TreatmentUpdate 71 By Sean Hosein Volume 8, no 7 October 1996 A publication of the Community AIDS Treatment Information Exchange (CATIE). Table of Contents I ANTI-HIV AGENTS A. AZT with and without indinavir B. AZT -- resistance may depend on dose C. DMP 266 D. Effect of 3TC and loviride on survival E. Indinavir and IL-2 -- one year later F. Ritonavir and saquinavir G. Saquinavir and indinavir -- some problems H. A new protease inhibitor -- 141W94 A word to readers In this issue we present results from the 35th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). Since much of the information is from abstracts, we may not be able to provide readers with the details that normally accompany our reports. Researchers did not release the long-term results of many of the studies. Promising results were seen in 2 combination studies: DMP 266 with indinavir, and ritonavir with saquinavir. The impact of these combinations on the development of new infections and survival was not discussed at the conference. I ANTI-HIV AGENTS A. AZT with and without indinavir Study details Doctors in Brazil, Canada and the US have enrolled 490 HIV-infected volunteers for this study. No subject was supposed to have used AZT or protease inhibitors before entering this study. Subjects had between 50 and 500 CD4+ cells and received either AZT 600 mg/day, or indinavir 800 mg/8 hours or a combination of both drugs. Results -- CD4+ cell counts At the 6th month of the study, researchers found that subjects in the following groups had increased numbers of CD4+ cells compared to their pre-study levels:  AZT - 28 cells  indinavir - 91 cells  combination - 85 cells The larger increase in the in CD4+ cell counts in the indinavir group compared to the AZT group was [statistically] significant. This means that use of indinavir was responsible for the greatest increase - not luck or chance. Results -- amount of virus When technicians measured changes in the amount of HIV in the blood they found the following changes:  AZT group -- a slight increase  indinavir -- a decrease in viral load to 1/8 times the pre-study level  combination -- a decrease to about 1 /11th the pre-study level The greater decrease in viral load in subjects receiving indinavir (alone or in combination) compared to that seen in the subjects receiving AZT was [statistically] significant, that is; not likely due to chance alone. Summary Use of indinavir alone or together with AZT caused an increase of at least 80 CD4+ cells and reduced production of HIV to 1/11th of its pre-study level. REFERENCES: 1. Leavitt R, Massari F, Nessly M, et al . Antiviral activity of indinavir plus AZT compared to indinavir or AZT alone in antiretroviral naive patients. Abstract I109. B. AZT -- resistance may depend on dose Study details Although people living with HIV/AIDS using AZT are usually prescribed 500 or 600 mg/day, anecdoctal reports suggest that people may be taking 300 or 400 mg/day. This dose reduction may reduce side effects and the cost of the drug. Doctors in Mexico city conducted a small study to find out the effect of different doses of AZT on the development of drug-resistant virus. Doctors recruited 15 HIV-infected subjects who had between 200 and 500 CD4+ cells. Subjects were assigned to the following groups:  AZT 500 mg/day  AZT 300 mg/day  no AZT (or any other anti-HIV drugs) Blood samples were taken from the subjects for analysis before they entered the study and at regular intervals. Results During the course of the study, technicians isolated HIV from blood samples and exposed the virus to AZT in lab experiments. They found at the end of the study, HIV from subjects who used the high dose of AZT required huge quantities (750 times the normal amount) of the drug to suppress production of HIV in the test tube. Virus taken from subjects using AZT 300 mg/day needed less drug (93 times the normal level) to block its activity. Subjects not receiving AZT had HIV that required even less drug to suppress its production. The difference between the concentrations of AZT required to suppress the virus before and after entering the study was [statistically] significant. Interpretation Although researchers are not sure which dose of AZT is best, 300 mg/day in combination with other anti-HIV agents may be a reasonable dose to use. The study could have been a more useful piece of research had the doctors also measured changes in viral load. REFERENCES: 1. Soto-Ramirez L, Renjifo B, Marlink R, et al . Dose-dependent HIV-1 Zidovudine resistance. Abstract I111. C. DMP 266 Background Scientists at the Merck pharmaceutical company