HBV co-infection is associated with persistently elevated liver stiffness measurement in HIV-positive adults: A 6-year single-centre cohort study in Nigeria.

BACKGROUND: In Nigeria, the effect of Hepatitis B virus (HBV) on long-term liver outcomes in persons with HIV (PLH) has not been described. We determined changes in liver stiffness measure (LSM) using transient elastography over 6 years in HIV mono-infected and HIV-HBV co-infected Nigerians initiating antiretroviral therapy (ART) and factors associated with LSM decline. METHODS: This single centre, cohort study enrolled ART-naïve HIV mono- and HIV-HBV co-infected adults (≥18 years) at the APIN Public Health Initiatives-supported HIV Care and Treatment Centre at Jos University Teaching Hospital, Nigeria, from 7/2011 to 2/2012. LSM at baseline, Years 3 and 6 were analysed using longitudinal models to estimate changes over time and their predictors. RESULTS: Data from 100 (31%) HIV-HBV co-infected and 225 (69%) HIV mono-infected participants were analysed. Median LSM at baseline was 6.10 (IQR: 4.60-7.90) kPa in co-infected and 5.10 (IQR: 4.40-6.10) kPa in mono-infected participants. In adjusted analyses, average LSM was not significantly different between Year 0 and 3 (ß = 0.02, -0.22 to 0.26, p = 0.87 and Year 0 and 6 (ß = -0.02, -0.23 to 0.27, p = 0.88) in both groups (p>0.05), but co-infected participants had significantly higher LSM than mono-infected throughout follow-up (ß = 0.018, 0.019-0.28, p < 0.001). Year 3 LSM differed according to ART initiation status by Year 3 (initiators - non-initiators: -0.87, -1.70 to -0.29). CONCLUSION: In this cohort, LSM remained higher among HIV-HBV co-infected versus HIV mono-infected participants throughout follow-up. Our findings emphasize the continuing need for monitoring of liver outcomes in HIV-HBV co-infected populations on ART and the importance of preventing HBV infection among PLH to optimize liver health.

Absence of human leukocyte antigen-B*57:01 amongst patients on antiretroviral therapy in Nigeria: Implications for use of abacavir.

Background: The presence of human leukocyte antigen (HLA) B*57:01 allele predicts hypersensitivity reaction (HSR) to abacavir (ABC), a nucleoside reverse-transcriptase inhibitor used for human immunodeficiency virus (HIV) treatment. However, the prevalence of this allele amongst Nigerians with HIV is yet to be established. We aimed to determine the prevalence of HLA-B*57:01 allele amongst Nigerians with HIV infection. Methods: We conducted a multicentre cross-sectional epidemiologic survey. Between April 2016 and April 2017, patients were enrolled across five HIV treatment facilities in Nigeria. Participants' demographic information and their history of ABC exposure were obtained, and venous blood was obtained for HLA typing. Results: One thousand five hundred and four (1504) adults were enrolled, with a mean age of 44.6 ± 10.7 years, 1078 (71.7%) were female. 1463 (97.3%) were on antiretroviral therapy. ABC use was reported by 12 (0.8%) participants and none reported HSR. Of 1500 blood samples that were processed, 1458 (97.2%) were successfully typed. Of these, 132 (9.1%) were HLA-B*57 positive using non-specific low-resolution HLA-B*5701 primer mix. On further analysis, none of the 132 samples (0%) had the HLA-B*5701 allele. Conclusion: HLA-B*5701allele is rare amongst Nigerians.

Changes in liver stiffness after ART initiation in HIV-infected Nigerian adults with and without chronic HBV.

