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1.  Editorial Commentary: Another Call to Cure Hepatitis B 
doi:10.1093/cid/civ475
PMCID: PMC4583579  PMID: 26082512
HBV-HCV coinfection; HBV reactivation; IP-10; ISG; interferon
2.  Comparison of HBV-active HAART regimens in an HIV-HBV multinational cohort: outcomes through 144 weeks 
AIDS (London, England)  2015;29(10):1173-1182.
Objectives
To explore factors associated with short and long-term HBV DNA suppression in a multinational cohort of HIV-HBV co-infected subjects receiving HBV-active antiretrovirals.
Methods
115 HIV-HBV co-infected subjects participating in one of two global ACTG randomized clinical trials of different antiretroviral regimens received either HBV-monotherapy with either lamivudine or emtricitabine (N=56) or HBV-dual therapy with TDF plus lamivudine or emtricitabine (N=59). Associations of pre-treatment characteristics with the primary (HBV DNA <200 IU/ml at 24 weeks) and longitudinal outcomes through 144 weeks were explored using logistic regression. HBV drug-resistance mutations were determined by pol sequencing in those with viral rebound.
Results
The proportion with HBV DNA<200 IU/ml was 60% (95% CI 50%–69%) at 24 weeks and 79% (95% CI 69%–88%) at 144 weeks. Pre-treatment factors associated with the primary outcome were HBV DNA, CD4 T-cell count, and AST, but only pre-treatment HBV DNA remained associated with long-term suppression (P<0.0001). HBV therapy group was not significantly associated with the primary outcome at 24 weeks; however, longitudinally, a greater proportion in the dual therapy group achieved HBV DNA<200 IU/mL (P=0.007). A higher proportion of hepatitis B e antigen negative subjects (n=57) achieved HBV DNA <200 IU/ml at any point, regardless of therapy group. All 12 subjects with emergence of lamivudine-resistant mutants were in the monotherapy group.
Conclusions
TDF-based dual HBV-active antiretroviral therapy is preferred to treat HIV-HBV co-infected patients. In resource-limited settings where TDF may not be universally available, lamivudine or emtricitabine HBV-monotherapy is a reasonable option in patients with low HBV replication.
doi:10.1097/QAD.0000000000000686
PMCID: PMC4535336  PMID: 26035319
hepatitis B; HIV; lamivudine; tenofovir; HBV treatment; emtricitabine
3.  Prevalence of hepatitis B and C viruses in HIV-positive patients in China: a cross-sectional study 
Introduction
Liver disease related to hepatitis B (HBV) and hepatitis C (HCV) may temper the success of antiretroviral therapy (ART) in China. Limited data exist on their prevalence in HIV-positive Chinese. A multi-centre, cross-sectional study was carried out to determine the prevalence and disease characteristics of HBV and HCV co-infection in HIV-positive patients across 12 provinces.
Methods
HIV-positive ART-naïve patients were recruited from two parent cohorts established during November 2008–January 2010 and August 2012–September 2014. Hepatitis B surface antigen (HBsAg), hepatitis B e antigen and HCV antibody (anti-HCV) status were retrieved from parent databases at the visit prior to ART initiation. HBV DNA was then determined in HBsAg+ patients. HCV RNA was quantified in anti-HCV+ patients. Aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 (FIB4) were calculated. Chi-square test, Kruskal–Wallis test and logistic regression were used for statistical analysis, as appropriate.
Results
Of 1944 HIV-positive patients, 186 (9.5%) were HIV–HBV co-infected and 161 (8.3%) were HIV–HCV co-infected. The highest HIV–HBV prevalence (14.5%) was in Eastern China while the highest HIV–HCV prevalence was in the Central region (28.2%). HIV–HBV patients had lower median CD4 + T cell count (205 cells/μL) than either HIV monoinfected (242 cells/μL, P=0.01) or HIV–HCV patients (274 cells/μL, P=0.001). Moderate-to-significant liver disease was present in >65% of the HIV–HCV, ~35% of the HIV–HBV and ~20% of the HIV monoinfected patients. Independent associations with moderate-to-significant liver disease based on APRI included HBV (Odds ratio, OR 2.37, P < 0.001), HCV (OR 9.64, P<0.001), CD4 count≤200 cells/μL (OR 2.55, P<0.001) and age ≥30 years (OR 1.80, P=0.001).
