Research Initiative Treatment Action (RITA!); Vol 5, No. 5 December 1999
In a review of recent data, which by this writing seem ancient, Anthony Fauci, MD, of the National Institutes of Health reported on the factors that drive HIV replication and maintain it as a chronic infection. In particular he noted the factors that restrain HIV replication such as CD8 cells and anti-inflammatory cytokines and the factors that sustain HIV replication, notably proinflammatory cytokines. The interaction of the two does not result in the eradication of HIV even with the help of highly active antiretroviral therapy (HAART). Virtually all HIV-infected individuals have been found to have latent reservoirs of long-lived resting cells. These reservoirs are established early on in infection, according to Fauci, and persist even when HAART drives HIV below the level of quantification. Fauci and others have used the intermittent administration of IL-2 to activate resting cells and try to purge them. (See "Why the fat lady hasn't sung: the limits of HAART" on page 8 of this issue.) Abstract 614.
David Ho, MD, of the Aaron Diamond AIDS Research Center in New York City delivered a lecture in which he questions the efficacy of HAART in completely stopping HIV replication. Experiments conducted by his group have shown that the latent reservoir of infected cells may, in fact, be infecting other cells. Such low level replication does not result resistance to the drugs but it is an impediment to the eradication of HIV from the body. According to Ho, the half-life of some these quiescently-infected cells may not be as long as predicted by some groups and that if full suppression could be achieved, eradication may still be possible. Abstract 2013a.
Marty Markowitz, MD, also of the Aaron Diamond AIDS Research Center, reported on four patients who had been treated during primary infection (between seven to 90 days after the onsets of symptoms) and who had viral loads of less than 50 copies for approximately 3 years. These patients elected to stop therapy voluntarily. All four patients had viral rebound to 20,893 copies and then dropped to 3,388 copies. One patient resumed therapy but the other patients remain off therapy. The percentage of CD4 T cells in the three patients off therapy decreased 6, 5 and 18%. The peak and subsequent decrease in viral load is thought to suggest some immunological control of the virus. Abstract LB-16.
In a study called "NoHRT," scientists from the National Institutes of Health looked at eighteen patients who stopped HAART after being suppressed (below 500 copies) for more than 12 months. At the time of cessation of therapy the patients had viral loads of less than 50 copies. Some of the patients had been on interleukin 2 (IL-2) as well as HAART. IL-2 has been proposed as a means of activating and purging latently infected resting cells. All patients had rebounds in viral load within two to 3 weeks. One patient was reported to rebound and then have a subsequent decrease in viral load. In this patient the virus came back after seven weeks and his viral load has been between 50 and 500 copies for 6 months off drugs. Abstract 689.
John W. Mellors, MD, of the University of Pittsburgh Graduate School of Public Health reported on the causes of treatment failure and the considerations in the institution of second-, and third-line therapies. Among the reasons noted for drug failure were (1) the inadequate potency of the drugs used (monotherapy and dual therapy); (2) subtherapeutic drug concentrations caused by incomplete adherence, individual variability in metabolism or negative drug interactions; and (3) drug toxicities that lead to a lack of adherence; (3) transmission of drug resistant viruses. He noted that second-, and third-line therapies are only completely suppressive 40 to 70% of the time. In choosing subsequent therapies Mellors suggested that patients and doctors should (a) gauge the remaining options; (b) switch early (within 6 weeks of viral rebound); (c) protect new drugs or classes of drugs whenever possible; (d) consider the likelihood of disease progression and the pace of new drug development and release. Abstract 615.
Much has been made of the importance of maintaining adequate drug levels and of the need to test for these levels in order to gauge for either lack of adherence or poor absorption. A French group of scientists reported on a study in which levels of saquinavir (Fortovase) and indinavir (Crixivan) were measured in hair samples of one hundred thirty-two patients. The sample results were correlated with the response to therapy and the development of protease gene mutations. Levels of the protease inhibitors were higher in patients who achieved viral suppression (responders). Among the nonresponders, those found to have higher levels of drug were also found to have developed protease gene mutations. Interestingly, the majority of patients who were found to have low level of drug detected in hair samples still had HIV strains susceptible to the drugs. This result suggests that failure in these cases may have been the result of inadequate drug exposure. Abstract 598.
Data were presented with respect to the latest experience with the use of ABT-378/r, Abbott Pharmaceutical's second generation protease inhibitor, in treatment-naïve patients and patients who have experienced virologic rebound with one other protease inhibitor. The "r" in the name of this drug refers to the small amount of ritonavir (Norvir) that is added to enhance the drug's activity. At thirty-six weeks on-treatment analysis showed that in naïve patients from 95 to 96% had viral load of less than 400 copies. Among those patients experienced with one previous protease inhibitor 78% had viral load of less than 400 copies. The most common side effects reported were diarrhea, nausea, asthenia and headache. Abstract LB-20.