BACKGROUND: There are limited data from sub-Saharan Africa on long-term liver fibrosis changes in HIV- and HIV/HBV-infected individuals. OBJECTIVES: To assess the effects of ART on liver stiffness measurement (LSM) using transient elastography (TE) in HIV- and HIV/HBV-infected Nigerian adults and examine factors associated with fibrosis regression. METHODS: We included ART-naive HIV- and HIV/HBV-infected adults (≥18 years) enrolled in a prospective, longitudinal study of liver disease between July 2011 and February 2015 at Jos University Teaching Hospital HIV Care and Treatment Centre in Nigeria. Patients initiated ART and had TE at baseline and follow-up (year 3). LSM cut-offs for Metavir scores were 5.9, 7.6 and 9.4 kPa for moderate fibrosis, advanced fibrosis and cirrhosis, respectively. We used multivariable regression to identify factors associated with TE (≥1 Metavir) stage decline. RESULTS: A total of 106 HIV- and 71 HIV/HBV-infected patients [70.5% female and median age = 34 years (IQR = 29-42 years)] were studied. Baseline LSM and median LSM decline were significantly higher in HIV/HBV- versus HIV-infected patients; 41% of HIV/HBV-infected patients regressed ≥1 Metavir stage versus 17% of HIV-infected patients (P < 0.01); LSM scores at year 3 were not significantly different between HIV- and HIV/HBV-infected patients. In multivariable analyses, patients with baseline CD4+ T cells ≥200 (versus <200) cells/mm3 and lower BMIs were more likely to experience LSM stage decline. CONCLUSIONS: HBV coinfection does not attenuate LSM declines in HIV-infected patients after ART initiation despite being a risk factor for more advanced liver disease prior to therapy. The inverse association between BMI and TE stage decline needs further investigation.

Long Term Exposure to Tenofovir Disoproxil Fumarate-Containing Antiretroviral Therapy Is Associated with Renal Impairment in an African Cohort of HIV-Infected Adults.

OBJECTIVES AND METHOD: There are growing concerns of tenofovir disoproxil fumarate (TDF)-associated renal toxicity. We evaluated the effect of long-term TDF exposure on renal function in a cohort of HIV-1-infected Nigerians between 2006 and 2015. Multivariate logistic regression was used to identify predictors of renal impairment at different time over 144 weeks of antiretroviral therapy (ART). RESULTS: Data of 4897 patients, median age 42 years (interquartile range: 36-49), and 61% females were analyzed. The prevalence of renal impairment increased from 10% at week 24 to 45% at 144 weeks in TDF-exposed participants compared to an increase from 8% at 24 weeks to 14% at 144 weeks in TDF-unexposed participants. Tenofovir disoproxil fumarate exposure predicted the risk of renal impairment at 144 weeks of ART (odds ratio: 2.36; 95% confidence interval: 1.28-4.34). CONCLUSION: Long-term exposure to TDF-based ART significantly increases the likelihood of renal impairment. The continued use of TDF-based regimen in our setting should be reviewed. We recommend the urgent introduction of tenofovir alafenamide-based regimen in the HIV treatment guidelines of Nigeria and other resource-limited countries.

Incidence and predictors of tenofovir disoproxil fumarate-induced renal impairment in HIV infected Nigerian patients.

INTRODUCTION: The use of tenofovir disoproxil fumarate (TDF) in the treatment of HIV infection has been associated with renal dysfunction. In Nigeria, data on the incidence and risk factors of TDF nephrotoxicity is sparse. We determined the cumulative incidence of and risk factors for TDF-induced renal impairment in HIV-infected individuals accessing care at the antiretroviral therapy (ART) clinic of Jos University Teaching Hospital, Nigeria. METHODS: This retrospective cohort analysis included patients aged ≥16 years that initiated ART between January 2008 and December 2011. Renal impairment, defined as glomerular filtration rate GFR <60 mL/min/1.73 sqm using the Modification of Diet in Renal Disease (MDRD) equation was assessed at baseline and at 48 weeks on ART. Logistic regression was performed to determine factors associated with incident renal impairment. RESULTS: The mean age was 39±9 years, and 67.1% were female. The cumulative incidence of renal impairment among the TDF-exposed and TDF-unexposed groups was 4.6% and 2.3% respectively (p<0.001). TDF exposure was significantly associated with renal impairment [OR=2.0, 95%CI=(1.48-2.89), p<0.001] in bivariate analysis. In multivariate analysis, older age (aOR=1.06, 95%CI=(1.05-1.08), p<0.001), TDF exposure [aOR=1.85, 95%CI=(1.31-2.60), p<0.001] and co-morbidities [aOR=2.71, 95%CI=(1.72-4.25), p<0.001] were significantly associated with renal impairment. CONCLUSION: TDF exposure, aging and comorbidities were predictors of renal toxicity among HIV positive patients. Regular monitoring of renal function in such high-risk individuals is recommended.