Conclusions
HBV and HCV prevalence is high in HIV-positive Chinese and differs by geographic region. HBV and HCV co-infection and HIV monoinfection are risks for moderate-to-significant liver disease. Only HIV–HBV is associated with greater HIV-related immunosuppression. Incorporating screening and management of hepatitis virus infections into Chinese HIV programmes is needed.
doi:10.7448/IAS.19.1.20659
PMCID: PMC4793284  PMID: 26979535
HIV; hepatitis B virus; hepatitis C virus; co-infection; prevalence; liver disease; CD4+T cell count
4.  Combination Antiretroviral Therapy Is Associated With Reduction in Liver Fibrosis Scores in HIV-1-Infected Subjects 
Medicine  2016;95(5):e2660.
Supplemental Digital Content is available in the text
Abstract
HIV increases the risk of liver disease as do two common coinfections, hepatitis B and C viruses (HBV and HCV). However, whether combination antiretroviral therapy (cART) reverses or exacerbates hepatic fibrosis remains unclear.
This was an observational retrospective study. cART-naïve HIV-infected subjects without a history of substance abuse (including alcohol) had liver disease stage determined by aspartate aminotransferase-to-platelet ratio indices (APRIs) and fibrosis-4 (FIB-4) before and 24 and 48 weeks after cART. All the data were retrieved from previously established cohorts. Values before and after cART were compared using Wilcoxon test for paired samples. Regression analyses were used to determine factors associated with moderate-to-severe liver disease.
Of the 1105 HIV-infected subjects, 120 were HBV coinfected and 64 were HCV coinfected. About 20% of HIV monoinfected participants had APRI and FIB-4 scores consistent with moderate-to-significant fibrosis compared to ∼36% of HIV–HBV coinfected and 67% to 77% of HIV–HCV coinfected participants. In adjusted analyses compared with HIV monoinfection, HBV coinfection was associated with 1.18-fold higher APRI (P < 0.001) and a 1.12-fold higher FIB-4 (P = 0.007) prior to cART; while HCV coinfection was associated with 1.94-fold higher APRI (P < 0.001) and a 1.43-fold higher FIB-4 (P < 0.001). After 48 weeks of cART, both fibrosis scores decreased in all subjects; however, HCV coinfection was still associated with higher fibrosis scores at week 48 compared to HIV monoinfection.
cART was associated with improvement in hepatic fibrosis scores in the majority of HIV-hepatitis coinfected and HIV-monoinfected Chinese participants.
doi:10.1097/MD.0000000000002660
PMCID: PMC4748910  PMID: 26844493
5.  Spontaneous Clearance of the Hepatitis C Virus Among Men Who Have Sex With Men 
Among men who have sex with men, the probability of and factors associated with spontaneous hepatitis C virus (HCV) clearance differ between sexually and percutaneously acquired infections. Determining the reasons for these differences could be important for HCV vaccine development.
Background. The probability of spontaneous hepatitis C virus (HCV) clearance ranges from 11% to 49%. Our previous cross-sectional study suggests that mode of acquisition explains some of this heterogeneity. We performed this prospective study to determine factors associated with spontaneous HCV clearance among men who have sex with men (MSM).
Methods. A mixture-cure model was used to evaluate the probability of spontaneous HCV clearance among 101 MSM in the Multicenter AIDS Cohort Study with acute HCV infection between 1984 and 2012.
Results. Spontaneous HCV clearance occurred in 46% of MSM (49% in non-injection drug users [IDUs] and 23% in IDUs). In the multivariable analysis, age <30 years (clearance ratio [CR] = 2.43; 95% confidence interval [CI], 1.53–3.87) and being human immunodeficiency virus (HIV) uninfected (CR = 2.97; 95% CI, 1.98–4.46) were independently associated with spontaneous clearance. Among men aged ≥30 years, being HIV uninfected, not having unprotected anal intercourse, older age, and being on highly active antiretroviral therapy were independently associated with higher clearance. The interferon lambda rs12979860 single nucleotide polymorphism (SNP) was not associated with spontaneous clearance among the 88 MSM who were not active IDUs (CR = 0.74; 95% CI, .46–1.21 for CC vs CT/TT genotype).
