Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts.
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/microL 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/microL, 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/microL, 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.
MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
P
P
Munderi
A S
AS
Walker
C
C
Kityo
A G
AG
Babiker
F
F
Ssali
A
A
Reid
J H
JH
Darbyshire
H
H
Grosskurth
P
P
Mugyenyi
D M
DM
Gibb
C F
CF
Gilks
D000328:Adult; D001835:Body Weight / Q000187:drug effects; D018791:CD4 Lymphocyte Count / Q000592:standards; D015224:Dideoxynucleosides / Q000009:adverse effects / Q000627:therapeutic use; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D012008:Recurrence; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014454:Uganda; D019562:Viral Load / Q000187:drug effects / Q000592:standards; D015215:Zidovudine / Q000009:adverse effects / Q000627:therapeutic use; D000099227:Abacavir
D015224:Dideoxynucleosides; D019259:Lamivudine; D019829:Nevirapine; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D000099227:Abacavir