Hepatitis B virus sequencing and liver fibrosis evaluation in HIV/HBV co-infected Nigerians.

OBJECTIVES: Molecular characteristics of hepatitis B virus (HBV), such as genotype and genomic mutations, may contribute to liver-related morbidity and mortality. The association of these characteristics with liver fibrosis severity in sub-Saharan Africa is uncertain. We aimed to characterise molecular HBV features in human immunodeficiency virus (HIV)/HBV co-infected Nigerians and evaluate associations between these characteristics and liver fibrosis severity before and after antiretroviral therapy (ART) initiation. METHODS: HIV/HBV co-infected Nigerians underwent liver fibrosis estimation by transient elastography (TE) prior to and 36 months after ART initiation. Basal core promoter/precore (BCP/PC) and preS1/preS2/S regions of HBV were sequenced from baseline plasma samples. We evaluated associations between HBV mutations and liver fibrosis severity by univariate and multivariable regression. RESULTS: At baseline, 94 patients underwent TE with median liver stiffness of 6.4 (IQR 4.7-8.7) kPa. Patients were predominantly infected with HBV genotype E (45/46) and HBe-antigen negative (75/94, 79.8%). We identified BCP A1762T/G1764A in 15/35 (43%), PC G1896A in 20/35 (57%), 'a' determinant mutations in 12/45 (26.7%) and preS2 deletions in 6/16 (37.5%). PreS2 mutations were associated with advanced fibrosis in multivariable analysis. At follow-up, median liver stiffness was 5.2 (IQR 4.1-6.6) kPa. No HBV molecular characteristics were associated with lack of fibrosis regression, although HIV virologic control, body mass index (BMI) and baseline CD4+ T-cell count were associated with a decline in fibrosis stage. CONCLUSION: Frequent BCP/PC and preS1/preS2/S mutations were found in ART-naïve HIV/HBV co-infected Nigerians. Median liver stiffness declined after initiation of ART, regardless of pre-ART HBV mutational pattern or virologic characteristics.

Prevalence of and risk factors for pulmonary tuberculosis among newly diagnosed HIV-1 infected Nigerian children.

INTRODUCTION: Studies on the prevalence of and risk factors for tuberculosis (TB) among newly diagnosed human immunodeficiency virus (HIV)-infected children in sub-Saharan Africa are scarce and in Nigeria there is paucity of reported data. We determined the prevalence of and risk factors for pulmonary TB (PTB) in newly diagnosed (treatment-naïve) HIV-1 infected children at the pediatric HIV clinic of the Jos University Teaching Hospital (JUTH) in Nigeria. METHODS: We performed a retrospective analysis of 876 children, aged 2 months - 13 years, diagnosed with HIV-1 infection between July 2005 and December 2012, of which 286 were diagnosed with PTB at presentation after TB screening. The study site was the AIDS Prevention Initiative in Nigeria (APIN)-supported Pediatric HIV clinic at JUTH, Jos. A multivariate forward logistic regression modelling was used to identify risk factors for PTB-HIV co-infection. RESULTS: The prevalence of PTB-HIV co-infection was 32% (286/876). Severe immunosuppression (SI) and World Health Organization (WHO) HIV clinical stage 3/4 were identified as independent risk factors for PTB-HIV co-infection in HIV infected children. The odds of PTB-HIV co-infection was increased two-fold in HIV-infected children with WHO clinical stage 3/4 compared to those with stage 1/2 (adjusted odds ratio (AOR) 1.76 [1.31-2.37], p<0.001) and 1.5-fold in children with SI compared to those without SI (AOR 1.52 [1.12-2.06], p=0.007). CONCLUSION: In our setting, the burden of PTB was high among newly diagnosed HIV-infected children, and late WHO HIV clinical stage and severe immunosuppression were associated with PTB-HIV co-infection. Therefore there is a clear need to improve strategies for early diagnosis of both HIV and PTB to optimize clinical outcomes.