Conclusions. The high probability of spontaneous HCV clearance together with the lack of an association between the rs12979860 SNP and spontaneous clearance among MSM who do not use injection drugs suggests that the immune mechanisms involved with a successful response to acute HCV differ by mode of virus acquisition. Understanding potential mechanistic differences could be important for HCV vaccine development.
doi:10.1093/cid/civ562
PMCID: PMC4599393  PMID: 26175521
hepatitis C virus; HIV; IL28B; injection drug use; MSM
7.  Incident Hepatitis C Virus Infection in Men Who Have Sex With Men: A Prospective Cohort Analysis, 1984–2011 
In the United States, incident hepatitis C among men who have sex with men has been ongoing since at least 1984. Risk factors included unprotected receptive anal intercourse with multiple partners, HIV infection, and lower CD4 T-cell count among HIV-infected men.
Background Prospective characterization of hepatitis C virus (HCV) transmission in both human immunodeficiency virus (HIV)–infected and –uninfected men who have sex with men (MSM) over the entire HIV epidemic has not been comprehensively conducted.
Methods To determine the trends in and risk factors associated with incident HCV in MSM since 1984, 5310 HCV antibody (anti-HCV)–negative MSM in the Multicenter AIDS Cohort Study were prospectively followed during 1984–2011 for anti-HCV seroconversion.
Results During 55 343 person-years (PYs) of follow-up, there were 115 incident HCV infections (incidence rate, 2.08/1000 PYs) scattered throughout the study period. In a multivariable analysis with time-varying covariates, older age (incidence rate ratio [IRR], 1.40/10 years, P < .001), enrollment in the later (2001–2003) recruitment period (IRR, 3.80, P = .001), HIV infection (IRR, 5.98, P < .001), drinking >13 alcoholic drinks per week (IRR, 1.68, P < .001), hepatitis B surface antigen positivity (IRR, 1.68, P < .001), syphilis (IRR, 2.95, P < .001), and unprotected receptive anal intercourse with >1 male partner (IRR, 3.37, P < .001) were independently associated with incident HCV. Among HIV-infected subjects, every 100 cell/mm3 increase in CD4 count was associated with a 7% (P = .002) decrease in the HCV incidence rate up to a CD4 count of 500 cells/mm3, whereas there was no association with highly active antiretroviral therapy.
Conclusions The spread of HCV among both HIV-infected and -uninfected MSM in the United States has been ongoing since the beginning of the HIV epidemic. In HIV-infected men with <500 CD4+ T cells, the HCV incidence rate was inversely proportional to CD4 T-cell count.
doi:10.1093/cid/cit197
PMCID: PMC3669529  PMID: 23532480
incident HCV; sexual transmission; MSM
8.  Characterization of HIV-HBV co-infection in a multi-national HIV-infected cohort 
AIDS (London, England)  2013;27(2):191-201.
Objective
To understand the HIV-hepatitis B virus (HBV) epidemic from a global perspective by clinically and virologically characterizing these viruses at the time of antiretroviral therapy (ART) initiation in a multi-national cohort.
Methods and design
HIV-infected subjects enrolled in two international studies were classified as HIV-HBV co-infected or HIV monoinfected prior to ART. HIV-HBV co-infected subjects were tested for HBV characteristics, hepatitis D virus (HDV), a novel non-invasive marker of liver disease, and drug-resistant HBV. Comparisons between discrete covariates used chi-square or Fisher’s exact tests (and Jonchkheere-Terpstra for trend tests) while continuous covariates were compared using Wilcoxon Rank-Sum Test.
Results
Of the 2105 HIV-infected subjects from 11 countries, the median age was 34 years and 63% were Black. The 115 HIV-HBV co-infected subjects had significantly higher ALT and AST values, lower body mass index, and lower CD4+ T-cell counts than HIV monoinfected subjects (median 159 cells/mL and 137 cells/mL, respectively, P=0.04). In the co-infected subjects, 49.6% had HBeAg-negative HBV, 60.2% had genotype A HBV, and 13% were HDV positive. Of the HBeAg-negative subjects, 66% had HBV DNA ≤2000 IU/ml compared to 5.2% of the HBeAg-positive subjects. Drug-resistant HBV was not detected.
Conclusions
Screening for HBV in HIV-infected patients in resource-limited settings is important since it is associated with lower CD4+ T-cell counts. In settings where HBV DNA is not available, HBeAg may be useful to assess the need for HBV treatment. Screening for drug-resistant HBV is not needed prior to starting ART in settings where this study was conducted.
doi:10.1097/QAD.0b013e32835a9984
PMCID: PMC3763734  PMID: 23032418
HIV; HBV; coinfection; global
9.  Genetic Polymorphism in IL28B Is Associated With Spontaneous Clearance of Hepatitis C Virus Genotype 4 Infection in an Egyptian Cohort 
The Journal of Infectious Diseases  2011;204(9):1391-1394.