have made a new group of drugs that reduce production of HIV in lab experiments. One of these chemicals is DMP 266 (formerly L743,726) which works by affecting the viral enzyme RT (reverse transcriptase). The critical effect of DMP 266 is that it has antiviral activity against HIV that can resist the effect of delavirdine and nevirapine. In some lab experiments, DMP 266-treated cells were protected from HIV for up to 10 weeks. Study details Doctors in the US enrolled 16 HIV-infected subjects (3 females, 13 males) who had an average of 221 CD4+ cells and a viral load averaging 131,000 copies (each copy represents 1 virus). Thirteen of the 16 subjects had used anti-HIV drugs before entering this study. During the first 2 weeks of the study, 5 subjects received either fake DMP 266 (placebo) or "DMP 266, 200 mg/day." In the third week all subjects received indinavir 800 mg/8 hours. Those subjects who were receiving DMP 266 during the previous two weeks continued to do so. Results Two weeks' use of DMP 266 resulted in a 98% decrease in the amount of HIV in the blood and an increase of 96 CD4+ cells. Subjects receiving fake DMP 266 had no changes in viral load or CD4+ cell counts. After 12 weeks of a combination of both antiviral agents, technicians found the amount of HIV had decreased to less than 1/1,000 of its pre-study level. Common side effects reported included "headache, dizziness, rash and diarrhea." On average, subjects had increases of 100 CD4+ cells. Use of DMP 266 may decrease levels of indinavir by 37%. Further studies of this promising combination are underway. REFERENCES: 1. Mayers D, Riddler S, Stein D, et al . A double-blind study to evaluate the antiviral activity, tolerability and pharmacokinetics of DMP 266 alone and in combination with indinavir. Abstract LB 08A. D. Effect of 3TC and loviride on survival Background In the CAESAR (Canada, Australia, Europe and South Africa) study doctors gave subjects fake 3TC (placebo), 3TC or a combination of 3TC and loviride in addition to whichever antiviral drugs they were already using. Thus, before entering the study subjects were using either AZT, AZT and ddC or AZT and ddI. The dose of 3TC used was 150 mg twice daily and that of loviride was 100 mg three times daily. Nearly 1900 subjects entered the study and had between 25 and 250 CD4+ cells at the start of the trial. Results -- Survival The following proportion of subjects in each group died:  placebo - 17%  3TC - 9%  3TC and loviride - 8% The researchers did not release information on changes in the amount of HIV in the blood of subjects. That subjects who received 3TC and/or loviride were less likely to:  die  develop life-threatening infections was [statistically] significant. In a regimen of 'nukes' (nucleoside analogues; AZT, ddC, ddI, d4T), taking 3TC and/or loviride is likely to decrease the risk of death or developing AIDS. REFERENCES: 1. Montaner J, Cooper DA, Katlama C, et al . CAESAR: confirmation of the clinical benefit of 3TC (Epivir) in HIV-1 disease: preliminary results. Abstract LB06. E. Indinavir and IL-2 -- one year later Interleukin-2 (IL-2) is a chemical produced by the immune system that can have a number of effects, one of which is helping T cells grow. IL-2 can also increase production of HIV by infected cells, so in experiments on HIV-infected subjects, researchers always use anti-HIV drugs with IL-2. In this experiment researchers recruited 36 HIV-infected subjects who had less than 300 CD4+ cells or 20% CD4+ cells. The subjects were then divided into three groups:  Group A: 13 subjects received by injection IL-2 up to 12 million units (12 MU) per day for "5 days every 2 months" and indinavir 600 mg every 6 hours.  Group B: 11 subjects received the same dose and schedule of IL-2 as group A. As well, they received indinavir 600 mg/6 hours only for 10 days every 2 months before, during and after they received IL-2.  Group C: 12 subjects received indinavir 800 mg every 8 hours for the duration of the study. Results The first part of this study lasted for 14 weeks. Below are the average CD4+ cell counts before subjects began to use the study drugs, followed by the counts at the 14th week:  Group A -- 205 and 363 cells  Group B -- 191 and 246 cells  Group C -- 144 and 230 cells We list below the decrease in HIV levels in the blood of subjects by the 14th week:  Group A -- 1.5 times less HIV  Group B -- 1.2 times less HIV  Group C -- 5 times less HIV After the 14th week subjects were allowed to add other anti-HIV drugs to their regimens and subjects in group C could also use IL-2. About one year after entering