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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 bPI-mono 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/mm3(47–136), increasing to 245 cells/mm3(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/mm3(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.

Background The aim of this study was to investigate long-term renal function in HIV-infected adults initiating antiretroviral therapy (ART) with a CD4+T-cell count <200 cells/mm3in Africa.Methods This was an observational analysis within the DART trial randomizing 3,316 adults to routine laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). Serum creatinine was measured pre-ART (all =360 µmol/l), at weeks 4 and 12, then every 12 weeks for 4-5 years; estimated glomerular filtration rate (eGFR) was determined using the Cockcroft-Gault formula. We analysed eGFR changes, and cumulative incidences of eGFR<30 ml/min/1.73 m2and chronic kidney disease (CKD; <60 ml/min/1.73 m2or 25% decrease if <60 ml/min/1.73 m2pre-ART; confirmed >3 months).Results At ART initiation, median CD4+T-cell count was 86 cells/mm3; 1,492 (45%) participants had mild (60–<90 ml/min/1.73 m2), 237 (7%) moderate (30–<60 ml/min/1.73 m2) and 7 (0.2%) severe (15–<30 ml/min/1.73 m2) decreases in eGFR. First-line ART was zidovudine/lamivudine plus tenofovir (74%), abacavir (9%) or nevirapine (17%). By 4 years, cumulative incidence of eGFR<30 ml/min/1.73 m2was 2.8% (n=90) and CKD was 5.0% (n=162). Adjusted eGFR increases to 4 years were 1, 9 and 6 ml/min/1.73 m2with tenofovir, abacavir and nevirapine, respectively (P<0.001), and 4 and 2 ml/min/1.73 m2for LCM and CDM, respectively (P=0.005; 2 and 3 ml/min/1.73 m2to 5 years; P=0.81).Conclusions On all regimens and monitoring strategies, severe eGFR impairment was infrequent; differences in eGFR changes were small, suggesting that first-line ART, including tenofovir, can be given safely without routine renal function monitoring.

Objective To describe the prevalence, incidence and predictors of severe anaemia in previously untreated symptomatic HIV-infected adults with CD4+T-cells <200 cells/mm3initiating zidovudine-containing regimens in Africa.Design DART is a randomized trial comparing two strategies for HIV/AIDS management in Uganda and Zimbabwe.Methods We analysed the occurrence of anaemia at weeks 4 and 12, and then every 12 weeks. We also evaluated sex, age, WHO stage, body mass index (BMI), baseline laboratory measurements and first regimen as predictors of developing grade 4 anaemia (<6.5 mg/dl) by week 48 using logistic regression.Results To May 2005, 3,314 participants (65% women, 23% at WHO stage 4, median age=37 years, baseline CD4+T-cell=86 cells/mm3and median baseline haemo-globin=11.4 g/dl) had a median 72 weeks follow-up. Prevalence of grade 4 anaemia was 0.7%, 2.0%, 0.5% and <0.5% at weeks 4, 12, 24 and =36, respectively. Overall, 219 (6.6%) participants developed grade 4 anaemia by week 48; women and those with lower haemoglobin, CD4+T-cell count and BMI at baseline were at significantly higher risk (P<0.05), but not those with lower neutrophils or receiving cotrimoxazole at baseline.Conclusions We observed a higher incidence of grade 4 anaemia than in studies from industrialized countries, which is likely to be due in part to population characteristics and in part to a higher rate of concurrent HIV-related clinical events. Clinical vigilance and haemoglobin measurements 4, 8 and 12 weeks after starting zidovudine could help to manage serious anaemia.