Nevirapine clearance from plasma in African adults stopping therapy: a pharmacokinetic substudy.

OBJECTIVE: To measure nevirapine elimination in African adults undertaking a structured treatment interruption (STI) in the DART trial. DESIGN: Cohort (16 women, 5 men; median weight 61 kg) within a randomized trial of management strategies. METHODS: Plasma nevirapine was measured by validated high performance liquid chromatography at 0,1,2,3 and 4 weeks after stopping the drug in a subset of patients undertaking an STI. All patients continued lamivudine plus zidovudine/stavudine for a further 7 days. RESULTS: Two patients with no or low plasma nevirapine concentration at baseline were excluded. Geometric mean plasma concentration when nevirapine was stopped in the remaining 19 patients was 6421 ng/ml (range, 3724-9473). Nevirapine was detected in 15/18 (83%) patients at 1 week, and 5/19 (26%) patients at 2 weeks but was not found any samples collected after 2 weeks. Only one patient had > 100 ng/ml (limit of quantification) at 2 weeks (415 ng/ml, female). The median times to reach thresholds of 200, 100 and 20 ng/ml (limit of detection) were estimated to be 7.6 [interquartile range (IQR), 7.0-10.1], 9.3 (IQR, 8.7-13.0) and 13.2 (IQR, 12.3-18.4) days, respectively, with 3/19 (16%) and 14/19 (74%) estimated to have reached < 20 ng/ml by 7 and 14 days, respectively. CONCLUSION: Although elimination of nevirapine was faster than previously published after a single dose, the data suggest that an additional staggered period of 7-10 days with dual nucleotide reverse transcriptase inhibitor cover is necessary for African patients discontinuing nevirapine.

Lopinavir/ritonavir monotherapy after 24 weeks of second-line antiretroviral therapy in Africa: a randomized controlled trial (SARA).

BACKGROUND: Boosted protease inhibitor (bPI) monotherapy (bPImono) potentially has substantial cost, safety and operational benefits. It has never been evaluated as second-line antiretroviral therapy (ART) in Africa. METHODS: After 24 weeks of lopinavir/ritonavir-containing second-line therapy, DART participants were randomized to remain on combination therapy (CT), or change to bPImono maintenance (SARA trial; ISRCTN53817258). Joint primary end points were CD4(+) T-cell changes 24 weeks later and serious adverse events (SAEs); retrospectively assayed viral load (VL) was a secondary end point. Analyses were intention-to-treat. RESULTS: A total of 192 participants were randomized to CT (n=95) or bPImono (n=97) and followed for median 60 weeks (IQR 45-84). Participants received median 4.0 years (IQR 3.5-4.4) first-line ART. Median CD4(+) T-cell count at first-line failure was 86 cells/mm(3) (47-136), increasing to 245 cells/mm(3) (173-325) after 24-week induction when 77% had VL<50 copies/ml. Overall, 44 (23%) were receiving second-line therapy with bPI and nucleoside reverse transcriptase inhibitors (NRTI) only, and 148 (77%) with bPI plus non-NRTI (NNRTI) with or without NRTI. At 24 weeks after randomization to CT versus bPImono, mean CD4(+) T-cell increase was 42 (CT, n=85) versus 49 cells/mm(3) (bPImono, n=88; adjusted difference 13 [95% CI -15, 43], P=0.37; non-inferior compared with predetermined non-inferiority margin [-33]). Virological suppression was greater for CT versus bPImono (trend P=0.009): 77% (70/91) versus 60% (56/94) were <50 copies/ml, and 5% (5) versus 14% (13) were ≥1,000 copies/ml, respectively. A total of 0 (0%) versus 5 (5%) participants had major protease inhibitor mutations and 3 (3%) versus 0 (0%) new NNRTI/NRTI mutations were detected during follow-up. Two participants (1 CT and 1 bPImono) died >24 weeks after randomization, and 5 (2 CT and 3 bPImono) experienced SAEs (P=0.51). CONCLUSIONS: bPImono following a 24-week second-line induction was associated with similar CD4(+) T-cell response, but increased low-level viraemia, generally without protease inhibitor resistance. Longer-term trials are needed to provide definitive evidence about effectiveness in Africa.