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LATE BREAKER ABSTRACTS
Abstract LB6a
Prolongation of Life and Prevention of AIDS in Advanced HIV Immunodeficiency
with Ritonavir.
Authors: B Cameron, M Heath-Chiozzi, S Kravcik, R Mills, A Potthoff, D Henry, The Advanced HIV Ritonavir Study Group and J Leonard.
Abstract LB6b
Anti-HIV Activity and Lymphocyte Surrogate Marker Response
Dynamics to Ritonavir Therapy in Advanced HIV Immunodeficiency.
Authors: M Heath-Chiozzi, J Leonard, D Henry, R Mills, A Potthoff, The Advanced HIV Ritonavir Study Group and B Cameron.
Results of an international, multi-center, randomized, placebo-controlled study of adding ritonavir or placebo to existing antiretroviral therapy showed improvement in both laboratory and clinical outcome in people with advanced HIV disease.
A total of 1,090 study participants were randomized to receive 600 mg ritonavir twice daily (543 patients) or placebo (547 patients) in combination with existing antiretroviral therapy. Participants had CD4 counts of 100 cells/mm3 or fewer and at least 9 months of previous antiretroviral therapy with up to but no more than 2 approved antiretroviral drugs. 3TC was considered as an experimental agent at that time (prior to its approval) and was not permitted as a concurrent therapy. On average, patients were taking 11 concomitant medications while on the study. In addition, participants had no active opportunistic infections at study entry.
Eight percent of participants in the ritonavir group were female as compared to 9% of those in the placebo group. Majority of the participants were white homosexual or bisexual males.
About 18% of patients had no other concurrent antiretroviral therapy during the course of the study (i.e., they received either ritonavir alone or placebo). Majority of patients (82%) had received ritonavir or placebo with concurrent antiretroviral treatments such as nucleoside monotherapy (AZT, d4T, ddI or ddC) or nucleoside combination therapy (AZT + ddC, AZT + ddI or AZT + d4T).
In a subset of patients for whom antiviral results were available (80 patients on ritonavir and 79 on placebo), mean baseline viral load levels were about 5.2 logs or about 178,000 copies/mL. In the ritonavir group, there was a maximum mean decrease of 1.3 logs in HIV RNA at week 2 which was returned to 0.8 log at week 16. By contrast, viral load levels remain relatively unchanged in the placebo group at week 16.
Immunologic data were available in a subset of patients (108 patients on ritonavir and 107 on placebo). Mean baseline CD4 counts were 31 and 26.4 cells/mm3 in ritonavir and placebo groups, respectively. Mean CD8 counts at baseline were 505.8 and 457.9 cells/mm3 in ritonavir and placebo groups, respectively.
There was a mean increase of 40 cells/mm3 in CD4 counts with ritonavir at week 4 which elevated further to 50 cells/mm3 at week 16. No CD4 count increases were seen with placebo. CD8 counts also increased with ritonavir by about 300 cells/mm3 at week 8 and remained 200 cells/mm3 above baseline at week 16. CD8 counts remain relatively unchanged with placebo.
A total of 85 (15.7%) clinical events occurred in the ritonavir group as compared to 181 (33.1%) events in the placebo group. There was a 58% reduction in AIDS-defining events or death with ritonavir relative to placebo. The effects of ritonavir on delaying disease progression and death were found to be statistically significant.
Most common clinical endpoints and their number of occurrences (ritonavir vs. placebo) were esophageal candidiasis (16 vs. 38), Kaposi's sarcoma (8 vs. 22), CMV retinitis (13 vs. 17), Pneumocystis carinii pneumonia or PCP (9 vs. 16), extraocular CMV (3 vs. 13), Mycobacterium avium intracellulare or MAI (6 vs. 9), wasting syndrome (2 vs. 8), lymphoma (3 vs. 6) and death as first event (17 vs. 27). Ritonavir therapy also prolonged survival. There were 26 (4.8%) deaths in the ritonavir group versus 46 (8.4%) in the placebo group. Overall, there was a 42% reduction in deaths.
Adverse events which required drug discontinuation in the ritonavir group (541 patients) were mostly gastrointestinal-related such as nausea (10%), vomiting (5.7%) and diarrhea (3.5%). Other adverse events with ritonavir included asthenia or weakness (4.3%), taste perversion (2%), headache (1.7%) and fever (1.3%). Some patients also experienced transient circumoral paresthesia or tingling sensation around the mouth. Most common laboratory abnormalities with ritonavir were reductions in red blood cell and white blood cell counts. Elevations in uric acid, SGPT/ALT, GGT, CPK and fasting triglycerides were also noted in few patients.
Dr. Leonard concluded that ritonavir significantly decreased HIV RNA, increased CD4 and CD8 cell counts, delayed progression of AIDS and improved survival. Ritonavir was generally well tolerated in the patient population studied. He also stated that use of ritonavir in combination with antiretroviral therapy earlier in the course of HIV disease may reduce the incidence of adverse events and increase overall efficacy.
COMMENTS: When considering the viral load performance of ritonavir in this specific study, it is important to remember that the population being studied is very advanced with mean CD4 counts at baseline of less than 30 cells/mm3. Being an advanced disease group, this could mean their viral population was more heterogeneous than a group with significantly higher CD4 count and viral load titer. Therefore, viral mutation can advance more efficiently than in a less advanced population.
Additionally, there were compliance problems in this study due to the elixir (liquid) formulation of ritonavir which has a characteristically unpleasant taste. [Abbott is now evaluating the gel capsule version of ritonavir]. Some study participants who were randomized to receive ritonavir may not have taken the drug as they were supposed to, but may have told study coordinators that they were taking it according to study instructions.
In the December 7, 1995 issue of the New England Journal of Medicine, data was reported by Martin Markowitz, et al. on an earlier Abbott study. When a more sensitive assay was used in a small subgroup of 20 patients out of the 62 enrolled, they found viral load decreased by a mean of 1.7 log. At 12 weeks, it was at 1.1 log. The mean maximum decrease was 1.94 log at week 8. Although this data is based on only 20 patients, it brings into question the discordance of the viral RNA data presented at the Conference.
It is uncertain how sustained this viral load response was beyond the study period reported in the Journal. Also, the ritonavir administered in the study was in the form of semi-solid gel capsule as opposed to liquid formulation, which lends itself to better compliance. Taken together, it is difficult to compare data from different studies.
The side effect profile detected from this earlier study was: liver enzymes, cholesterol and triglycerides increased significantly during week 1. Elevations in cholesterol and triglycerides persisted through the 32 weeks of the study. There were increases from baseline of 30 to 40% for cholesterol and of 200 to 300% for triglycerides.
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