rate among those in MCO compared with FFS. The results were highly significant.

Limitations of the study include the fact that quality of life (QOL) measurements were not used. It is possible that the extra year of life for FFS enrollees may have earned poor QOL ratings. Second, since the study ended in March 1995, many new HIV therapies have been approved by FDA, changing progression and mortality statistics. Combinations including protease inhibitor drugs have dramatically affected QOL for many people with HIV/AIDS. Also, the treating physicians' HIV/AIDS experience was not reported. Increased HIV/AIDS treatment experience on the part of physicians directly correlates with increased patient survival (see BETA, June 1996, pages 43-44).

BETA: 43-44. June 1996.

Palenicek J and others. Poorer survival among AIDS patients enrolled in managed care organizations (MCO) versus traditional indemnity insurance. 36th ICAAC. Abstract and presentation N24.

Other

"Shooter's Botulism" Epidemic in California Injection Drug Users

• Wound botulism linked to contaminated Òblack tarÓ heroin
• Greatest risk from Òskin poppingÓ (injecting under the skin rather than into a vein)
• Botulism causes muscle paralysis and is potentially lethal
• 22 cases in California

Werner SB and others. "Shooter's Botulism": epidemic wound botulism in California. 36th ICAAC. Abstract and poster presentation K109.

PMEA Effective for Chronic Hepatitis B Infection

• Once daily oral dose used
• Hepatitis B viral DNA in blood decreased by 2 log copies/mL
• PMEA also effective against HIV and many herpesviruses, including cytomegalovirus
• Hepatitis B infection is very common among HIV positive people

Gilson RJ and others. Adefovir dipivoxil (Bis-POM PMEA) treatment for chronic hepatitis B infection: a placebo-controlled Phase I/II study. 36th ICAAC. Late-breaker abstract and oral presentation LB1.

Xiong XF and others. Inhibition of human cytomegalovirus DNA polymerase by PMEA and PMPA diphosphates. 36th ICAAC. Abstract and poster presentation H29.

Treating Peptic Ulcer Bacteria Alleviates Abnormally Low Stomach Acid Levels

• Treatment leads to improved absorption of many antibiotics
• Ulcer-causing Helicobacter pylori infection is common in HIV positive individuals

36th ICAAC. Abstract A56.

Hepatitis G Virus Identified

• Newly identified strain causes hepatitis disease in injection drug users and blood transfusion recipients
• Transmission of hepatitis G virus from infected women to newborns occurs in 33%, although no infant had hepatitis disease

Penciclovir Cream Effective for Recurrent Oral Herpes Simplex

• Penciclovir is first medication ever statistically shown to speed healing time and decrease pain of herpes simplex lesions on lips
• Study participants were HIV negative, but the drug may provide benefits for HIV positive people as well

The first topical antiviral cream to impact the clinical course of lesions on the lips ("cold sores" or "fever blisters") due to herpes simplex type 1 (HSV-1) was reported at ICAAC. Researchers from the University of Alberta in Canada reported their findings on using a cream containing 1% penciclovir, an experimental antiviral agent. A total of 2,364 patients from 74 centers in various countries were enrolled into the double-blind, placebo-controlled trial. All had a history of recurrent herpes simplex lesions on the lips.

Enrollees began using the cream at the first prodromal (pre-outbreak) symptoms of herpes reactivation. When compared to placebo patients, those using penciclovir cream saw their herpes lesions heal 29% faster, had resolution of pain 32% faster and stopped shedding herpes simplex virus 47% sooner. All results were statistically significant. Patients who did not initiate therapy during the prodromal phase also derived benefits. The results are very similar to those of a trial of penciclovir at 31 centers in the U.S.

While the study included only HIV negative participants, the drug may be of benefit to those with HIV/AIDS, who may experience recurrent and prolonged herpes outbreaks. Studies enrolling HIV positive people are clearly indicated. Penciclovir is approved in the United Kingdom under the brand name Vectavir.

In a related abstract, an experimental formulation of foscarnet (Foscavir) 3% cream was also shown to significantly reduce lesion size and pain of ultraviolet radiation-induced herpes simplex labialis (on the lips) in 78 HIV negative adults. Foscarnet is an FDA-approved intravenous drug used to treat CMV disease in people with AIDS.

