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Published in the Bulletin of Experimental Treatments for AIDS Summer 1999 issue, by the San Francisco AIDS Foundation. Highlights From Recent Conferences: |
Research NotesBy Harvey S. Bartnof, MD ANTIRETROVIRAL THERAPYIs There a Role for Drug Holidays in HIV/AIDS Treatment?
At the STHI workshop, the topic of drug holidays was raised several times. A drug holiday refers to a temporary suspension of antiretroviral therapy. Very preliminary interim results from one study suggest a potential benefit from taking a drug holiday in persons who have experienced HIV viral load rebound ("drug failure") after significant prior anti-HIV drug exposure. In the past, most researchers believed that people with HIV should never take drug holidays, because in almost all people viral load would rebound, and the multiplying HIV strains would likely be resistant to the drug(s) that were discontinued. If this happened, viral suppression might not occur when the drug(s) were resumed, even if the drug(s) had induced undetectable viral load before the drug holiday. Moreover, after a period of viral load rebound, CD4 cell count would eventually begin to decline. The Department of Health and Human Service's Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents state that discontinuation of anti-HIV drug therapy may be indicated in persons who no longer derive benefit from it and for whom there are no other treatment options. This would apply to some people with HIV who have previously used multiple combination regimens that have included all or most of the available anti-HIV drugs. Veronica Miller, MD, from Goethe University in Frankfurt, Germany, presented interim data on 39 persons who took a drug holiday after experiencing viral load rebound. All had significant histories of antiretroviral drug exposure. The drug holidays lasted for two months or longer. After drug discontinuation, a trial of mega-HAART was started with six or more anti-HIV drugs. During the period without treatment, the participants' mean HIV RNA viral load increase was 0.7 log copies/mL and their mean CD4 cell count decreased from 89 cells/mm3 to 49 cells/mm3. A CD4 cell count in this range (i.e., below 100 cells/mm3) indicates a high risk of developing a major opportunistic infection (OI). Interestingly, when Miller performed resistance tests on the participants' HIV strains at the end of the drug holidays, two-thirds had no remaining detectable drug-resistant strains. Several HIV clones were tested. All participants had resistant virus before the drug holiday. The participants' HIV strains had reverted to wild type while not under the pressure of antiretroviral drugs (wild type refers to the usually non-resistant strain of HIV with which a person was originally infected). The remaining third of participants still had persistent drug-resistant HIV at the end of their drug holidays. Twelve months after mega-HAART was started, the two-thirds whose HIV had reverted to wild type strains had a much greater viral load reduction than the third who maintained drug-resistant strains. The wild type group had a mean viral load reduction of 2.8 log copies/mL, while the persistently resistant group had a mean viral load reduction of only 1 log copies/mL. Moreover, after six months, 78% of the wild type group had an undetectable HIV RNA viral load (limit of detection 500 copies/mL), compared with only 17% of the persistently resistant group. These results suggest several questions. The most obvious explanation for the differences in viral load decline after starting mega-HAART is that the participants with wild type HIV probably have a persistent minority population of drug-resistant HIV that was not measured at the end of the drug holiday. These resistant strains may be sequestered in lymph tissue or elsewhere. It is quite possible that after a longer period of observation while taking mega-HAART, these resistant strains could multiply and become predominant. But then, perhaps, another drug holiday could be taken, followed by another episode of mega-HAART. The possibilities are interesting, yet merely speculative at this time. Additional testing and longer follow-up should provide some answers. Until then, these interim results should be considered highly experimental. Note that during the drug holiday, CD4 cell counts dropped into a dangerous range. In another session at the STHI workshop, D. William Cameron, MD, from the University of Ottawa also discussed drug holidays. He and his colleagues are planning to enroll HIV positive persons into a study in which one arm would take a drug holiday. Study participants are required to have experienced viral load rebound at least twice, with at least two different antiretroviral combinations. Participants will be randomized into two groups. One will receive mega-HAART with six to nine anti-HIV drugs for six months. The other will start a six-month drug holiday. After