Single-nucleotide polymorphisms (SNPs) around IL28B are associated with spontaneous hepatitis C virus (HCV) clearance of genotypes 1 and 3 in white and African-American populations. This study investigated whether the IL28B SNP (rs12979860) is associated with spontaneous clearance of HCV, principally genotype 4, in 162 Egyptians (80 with clearance). The protective C allele was more common in those with spontaneous clearance (76.3% vs 57.9%; P = .0006). Individuals with clearance were 3.4 (95% confidence interval, 1.8–6.5) times more likely to have C/C genotype. Thus, IL28B plays a role in spontaneous clearance of HCV genotype 4 in North Africa.
doi:10.1093/infdis/jir536
PMCID: PMC3182308  PMID: 21933876
10.  IL28B polymorphism does not determine hepatitis B virus or HIV outcomes 
The Journal of infectious diseases  2010;202(11):1749-1753.
An IL28B haplotype strongly determines the outcome of natural and interferon-α treated HCV infection. To assess if the polymorphism marking the haplotype (rs12979860) also affects other interferon-α responsive chronic viral illnesses, namely hepatitis B virus (HBV) and human immunodeficiency virus-1 (HIV), we genotyped 226 individuals with HBV persistence, 384 with HBV recovery, and 2548 with or at high-risk for HIV infection. The C/C genotype of rs12979860 was not associated with HBV recovery (OR 0.99), resistance to HIV infection (0.97), or HIV disease progression (P>0.05). This IL28B SNP affects the immune response to HCV but not to HBV or HIV.
doi:10.1086/657146
PMCID: PMC2974014  PMID: 20977343
IL28B; HIV; HBV; genetics; polymorphism
11.  Favorable Socioeconomic Status and Recreational Polydrug Use Are Linked With Sexual Hepatitis C Virus Transmission Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men 
Open Forum Infectious Diseases  2016;3(3):ofw137.
Increasing incident HCV infections were found between 2011-2014 after declining between 2008-2010 among HIV-infected men in a Community Health Center in Baltimore. The reemerging epidemic was associated with sexual transmission and polydrug use among MSM with favorable socioeconomic status.
Background. Sexual transmission of hepatitis C virus (HCV) among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) is an emerging issue. Studies addressing the temporal trends and risk factors associated with incident HCV in HIV-infected MSM in the community-based primary care settings in the United States are scarce.
Methods. Using a retrospective cohort study design, HCV incidence, defined as HCV antibody seroconversion, was determined in 1147 HIV-infected men receiving care at Chase Brexton Health Care clinics in Baltimore, Maryland between 2004 and 2014. Multivariate regression analyses were used to identify factors associated with incident HCV.
Results. There were 42 incident HCV infections during 5242 person-years (PY) of follow up (incidence rate [IR], 8.01/1000 PY). Thirty-seven (88%) of the incident infections were in MSM, of whom 31 (84%) reported no injection-drug use (IDU). The annual IRs for MSM were 13.1–15.8/1000 PY between 2004 and 2007, decreased to 2.7–6.2/1000 PY between 2008 and 2011, and increased to 10.4/1000 PY and 13.3/1000 PY in 2013 and 2014, respectively. Injection-drug use was strongly associated with incident HCV among all MSM (IR ratio [IRR], 14.15; P = .003); however, among MSM without IDU, entering care between 2010 and 2013 (IRR, 3.32; P = .01), being employed (IRR, 3.14; P = .03), and having a history of ulcerative sexually transmitted infections (IRR, 3.70; P = .009) or of polydrug use (IRR, 5.54; P = .01) independently predicted incident HCV.
Conclusions. In this cohort of HIV-infected men, a re-emerging HCV epidemic was observed from 2011 to 2014 among MSM. In addition to IDU, high-risk sexual behaviors, favorable socioeconomic status, and polydrug use fueled this increase in HCV infections.
doi:10.1093/ofid/ofw137
PMCID: PMC5047398  PMID: 27703998
HIV; MSM; polydrug use; sexual HCV transmission; socioeconomic status
12.  Large-Scale candidate gene analysis of spontaneous hepatitis C virus clearance 
The Journal of infectious diseases  2010;201(9):1371-1380.