The experimental protease inhibitor tipranavir has shown potent antiretroviral activity in vitro against HIV isolates that are resistant to many other antiretroviral agents. For this reason, it has gained much attention as a potential second-, or third- line therapy for those patients who have failed other protease inhibitors. One concern has been the number of pills needed for adequate drug concentrations in the body. Previous reports indicated that patient might have to take as many as thirty pills to get the full effect of tipranavir. Two studies using tipranavir in combination with escalating doses of ritonavir demonstrated favorable drug interaction with the levels of tipranavir increasing and the level of ritonavir decreasing. Such favorable interaction could make it possible to reduce the pill burden anticipated for tipranavir. Abstract 657.
A multicenter study of tenofovir disoproxil fumarate, a nucleotide analog with activity against HIV, was presented among the late-breaker abstracts. In this study 189 patients with viral loads between 400 and 100,000 copies on stable antiretroviral therapy with four or fewer agents were randomized to add tenofovir at three escalating doses. Interim analysis of the data showed patients in the 300 mg once a day dose had the best virologic response with a 0.83 log drop in viral load. Abstract LB-19.
A study entitled CNA3005 compared the use of abacavir (Ziagen) and zidovudine/lamivudine (Combivir) against indinavir and zidovudine/lamivudine in patients starting therapy for the first time. Patients were stratified as follows: in group A patients having viral loads of between 10,000 and 100,000 copies and in group B patients having viral loads of greater than 100,000 copies. Because this study was blinded all participants took doses three times a day even though the abacavir regimen only requires twice a day dosing. In essence the participants in the abacavir arm took placebos for the mid-day dose. The results showed the abacavir and indinavir arms to be equivalent in patients in group A. In patients in group B, where the viral loads exceeded 100,000 copies, the indinavir regimen performed better. Since patients are most likely to miss the mid-day dose it is likely that this study created a situation where one arm (the indinavir) was adversely affected by patient inadherence. Commentators observed that this may have not been a true comparison of these two regimens but rather a study of how well patients coped with complicated schedules. Abstract 505.
Forty-eight week data on the Atlantic Study was presented as a late breaker abstract. The Atlantic Study compared the combinations of stavudine (Zerit), didanosine (Videx) with nevirapine (Viramune), lamivudine (Epivir) or indinavir on treatment naïve patients. The results were similar to those of the CNA3005 study in that patients with viral loads greater than 100,000 copies did better on the indinavir-containing regimen or the nevirapine arm than on the all nucleoside analog regimens. Abstract LB-22.
DuPont 006 was a study reporting seventy-two week data on the comparison of zidovudine/lamivudine/efavirenz (Sustiva), zidovudine/lamivudine/indinavir and efavirenz/indinavir. The 48-week data on this study showed the zidovudine/lamivudine/efavirenz arm to be superior to the other two arms in a cohort of 450 patients. As a result of these results efavirenz was added as a preferred choice for first line therapy in the Department of Health and Human Service's "Guideline for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents." The seventy-two-week data were based on the 450 original participants as well as an expanded group of 1,266 subjects. This expanded data confirmed the superiority of the efavirenz arm. Some concern was expressed that expansion of the study occurred after the first results had been announced and that these results may have influenced patient adherence and retention. Abstract 507.
START I was a comparison of indinavir with either stavudine/lamivudine or zidovudine/lamivudine in treatment naïve patients with more than 200 CD4 T cells and viral loads in excess of 5,000 copies. Using an intent-to-treat analysis at 48 weeks the percentage of patients with viral loads below 500 and 50 copies were equivalent in both arms. The median CD4 T cell rises in the stavudine arm were 227 versus 198 in the zidovudine arm. Abstract 506.
For some time clinicians have been prescribing didanosine (Videx) once a day. Until recently no clinical trial data existed to verify that once a day dosing of didanosine in a triple drug regimen was safe and efficacious. Data on the comparison of the combination of didanosine (400 mg once daily)/stavudine/nelfinavir (Viracept) versus zidovudine/lamivudine/nelfinavir in treatment naïve subjects were presented. The decrease in viral load was statistically similar in both groups as was the increase in CD4 T cells. Abstract 1973. In November the US Food & Drug Administration (FDA) approved the once daily dosing of didanosine.
The issue of what causes lipodystrophy has been a highly debated one. Spanish researchers followed one hundred and fifty-six patients from January 1997 to May 1999 for body composition changes as determined by anthropometric measurements and bioelectrical impedance. Patients were on protease inhibitor containing regimens with various combinations of nucleoside analog therapies. The incidence of lipodystrophy varied from a low 4.2% in those taking zidovudine/lamivudine with a protease inhibitor to a high of 89.4% for those taking stavudine/didanosine with a protease inhibitor. Of interest, the researchers reported a high incidence of lipodystrophy occurring shortly after starting protease inhibitor treatment. Abstract 1302.
In a multicenter study involving 1,077 patients seen in 8 clinics in 7 cities, patients were assessed by clinicians from October 1998 to December 1998. The researchers found that time since HIV diagnosis was significantly associated with the severity of lipodystrophy. Age of the patient was independently associated with the level of lipodystrophy. Finally, the lower the minimum CD4 percentage had been and the greater its rebound the more likely and more severe the lipodystrophy. The implications of this study seem to be that there are multiple factors associated with the likelihood and severity of the occurrence of lipodystrophy. Abstract 1299.