six months, participants and their physicians will decide whether to continue anti-HIV therapy for the next year and a half. At the end of the two-year period, participants will be analyzed for differences in CD4 cell counts, viral loads, OIs, deaths, and quality of life. Quality-of-life measurements would be taken by means of a questionnaire periodically throughout the two-year period. Cameron hypothesized that the side effects of a mega-HAART regimen may be worse than the symptoms of HIV disease during a drug holiday. However, the risk may be more OIs and a shorter survival time. OI prophylaxis would be given in accordance with standard CD4 cell-based guidelines. These presentations indicate that drug holidays may have a role in the treatment of people with significant anti-HIV drug exposure who have experienced viral load rebound. Additional research in this area is continuing. Until more is known, taking a drug holiday is still risky. Do not stop taking drugs without discussing the possibility with your physician. Cameron, D.W. and others. Proposed trial of treatment alternatives in persons with advanced virological failure of HAART. STHI. Abstract 033. Miller, V. and others. Mega-HAART, resistance, and drug holidays. STHI. Abstract 030. Efavirenz/d4T/3TC Is a Potent Combination
Cohen, C. and others. A phase II, open-label, multicenter study to characterize the effectiveness and safety of efavirenz in combination with stavudine and lamivudine in antiretroviral-naive HIV-infected persons (Study DPC 266-043). 9th European Congress of Clinical Microbiology and Infectious Diseases. Berlin, Germany. March 21-24, 1999. Abstract 006. HAART Salvage Therapy Shows Benefits
Roy Gulick, MD, from Cornell University presented the results of AIDS Clinical Trials Group (ACTG) 359 at the STHI workshop. This complex trial included six arms, and attempted to determine the benefits of specific two- to three-class drug regimens in participants who had experienced viral load rebound while taking a combination containing indinavir (Crixivan). None of the participants had previously taken non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Two hundred and seventy-seven persons were enrolled in the study. The delavirdine dose used was 600 mg twice daily. The ritonavir plus saquinavir doses were 400 mg each, taken twice daily. The doses in the nelfinavir plus saquinavir arms were 750 mg and 800 mg, respectively, each taken three times daily. The dose of adefovir was 120 mg daily. The interim results after 16 weeks were presented at STHI. The arm with the highest level of undetectable viral load was the delavirdine/nelfinavir/saquinavir arm at 46% (limit of detection 500 copies/mL). The level of undetectable viral load was 33% in the delavirdine/ritonavir/saquinavir arm. The other arms included the same two double protease inhibitor combinations, and adefovir was either substituted for or added to delavirdine. When adefovir was added to delavirdine, the undetectable levels were 36% and 31%, respectively, in the nelfinavir/saquinavir and ritonavir/saquinavir arms. When adefovir was substituted for delavirdine, the undetectable levels were lowest, at 16-20%. Life-threatening or severe laboratory abnormalities occurred in 37% of participants. The adefovir-containing arms had significantly fewer laboratory abnormalities than the delavirdine-containing arms. Interestingly, detailed drug interaction studies revealed that adefovir significantly decreased blood levels of delavirdine. Therefore, these two drugs should not be combined in the same regimen. The short-term interim results indicate that a significant percentage of persons who have experienced HIV viral load rebound after taking an indinavir-containing regimen can achieve undetectable viral load with a regimen of delavirdine plus saquinavir plus either nelfinavir or ritonavir. Adding adefovir to these regimens provides no additional benefit. Substituting adefovir for delavirdine leads to lesser benefits. The results also indicate that the twice daily 600 mg dosing of delavirdine may be an alternative to the standard three times daily 400 mg dosing (see BETA, January 1999). Gulick, R.M. and others. Salvage therapy with saquinavir soft-gel capsules in combination with ritonavir or nelfinavir and delavirdine, adefovir dipivoxil, or both: ACTG 359. STHI. Abstract 020. Multidrug Salvage Regimens Show Benefits
