Lamivudine vs Tenofovir in HIV/HBV Coinfection
Lamivudine vs Tenofovir in HIV/HBV Coinfection
The PharmAccess African Studies to Evaluate Resistance Monitoring study is a multicenter prospective cohort of HIV-1–infected adults receiving cART, as previously profiled. HIV-related outcomes have been reported. The current analysis included all participants at 6 sites in South Africa and Zambia who initiated standard first-line cART containing 2 nucleoside reverse transcriptase inhibitors and a nonnucleoside reverse transcriptase inhibitor because of advanced immunodeficiency (CD4 cell count < 200 cells/μL) or HIV disease [World Health Organization (WHO) clinical stage 3 or 4], in accordance with national guidelines. Individuals who had previously used any antiretroviral drugs as prophylaxis or treatment were excluded. The collaborating sites did not routinely screen for HBV coinfection before cART initiation. Participants were classified as HIV–HBV coinfected if they were HBsAg seropositive and further classified according to HBV-active therapy: lamivudine monotherapy versus tenofovir (combined with emtricitabine or lamivudine). Participants provided written informed consent at enrollment. The protocols of the PharmAccess African Studies to Evaluate Resistance Monitoring study and HBV substudy were approved by the appropriate national and local research ethics committees.
Participants were followed up as per local standard of care guidelines. Routinely collected clinical and laboratory data were extracted and entered into a central database. Self-reported drug adherence was assessed at each follow-up clinical visit. Plasma was collected in EDTA tubes at the baseline visit and after 12 months of cART (window from 11 to 15 months) and stored at -80°C for retrospective analysis. The end points of interest after 12 months of cART were CD4 lymphocyte recovery, HBsAg loss, HBV-DNA suppression (HBV-DNA < 20 IU/mL), and drug-resistance mutations.
HBV testing was conducted at the Department of Molecular Medicine and Hematology of the University of the Witwatersrand in Johannesburg, South Africa. All technical failures were retested at Sanquin in Amsterdam, The Netherlands. HBsAg (lower limit of detection 0.05 IU/mL) and Hepatitis B core antibody (anti-HBc) were determined using a commercial enzyme immunoassay (Abbott Architect, Abbott Park, IL). HBV-DNA was assessed quantitatively with Abbott RealTime HBV (lower limit of detection 10 IU/mL) (Abbott, Des plaines, IL) or Cobas AmpliPrep/Cobas TaqMan (lower limit of detection 20 IU/mL) (Roche Molecular Diagnostics, Pleasanton, CA). HBV polymerase gene (including major part of S and part of pre-S2) was amplified and sequenced.
The study sample size was based on estimated proportions of patients with an HBV drug-resistance mutation after 12 months of cART, at 23% for lamivudine and 0% for tenofovir. To achieve a statistical power of 80% at a 2-sided significance level of 5%, the sample size was n = 33 for each HBV treatment group, accounting for 10% attrition. HBsAg prevalence was estimated accounting for the sampling weights of the sites, expressed with a 95% confidence interval (CI) based on the normal approximation to the binomial distribution. For comparisons between 2 groups, χ test was used for categorical data and t test or Kruskal–Wallis test for continuous data. Logistic regression with robust random errors, accounting for clustering of observations within sites, was used to predict HBV virologic failure (HBV-DNA ≥ 20 IU/mL) by baseline characteristics. All variables were evaluated univariately, and those associated (P < 0.15) with the outcomes were stepwise entered into the multivariate model. Results were expressed as odds ratios (ORs) with 95% CI and P values. Linear mixed models with 4 slopes were used to estimate the gain in CD4 cell counts from cART initiation between the infection (HIV versus HIV–HBV) and treatment groups. The slopes were defined at 3 monthly intervals of follow-up. All CD4 cell counts measured routinely before and after start of ART were used. The model was adjusted for age, sex, baseline CD4 cell count, WHO clinical stage, pretherapy HIV-RNA and HBV-DNA, and types of nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drugs. Results were expressed as difference in CD4 counts with 95% CI and P values. Reported P values are 2 sided, and a P value <0.05 was considered statistically significant. All analyses were performed using Stata version 11 (StataCorp LP, College Station, TX).
