Of 765 participants randomized to receive EFV (2 NRTIs [n
= 382] or 3 NRTIs [n
= 383]), 70 (9%; 15 female) with median pretherapy CD4+
T cell counts of 246 cells/mm3
substituted NVP for EFV because of CNS symptoms (n
= 47), skin symptoms (n
= 18), fatigue (n
= 3), elevated transaminase levels (n
= 1), or hypertriglyceridemia (n
= 1) (). Most substitutions (78%) occurred within 24 weeks after initiation of treatment. NVP was started within 2 weeks after EFV therapy discontinuation in 71% of participants (53% within 1 week); participants who switched therapy because of skin symptoms had a longer duration between EFV discontinuation and NVP initiation (44% and 89% started NVP therapy within 2 and 4 weeks after EFV therapy discontinuation, respectively). Baseline characteristics and disposition of the cohort are reported elsewhere [7
Baseline Characteristics of 70 Participants Who Switched from Efavirenz (EFV) Therapy to Nevirapine (NVP) Therapy, by Reason for Switch
The median CD4+ T cell count and HIV RNA level at the time of substitution were 323 cells/mm3 and 279 copies/mL, respectively. The only statistically significant predictor of substitution of NVP was a history of psychiatric disorder. Most participants experienced resolution of CNS symptoms after switching to NVP (46 of 47 patients); 5 reported new CNS symptoms, but none discontinued NVP because of CNS AEs. Fifteen participants discontinued NVP therapy within 32 weeks after substitution because of AEs (n = 8; skin symptoms [n = 4], hepatotoxicity [n = 3], and other [n = 1]); virologic failure (n = 3), and participant decision or loss to follow-up (n = 4). CD4+ T cell counts at time of substitution were 28, 316, 316, and 549 cells/mm3 in participants who discontinued NVP therapy because of skin symptoms and 72, 174 and 1003 cells/mm3 in participants who discontinued NVP therapy because of hepatotoxicity.
Three participants had persistent skin symptoms after substitution. Of fifteen participants (83%) who experienced resolution of skin symptoms, 5 experienced a recurrence while receiving NVP and 4 (1 woman) subsequently discontinued NVP therapy because of skin symptoms. CD4+ T cell counts at time of substitution were similar in the 4 participants who discontinued NVP therapy and in those who did not. Participants who switched because of skin symptoms discontinued EFV therapy earlier than did those who switched because of CNS AEs or other reasons. EFV-related fatigue resolved in all 3 participants.
The prevalence of grade 3/4 hepatotoxicity was 14% (10 of 70 participants) in participants who switched to NVP (incidence, 2.2 cases per 1000 patient-years; 95% CI, 1.5–3.1 cases per 1000 patient-years). The mean prevalence of grade 3/4 hepatotoxicity in bootstrapped nonsubstituting cohorts was 6% (incidence, 0.8 cases per 1000 patient-years; 95% CI, 0.06–1.0 cases per 1000 patient-years). The only grade 3/4 hepatic AEs in participants who substituted NVP occurred in men. Rates of grade 2–4 AEs after substitution were similar among participants with an HIV RNA level <200 copies/mL and among those with and HIV RNA level >200 copies/mL at time of substitution.
Of 70 NVP-substituting participants, 67 had their HIV RNA level measured 16–32 weeks after substitution. In the intent-to-treat analysis ignoring treatment status, 45 (67%) of 67 participants had suppressed viral load (HIV RNA level <50 copies/mL) 24 weeks after substitution. With missing and off-treatment evaluations considered as treatment failure (HIV RNA >50 copies/ml), 41 (59%) of 70 participants had a suppressed viral load. In the as-treated analysis (participants receiving treatment at the time of the 24-week postsubstitution evaluation), 41 (76%) of 54 participants had a suppressed viral load.
A total of 384 participants experienced a non–life-threatening CNS or rash AE while receiving EFV therapy; 239 of these patients were eligible for the switching strategy analysis (25 [10%] were classified in the NVP strategy group) (). Baseline characteristics were well matched. Compared with the EFV strategy group, the NVP strategy group had a significantly greater hazard of strategy discontinuation (hazard ratio [HR], 2.2; 95% CI, 1.3–3.9; P = .005), a higher hazard of virologic failure (HR, 2.3; 95% CI, 1.2–4.4; P = .014), and greater risk of strategy failure (HR, 2.1; 95% CI, 1.2–3.6; P=.01). However, after adjusting for patient characteristics at ACTG A5095 baseline and time of the initial targeted AE, all of the associations were attenuated and were no longer statistically significant (strategy discontinuation: HR, 1.6 [95% CI, 0.9–2.9] P =.15; virologic failure: HR, 1.4 [95% CI, 0.6–3.0] P =.46; strategy failure: HR, 1.5 [95% CI, 0.8–2.7] P =.24). Key confounding factors associated with the shift in the estimated effect size were whether the subject temporarily discontinued anti-retroviral therapy within 4 weeks after the targeted AE and the grade of the targeted AE.
Figure 1 Toxicity management strategy. CNS, central nervous system; EFV, efavirenz; NVP, nevirapine; SS, skin symptoms. *EFV strategy included participants who continued to receive EFV for 30 days after the initial targeted toxicity; participants may have made (more ...)