Three separate presentations at the STHI workshop showed favorable results for different salvage therapy regimens that include five to nine anti-HIV drugs. Conference co-chair Julio Montaner, MD, of the BC Centre for Excellence in HIV/AIDS, in Vancouver, Canada, presented interim trial results of his group's salvage therapy protocol. Sixty-seven persons who had experienced recurrent viral load rebound using several different combination regimens were enrolled in a study of "multidrug rescue therapy" (MDRT). Up to nine anti-HIV drugs were given, including four nucleoside analogs, two NNRTIs, two protease inhibitors, and hydroxyurea. Side effects were common. Using a strict "intent to treat" analysis, 34% of participants achieved three consecutive undetectable viral load measurements, 50% achieved two such measurements, and 63% achieved one undetectable measurement. Howard Grossman, MD, from St. Luke's-Roosevelt Hospital in New York presented somewhat similar results in a group of 34 participants with significant prior anti-HIV drug experience. Grossman's group enrolled these persons into a "complex multidrug regimen" with six to eight anti-HIV drugs (up to 35 pills daily). As a backbone of therapy, all persons took the newer drugs abacavir (Ziagen), efavirenz, and adefovir. In contrast to the Montaner report above, Grossman indicated that persons reported "good tolerability." During the course of eight months of therapy, 70% of participants achieved at least two undetectable viral load measurements (limit of detection 40 copies/mL), while 52% achieved three or more such measurements. The third report of a similar success was presented by Michael Youle, MD, from the Royal Free Centre for HIV Medicine in London. Sixty-three persons who had experienced HIV viral load rebound on a protease inhibitor combination were started on a new multidrug regimen of five to seven drugs. Before starting, however, participants were off drugs for a mean of eight weeks. The new regimen included efavirenz, ritonavir, indinavir, hydroxyurea, and ddI. Only 79% of enrollees completed 28 weeks of therapy; 57% had some change in their therapy. Of those who completed 28 weeks ("on treatment" analysis), 91% achieved an undetectable viral load (limit of detection 400 copies/mL). The median CD4 cell count increase was 120 cells/mm3. Interestingly, participants were 15% more likely to achieve an undetectable viral load for each drug holiday month before starting the new multidrug regimen. Youle's results are somewhat better than those of Montaner and Grossman because the London participants had less anti-HIV drug experience, and had experienced only one episode of viral load rebound on a protease inhibitor-containing combination regimen. Grossman, H. and others. Mega-HAART: complex protective regimens for HAART failure. STHI. Abstract 023. Montaner, J.S.G. and others. Multidrug rescue therapy for HIV-infected individuals with prior virological failure to multiple regimens: results from a second cohort. STHI. Abstract 016. Youle, M. and others. Surrogate marker responses to multidrug combinations comprising hydroxyurea, efavirenz, double protease inhibitors (PIs), and nucleoside analogues in PI failures. STHI. Abstract 018. New Guidelines for Sildenafil plus Protease Inhibitors
There have been several reports regarding sildenafil in the literature, some of which are relevant to people with HIV who are also taking HAART regimens that include protease inhibitors (see BETA, April 1999). Sildenafil is approved by the Food and Drug Administration (FDA) for the treatment of erectile dysfunction. The American Heart Association and the American College of Cardiology have published guidelines for taking sildenafil with other medications including protease inhibitors. Since protease inhibitors inhibit the metabolism of sildenafil (and many other drugs) via the cytochrome P450 enzyme system in the liver, dangerously high blood levels of sildenafil may occur. This may lead to adverse effects, the most dangerous of which is low blood pressure. In the worst cases, death has occurred. However, most of the reported cases of death associated with sildenafil have been in men older than 65 years of age, many of whom were taking other prescription drugs for their heart or high blood pressure or both. The metabolism of sildenafil is slower in people older than 65 and in those with chronic liver diseases, including chronic hepatitis B or C. Another toxicity associated with high blood levels of sildenafil is priapism, or prolonged, painful erection. This can represent a medical emergency in some cases when erection is no longer desired but persists. Even without concurrent protease inhibitor therapy, the effects of sildenafil are accentuated by other drugs that dilate blood vessels and thereby lower blood pressure. Examples include nitrate drugs used to treat angina (chest pain) and recreational inhalant nitrites ("poppers"), which are sometimes used as sexual stimulants (see BETA, July 1998). As with protease inhibitors, other medications commonly used by persons with HIV can have the same inhibitory effect on the cytochrome P450 liver enzymes, including macrolide antibiotics, oral antifungal drugs, and the histamine/acid blocker cimetidine (Tagamet). Several antibiotics including clarithromycin (Biaxin), azithromycin (Zithromax), and erythromycin, and oral antifungal drugs including fluconazole (Diflucan), ketoconazole (Nizoral), and itraconazole (Sporanox) are used to prevent or treat HIV-related OIs. The American Heart Association guidelines state that
