The virological durability of first-line ART among HIV-positive adult patients in resource limited settings without virological monitoring: a retrospective analysis of DART trial data.

BACKGROUND: Few low-income countries have virological monitoring widely available. We estimated the virological durability of first-line antiretroviral therapy (ART) after five years of follow-up among adult Ugandan and Zimbabwean patients in the DART study, in which virological assays were conducted retrospectively. METHODS: DART compared clinically driven monitoring with/without routine CD4 measurement. Annual plasma viral load was measured on 1,762 patients. Analytical weights were calculated based on the inverse probability of sampling. Time to virological failure, defined as the first viral load measurement ≥200 copies/mL after 48 weeks of ART, was analysed using Kaplan-Meier plots and Cox regression models. RESULTS: Overall, 65% of DART trial patients were female. Patients initiated first-line ART at a median (interquartile range; IQR) age of 37 (32-42) and with a median CD4 cell count of 86 (32-140). After 240 weeks of ART, patients initiating dual-class nucleoside reverse-transcriptase inhibitor (NRTI) -non-nucleoside reverse-transcriptase (NNRTI) regimens containing nevirapine + zidovudine + lamivudine had a lower incidence of virological failure than patients on triple-NRTI regimens containing tenofovir + zidovudine + lamivudine (21% vs 40%; hazard ratio (HR) =0.48, 95% CI:0.38-0.62; p < 0.0001). In multivariate analyses, female patients (HR = 0.79, 95% CI: 0.65-0.95; p = 0.02), older patients (HR = 0.73 per 10 years, 95% CI: 0.64-0.84; p < 0.0001) and patients with a higher pre-ART CD4 cell count (HR = 0.64 per 100 cells/mm3, 95% CI: 0.54-0.75; p < 0.0001) had a lower incidence of virological failure after adjusting for adherence to ART. No difference in failure rate between the two randomised monitoring strategies was observed (p= 0.25). CONCLUSIONS: The long-term durability of virological suppression on dual-class NRTI-NNRTI first-line ART without virological monitoring is remarkable and is enabled by high-quality clinical management and a consistent drug supply. To achieve higher rates of virological suppression viral-load-informed differentiated care may be required. TRIAL REGISTRATION: Prospectively registered on 18/10/2000 as ISRCTN13968779 .

Impact of the N348I mutation in HIV-1 reverse transcriptase on nonnucleoside reverse transcriptase inhibitor resistance in non-subtype B HIV-1.

We investigated the effect of N348I alone and with M184V on nonnucleoside reverse transcriptase inhibitor (NNRTI) drug susceptibility and replicative capacity in B and non-B HIV-1 isolates. N348I reduced the susceptibility to all NNRTI drugs across subtypes. The replication capacity of all viruses in a variety of cell lines was impaired by N348I. Interestingly, the N348I and M184V double mutation compensated for the reduced NNRTI drug susceptibility observed in the N348I single mutant and marginally improved viral replicative capacity.

Molecular characterization of hepatitis B virus isolates from Zimbabwean blood donors.

Hepatitis B virus (HBV) is endemic in Africa, being hyperendemic in sub-Saharan Africa. Genotypes A, D, and E circulate in Africa, showing a distinct geographical distribution. The aim of the present study was to determine the HBV genotype distribution in blood donors from different geographical locations in Zimbabwe. Using a restriction fragment polymorphism assay, sequencing of the basic core promoter/precore region and of the complete S open reading frame showed that 29 HBV isolates from geographically distinct regions belong to subgenotype A1. The complete genome of two of these Zimbabwean HBV isolates was sequenced. Forty-four percent of the Zimbabwean HBV isolates (11/23) were characterized by a G1862C missense mutation, which causes a Val to Leu amino acid substitution at position 17 of the precore region. The majority of Zimbabwean HBV isolates clustered with a number of South African HBV isolates, with which they shared characteristic amino acids in the preS1, preS2, and polymerase spacer regions. The wide distribution of subgenotype in Africa, as well as the high intragroup divergence and the geographical clustering of the African and Asian subgenotype A1 HBV isolates indicate that this subgenotype has a long period of endemicity in these regions.

Hepatitis B serological markers and plasma DNA concentrations.

OBJECTIVES: To examine hepatitis B (HBV) serological markers and plasma DNA concentrations in a large group of untreated HBV/HIV-coinfected individuals in two sub-Saharan settings. DESIGN: Baseline analysis of a randomized controlled trial. METHODS: DART was a large trial of treatment monitoring practices in HIV-infected adults with advanced disease starting antiretroviral therapy at centres in Kampala or Entebbe, Uganda (n = 2317) and Harare, Zimbabwe (n = 999). HBV serological markers [antibody to HBV core antigen, HBV surface antigen (HBsAg), antibody to HBV surface antigen, HBV 'e' antigen (HBeAg), and antibody to hepatitis B 'e' antigen] and plasma HBV DNA viral load were measured retrospectively on stored baseline samples. Logistic regression was used to examine associations with baseline demographic and clinical factors. RESULTS: The rate of HBsAg positivity was significantly higher in Zimbabwe than Uganda (12.2 vs. 7.7%, adjusted odds ratio = 1.54, P < 0.001) despite a similar prevalence of antibody to HBV core antigen (56.3 vs. 52.4%) in the two settings. Overall, HBsAg positivity was associated with male sex (adjusted odds ratio = 1.54, P < 0.001) but not with age, WHO disease stage, or CD4 cell count. HBeAg was detected among 37% of HBsAg-positive patients, with higher rates among those with advanced WHO stage (P = 0.02). Also in HBsAg-positive patients, HBV DNA was undetectable in 21%, detectable but below the level of quantification in 14%, and quantifiable in 65%. A total of 96% of HBeAg-positive and 70% of HBeAg-negative patients had detectable HBV DNA; 92 and 28% of patients, respectively, had HBV DNA viral load more than 2000 IU/ml. CONCLUSION: High rates of HBV coinfection were observed, highlighting the importance of ensuring that coinfected patients receive an antiretroviral regimen, whether first-line or not, that is active against both viruses.