Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine.

In the OCTANE/A5208 study of initial antiretroviral therapy (ART) in women exposed to single-dose nevirapine (sdNVP) ≥ 6 mo earlier, the primary endpoint (virological failure or death) was significantly more frequent in the NVP-containing treatment arm than in the lopinavir/ritonavir-containing treatment arm. Detection of NVP resistance in plasma virus at study entry by standard population genotype was strongly associated with the primary endpoint in the NVP arm, but two-thirds of endpoints occurred in women without NVP resistance. We hypothesized that low-frequency NVP-resistant mutants, missed by population genotype, explained excess failure in the NVP treatment arm. Plasma samples from 232 participants were analyzed by allele-specific PCR at study entry to quantify NVP-resistant mutants down to 0.1% for 103N and 190A and to 0.3% for 181C. Of 201 women without NVP resistance by population genotype, 70 (35%) had NVP-resistant mutants detected by allele-specific PCR. Among these 70 women, primary endpoints occurred in 12 (32%) of 38 women in the NVP arm vs. 3 (9%) of 32 in the lopinavir/ritonavir-containing arm (hazard ratio = 3.84). The occurrence of a primary endpoint in the NVP arm was significantly associated with the presence of K103N or Y181C NVP-resistant mutations at frequencies >1%. The risk for a study endpoint associated with NVP-resistant mutant levels did not decrease with time. Therefore, among women with prior exposure to sdNVP, low-frequency NVP-resistant mutants were associated with increased risk for failure of NVP-containing ART. The implications for choosing initial ART for sdNVP-exposed women are discussed.

Pharmacokinetic comparison of generic and trade formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian adults.

BACKGROUND: The Malawian antiretroviral program uses generic Triomune (stavudine, lamivudine, and nevirapine). OBJECTIVE: To determine the pharmacokinetics and bioequivalence of generic and trade formulations of stavudine, lamivudine, and nevirapine in HIV-infected Malawians. METHODS: This randomized, open label, cross-over study comprised of six men and six women currently receiving Triomune-40 TM who were randomized to the generic or trade formulation of stavudine (40 mg twice daily), lamivudine (150 mg twice daily) and nevirapine (200 mg twice daily). After at least 21 days, the alternate formulation was administered. At the end of each period, six blood samples were collected over 8 h. Bioequivalence was achieved if the 90% confidence interval (CI) for the geometric mean ratio (GMR) of generic:trade formulations for maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) was within 0.8-1.25. RESULTS: Mean patient age, weight, and height were 38.4 years (SD, 7.7), 71.2 kg (SD, 7.0), and 164.8 cm (SD, 6.3), respectively. The GMR for stavudine, lamivudine, and nevirapine were 1.4 (90% CI, 1.2-1.7), 1.1 (90% CI, 0.8-1.6), and 0.9 (90% CI, 0.7-1.2), respectively, for Cmax; and 1.1 (90% CI, 1.0 1.2), 1.0 (90% CI, 0.7-1.3), and 0.9 (90% CI, 0.7-1.1), respectively, for AUC0-8h. Regardless of formulation, Malawians had higher nevirapine exposures compared with historical reports of Western HIV-infected patients. CONCLUSIONS: Although exposures were similar, Triomune did not meet the strict definition of bioequivalence for these drugs. Patients taking Triomune had notably higher stavudine Cmax values. Antiretroviral pharmacokinetics and bioequivalence of generic formulations should be evaluated in the populations in which they are being used.

Lessons learned from a paying antiretroviral therapy service in the public health sector at Kamuzu Central Hospital, Malawi: 1-year experience.

BACKGROUND: In October 2001, a paying antiretroviral therapy service was introduced at a Central Hospital in Malawi using stavudine 40 mg/lamivudine 150 mg/nevirapine 200 mg (triomune). The objective of this study was to determine characteristics of patients seeking antiretroviral therapy, retention in care, clinical outcomes, and outlines for program improvement. METHODS: Retrospectively, all patients seeking anti-retroviral therapy initiation (October 2001 to October 2002; follow-up through April 2003) were evaluated for laboratory results, retention in care, toxicity, and mortality. Hazard ratios for factors associated with dropout were determined. RESULTS: Of 757 patients seeking evaluation, 625 began treatment. Documented mortality rate was 61 of 757. Total dropout rate was 50%. Factors associated with dropout include CD4 count <50 cells/mm(3) and Kaposi's sarcoma. Twenty-seven of 625 patients discontinued therapy for toxicity. CONCLUSIONS: The paying antiretroviral therapy program showed an unacceptable dropout rate associated with advanced baseline disease. Severe toxicity rate was low. Areas for improved program performance include lower cost, wide and earlier access to antiretroviral therapy, and targeted retention strategies.

Pharmacokinetics of generic and trade formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian children.

BACKGROUND: The aim of this study was to evaluate the pharmacokinetics of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in HIV-infected Malawian children receiving quartered tablet multiples of Triomune 40 (generic tablet [GT]) compared with individual generic liquid (GL) and trade liquid (TL). METHODS: This was a prospective randomized three-way crossover study. Patients (8-<12 kg, 18-<22 kg or 28-<32 kg body weight) taking Triomune 40 were recruited and randomized to receive GT twice daily (one-quarter, one-half or three-quarter tablets using Malawi treatment guidelines), GL twice daily (in the equivalent dose of GT) or TL twice daily (dosed using weight and age from US Department of Health and Human Services paediatric treatment guidelines). After 10 days of one formulation, 6-h pharmacokinetic sampling was performed, and patients were crossed over to subsequent formulations. Baseline concentration (C(0 h)), area under the curve (AUC)(0-6 h), maximum plasma concentration (C(max)) and time to C(max) were generated for each antiretroviral treatment. RESULTS: A total of 7 males and 11 females (6 in each GT dosing group) with a median (range) age of 7.2 years (1.3-13.6), weight of 19 kg (9.0-30.5) and height of 109 cm (75-132) were recruited. Combining all patients, no difference in pharmacokinetics was noted among the formulations for all drugs. However, patients in the one-quarter GT dosing group (8-<12 kg) had lower 3TC exposures than with the GL or TL (3TC AUC(0-6 h) 1,102, 1,720 and 2,060 h*ng/ml, respectively; P<0.005) and had more subtherapeutic NVP C(0 h) (10 of 13 occasions versus the one-half and three-quarter tablet groups). Compared with Western paediatric cohorts, Malawians had concentrations 30-40% lower for 3TC and d4T and 50% higher for NVP. CONCLUSIONS: Quartered multiples of Triomune 40 are appropriate for children 18-<22 kg and 28-<32 kg in weight; however, alternative formulations are suggested in children weighing 8-<12 kg.