Some physicians will consider prescribing sildenafil for patients taking protease inhibitors; however, in such cases the starting dose of sildenafil should be very low, e.g., 12.5 mg (half of a 25 mg tablet). In addition to the recommendations above, the FDA has directed the pharmaceutical industry to amend the package inserts for protease inhibitor drugs to include warnings about concurrent sildenafil use. It should be noted that HIV positive persons in their thirties or older may be at increased risk for coronary artery disease and heart attack if they have one or more cofactors that magnify the risk. Such cofactors include high cholesterol (which can be induced or worsened by protease inhibitors and some NNRTIs), high blood pressure, diabetes (which can also be induced or worsened by HAART), family history of early heart attack, and cigarette smoking (see BETA, October 1998). In related news, there have been reports that sildenafil can be purchased through some Web outlets on the Internet, often without a prescription. One physician has been arrested for prescribing sildenafil over the Internet without the physical examination that is a legal part of the physician/patient relationship. Other people have filled their sildenafil prescription several times by faxing the original prescription to more than one online pharmacy. Sildenafil ads with discounted prices are advertised regularly in certain newspapers. These newer means of acquiring prescription medications may leave uninformed consumers at risk for serious side effects and possibly death. Another related issue is the controversy surrounding HAART and its potential link with erectile dysfunction. There have been three recent letters to the editor in the Lancet on this subject. In the March 6 issue, Eduardo Martinez, MD, and colleagues described 14 HIV-infected men who developed sexual dysfunction after starting a protease inhibitor. In the same issue, Rak Nandwani, MD, and colleagues described ten HIV-infected men taking HAART who developed erectile dysfunction. In the May 22 issue, R. Colebunders, MD, and colleagues indicated that erectile dysfunction occurred in 35% of 77 men taking HAART regimens that include a protease inhibitor. In the same letter it was reported that 42% of the 77 men and 40% of 20 women taking HAART regimens that include a protease inhibitor reported a "decrease in their sexual appetite since the start of their treatment." These reports contrast with an earlier report that indicated a much lower but measurable rate of sexual dysfunction (4%) in 104 persons taking HAART regimens that include a protease inhibitor. However, the subjects of this report spontaneously gave the information and were not specifically asked about sexual dysfunction. This report was part of a study presented at the 6th Conference on Retroviruses and Opportunistic Infections (CROI) this past February. In his letter, Colebunders emphasized the importance of asking persons taking HAART about sexual dysfunction. He is concerned that HIV positive persons may stop taking HAART if they develop this problem or are concerned that they may develop it. Larger studies will need to be undertaken before sexual dysfunction resulting from HAART can be accurately quantified. Nonetheless, these reports suggest that it likely does occur, at least in some people. Cheitlin, M.D. and others. Use of sildenafil (Viagra) in persons with cardiovascular disease. Journal of the American College of Cardiology 33(1): 273-282, 1999; Circulation 99(1): 168-177, 1999. Colebunders, R. and others. Sexual dysfunction with protease inhibitors. The Lancet 353: 1802. May 22, 1999. Martinez, E. and others. Sexual dysfunction with protease inhibitors. The Lancet 353: 810-811. March 6, 1999. Nandwani, R. and others. Possible interaction between sildenafil and HIV combination therapy. The Lancet 353: 840. March 6, 1999. Weakened HIV Strain Leads to Slower Progression
A report of long-term follow-up of the Sydney Blood Bank Cohort was published in the June 3 issue of the New England Journal of Medicine. This group of eight blood transfusion recipients in Sydney, Australia, became infected with HIV in the early 1980s via blood donated from a man found to be HIV positive in 1984. Due to luck and careful detective work, it was determined that all nine persons were infected with an HIV strain with a mutated nef gene. The nef gene product is a regulatory protein that promotes replication of HIV and causes cell surface changes that trick the immune system into not recognizing cells as being infected with HIV. Follow-up of these nine persons in the late 1980s revealed slow to nonexistent progression of HIV disease. The group's HIV viral loads remained undetectable or very low for years, while their CD4 cell counts remained normal or minimally decreased. It appeared that HIV strains with a mutated nef gene were attenuated, or weakened. Other