Raborn GW for the Penciclovir Topical Collaborative Study Group. Penciclovir cream for recurrent herpes simplex labialis: an effective new treatment. 36th ICAAC. Abstract and oral presentation H81.

Spruance SL and others. Foscarnet cream in the treatment of experimental ultraviolet radiation-induced herpes labialis: a double-blind, placebo-controlled, multicenter trial. 36th ICAAC. Abstract and poster presentation H114.

Part II: Highlights from the 3rd International Congress on Drug Therapy in HIV Infection

The Third International Congress on Drug Therapy in HIV Infection was held November 3-7, 1996, in Birmingham, England.

20-Week Data on Ritonavir/Saquinavir Combination

Bill Cameron, MD, of Ottawa General Hospital and Associate Professor at the University of Ottawa, presented 20-week data on the safety and efficacy of combination therapy with ritonavir and saquinavir. The multicenter, open-label study randomized approximately 140 patients to one of 4 treatment arms: 1) 400 mg twice daily ritonavir plus 400 mg twice daily saquinavir, 2) 600 mg twice daily ritonavir plus 400 mg twice daily saquinavir, 3) 400 mg 3 times daily ritonavir plus 400 mg 3 times daily saquinavir, or 4) 600 mg twice daily ritonavir plus 600 mg twice daily saquinavir. All patients had baseline CD4 counts of 100-500 cells/mm³, and none had previous exposure to protease inhibitor drugs. After 20 weeks of treatment, median viral load level declined by more than 99.9%, or 3.2 logs, and median CD4 count increased by 96 cells/mm³ in participants in arms 1 and 2 (51 individuals). After 12 weeks of treatment, median viral load level decreased by 2.69 logs and median CD4 count increased by 114 cells/mm³ in participants in arms 3 and 4 (44 individuals). The combined regimens were generally well tolerated, with 7% of participants discontinuing due to adverse effects. The most commonly reported adverse events, which were generally mild and transient in nature, were tingling around the mouth, diarrhea, fatigue and nausea.

Ritonavir plus AZT plus 3TC in Antiretroviral-Naive Patients

Sven Danner, MD, and Daan Notermans, MD, of the Academic Medical Centre in Amsterdam, presented virology data from an open-label, randomized, 2-arm pilot study of 600 mg twice daily ritonavir plus 300 mg twice daily AZT plus 150 mg twice daily 3TC. A total of 33 HIV positive antiretroviral-naive individuals with CD4 cell counts less than 50 cells/mm³ and RNA viral loads of more than 30,000 copies/mL were randomized to start the 3 drugs simultaneously (arm 1: 17 individuals) or to start ritonavir monotherapy for 3 weeks followed by the addition of AZT and 3TC (arm 2: 16 individuals). At baseline, median plasma HIV RNA levels were 5.27 and 5.37 logs and median CD4 cell counts were 177 cells/mm³ and 134 cells/mm³ in arm 1 and arm 2, respectively. After 24 weeks of therapy, levels of HIV RNA were reduced by 2.8 logs below baseline in patients in both arm 1 (10 individuals) and arm 2 (10 individuals). CD4 cell counts increased by 180 cells/mm³ (arm 1) and 100 cells/mm³ (arm 2) above baseline over 24 weeks. To compare viral load levels in plasma and lymphoid tissues, tonsil biopsies were performed at initiation of therapy and at 3 later times during the study. Recent data from Ashley Haase, MD, and colleagues at the University of Minnesota showed that 90% of tonsillar biopsies consist of lymphoid tissues. In this study, tonsillar lymphatic tissue was processed by Haase and tissue HIV quantification was performed at Chiron Corporation using the ultrasensitive branched-chain DNA (bDNA) assay. This assay has a lower limit of detection of 30 copies/milligram.

