BackgroundLevels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART.MethodsPre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels.ResultsMedian baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9–6.7) for hsCRP, 2.6 (95%CI 1.4–4.9) for D-dimer, and 3.8 (95% CI: 1.8–7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001).ConclusionsAmong patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted.Trial RegistrationParent Study: ClinicalTrials.gov NCT00342355

In summary, the use of lamivudine-containing ART in HIV/HBV participants in PHIDISA II resulted in little additional benefit over that of ART itself and failed to impact on the greater mortality in this group. These data provide strong support for recent guidelines advocating the use of tenofovir in all HIV-HBV-coinfected individuals initiating ART.

Background Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings. Methods In the Republic of South Africa, antiretroviral-naive HIV-infected individuals >14 years old, with <200 CD4+ cells/mm3 or prior AIDS diagnosis were randomized to: EFV or LPV/r with either ZDV+ddI or d4T+3TC in an open-label 2×2 factorial study and followed for: the primary outcome of AIDS or death; pre-specified secondary outcomes including CD4+ and viral load changes, treatment discontinuations and grade 4 events. Results 1771 persons were randomized and followed for a median of 24.7 months. AIDS or death occurred among 163 participants assigned EFV and 157 LPV/r (HR=1.04; 95% CI 0.84–1.30) and among 170 assigned ZDV+ddI and 150 assigned d4T+3TC (HR=1.15; 95% CI: 0.93–1.44). HIV RNA was lower (p<0.001) and CD4+ count greater (p<.01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T due to toxicity (12.6%) than other treatments (<5%). Conclusion EFV or LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest these treatments be used cautiously as initial therapy. Trial Registration clinicaltrials.gov Identifier: NCT00342355

We found no difference in clinical and viro-immunologic outcomes between NNRTI- and PI/r-based therapy.

Female sex and increased BMI were associated with severe LA in this large randomized trial of first-line ARV in South Africa. While female sex, increased BMI and d4T are previously described risk factors for the development of clinically significant lactate elevations, the independent risk associated with EFV is a novel observation warranting further investigation.