case reports of HIV positive persons infected with nef-mutated HIV strains also did not show progression of HIV disease to AIDS. In the most recent report, Jennifer Learmont, MD, and colleagues present a 14-year follow-up of the Sydney Blood Bank Cohort. The results indicate that the cohort's nef-mutated HIV strain is weakened and causes a slower rate of HIV disease progression. Two of the eight persons originally in the cohort have died of causes unrelated to HIV. Their ages at death were 77 and 83. A third person died in 1987 at 22 years of age due to an AIDS-defining illness (Pneumocystis carinii pneumonia [PCP]) after taking immune-suppressing drugs for lupus, an autoimmune disease. The other five remaining persons and the original donor have no symptoms, HIV-related or otherwise, after 14-18 years of HIV infection. However, three of those six have had detectable HIV RNA viral load measurements (median range 645-2,850 copies/mL), and their CD4 cell counts have decreased by 16-73 cells/mm3 per year. The other three continue to have an undetectable viral load (limit of detection 200 copies/mL), but two have had CD4 cell count declines of 9 and 30 cells/mm3 per year, respectively. The original blood donor started antiretroviral therapy in February 1999. This person's highest viral load was 20,812 copies/mL and his lowest CD4 cell count was 282 cells/mm3. The results show that this nef-mutated HIV strain is weakened, but can cause HIV disease progression at a slower rate in some people. Others remain free of HIV-related illnesses and immune system decline after 14-18 years. In an accompanying editorial by Kathleen Collins, MD, PhD, and Gary Nabel, MD, PhD, a note of caution is given regarding the potential risks of using an attenuated nef-mutated HIV strain as a vaccine candidate. They suggest that additional attenuation of the mutated strain could produce a potential vaccine candidate with less risk. They also indicate that designer drugs that bind or inactivate the nef gene product (e.g., antibodies to the nef gene product) represent a new, potentially effective anti-HIV therapy. Additional follow-up of the surviving six persons will likely provide more insight into this unique group of people with HIV. Collins, K.L. and Nabel, G.J. Naturally attenuated HIV-lessons for AIDS vaccines and treatment. New England Journal of Medicine 340(22): 1756-1757. June 3, 1999. Learmont, J.C. and others. Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1-a report from the Sydney Blood Bank Cohort. New England Journal of Medicine 340(22): 1715-1722. June 3, 1999. HAART Clears Hepatitis B Virus
One reported adverse effect of some protease inhibitor drugs is liver toxicity, indicated by increased levels of liver enzymes (ALT/SGPT and AST/SGOT). This effect has been more likely to occur in HIV-infected persons who were also infected with either hepatitis B virus or hepatitis C virus (HCV). Many physicians would stop anti-HIV therapy in such cases if liver enzyme levels become too high. However, a case report from the Hospital Universitario San Carlos in Madrid, Spain, indicates an explanation other than drug toxicity for elevated liver enzymes. In the June 3, 1999 issue of the New England Journal of Medicine, Maria Velasco, MD, and colleagues reported on a case in which a man co-infected with HIV and HBV cleared his chronic hepatitis B after a hepatitis flare developed after he started HAART. The man's HBV infection had previously not responded to alpha-interferon therapy. Initially, his blood tests indicated chronic HBV infection as shown by positive hepatitis B surface antigen, e antigen, and HBV DNA. A liver biopsy indicated chronic active hepatitis. He was negative for other hepatitis viral infections. Ritonavir was added to the man's anti-HIV therapy of ddI/AZT. Nine weeks later, he developed vomiting and an enlarged liver, and his liver enzyme levels increased significantly. However, his physicians continued his anti-HIV therapy. Two weeks later, the man's symptoms resolved. Five months later, his liver enzyme levels became normal and he tested negative for HBV surface antigen, e antigen, and HBV DNA. Simultaneously he developed antibodies to HBV surface antigen. These tests indicate that the man cleared his chronic HBV infection. During this same period his HIV viral load decreased by 1 log copies/mL and his CD4 cell count steadily increased to 384 cells/mm3. This is the third case of an improved course of HBV infection after a HAART regimen that included ritonavir was started in HIV/HBV co-infected persons. In one of these people, HBV infection also was cleared. The authors of the recent report emphasize that an increase in liver enzyme levels after starting HAART in HIV/HBV co-infected persons may represent a hepatitis flare that is related to immune reconstitution. This may be followed by clearance and resolution of HBV infection. The hepatitis flare may not represent antiretroviral drug