Human genetic variation is a determinant of recovery from an acute hepatitis C virus (HCV) infection, but, to date, single nucleotide polymorphisms (SNPs) in a limited number of genes have been studied with respect to HCV clearance. We determined whether SNPs in 112 selected immune-response genes are important for HCV clearance by genotyping 1536 SNPs in a cohort of 343 persons with natural HCV clearance and 547 persons with HCV persistence. PLINK and Haploview software packages were used to perform association, permutation, and haplotype analyses stratified by African-American (AA) and European-American (EA) race. Of the 1536 SNPs tested, 1426 were successfully genotyped (92.8%). In AAs, we identified 18 SNPs located in 11 gene regions that were associated with HCV outcome (empirical p-value < 0.01). In EAs, there were 20 SNPs located in eight gene regions associated with HCV outcome. Four of the gene regions studied (TNFSF18, TANK, HAVCR1 and IL18BP) contained SNPs with empirical p-values < 0.01 in both of the race groups.
Conclusion
In this large-scale analysis of 1426 genotyped SNPs in 112 candidate genes, we identified four gene regions that are likely candidates for a role in HCV clearance or persistence in both AAs and EAs.
doi:10.1086/651606
PMCID: PMC2853721  PMID: 20331378
TANK; TNFSF18; HAVCR1; IL18BP; genetics
13.  Virology and clinical sequelae of drug-resistant HBV in HIV-HBV co-infected patients on HAART 
Antiviral therapy  2010;15(3 Pt B):487-491.
Summary
Several of the nucleos(t)ide analogues used to treat HIV also inhibit hepatitis B virus (HBV) replication, with lamivudine being the oldest of this group. Thus, prior to licensing of tenofovir, many HIV-HBV co-infected subjects received lamivudine as the only active drug against HBV as part of the anti-HIV regimen setting the stage for emergence of drug-resistant HBV. In co-infected persons, lamivudine-resistant HBV develops more rapidly than in HBV moninfected persons, but it is not known if this is true for the newer agents. Due to overlapping reading frames of the HBV Polymerase and Surface antigens, drug-resistant changes in HBV Pol can lead to mutations in the envelope. This review will discuss studies of drug-resistant HBV in HIV-infected persons including drug-resistant mutations that have been identified and clinical sequelae of these mutations.
doi:10.3851/IMP1553
PMCID: PMC2946104  PMID: 20516569
14.  Impact of hepatitis B virus infection on HIV response to antiretroviral therapy in Nigeria 
Background
As HAART is introduced into areas of the world with high hepatitis B virus (HBV) endemicity, it is important to determine the influence of HBV on HIV-HBV co-infected persons receiving antiretroviral therapy (ART).
Methods
We studied 1,564 HIV-infected subjects in Jos, Nigeria who initiated ART. HIV-HBV co-infected participants had HBeAg and HBV DNA status determined. CD4+ T-cell count and HIV viral load at ART initiation were compared between HIV mono-infected and HIV-HBV co-infected subjects using univariate methods. Regression analyses were used to determine if HBeAg status or HBV DNA at ART initiation were associated with baseline HIV parameters or ART response.
Results
The CD4+ T-cell counts of the 262 (16.7%) HIV-HBV co-infected participants was 107 cells/mL compared to 130 cells/mL in HIV monoinfected participants (p <0.001) at ART initiation. HIV-HBV co-infected participants also had higher HIV viral loads than HIV monoinfected subjects (4.96 vs. 4.75 log10 copies/mL; p = 0.02). Higher HBV DNA and detectable HBeAg were independently associated with lower CD4+ T-cell counts at ART initiation but not with higher HIV viral load. In a multivariable model, HBeAg-positive subjects were less likely to suppress HIV replication to ≤400 copies/ml (OR 0.54, p=0.03) at 24 weeks, but they had similar CD4+ T cell increases. At 48 weeks, there was no significant effect of HBeAg status on ART response.
Conclusions
In HIV-infected Nigerian individuals, HBV co-infection, especially in those with high levels of HBV replication, was associated with lower CD4+ T-cell counts at ART initiation independent of HIV RNA level. Subjects with HBeAg positive status had a slower virological response to ART. Further work is needed to understand the effects of HBV on CD4+ T-cells.
doi:10.1086/605675
PMCID: PMC2753765  PMID: 19772386
hepatitis B; HIV; CD4 cell counts; antiretroviral therapy; Africa
15.  Host Genetic Factors and Antiviral Immune Responses to HCV 
Clinics in liver disease  2008;12(3):713-xi.