Clinical Utility of Pharmacy-Based Adherence Measurement in Predicting Virologic Outcomes in an Adult HIV-Infected Cohort in Jos, North Central Nigeria.

OBJECTIVES: We examined the association between adherence to drug-refill visits and virologic outcomes in a cohort of HIV-infected adults on combination antiretroviral therapy (cART) in North Central Nigeria. METHODS: Retrospectively, 588 HIV-infected, cART-naive adults (aged ≥15 years), initiated on first-line ART between 2009 and 2010 at the Jos University Teaching Hospital, were evaluated. Association between adherence to drug-refill visits, virologic (viral load>1000 copies/mL), and immunologic failure was assessed using multivariable logistic regression. RESULTS: After a median of 12 months on cART, 16% (n=94) and 10% (n=59) of patients had virologic and immunologic failures, respectively. In the final multivariable model, suboptimal adherence to drug-refill visits was a significant predictor of both virologic (adjusted odds ratio [AOR] 1.6; 95% confidence interval [CI]:1.2-2.3) and immunologic (AOR 1.92; 95% CI:1.06-3.49) failures. CONCLUSION: Adherence to drug refill is a useful predictor of successful virologic control and could be utilized for routine monitoring of adherence to cART in our clinical setting.

Nonadherence to First-Line Antiretroviral Therapy among Human Immunodeficiency Virus-1 Infected Children at the Jos University Teaching Hospital; Jos; Nigeria

Background: Nonadherence to antiretroviral therapy (ART) may encourage the development of resistance to antiretroviral drugs (ARVs). Poor adherence is known to be associated with ART failure which could compromise the benefits of ART in children. Therefore; it is important to identify the reasons why children on ART may fail to take their ARVs. In this study; we described the characteristics of human immunodeficiency virus-1 (HIV-1) infected children with ART nonadherence as well as the reasons for their nonadherence. Methodology: A retrospective cohort study in which data on 580 HIV-1 infected children enrolled on ART between February 2006 and December 2010 at the pediatric HIV clinic of the Jos University Teaching Hospital; Jos; was analyzed. Subjects were aged 2 months to 15 years. Information on adherence was obtained by child or caregiver self-report. They also had repeated adherence counseling during each clinic follow-up visit and were taught the use of alarm clocks daily for reminding them of when the next ARV dose will be due. Results: There were 30 (5.2) children with non-adherence to ART. Among children with nonadherence; majority were: Children aged 1-10 years (76.7); males (53.3) and did not know their diagnosis of HIV (90.9). The odds of nonadherence was two times higher among children who failed first-line ART compared with those who did not (odds ratio [95 confidence interval]; 2.28 [1.03-5.02]; P = 0.04). The most common reason for nonadherence was: Forgot to take medications (46.7). Conclusion: The low rate of nonadherence to ART in this study could be attributed to repeated adherence counseling during each clinic follow-up visit and the use of alarm clocks daily for reminders on when the next ARV dose will be due

Rates and impact of hepatitis on human immunodeficiency virus infection in a large African cohort.