toxicity, and HAART should be continued if possible. Other immune flare-related illnesses have been reported within the first few months after starting HAART (see BETA, January 1999, and BETA, April 1998), including cytomegalovirus vitritis (eye inflammation), herpes zoster (shingles), and Mycobacterium avium complex (MAC). However, such symptoms are unlikely to occur after six months on HAART. It is possible that a similar phenomenon could occur in persons co-infected with HIV and HCV. Whether resolution of HBV infection could occur with HAART regimens that do not contain ritonavir is not known. Velasco, M. and others. Resolution of chronic hepatitis B after ritonavir treatment in an HIV-infected individual. New England Journal of Medicine 340(22): 1765-1766. June 3, 1999. HAART Projected to Eradicate HIV after 61 Years
While HAART was initially labeled as being the ticket to HIV eradication, subsequent measurements indicate that resting lymphocytes represent a significant reservoir of HIV. Original estimates indicated that up to about 20 years of HAART would be required to eliminate the million-cell pool of HIV. Now, Robert Siliciano, MD, and colleagues from Johns Hopkins University have performed more detailed analyses. Their results suggest that due to the resting cells' long half-life (the time required for an original amount to be decreased by half), 61 years of HAART would be required to eradicate HIV; the group's minimum estimate for eradication is approximately 20 years. Siliciano presented his results at the THRRIS conference and they were subsequently published in Nature Medicine. The research indicates that adjunct therapies in addition to HAART will be necessary to flush out the reservoir of latent HIV and achieve an effective "cure" without lifelong treatment (see BETA, January 1999). Such adjunct therapy could include interleukin 2, the Remune vaccine, or another therapeutic vaccine. Note that an effective "cure" does not necessarily require complete eradication of all HIV genetic material, but rather lifelong control of HIV that would protect against subsequent HIV exposure. Eradication of HIV alone, without an effective anti-HIV immune response, would leave a person susceptible to repeat HIV infection after subsequent exposures. Other new research reported in the New England Journal of Medicine indicates that even among persons with undetectable HIV RNA viral loads in blood plasma, some continue to have low-level HIV replication in resting cells. Linqi Zhang, MD, and colleagues from the Aaron Diamond AIDS Research Center in New York examined the gene sequences of latently infected lymphocytes in eight persons who had an undetectable HIV RNA viral load for two to three years after starting HAART. The researchers found that the gene sequences in two of these eight persons had evolved over time; the sequences had not mutated to a drug-resistant form, but were no longer the same as previous tests had shown. The authors concluded that "combination antiretroviral regimens suppress HIV-1 replication in some but not all persons." In the same issue of the New England Journal of Medicine, Manohar Furtado, MD, and colleagues from Northwestern University reported similar results using mononuclear blood cells. The researchers found unspliced and spliced HIV RNA in the cells, an indication of viral replication. In an accompanying editorial, Roger Pomerantz, MD, from Jefferson Medical College stated that the results of the newly published reports were not taken into account in Siliciano's 61-year estimate. Pomerantz therefore suggests that some persons may require an even longer period of HAART to completely eradicate HIV from latent reservoirs, and that adjunctive therapy will likely be necessary for effective HIV treatment. Finzi, D. and others. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in persons on effective combination therapy. Nature Medicine 5(5): 512-517. May 1999. Furtado, M.R. and others. Persistence of HIV-1 transcription in peripheral blood mononuclear cells in persons receiving potent antiretroviral therapy. New England Journal of Medicine 340(21): 1614-1622. May 27, 1999. Pomerantz, R. Residual HIV-1 disease in the era of highly active antiretroviral therapy. New England Journal of Medicine 340(21): 1672-1674. May 27, 1999. Siciliano, R. and others. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Medicine 5(5): 515-519. May 1999. Zhang, L. and others. Quantifying residual HIV-1 replication in persons receiving combination antiretroviral therapy. New England Journal of Medicine 340(21): 1605-1613. May 27, 1999. Adefovir More Effective with 3TCAdefovir dipivoxil is an experimental nucleotide analog reverse transcriptase inhibitor (see BETA, April 1999 and October 1998). An update on this medication was presented at the STHI workshop. Several studies indicate that the drug leads to greater HIV viral load reductions when used as part of a regimen that also includes 3TC. Adefovir demonstrates efficacy if 3TC resistance and low-level AZT resistance are present. Adefovir has also shown benefit against HIV strains with resistance to multiple nucleoside analogs (i.e., strains with the Q151M mutation). Michael Miller, PhD, from Gilead Sciences presented phase I/II trial results from a study of an adefovir combination in 24 children with significant antiretroviral drug experience. Benefits were seen when adefovir was combined with nelfinavir and with nucleoside analog therapy. Persons whose HIV viral load did not decrease with HAART (non-responders) tended to have or develop some protease inhibitor drug resistance. Durable (24-36 week) responders tended to have some resistance to multiple nucleoside analogs. Miller, M. and others. Adefovir dipivoxil is active in persons with lamivudine- or zidovudine/lamivudine-resistant HIV. STHI. Abstract 004. Miller, M. and others. Durable HIV RNA reductions seen in paediatric persons with pre-existing nucleoside resistance mutations treated with adefovir dipivoxil, nelfinavir, and other nucleoside inhibitors. STHI. Abstract 017. Hydroxyurea/ddI Used Successfully in AfricaTwo physicians in Africa have indicated some success using only two anti-HIV drugs, which they described in discussions at the THRRIS conference. Although such treatment is considered substandard in the developed world, most people with HIV in the developing world will never have access to triple combination therapy that costs $12,000 to $15,000 annually. However, at a price of approximately $1,200 annually for hydroxyurea plus ddI, some middle-class people in certain African countries would be able to afford the two drugs, usually with private or public health insurance. The triple combination of these two drugs plus d4T would cost approximately $2,040 annually. Hydroxyurea (see BETA, October 1998) was first synthesized in 1869 and has been FDA-approved for decades as a cancer therapy; it is also used to treat sickle cell anemia. It does not directly inhibit HIV, but it makes ddI much more efficient as an anti-HIV therapy, and thereby markedly decreases the rate of development of ddI-resistant HIV strains. Steve Miller, MD, from Johannesburg, South Africa, presented interim study results at THRRIS. He prescribed the hydroxyurea/ddI combination for 127 persons (57% women). Those with a baseline HIV RNA viral load level greater than 100,000 copies/mL had d4T added as a third drug. Most persons had no prior anti-HIV therapy. The mean baseline HIV RNA viral load was approximately 80,000 copies/mL. After 48 weeks, 76% of treatment-naive persons had an undetectable viral load (limit of detection 400 copies/mL). For persons with prior anti-HIV treatment, the percentage with an undetectable viral load was 72%. The CD4 cell count increase was approximately 90 cells/mm3 for all persons. This CD4 cell count increase is less than what would typically be seen with standard HAART, but the percentage of undetectable viral load is comparable. Side effects were typical for the drugs taken, including nausea, vomiting, tingling in the feet (peripheral neuropathy), partial hair loss (due to hydroxyurea), low blood cell counts, and pancreatitis (inflammation of the pancreas, an abdominal organ). Fifteen percent of African-American participants had increased skin pigmentation on the palms, soles of the feet, and nails. However, no person stopped therapy due to adverse effects. Miller will continue to follow the people in this observational study. Diana Dickinson, MD, presented observational data from Gaborone, Botswana. Her 150 participants were also treated with ddI plus hydroxyurea, with or without d4T. Due to the enhanced blood levels of ddI associated with the use of hydroxyurea, Dickinson used a ddI dose of 300 mg daily. Interim data were available for only 50 persons who completed nine months of therapy. For persons who took hydroxyurea/ddI, the mean viral load reduction was 1.9 log copies/mL. For those who took hydroxyurea/ddI/d4T, the reduction was 2.4 log copies/mL. All persons had a viral load decrease regardless of baseline CD4 cell count or viral load. Changes in CD4 cell counts and percentages with undetectable viral load were not reported. The side effect profile was quite similar to that observed by Miller. However, 8% of Dickinson's participants stopped therapy due to side effects. Dickinson noted that most of her patients were able to return to work after having been disabled due to HIV disease symptoms. These two reports from Africa suggest that there may be a significant minority of HIV positive persons in Africa and other developing countries who could have access to ddI plus hydroxyurea as a viable option for anti-HIV treatment. Unfortunately, the vast majority would not be able to afford the $1,200 annual price tag. Dickinson, D.B. African experiences with didanosine- and hydroxyurea-containing regimens. THRRIS. Miller, S. Combination therapy in Africa. THRRIS.