Human genome variations explain some of the heterogeneity in the immune response to antigenic stimuli. Such differences in response to hepatitis C virus (HCV) antigens can account for the ability of the immune response to clear HCV after an acute infection or to develop more rapidly progressive liver disease. Several studies have examined polymorphisms in several candidate immune-response genes for their relationship to these HCV outcomes. Results of some of these studies complement knowledge gained from immunology studies and others offer new insights into HCV biology. This review summarizes published studies on variation in immune-response genes and HCV outcomes.
doi:10.1016/j.cld.2008.03.002
PMCID: PMC2597299  PMID: 18625436
human; genetics; polymorphisms; hepatitis C; fibrosis
16.  Incident Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Men Who Have Sex With Men From Pre-HAART to HAART Periods 
Annals of internal medicine  2015;163(9):673-680.
Background
Men who have sex with men (MSM) are at high risk for hepatitis B virus (HBV) infection. Data on the effect of highly active antiretroviral therapy (HAART) on incident HBV infection in HIV-infected and HIV-uninfected MSM are limited.
Objective
To determine predictors of incident HBV infection in MSM during pre-HAART and HAART periods.
Design
Observational cohort study.
Setting
Cohort of MSM who have, or are at risk for, HIV infection.
Patients
2375 HBV-uninfected MSM in the Multicenter AIDS Cohort Study.
Measurements
Poisson regression was used to compare incidence rates of HBV infection in the pre-HAART and HAART eras and to identify factors associated with incidence of HBV infection.
Results
In 25 322 person-years of follow-up, 244 incident HBV infections occurred. The unadjusted incidence rate was higher in HIV-infected MSM than in HIV-uninfected MSM (IRR, 1.9 [95% CI, 1.5 to 2.4]) and was significantly lower in the HAART era than in the pre-HAART era among HIV-infected (IRR, 0.2 [CI, 0.1 to 0.4]) and HIV-uninfected (IRR, 0.3 [CI, 0.2 to 0.4]) MSM. Age younger than 40 years (IRR, 2.3 [CI, 1.7 to 3.0]), more than 1 recent sexual partner (IRR, 3.1 [CI, 2.3 to 4.2]), and HIV infection (IRR, 2.4 [CI, 1.8 to 3.1]) were independently associated with higher incidence of HBV infection, whereas HBV vaccination was protective (IRR, 0.3 [CI, 0.2 to 0.4]). Highly active antiretroviral therapy with HIV RNA levels less than 400 copies/mL was associated with protection (IRR, 0.2 [CI, 0.1 to 0.5]), but HAART in those with HIV RNA levels of 400 copies/mL or greater was not.
Limitation
The observational nature limits inferences about causality.
Conclusion
Effective HAART is associated with lower incidence of HBV infection; however, even in the HAART era, incidence of HBV infection remains high among MSM.
Primary Funding Source
National Institute of Allergy and Infectious Diseases.
doi:10.7326/M15-0547
PMCID: PMC4630157  PMID: 26457744
17.  HLA-Cw*04 and Hepatitis C Virus Persistence 
Journal of Virology  2002;76(10):4792-4797.
In studies of acute hepatitis C virus (HCV) infection, the early host immune response is one of the determinants of viral persistence. The class I human leukocyte antigens (HLA), which present foreign antigen to cytolytic T cells, are integral components of this response. We hypothesized that the highly polymorphic HLA genes affect the outcome of an HCV infection. To test this hypothesis, we molecularly typed 231 persons with well-documented clearance of an HCV infection and 444 matched persistently infected persons. HLA-A*1101 (odds ratio [OR], 0.49; 95% confidence interval [95% CI], 0.27 to 0.89), HLA-B*57 (OR, 0.62; 95% CI, 0.39 to 1.00), and HLA-Cw*0102 (OR, 0.43; 95% CI, 0.21 to 0.89) were associated with viral clearance, whereas HLA-A*2301 (OR, 1.78; 95% CI, 1.01 to 3.11) and HLA-Cw*04 (OR, 1.78; 95% CI, 1.21 to 2.59) were associated with viral persistence. HLA-Cw*04 is in strong linkage disequilibrium with HLA-B*53 and HLA-B*35, but only HLA-B*53 (OR, 1.70; 95% CI, 0.95 to 3.06) and the Cw*04-B*53 haplotype (OR, 1.76; 95% CI, 0.94 to 3.26) were weakly associated with viral persistence. HLA-B*53 has similar, but not necessarily identical, binding specificity to some HLA-B*35 subtypes (B*35-Px group). The association with the B*35-Px group was less strong than with HLA-B*53 alone. The association of HLA-Cw*04 with HCV persistence was codominant (two copies of the gene were more strongly associated with persistence than one copy). However, HLA-Cw*04 was not associated with HCV RNA levels among the persistently infected individuals. Since Cw*04 is a ligand for the killer immunoglobulin-like receptors on natural killer cells, these cells may be involved in recovery from HCV infection. Further investigation is needed to understand the relationship between class I alleles and HCV clearance.