This British study looked at the triglyceride and cholesterol levels of patients who had previously taken a protease inhibitor regimen and were switched to a regimen containing ritonavir and indinavir. Thirty of 63 patients had three or more lipid measurements during 32 weeks of follow-up. Of these, 93.4% had a median 52.9% rise in cholesterol and an 88.5% rise in triglycerides. The rise in lipids appeared to been directly related to the dose of the ritonavir in the combination. Abstract 1290.
An Italian study involving fifty-six clinical centers and 607 patients studied when is it safe to discontinue primary prophylaxis for Pneumocystis carinii pneumonia (PCP). Primary prophylaxis is used for patients who are at risk but have never had an episode of PCP. In this study patients whose CD4 T cell counts had increased to over 200 cells as a result of HAART and stayed at least at that level for more than 3 months were randomized to either remain on prophylaxis or discontinue it. Patients in the no prophylaxis arm were offered prophylaxis if their counts fell back below 200 CD4 T cells. During a mean follow-up of 6.7 months no incidences of PCP in either arm were reported. Despite the short follow-up this study seems to indicate that discontinuing PCP prophylaxis does not represent a significant risk for patients with at least 200 CD4 T cells. A similar Spanish study included 42 patients who were on secondary prophylaxis (after an initial episode of PCP) and had sustained CD4 T cell counts of at least 200 cells for three months or longer. In that study no incidences of PCP were reported. Abstract 1165; Abstract LB-24.
Interim results from ACTG 362 indicate that prophylactic treatment for Mycobacterium avium complex (MAC) can be safely discontinued in subjects who have had an increase in CD4 T cell counts from less than 50 to more the one 100 cells. In the study 543 patients were randomized in approximately equal numbers to once weekly treatment with azithromycin (Zithromax) or placebo. Patients who experienced a decline in CD4 T cell counts were switched to open label azithromycin. At a median 56-week follow-up there were no significant differences in the rate of MAC infection between the two arms. Abstract LB-23
Sixteen patients with a history of persistent diarrhea associated with protease inhibitor use received nutritional counseling and a two-week supply of psyllium husk fiber bars. Patients were instructed to take 2 bars one hour before bedtime. Of the fourteen patients who responded, 93% reported their diarrhea symptoms as improved. All patients liked the taste of the bars and found it easy to adhere to the regimen. Abstract 1307.
This was an open-label, prospective study of fifteen patients with a history of nelfinavir-induced diarrhea. All patients had been on at least one anti-diarrhea medication. After a minimum of 48 hours patients were reevaluated. Prior to the calcium use 87% had reported their diarrhea as mild to moderate and 13% had reported it as severe. After calcium use 87% of patients reported normal stools and 13% reported mild diarrhea. All reported their symptoms as dramatically improved. Abstract 1308.
Recombinant human erythropoietin (Procrit, Epogen) is a treatment option for patients suffering from anemia. Generally it is given by injection three times a week. This was interim analysis of an ongoing trial of weekly injections of erythropoietin in patients with anemia. To date 66 patients with anemia were given a weekly injection with 40,000 International Units of erythropoietin. The mean hemoglobin increased 3.1 g/dL. While anemia is less common than in the past, these results indicate that this more convenient regimen may be used in patients who do need treatment for anemia. Abstract 1313.
Seventy-one heavily treatment experienced patients enrolled in an ongoing study. After patients changed therapies plasma was tested retrospectively using phenotypic testing (Virologic's Phenosense test). The median duration of follow-up was 15 months and median time to treatment failure was 41 days. The researchers reported that protease inhibitor experience, the number of medications in the previous regimen and loss of phenotypic were all predictors of treatment failure. Multivariate analysis, however, revealed that only loss of phenotypic susceptibility independently predicted treatment failure. Medication history was only important when susceptibility was removed from the model. Abstract LB-17.
Scientists have shown that mycophenolic acid, a drug used in organ transplantation, has a synergistic effect when combined with abacavir (Ziagen) in the test tube. Mycophenolic acid (also known as mycophenolate or by the brand name, CellCept) depletes guanosine, one the essential DNA building blocks. Abacavir is an analog of guanosine and as such, must compete with the body's natural production of guanosine in order to have a therapeutic effect. By depleting naturally occurring guanosine, mycophenolic acid improves abacavir's chances of being taken up by the cell. Scientists have determined that the combination of mycophenolic acid and abacavir is highly active against abacavir-resistant virus. While mycophenolic acid, as CellCept, can currently be prescribed, it should be noted that studies in humans of the abacavir/mycophenolic acid combination have just begun. Mycophenolic acid can be immunosuppressive, but it is anticipated that the doses given with abacavir will be significantly lower than those used in transplant patients and thus, less likely to cause immunosuppression. Finally, it should be noted that mycophenolic acid is anticipated to be antagonistic with stavudine and zidovudine and thus, should not be taken in combination with either of those two drugs.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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