AZT plus ddI plus Nevirapine Reduces HIV Viral Load to below Limit of Detection

Brian Conway, MD, head of the Clinical Retroviral Laboratory at the British Columbia Centre for Excellence in HIV/AIDS in Vancouver, presented findings from the Italy-Netherlands-Canada-Australia-States (INCAS) study. A total of 151 antiretroviral-naive, asymptomatic HIV positive individuals with CD4 counts of 200-600 cells/mm³ were randomized to receive AZT plus ddI, AZT plus nevirapine, or AZT plus ddI plus nevirapine. After 1 year of therapy, 50% of those who received triple combination therapy had plasma viral load levels reduced below the level of detection of the available assay (200 copies/mL). In comparison, only 11% of those receiving AZT plus ddI and none of those receiving AZT plus nevirapine had undetectable levels of virus after 1 year of therapy. In addition, 8 of 12 participants in the triple therapy group had undetectable viral loads using the more sensitive assay recently developed by John Sninsky, PhD, of Roche Molecular Sytems. His assay has a limit of detection of 20 copies/mL. All participants in the 2 dual therapy groups had viral load levels above 20 copies/mL.

AZT plus ddI Plus Nevirapine Reduces Viral Load in Lymph Nodes and Blood

Marianne Harris, MD, Clinical Research Advisor at the HIV Clinical Trials Network in Vancouver, BC, reported results of a substudy of the INCAS trial. At the completion of the study, a subset of 22 Canadian participants underwent lymph node biopsies. Participants who received triple combination therapy (AZT plus ddI plus nevirapine) for 1 year had median viral load levels of 11x106 equivalents/gram in lymph node tissue and 5,300 copies/mL in plasma. Three of 6 participants on triple drug therapy had viral load levels in lymph nodes below the level of detection (10x106 equivalents/gram of tissue). By contrast, participants who received AZT plus ddI had a median lymph node viral load of 27x106 equivalents/gram and a median plasma viral load of 26,900 copies/mL. In a group of 10 matched HIV positive individuals who had not received any antiretroviral therapy, median lymph node viral load was 206x106 equivalents/gram and median plasma viral load was 48,100 copies/mL.

Part III: Research Highlights from the Medical Literature

HIV Therapies

Interleukin 2 Infusions Effectively Increase CD4 Cell Counts

• IL-2 was combined with nucleoside analog therapy
• CD4 counts increased by 488 cells/mm³ over 12 months
• HIV viral load levels remained unchanged

Researchers from the National Institutes of Health (NIH) have previously reported that intermittent interleukin-2 (IL-2, aldesleukin, Proleukin) infusions given to HIV positive persons significantly increased their CD4 cell counts (see BETA June 1995, pages 47-48). The same group of researchers has expanded their studies to more patients and for a longer follow-up period.

Sixty HIV positive individuals were enrolled in the current study. All had CD4 counts greater than 200 cells/mm³. HIV viral load measurements were determined, but there were no specified levels for inclusion in the study. Since the earlier report revealed some transient increases in HIV viral load after IL-2 infusions, the current study called for nucleoside analog therapy along with IL-2. The types of nucleoside analog therapy were determined by the patient and the referring physician. Variations included monotherapy or combination therapy with AZT, ddI, ddC and/or d4T (Zerit).

IL-2 was given daily for 5 days every 2 months over a 14-month period. The dose of IL-2 was started at 18 million international units (IU). In the latter half of the study, this dose was decreased to a mean daily dose of 8 million IU. Patients were hospitalized on the days of IL-2 infusions.

After an average of 12 months, those who received IL-2 plus nucleoside analog therapy sustained a mean increase in CD4 count from 428 cells/mm³ to 916 cells/mm³ (a 418 cells/mm³ increase). The control group (nucleoside analog therapy without IL-2) sustained a mean decrease in the CD4 count from 406 cells/mm³ to 349 cells/mm³ (a 57 cells/mm³ decrease). During the 12 months there were no significant differences in HIV viral load between the 2 groups.

After the first year of the study, participants were allowed to continue (or control participants allowed to begin) open-label IL-2. The original CD4 cell count increases in the IL-2 group were maintained for 2 years. In 5 patients, CD4 counts remained above 1,000 cells/mm³ for at least 18 months after IL-2 was discontinued. The authors determined that the CD4 cell count increases were not due to redistribution of CD4 cells. Instead, increased lymphocyte proliferation and lymph node enlargement was observed.