doi:10.1128/JVI.76.10.4792-4797.2002
PMCID: PMC136132  PMID: 11967296
18.  Differences in hepatitis C virus (HCV) prevalence and clearance by mode of acquisition among men who have sex with men (MSM) 
Journal of viral hepatitis  2013;21(10):696-705.
Objective
To compare the characteristics associated with hepatitis C virus (HCV) antibody (anti-HCV) prevalence and HCV clearance between injection drug using (IDU) and non-IDU men who have sex with men (MSM).
Methods
Stored serum and plasma samples were tested for anti-HCV and HCV RNA to determine the HCV status of 6925 MSM at enrollment into the Multicenter AIDS Cohort Study (MACS). Prevalence and clearance ratios (PR and CR) were calculated to determine the characteristics associated with HCV prevalence and clearance. Multivariable analyses were performed using Poisson regression methods with robust variance estimation.
Results
Anti-HCV prevalence was significantly higher among IDU than non-IDU MSM (42.9% vs. 4.0%) while clearance was significantly lower among IDU MSM (11.5% vs. 34.5% among non-IDU MSM). HIV infection, Black race, and older age were independently associated with higher prevalence in both groups while smoking, transfusion history, and syphilis were significantly associated with prevalence only among non-IDU MSM. The rs12979860-C/C genotype was the only characteristic independently associated with HCV clearance in both groups, but the effects of both rs12979860-C/C genotype (CR=4.16 IDUs vs. 1.71 non-IDUs; p=0.03) and HBsAg positivity (CR=5.06 IDUs vs. 1.62 non-IDUs; p=0.03) were significantly larger among IDU MSM. HIV infection was independently associated with lower HCV clearance only among non-IDU MSM (CR=0.59, 95% CI=0.40–0.87).
Conclusions
IDU MSM have higher anti-HCV prevalence and lower HCV clearance than non-IDU MSM. Differences in the factors associated with HCV clearance suggest that the mechanisms driving the response to HCV may differ according to the mode of acquisition.
doi:10.1111/jvh.12198
PMCID: PMC4187219  PMID: 25280229
Hepatitis C; HIV; IFNL4; IL28B; Injection Drug Use; MSM
19.  HIV outcomes in Hepatitis B virus coinfected individuals on HAART 
Background
Understanding the impact of hepatitis B virus (HBV) coinfection on HIV outcomes in the HAART era continues to be a critical priority given the high prevalence of coinfection and the potential for impaired immunologic, virologic and clinical recovery.
Methods
Participants from the U.S. Military HIV Natural History Study with an HIV diagnosis, on HAART and serologically confirmed HBV infection status at HAART initiation (HI) were classified into four HBV infection (HB) groups. HIV virologic, immunologic, and clinical outcomes were evaluated by HB status.
Results
Of 2536 HIV positive HAART recipients, with HBV testing results available to determine HB status in the HI window, HB status at HI was classified as HB negative (n=1505; 66%), resolved HB (n=518; 23%); isolated HBcAb (n=139; 6%) or; chronic HB (n=131; 6%). HIV virologic suppression and failure at 6 months or 1 year were not significantly different by HB status. A significantly faster rate of increase in CD4 cell count during the period between 4 and 12 years was observed for chronic HB relative to HB negative.
Chronic and resolved HB were associated with an increased risk of AIDS/death compared to HB negative individuals (chronic HB; HR=1.68; 95% CI 1.05–2.68, resolved HB; HR=1.61; 95% CI 1.15–2.25).
