Effect of Lamivudine in HIV-Infected Persons with Prior Exposure to Zidovudine/Didanosine or Zidovudine/Zalcitabine

Abstract

Nucleoside analog-based regimens remain an integral component of combination therapy for use in both antiretroviral treatment-naive and experienced HIV-infected patients. To further define treatment responses to new antiretroviral therapy in patients with long-term experience to dual nucleoside analog therapy (zidovudine [ZDV] plus didanosine [ddI] or ZDV plus zalcitabine [ddC]), 325 subjects derived from the AIDS Clinical Trials Group (ACTG) 175 trial were randomized to three different combination regimens: (1) continuation of ZDV + ddI or ZDV + ddC (continuation arm), (2) addition of 3TC to ZDV + ddI or ZDV + ddC (addition arm), or (3) a switch to ZDV + 3TC therapy (switch arm). Both the addition and switch arms sustained significantly greater short-term (baseline to week 4) mean CD4+ cell count increases compared with the continuation arm (+36, +28 versus -4 cells/mm3; p = 0.012) and long-term CD4+ cell count responses (baseline to weeks 40/48: +32, +19 versus -9 cells/mm3; p = 0.003). Superior short-term (baseline to week 8) mean decreases in plasma HIV RNA (p < 0.001) were achieved by both the addition and switch arms (0.53 log10 and 0.54 log10 copies/ml, respectively) compared with the continuation arm (0.13 copies/ml) whereas no differences in long-term virologic suppression were observed (p = 0.30). At week 48, no differences were observed in the proportions of subjects who had HIV RNA levels below 500 copies/mL: 18% of subjects in each treatment arm (3-way p = 1.0). Overall, the treatments were well tolerated and only nine subjects (3%) died or developed one or more AIDS-defining events. While this study confirms the intrinsic antiretroviral activity of 3TC, only modest marker changes and limited short-term viral suppression are seen with incremental addition of the drug. The current approach of using 3TC in maximally suppressive regimens is preferred.

Nucleoside Analogue Use Before and During Highly Active Antiretroviral Therapy and Virus Load Rebound

“…This is consistent with the results of Katzenstein et al [27], who found a benefit from zidovudine plus lamivudine over zidovudine alone in patients with didanosine experience, and with findings of AIDS Clinical Trial Group 303, in which a switch to zidovudine with lamivudine was associated with a better virologic response than continuing zidovudine with didanosine or zalcitabine [28]. It has been noted that, in a minority of patients who had only received didanosine or zalcitabine, the M184V mutation can be found [12].…”

Nelfinavir, Efavirenz, or Both after the Failure of Nucleoside Treatment of HIV Infection

“…The AIDS Clinical Trials Group (ACTG) 302 12 and ACTG 303 13 "rollover" studies that followed the ACTG 175 study 14 were randomized, partially blinded trials in which regimens of new nucleoside analogues or stavudine monotherapy were evaluated in patients who had received zidovudine alone, zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine monotherapy while participating in the ACTG 175 study (Fig. 1).…”