Side effects from IL-2 included fatigue, headache, oral sores, abdominal pains, fever and diarrhea. Ten percent to 20% of patients experienced each of the following: low granulocyte (a type of white blood cell) counts, low calcium levels, low phosphorus levels and increased alkaline phosphatase (a bile enzyme) levels. One-third experienced an asymptomatic increase in blood bilirubin levels. All patients experienced at least one moderate or serious side effect, usually a "flu-like" symptom. One patient in the IL-2 arm died after stopping IL-2 therapy; he developed Mycobacterium avium complex disease and progressive multifocal leukoencephalopathy. Ten of 30 patients in the IL-2 arm missed some IL-2 doses due to side effects or a CD4 count that was too high (greater than 3,000 cells/mm³).

It is likely that IL-2 therapy will have some role as an immune modulator combined with antiretroviral therapy in the treatment of HIV disease. Several researchers have treated patients with self-administered injections of IL-2 with moderate success (see BETA September 1996, pages 30-31).

BETA: 47-48. June 1995.

BETA: 30-31. September 1996.

Kovacs JA and others. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. New England Journal of Medicine 335:1350-1356. October 31, 1996.

ACTG 175 Results Published

• Anti-HIV therapy is indicated for those with CD4 counts less than 500 cells/mm³ Therapy with either AZT/ddI or AZT/ddC or ddI alone is better than AZT alone AZT monotherapy is substandard care

Results of the AIDS Clinical Trials Group (ACTG) 175 study were published in the October 10, 1996 issue of the New England Journal of Medicine. These data have been presented previously in BETA (December 1995, page 25), but the final results underscore major changes in treatment for HIV/AIDS.

The double-blind study enrolled 2,467 HIV positive persons with CD4 counts between 200 and 500 cells/mm³. The trial evaluated the effects of nucleoside analog monotherapy (600 mg daily of AZT or 400 mg daily of ddI) versus double nucleoside analog therapy (AZT plus either ddI 400 mg daily or ddC 2.25 mg daily). Prior anti-HIV therapy had been taken by 43% of the group. Participants were followed for 2.75 years.

The results showed that, when compared with AZT monotherapy, the risk of progression to AIDS or death was 36% lower with AZT/ddI, 23% lower with AZT/ddC, and 31% lower with ddI alone. When compared with AZT alone, the risk of death was 45% lower with AZT/ddI, 29% lower with AZT/ddC, and 49% lower with ddI monotherapy. The results were statistically significant, except for the AZT/ddC arm, which was only significant for those without prior anti-HIV therapy.

Viral load changes were measured in a subset of 391 patients. Reductions in HIV viral load at 8 weeks correlated with increased survival and decreased AIDS progression. The HIV viral load reductions were 0.3 log copies/mL in the AZT monotherapy group, 0.9 log copies/mL in the AZT/ddI group, 0.9 log copies/mL in the AZT/ddC group and 0.6 log copies/mL in the ddI monotherapy group. The results were statistically significant.

In an accompanying editorial, Lawrence Corey, MD, and King Holmes MD, PhD, both from the University of Washington, emphasized some important conclusions from the study. They conclude that 1) all HIV positive people with CD4 counts less than 500 cells/mm³ can benefit from and should be encouraged to take antiretroviral therapy; 2) AZT alone is no longer a satisfactory initial therapy for HIV infection; 3) therapy for HIV positive people with CD4 counts between 200 and 500 cells/mm³ should consist of a combination of nucleoside analogs, although ddI monotherapy is an alternative (the researchers acknowledge that other combinations, such as those including protease inhibitors, have led to more profound clinical improvements); and 4) HIV viral load measurements will indicate whether current therapy is working and whether therapy is likely to affect prognosis.

BETA: page 25. December 1995.

Hammer SM and others. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. New England Journal of Medicine 335:1081-1090. October 10, 1996.

3TC Also Effective against Hepatitis B Virus

Many people with HIV infection also are infected with the hepatitis B virus (HBV). The majority of those who acquired HBV infection before their HIV infection have had an adequate immune response and cleared the HBV. However, some have not, and have progressed to a state of chronic HBV infection. Researchers from Paris, France, have reported that the antiretroviral drug 3TC, used to treat HIV disease, also has beneficial effects against HBV.

Forty people (39 men and 1 woman) infected with both HIV and HBV were treated with 3TC monotherapy, 600 mg daily for 12 months. All were refractory to or were unable to tolerate other therapies. This was an open-label trial.