Methods
Study Population and Design
The PharmAccess African Studies to Evaluate Resistance Monitoring study is a multicenter prospective cohort of HIV-1–infected adults receiving cART, as previously profiled. HIV-related outcomes have been reported. The current analysis included all participants at 6 sites in South Africa and Zambia who initiated standard first-line cART containing 2 nucleoside reverse transcriptase inhibitors and a nonnucleoside reverse transcriptase inhibitor because of advanced immunodeficiency (CD4 cell count < 200 cells/μL) or HIV disease [World Health Organization (WHO) clinical stage 3 or 4], in accordance with national guidelines. Individuals who had previously used any antiretroviral drugs as prophylaxis or treatment were excluded. The collaborating sites did not routinely screen for HBV coinfection before cART initiation. Participants were classified as HIV–HBV coinfected if they were HBsAg seropositive and further classified according to HBV-active therapy: lamivudine monotherapy versus tenofovir (combined with emtricitabine or lamivudine). Participants provided written informed consent at enrollment. The protocols of the PharmAccess African Studies to Evaluate Resistance Monitoring study and HBV substudy were approved by the appropriate national and local research ethics committees.
Data Collection and Outcomes
Participants were followed up as per local standard of care guidelines. Routinely collected clinical and laboratory data were extracted and entered into a central database. Self-reported drug adherence was assessed at each follow-up clinical visit. Plasma was collected in EDTA tubes at the baseline visit and after 12 months of cART (window from 11 to 15 months) and stored at -80°C for retrospective analysis. The end points of interest after 12 months of cART were CD4 lymphocyte recovery, HBsAg loss, HBV-DNA suppression (HBV-DNA < 20 IU/mL), and drug-resistance mutations.
Laboratory Testing
HBV testing was conducted at the Department of Molecular Medicine and Hematology of the University of the Witwatersrand in Johannesburg, South Africa. All technical failures were retested at Sanquin in Amsterdam, The Netherlands. HBsAg (lower limit of detection 0.05 IU/mL) and Hepatitis B core antibody (anti-HBc) were determined using a commercial enzyme immunoassay (Abbott Architect, Abbott Park, IL). HBV-DNA was assessed quantitatively with Abbott RealTime HBV (lower limit of detection 10 IU/mL) (Abbott, Des plaines, IL) or Cobas AmpliPrep/Cobas TaqMan (lower limit of detection 20 IU/mL) (Roche Molecular Diagnostics, Pleasanton, CA). HBV polymerase gene (including major part of S and part of pre-S2) was amplified and sequenced.
Statistical Analyses
The study sample size was based on estimated proportions of patients with an HBV drug-resistance mutation after 12 months of cART, at 23% for lamivudine and 0% for tenofovir. To achieve a statistical power of 80% at a 2-sided significance level of 5%, the sample size was n = 33 for each HBV treatment group, accounting for 10% attrition. HBsAg prevalence was estimated accounting for the sampling weights of the sites, expressed with a 95% confidence interval (CI) based on the normal approximation to the binomial distribution. For comparisons between 2 groups, χ test was used for categorical data and t test or Kruskal–Wallis test for continuous data. Logistic regression with robust random errors, accounting for clustering of observations within sites, was used to predict HBV virologic failure (HBV-DNA ≥ 20 IU/mL) by baseline characteristics. All variables were evaluated univariately, and those associated (P < 0.15) with the outcomes were stepwise entered into the multivariate model. Results were expressed as odds ratios (ORs) with 95% CI and P values. Linear mixed models with 4 slopes were used to estimate the gain in CD4 cell counts from cART initiation between the infection (HIV versus HIV–HBV) and treatment groups. The slopes were defined at 3 monthly intervals of follow-up. All CD4 cell counts measured routinely before and after start of ART were used. The model was adjusted for age, sex, baseline CD4 cell count, WHO clinical stage, pretherapy HIV-RNA and HBV-DNA, and types of nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drugs. Results were expressed as difference in CD4 counts with 95% CI and P values. Reported P values are 2 sided, and a P value <0.05 was considered statistically significant. All analyses were performed using Stata version 11 (StataCorp LP, College Station, TX).
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