ABSTRACT
OBJECTIVE: Concentrations of tenofovir diphosphate (TFV-DP) and lamivudine triphosphate (3TC-TP) in cells are correlates of medication adherence and antiviral activity. However, studies have yet to characterize the simultaneous relationship between TFV-DP and 3TC-TP concentrations with HIV and hepatitis B virus (HBV) suppression. METHODS: Individuals with HIV/HBV coinfection on tenofovir disoproxil fumarate (TDF)-containing antiretroviral therapy (ART) were enrolled. Peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) samples were collected and steady-state TFV-DP and 3TC-TP concentrations quantified using validated methods. The relationship between patient factors, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS with HBV and HIV viral suppression were examined. RESULTS: Of 138 participants on TDF-containing ART for a median duration (range) of 6 (0.75-15) years, the median age was 43âyears and 64% were women. Overall, 128 (92.8%) and 129 (93.5%) had suppressed HIV and HBV viral loads, respectively. Of the 128 participants with suppressed HIV, 122 (95.3%) had suppressed HBV. Self-reported ART adherence, recent change to dolutegravir-based ART, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS were associated with HIV RNA suppression, while HBe antigen positivity, HIV suppression, and TFV-DP concentrations in DBS were associated with HBV DNA suppression (including six persons with HBV nonsuppression and HIV suppression). CONCLUSION: Long-term TDF/3TC-conatining ART was highly efficacious in individuals with HIV/HBV coinfection. Higher TFV-DP concentrations were predictive of suppression for both viruses. Persistent HBV viremia on TDF/3TC-containg ART requires additional research, but may represent poor adherence and the need for adherence interventions or novel antivirals.
Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents , Coinfection , Cytidine Triphosphate/analogs & derivatives , Dideoxynucleotides , HIV Infections , Organophosphates , Humans , Female , Adult , Male , Hepatitis B virus , Anti-HIV Agents/therapeutic use , Leukocytes, Mononuclear , Coinfection/drug therapy , Lamivudine/therapeutic use , Tenofovir/therapeutic use , Viremia/drug therapyABSTRACT
OBJECTIVE: Limited pharmacokinetic/pharmacodynamic data are a barrier to the scale-up of dolutegravir-based antiretroviral therapy (ART) in children. We examined the pharmacokinetics/pharmacodynamics of the adult film-coated dolutegravir 50âmg tablets in children with HIV infection weighing at least 20âkg. DESIGN: A prospective, observational, pharmacokinetic, and safety study. METHODS: Treatment-experienced children with HIV weighing at least 20âkg and evidence of viral load suppression on ART were enrolled and switched to dolutegravir-based therapy. After at least 4âweeks and 7âmonths on dolutegravir-based therapy, blood samples were collected at 0, 1, 4, 8, 12, and 24-h postdose. Dolutegravir concentrations were measured using validated LCMS/MS and pharmacokinetic parameters calculated by noncompartmental analysis. Descriptive statistics were used to summarize pharmacokinetic parameters and comparisons with published reference values. RESULTS: Of 25 participants, 92% were on efavirenz-based ART and 60.0% were men. Dolutegravir mean exposure, peak and trough concentrations at both pharmacokinetic visits were higher than the mean reference values in adults and children weighing 20âkg to less than 40âkg treated with 50âmg once daily, but were closer to the mean values in adults given 50âmg twice a day. Children weighing 20âkg to less than 40âkg had even higher dolutegravir exposures. The regimens were well tolerated with good virologic efficacy through week 48. CONCLUSION: The higher dolutegravir exposure in our study population suggests that further studies and close monitoring should investigate the adverse effects of dolutegravir in more children and in the long term.