Among the 27 patients with a high baseline blood level of HBV DNA, 96% sustained marked reductions. Among those with low baseline levels, the 12-month therapy resulted in undetectable HBV DNA blood levels when measured by PCR. No serious adverse effects were reported. Larger placebo-controlled trials are indicated.

Benhamou Y and others. Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Annals of Internal Medicine 125:705-712. November 1, 1996.

Candidiasis

Drug-Resistant Oral Candidiasis Resolves with ddI plus Saquinavir

• Strain was resistant to fluconazole, itraconazole and oral amphotericin B

Barry Zingman, MD, from Montefiore Medical Center, has described a case report of HIV-related, resistant oral candidiasis that resolved with a combination of HIV therapies. The patient was a 34-year-old man with a CD4 count of 4 cells/mm³. He had oral candidiasis that was resistant to high dose fluconazole (Diflucan), itraconazole (Sporanox) and oral solution amphotericin B. Zingman reported that the patient's candidiasis resolved after combination antiretroviral therapy was instituted with ddI 125 mg twice daily plus saquinavir 600 mg 3 times daily. The patient did use nystatin, an antifungal, once weekly; however, such an infrequent dose of nystatin would have little effect on the Candida. The patient also experienced a weight gain of 16 pounds after combination therapy was instituted.

Zingman BS. Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir. New England Journal of Medicine 335(25):1674-1675. June 20, 1996.

Prophylaxis for Oral Candidiasis with Nystatin Pastilles

• 2 daily pastilles (lozenges) are effective in preventing oral candidiasis

MacPhail L and others. Prophylaxis with nystatin pastilles for HIV-associated oral candidiasis. Journal of Acquired Immunodeficiency Syndromes and Retrovirology 12:470-476. November 1996.

Cryptosporidium parvum

Outbreak of Cryptosporidium parvum Traced to Chicken Salad

Cryptosporidium parvum diarrhea represents one of the most difficult to treat AIDS-related opportunistic infections. Most transmission of Cryptosporidium parvum has occurred due to consumption of contaminated surface or ground water, from animal-to-person contact, or from person-to-person (usually sexual) contact. Only rare reports have indicated transmission by food.

The CDC reported an outbreak of Cryptosporidium parvum diarrhea among 15 HIV negative people who ate chicken salad at a social event in Blue Earth County, MN, in 1995. Drinking water at the function was not associated with diarrheal illness. The hostess who prepared the food operated a licensed day-care home. She had prepared the salad while day-care children were in her home. She acknowledged changing diapers before making the salad, but reported that she "routinely followed handwashing practices." Cryptosporidium cysts were detected in 1 of 15 people with the illness. All others had recovered from their illness by the time the investigation occurred.

The CDC concluded that the history, incubation period, symptoms, course of illness and the isolation of Cryptosporidium parvum from one stool sample indicate that the chicken salad was the source of the outbreak. An infant in day-care may have been an asymptomatic source.

Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report 45:783-784, 1996.

Kaposi's Sarcoma

Human Chorionic Gonadotropin Beneficial when Injected into KS Tumors

Researchers from the University of Southern California have reported that injecting Kaposi's sarcoma tumors with human chorionic gonadotropin (HCG) causes them to regress. The beneficial, anti-KS effects of the pregnancy hormone HCG have been discussed previously in BETA (March 1996, page 14).

The double-blind, placebo-controlled Phase I/II trial enrolled 36 patients with AIDS-related KS. KS lesions were injected with HCG at dose levels of 250, 500, 1,000 or 2,000 international units 3 times per week for 2 weeks. The researchers used A.P.L. (manufactured by Wyeth-Ayerst), the commercial HCG preparation they determined to have the greatest potency.

The response rates for the various doses were: 250 IU -- 1 of 12 or 8% response; 500 IU -- 5 of 12 or 42% response; 1,000 IU -- 5 of 12 or 42% response; and 2,000 IU -- 10 of 12 or 83% response. A complete regression of the injected KS tumor occurred in 1 of 12 or 8% at 250 IU; 1 of 12 or 8% at 500 IU; 2 of 12 or 16% at 1,000 IU; and 5 of 12 or 42% at 2,000 IU. None of the placebo-injected KS tumors responded to treatment. The results were statistically significant. Interestingly, there was a complete resolution of a few KS lesions not injected with HCG in patients given the highest dose. This suggested an effect of the HCG injections at other bodily locations due to absorption into the bloodstream.