AIM: To determine the rates and impact of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections on response to long-term highly active antiretroviral therapy (HAART) in a large human immunodeficiency virus (HIV) population in Nigeria. METHODS: HBV and HCV as well as HIV infections are endemic in sub Saharan Africa. This was a retrospective cohort study of 19,408 adults who were recruited between June 2004 and December 2010 in the AIDS Prevention Initiative in Nigeria in Nigeria programme at Jos University Teaching Hospital. Serological assays, including HBV surface antigen (HBsAg) and hepatitis C antibody were used to categorise hepatitis status of the patients. HBsAg was determined using enzyme immunoassay (EIA) (Monolisa HBsAg Ultra3; Bio-Rad). HCV antibody was tested using third generation EIA (DIA.PRO Diagnostic, Bioprobes srl, Milan, Italy). HIV RNA levels were measured using Roche COBAS Amplicor HIV-1 monitor test version 1.5 (Roche Diagnostics, GmbH, Mannheim, Germany) with a detection limit of 400 copies/mL. Flow cytometry was used to determine CD4+ cell count (Partec, GmbH Munster, Germany). Comparison of categorical and continuous variables were achieved using Pearson's χ(2) and Kruskal Wallis tests respectively, on MedCalc for Windows, version 9.5.0.0 (MedCalc Software, Mariakerke, Belgium). RESULTS: With an overall hepatitis screening rate of over 90% for each virus; HBV, HCV and HBV/HCV were detected in 3162 (17.8%), 1983 (11.3%) and 453 (2.5%) HIV infected adults respectively. The rate of liver disease was low, but highest among HIV mono-infected patients (29, 0.11%), followed by HBV co-infected patients (15, 0.08%). Patients with HBV co-infection and triple infection had higher log10 HIV RNA loads (HBV: 4.6 copies/mL vs HIV only: 4.5 copies/mL, P < 0.0001) and more severe immune suppression (HBV: 645, 55.4%; HBV/HCV: 97, 56.7%) prior to initiation of HAART compared to HIV mono-infected patients (1852, 48.6%) (P < 0.0001). Of 3025 patients who were 4.4 years on HAART and whose CD4 cell counts results at baseline and end of follow up were available for analyses, CD4 increase was significantly lower in those with HBV co-infection (HBV: 144 cells/mm(3); HBV/HCV: 105 cells/mm(3)) than in those with HCV co-infection (165 cells/mm(3)) and HIV mono-infection (150 cells/mm(3)) (P = 0.0008). CONCLUSION: High rates of HBV and HCV infections were found in this HIV cohort. CD4 recovery was significantly diminished in patients with HBV co-infection.

Hepatitis B Co-Infection is Associated with Poorer Survival of HIV-Infected Patients on Highly Active Antiretroviral Therapy in West Africa.

BACKGROUND: Hepatitis B has been reported to be high in HIV-infected African populations. However, the impact of this co-infection on the survival of HIV-infected Africans on long-term highly active antiretroviral therapy (HAART) remains poorly characterised. We investigated the impact of HBV/HIV co-infection on survival of HIV infected patients undergoing antiretroviral therapy in a West African population. METHODS: This was a clinic-based cohort study of HIV-infected adults enrolled in Nigeria, West Africa. Study subjects (9,758) were screened for hepatitis B and hepatitis C at HAART initiation. Kaplan-Meier survival and Cox proportional hazards models were used to estimate probability of survival and to identify predictors of mortality respectively, based on hepatitis B surface antigen status. All patients had signed an informed written consent before enrolment into the study; and we additionally obtained permission for secondary use of data from the Harvard institutional review board. RESULTS: Patients were followed up for a median of 41 months (interquartile range: 30-62 months) during which, 181 (1.9%) patients died. Most of the deaths; 143 (79.0%) occurred prior to availability of Tenofovir. Among those that were on antiretroviral therapy, hepatitis B co-infected patients experienced a significantly lower survival than HIV mono-infected patients at 74 months of follow up (94% vs. 97%; p=0.0097). Generally, hepatitis B co-infection: HBsAg-positive/HIV-positive (Hazards Rate [HR]; 1.5: 95% CI 1.09-2.11), co-morbid tuberculosis (HR; 2.2: 95% CI 1.57-2.96) and male gender (HR; 1.5: 95% CI 1.08-2.00) were significantly predictive of mortality. Categorising the patients based on use of Tenofovir, HBV infection failed to become a predictor of mortality among those on Tenofovir-containing HAART. CONCLUSIONS: HBsAg-positive status was associated with reduced survival and was an independent predictor of mortality in this African HIV cohort on HAART. However, Tenofovir annulled the impact of HBV on mortality of HIV patients in the present study cohort.