Highest Rate of Undetectable Viral Load Seen among Prisoners
At the THRRIS conference, the highest rate of undetectable HIV viral load was reported among a group of prisoners in Florida. According to Margaret Fischl, MD, in an informal discussion at the conference, more than 95% of the prison group she studied had an undetectable viral load. This high rate is believed to be due to a treatment adherence rate of 100%, which was possible because the incarcerated group were given each medication dose by a nurse who observed them swallowing their pills. This information supports the idea that adherence is likely to be one of the most important aspects of successful HIV treatment. Highest Cytotoxic Response in Persons Taking Immunosuppressive DrugsIn another informal discussion at the THRRIS conference, Bruce Walker, MD, from Massachusetts General Hospital reported the highest cytotoxic (cell-killing) T-lymphocyte response directed against HIV that he has ever observed. The person studied was an HIV positive woman with Takayasu's arteritis, an autoimmune disease characterized by antibodies directed against arteries. She was taking prednisone (a steroid immune blocker) and methotrexate (an anti-metabolite drug) to treat her arteritis. These drugs lead to decreased immune system activation. The woman was not taking anti-HIV therapy and her HIV viral load and CD4 cell count measurements were not reported. Understanding the mechanisms involved in her potent anti-HIV cytotoxic T-cell response may lead to new therapeutic approaches for treating HIV and possibly to an effective HIV vaccine. Most physicians would consider prolonged therapy with those two medications too risky for people with HIV infection. Some Protease Inhibitor Resistance May Be Missed by Genotypic TestsMark Wainberg, MD, from the McGill University AIDS Center in Montreal, Canada, commented at the THRRIS conference on certain limitations of genotypic resistance tests. He stated that most genotypic resistance tests for the protease inhibitor drugs indicate resistance only in the protease enzyme. However, resistance may occur due to a genetic mutation in the gag (core) gene, which would be missed by standard genotypic resistance testing. The presence of such a mutation would likely be detected by a phenotypic resistance test. Drug Cycling: An Update
At the THRRIS conference, Franco Lori, MD, presented an update of a person who has been dubbed "the Berlin patient" (see BETA, April 1999 and April 1998). Certain aspects of this case also were reported in the May 27, 1999 issue of the New England Journal of Medicine. Interest in this person has been high since Lori first presented the case history at the 5th CROI in February 1998. The 29-year-old gay man developed symptoms of acute (primary) HIV infection and started anti-HIV therapy before his HIV antibody test turned completely positive. His baseline HIV viral load was approximately 85,000 copies/mL and his CD4 cell count was 370 cells/mm3. After starting on triple therapy with indinavir/ddI/hydroxyurea, his HIV RNA viral load became undetectable (limit of detection 500 copies/mL). After two weeks, the man's anti-HIV drugs were stopped for one week due to epididymitis (testicular infection), and his HIV viral load rebounded to greater than 5,000 copies/mL. Then, the same triple therapy was restarted and his viral load again became undetectable. However, after approximately two more months, therapy was again stopped when the man contracted acute hepatitis A virus infection. Surprisingly, his HIV viral load did not rebound and has remained undetectable after another 19 months with no anti-HIV therapy. More recent, detailed analyses of this man's immune system reveal normal measurements for CD4 cell count (710 cells/mm3), CD4/CD8 cell ratio (1.0), and naive CD4 and CD8 cell counts. However, no neutralizing antibodies to HIV were detected. The man's blood did show a vigorous CD8 lymphocyte cytotoxic anti-HIV response. Detailed measurements indicated the presence of HIV DNA and RNA, but at low levels. The HIV DNA that was detected could be grown in vitro when stimulated. Therefore, despite the man's vigorous immune response and favorable immune measurements, HIV was not eradicated, but rather was "controlled." Certain aspects of this and two other similar cases indicate that, under certain conditions, HIV may be controlled. However, it is not known which aspects of this case allowed for control of HIV. It could be due to the fact that the man was treated very early in the course of his HIV infection, due to the hydroxyurea/ddI/indinavir combination, or related to the intermittent start-stop-restart-restop nature of the therapy. Future research hopefully will provide answers. Until then, persons with HIV should be aware that stopping anti-HIV therapy is risky, since viral rebound is the usual course and drug-resistant HIV strains may develop. Lisziewicz, J. and others. Control of HIV despite the discontinuation of antiretroviral therapy. New England Journal of Medicine 240(21): 1683-1684. May 27, 1999. Lori, F. HIV-specific immune reconstitution with hydroxyurea-containing therapies. THRRIS. Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee of the San Francisco AIDS Foundation since 1987. Page last updated 5 October 1999 |
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