Side effects, described as mild, included dizziness, nausea, headache, anxiety and pain at the site of injection. There were some minor changes in the normal levels of pituitary hormones (luteinizing hormone and follicle-stimulating hormone) that regulate production of testosterone and sperm. Levels of testosterone increased insignificantly in a majority of patients.

The beneficial effects of HCG were attributed to apoptosis, or programmed cell death. Further studies are indicated.

In an accompanying editorial, Susan E. Krown, MD, from Memorial Sloan-Kettering Cancer Center, emphasized that the beneficial effect may be derived not from the entire HCG molecule itself, but from specific portions or breakdown products. She also pointed out that the current pharmacy price of HCG is $264 for a 20,000 IU vial. Krown added that the treatment was helpful only for cosmetic improvements, with little effect on most other existing KS tumors or those that could occur in the future.

BETA: page 14. March 1996.

Gill PS and others. The effects of preparations of human chorionic gonadotropin on AIDS-related Kaposi's sarcoma. New England Journal of Medicine 335:1261-1269. October 24, 1996.

Krown SE. Kaposi's sarcoma -- what's human chorionic gonadotropin got to do with it? New England Journal of Medicine 335:1309-1310. October 24, 1996.

KSHV Antibody Test Turns Positive Before KS Lesions Appear

The co-discoverers of the Kaposi's sarcoma-associated herpesvirus and researchers from the CDC have reported additional information adding to the evidence that KSHV is a cause of KS. BETA previously reported on the discovery of KSHV by Yuan Chang, MD, and Patrick Moore, MD, from Columbia University (see BETA March 1996, page 14). Using Chang and Moore's immunoblot assay for antibodies to KSHV, researchers determined that 21 of 40 patients with AIDS-related KS became KSHV antibody positive 6-75 months before showing symptoms of KS disease. The median duration of KSHV positivity before KS was 33 months. The researchers found no KSHV antibodies in the following groups: 122 blood donors, 22 patients with Epstein-Barr virus infection and 20 HIV-positive men with hemophilia. The report was published in the July 25, 1996 issue of New England Journal of Medicine.

Gao S-J and others. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related nuclear antigens before the development of Kaposi's sarcoma. New England Journal of Medicine 335:233-241. July 25, 1996.

Rate of Antibodies to KSHV Measured in Various Populations

• Rates are most similar to those of antibodies to genital herpes simplex virus
• Patterns follow the epidemiology of Kaposi's sarcoma
• Antibodies to KSHV are less common in the general population in developed countries
• 2-8% of U.S. children are KSHV antibody positive, suggesting a non-sexual route of transmission
• Over half of the general population in Uganda and Zaire is KSHV antibody positive

Simpson GR and others. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 349: 1133-1138. October 26, 1996.

Leanette ET and others. Antibodies to human herpevirus type 8 in the general population and in Kaposi's sarcoma. Lancet 348:858-861. September 28, 1996.

O'Leary JJ. Seeking the cause of Kaposi's sarcoma. Nature Medicine 2(8): 826-863. August 1996.

Kedes DH and others. The seroepidemiology of human herpevirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nature Medicine 2(8): 918-924. August 1996.

Gao S-J and others. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nature Medicine 2(8): 925-928. August 1996.

Tuberculosis

Rate of Drug-Resistant Tuberculosis Increasing in San Francisco

• Risk of drug resistance increased if AIDS is present, if patient is non-compliant with taking tuberculosis medications and if gastrointestinal symptoms are present.

Bradford WZ and others. The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA. Lancet 348:928-931. October 5, 1996.

Progression and Natural History of HIV/AIDS

• Single Mutation in CKR5 Receptor Leads to Slower HIV Progression

Huang Y and others. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nature Medicine 2(11): 1240-1243. November 1996.

Rowe PM. CKR5 deletion heterozygotes progress slower to AIDS. Lancet 348:947. October 5, 1996.

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

Henry E. Chang is Research Director at the AIDS Healthcare Foundation in Los Angeles.

Page last updated 17 December 1996

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