Objectives: To assess if cyclical therapy with four reverse transcriptase inhibitors is less toxic and as active, based on virological and immunological markers, as the same four drugs given together over a 64-week period.Methods: An open randomized trial comparing concurrent therapy (T4) with zidovudine, lamivudine, loviride and zalcitabine with the same four drugs given cyclically each for 8 weeks (C4) and with concurrent zidovudine and lamivudine (T2), all given for a total of 64 weeks. The primary endpoint was the change in plasma HIV RNA level from baseline at weeks 32 and 64. Phenotypic and genotypic resistance, CD4+ cell counts, and clinical and laboratory assessments of safety were also compared. Patients were followed for up to a further 32 weeks beyond 64 weeks. Eligible patients had CD4+ cell counts between 50 and 350 x 10(6)/l and no prior antiretroviral therapy.Results: One hundred individuals (34 T4, 34 C4, 32 T2) were recruited between 31 July 1995 and 11 July 1996, of whom 22 had AIDS; the mean (SD) HIV RNA at baseline was 4.9 (0.7) log(10) copies/ml and the median (interquartile range) CD4+ cell count was 170 (100-260) x 10(6)/l. A total of 28 T4, 19 C4 and 26 T2 participants were still on the allocated regimen at week 64. A new AIDS event or death was reported in three T4, seven C4 and five T2 participants (P = 0.7). Serious adverse events that were likely to be drug related were observed in three T4, one C4 and four T2 participants. The reduction from baseline in HIV-1 RNA (log(10) copies/ml) was greatest in the T4 arm; at 32 weeks the mean reduction (SD) was 1.45 (0.72), 0.42 (0.45) and 1.05 (0.70) in T4, C4 and T2 respectively (global P = 0.0001) and at week 64 1.24 (0.86), 0.73 (0.91) and 0.78 (0.55) respectively (P = 0.02). The pattern of CD4+ change mirrored the changes in HIV RNA. Very few mutations associated with resistance to loviride or zalcitabine were seen. The mutation at codon 215 associated with zidovudine resistance was detected (>5% of population mutant) in 11 out of 24 T4 participants compared with three out of 21 C4 and 11 out of 20 T2 participants at week 64 (P = 0.02). Further assays of viral resistance including phenotypic assays are ongoing and results will be reported separately. (C) 1999 Lippincott Williams & Wilkins.
Background Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first‐line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti‐tuberculosis therapy, and sparing two drug classes for second‐line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa. Methods A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral‐naïve HIV‐infected adults with CD4 counts <200 cells/μL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo‐controlled to 24‐week primary toxicity endpoint, and then open‐label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV‐1 RNA assayed retrospectively. Exploratory efficacy analyses are intention‐to‐treat. Results The median pre‐ART CD4 count was 99 cells/μL, and the median pre‐ART viral load was 284 600 HIV‐1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow‐up, 25 (4%) died and 12 (2%) were lost to follow‐up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs . 34 (11%) receiving nevirapine ( P =0.09). At 48 weeks, 62% of participants receiving abacavir vs . 77% of those receiving nevirapine had viral loads <50 copies/mL ( P <0.001), and mean CD4 count increases from baseline were +147 vs . +173 cells/μL, respectively ( P =0.006). Nine participants (3%) receiving abacavir vs . 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24–1.25; P =0.15]; 20 receiving abacavir vs . 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34–1.05; P =0.07) and 48 receiving abacavir vs . 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46–0.96; P =0.03). Seventy‐one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine ( P <0.001). Conclusions The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.
The Quattro Trial compared the use of four HIV-1 reverse transcriptase (RT) inhibitors (zidovudine, lamivudine, loviride and zalcitabine), given either as four-drug combination therapy or monotherapy, with 8-week cycles of each drug, with zidovudine/lamivudine dual therapy. Observations of resistance associated and other mutations in the RT gene were made to determine whether therapy failure could be explained by acquisition of these mutations and whether novel mutation patterns developed. As in the intent-to-treat analysis, the use of cyclical monotherapy gave a smaller reduction in plasma virus load at 64 weeks (0.4 log10 copies/ml below baseline) than the quadruple or dual therapy arms (1.3 and 0.8 log10 copies/ml below baseline). Cyclical therapy appeared to generate less genotypic resistance to zidovudine, loviride or zalcitabine than the other arms. Resistance to lamivudine (mutation M184V) developed rapidly in all three arms. Resistance to zidovudine was acquired by a larger proportion of subjects on dual therapy than on quadruple therapy. Resistance to loviride or zalcitabine was rarely observed. During lamivudine monotherapy the M184V mutation was rapidly acquired and viral load rebounded. Zalcitabine monotherapy initially selected M184V mutants, but these were lost as therapy continued. Novel mutations that may have been associated with combination or cyclical quadruple therapy were observed infrequently. There was no clear correlation between changes in response to therapy and the development of previously described resistance mutations or with novel mutations in the RT gene.
Objectives: To evaluate the role of viral load, as measured by HIV-1 RNA, and CD4 cell counts as surrogates for clinical outcome using the data from the Delta trial. Methods: A total of 1280 participants (40% of the 3207 participants in the Delta trial) with baseline and at least one other serum sample stored at -70°C were included in the extended virology study, of whom 411 were allocated to zidovudine (ZDV) alone, 439 to ZDV plus didanosine (ddI) and 430 to ZDV plus zalcitabine (ddC). The extent to which changes in HIV or CD4 cell levels up to week 32 can explain the benefit of combination therapy was investigated by fitting these marker levels in addition to allocated treatment to Cox proportional hazards models for time to death and to disease progression. Findings: RNA at baseline and changes at weeks 8, 16 and 32 were independent and highly significant predictors of disease progression or death. The hazard of progression was increased fourfold (P<0.0004) for each log10 higher baseline RNA and was reduced by 43% (P=0.004) and by 38% (P=0.002) for each log10 reduction at weeks 8 and 16, respectively. Compared with ZDV monotherapy, the progression rate was reduced by 43% (P = 0.0001) by ZDV plus ddI and by 36% (P = 0.001) by ZDV plus ddC. After adjusting for RNA up to week 16, however, there was a highly significant treatment effect favouring ZDV monotherapy, which was not explained by RNA: the adjusted progression rates were 66% higher (P = 0.005) for ZDV plus ddI and 67% higher (P=0.004) for ZDV plus ddC compared with ZDV alone. In contrast, after adjusting for CD4 to week 16 there remained a significant treatment effect favouring combination therapy: compared with ZDV monotherapy, the progression rate was reduced by 29% (P<0.0001) by ZDV plus ddI and 12% (P=0.1) by ZDV plus ddC. Adjustment for both RNA and CD4 to week 16 resulted in a relative increase in the hazard of progression (49% (P = 0.04) for ZDV plus ddI and 37% (P=0.09) for ZDV plus ddC) not explained by the two markers combined. Conclusion: Clinical benefit from combinations of ZDV plus ddI or ZDV plus ddC was underestimated by CD4 cell counts and overestimated by RNA levels and by the two markers combined. Neither HIV RNA levels nor CD4 cell counts appear to be complete surrogates for clinical outcome.
In a randomized comparison of nevirapine or abacavir with zidovudine plus lamivudine, routine viral load monitoring was not performed, yet 27% of individuals with viral failure at week 48 experienced resuppression by week 96 without switching. This supports World Health Organization recommendations that suspected viral failure should trigger adherence counseling and repeat measurement before a treatment switch is considered.
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