the study fewer subjects remained and only 8 subjects in each group were receiving IL-2. By this time the average CD4+ cell counts were:  Group A -- 536 cells, 9 subjects  Group B -- 386 cells, 8 subjects  Group C -- 302 cells, 12 subjects Toxicity and lack of effect Subjects experienced "typical" side effects from use of IL-2 (fever, headache, muscle/joint pain, fatigue), and at least 2 subjects developed kidney stones. During the first year of the study no subjects died. In the 2nd year one subject developed PCP and 1 subject not receiving IL-2 developed dementia. Four subjects in group A, 2 in group B and 2 in group C stopped using IL-2 because it did not increase their CD4+ cell counts. Interpretation The use of indinavir and IL-2 caused a small decrease in the viral load and also increased CD4+ cell counts. Use of combination anti-HIV therapy together with IL-2 may be useful in the long term. REFERENCES: 1. Falloon J, Owen C, Metcalf C, et al . Indinavir and IL-2 in HIV: one year follow up. Abstract I108. F. Ritonavir and saquinavir Study details Researchers in the US and Canada have enrolled at least 136 subjects with CD4+ cell counts between 100 and 500 cells who had never used protease inhibitors. Before entering this study subjects were not improving despite use of AZT and related drugs. Subjects were randomly assigned to receive one of three regimens:  ritonavir 800 mg/day and saquinavir 800 mg/day  ritonavir 1200 mg/day and saquinavir 800 mg/day  ritonavir 1200 mg/day and saquinavir 1200 mg/day Results After 3 months in the study, levels of HIV in the blood fell by over 99% in half the subjects and CD4+ cell counts rose by more than 100 cells. Nine subjects have left the study, 7 in the first dose group. Side effects included " diarrhea, fatigue, nausea and tingling around the mouth." No information on the effect of the combination on the development of infections or survival has been released. REFERENCES: 1. Cohen C, Sun E, Cameron W, et al . Ritonavir-saquinavir combination treatment in HIV-infected patients. Abstract LB 07B. G. Saquinavir and indinavir -- some problems In an attempt to increase the anti-HIV activity of protease inhibitors researchers are testing several drug combinations in lab experiments. At low concentrations, indinavir used with saquinavir have increased anti-HIV activity than either drug used alone. At higher concentrations the anti-HIV effects of the drugs are reduced. When technicians tested the combination against HIV that was resistant to AZT, every concentration of the 2 drugs had reduced anti-HIV activity than when each was used alone. REFERENCES: 1. Merril DR, Manion DJ, Chou T-C, et al . Protease inhibitor combination regimens against HIV-1 in vitro. Abstract I002. H. A new protease inhibitor -- 141W94 141W94 To study the effects of this drug 141W94 researchers recruited 42 adult (7 females, 35 males) HIV-infected subjects. Ninety-two percent were either free from symptoms or had mild symptoms of HIV infection. None were supposed to have used protease inhibitors before entering this study. Researchers divided the subjects into 4 groups and gave them several doses of 141W96; 600 mg/day, 900 mg/day, 1800 mg/day and 2400 mg/day for 4 weeks. Results -- amount of virus At the start of the study subjects had relatively high levels of HIV in their blood. As well, half the subjects had at least 254 CD4+ cells. The greater the dose of 141W94 used, the greater the decrease in viral load. Subjects receiving 900 mg/day or more of the protease inhibitor had their viral load fall to 1/10th of its pre-study level. Those subjects receiving 2,400 mg of the study drug had their viral load decrease to 1/100th of its prestudy level. Results -- changes in CD4+ cell counts The changes in CD4+ cell counts did not mirror the trends in viral load. Half the subjects in the groups below had the following increases in CD4+ cell count:  600 mg/day -- 64 cells  900 mg/day -- 85 cells  1,800 mg/day -- 35 cells  2,400 mg/day -- 110 cells Toxicity Common side effects included "diarrhea, loose stools, rash and headache." Three subjects left the study early because of rash (2 subjects) and "worsening [intestinal inflammation]." REFERENCES: 1. The 141W94 International Study group. Preliminary data on the safety and antiviral efficacy of the novel protease inhibitor 141W94 in HIV-infected patients with 150 to 400 CD4+ cells/mm3. Abstract LB 07A. Copyright (c) 1996 - CATIE. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. Direct Dial: v.34+: 714.248.2836; v.120/ISDN: 714.248.0433 Internet: telnet:aegis.com www: http://www.aegis.com