Subject(s)
Anti-HIV Agents , HIV Infections , HIV-1 , Male , Adult , Humans , Child , Female , HIV Infections/drug therapy , Prospective Studies , Oxazines/therapeutic use , Heterocyclic Compounds, 3-Ring , Pyridones/therapeutic use , Tablets/therapeutic use , Viral Load , Anti-HIV Agents/therapeutic useABSTRACT
INTRODUCTION: Tuberculosis (TB) is currently causing more deaths than Human Immunodeficiency Virus (HIV) globally. Ghana as one of the 30 high burden TB/HIV countries has a high annual TB case-fatality rate of 10%. The study sought to assess the effect of HIV infection on TB treatment outcomes and assess the time to mortality after treatment onset. METHODS: We conducted a review of treatment files of TB patients who were treated from January 2013 to December 2015 in two urban hospitals in the Accra Metropolis. Modified Poisson regression analysis was used to measure the association between HIV infection and TB treatment outcomes. Kaplan-Meier survival estimates were used to plot survival curves. RESULTS: Seventy-seven percent (83/107) of HIV infected individuals had successful treatment, compared to 91.2% (382/419) treatment success among HIV non-infected individuals. The proportion of HIV-positive individuals who died was 21.5% (23/107) whilst that of HIV-negative individuals was 5.5% (23/419). Being HIV-positive increased the risk of adverse outcome relative to successful outcome by a factor of 2.89(95% CI 1.76-4.74). The total number of deaths recorded within the treatment period was 46; of which 29(63%) occurred within the first two months of TB treatment. The highest mortality rate observed was among HIV infected persons (38.6/1000 person months). Of the 107 TB/HIV co-infected patients, 4(3.7%) initiated ART during TB treatment. CONCLUSION: The uptake of ART in co-infected individuals in this study was very low. Measures should be put in place to improve ART coverage among persons with TB/HIV co-infection to help reduce mortality.
Subject(s)
Antitubercular Agents/therapeutic use , HIV Infections/epidemiology , Tuberculosis/drug therapy , Adolescent , Adult , Cohort Studies , Coinfection , Female , Ghana/epidemiology , HIV Infections/mortality , HIV Seropositivity/epidemiology , Hospitals, Urban , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Poisson Distribution , Retrospective Studies , Time Factors , Treatment Outcome , Tuberculosis/mortality , Young AdultABSTRACT
BACKGROUND: Incomplete hepatitis B virus (HBV) suppression during antiretroviral therapy (ART) in HIV and HBV coinfected patients is common, but underlying factors are not fully elucidated. We hypothesize that genetic factors that influence nucleoside analog pharmacokinetics will affect HBV treatment response. METHODS: HIV/HBV coinfected patients on tenofovir disoproxil fumarate/lamivudine (TDF/3TC)-containing ART were enrolled. Selected ABCC4 single nucleotide polymorphisms (SNPs) with known effects on nucleoside pharmacokinetics were genotyped using TaqMan assays. Relationship between ABCC4 SNPs and unsuppressed HBV DNA (HBV DNA ≥20 IU/mL) were examined. RESULTS: Of the 50 participants on TDF/3TC-containing ART for a median (range) of 1.5 (1-7.4) years, 20 (40%) had unsuppressed HBV DNA. Participants with unsuppressed compared with those with suppressed HBV DNA were more likely to have negative HBe antibody, lower body mass index, and lower CD4 count at enrollment. Carriers of ABCC4 rs11568695 (G3724A) variant allele were more likely than noncarriers to have unsuppressed HBV (61.1% vs. 29.0%, P = 0.038). Among 36 patients with suppressed HIV RNA (presumed good ART adherence), ABCC4 rs11568695 variant carriers were more likely than noncarriers to have unsuppressed HBV (58.8% vs. 20.0% P = 0.021). Logistic regression analysis that included genetic and nongenetic factors identified ABCC4 rs11568695 variant allele, body mass index, and male sex as predictors of unsuppressed HBV DNA. CONCLUSIONS: We identified a novel association between ABCC4 rs11568695 SNP and poor HBV treatment response. If confirmed in further studies, ABCC4 genotyping could be used to identify individuals who may need intensified HBV therapy.