Conclusions
HB status did not have a significant impact on HIV virologic outcomes, however, CD4 cell count reconstitution post HI and the risk of an AIDS event or death post HI may be associated with HB status.
doi:10.1097/QAI.0000000000000142
PMCID: PMC4034265  PMID: 24694929
Hepatitis B virus; chronic hepatitis B; human immunodeficiency virus; highly active antiretroviral therapy
20.  Factors Associated with Delayed Hepatitis B Viral Suppression on Tenofovir Among HBV-HIV Coinfected Patients in the CNICS Cohort 
Background
Despite widespread use in HIV and hepatitis B virus (HBV) infection, the effectiveness of tenofovir (TDF) has not been studied extensively outside of small HBV-HIV coinfected cohorts. We examined the effect of prior lamivudine treatment (3TC) and other factors on HBV DNA suppression with TDF in a multi-site clinical cohort of coinfected patients.
Methods
We studied all patients enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort from 1996-2011 who had chronic HBV and HIV infection, initiated a TDF-based regimen continued for ≥3 months and had on-treatment HBV measurements. We used Kaplan-Meier curves and Cox-Proportional hazards to estimate time to suppression (HBV DNA level <200 IU/ml or <1000 copies/ml) by selected covariates.
Results
Among 397 coinfected patients on TDF, 91% were also on emtricitabine or 3TC concurrently, 92% of those tested were HBeAg-positive, 196 (49%) had prior 3TC exposure; 192 (48%) achieved HBV DNA suppression over a median of 28 months (IQR 13-71). Median time to HBV DNA suppression was 17 months for those who were 3TC-naïve and 50 months for those who were 3TC-exposed. After controlling for other factors, prior 3TC exposure, baseline HBV DNA level >10,000 IU/ml, and lower nadir CD4 count were independently associated with decreased likelihood of HBV DNA suppression on TDF.
Conclusion
These results emphasize the role of prior 3TC exposure and immune response on delayed HBV suppression on TDF.
doi:10.1097/QAI.0000000000000126
PMCID: PMC3981874  PMID: 24500175
hepatitis B virus; tenofovir; lamivudine; HIV
21.  Admixture Analysis of Spontaneous Hepatitis C Virus Clearance in Individuals of African-Descent 
Genes and immunity  2014;15(4):241-246.
Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75–85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African-descent have lower rates of clearance compared to individuals of European-descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 SNPs from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18×10−8) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.
doi:10.1038/gene.2014.11
PMCID: PMC4308959  PMID: 24622687
Hepatitis C; Chronic Infection; Admixture; African Ancestry
22.  Assessment of Liver Fibrosis by Transient Elastography in Patients With HIV and Hepatitis B Virus Coinfection in Nigeria 
We describe the prevalence and risk factors for advanced liver fibrosis (≥9.3 kPa) using transient elastography in human immunodeficiency virus (HIV)–monoinfected and HIV/HBV (hepatitis B virus)–coinfected, antiretroviral naive adults in Nigeria. HBV coinfection and HBV DNA levels significantly increased the risk of advanced fibrosis in HIV and HIV/HBV patients, respectively.
doi:10.1093/cid/cit564
PMCID: PMC3840401  PMID: 24014732
HIV; HBV; liver fibrosis; Africa
23.  Risk Factors for Fatty Liver in the Multicenter AIDS Cohort Study 
OBJECTIVES
Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase the risk of fatty liver disease. We determined the prevalence of and risk factors for fatty liver by comparing HIV-infected men with HIV-uninfected men who have sex with men in the Multicenter AIDS Cohort Study (MACS).
METHODS
In 719 MACS participants who consumed less than three alcoholic drinks daily, fatty liver was defined as a liver-to-spleen attenuation ratio < 1 on noncontrast computed tomography (CT). We genotyped single nucleotide polymorphisms in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene and in other genes previously associated with nonalcoholic fatty liver disease. Risk factors for fatty liver were determined using multivariable logistic regression.
RESULTS
Among 254 HIV-uninfected men and 465 HIV-infected men, 56 % were White with median age 53 years and median body mass index 25.8 kg/m 2. The vast majority of HIV-infected men (92 %) were on ART, and 87 % of the HIV-infected men were treated with a nucleoside reverse transcriptase inhibitor for a median duration of 8.5 years. Overall, 15 % of the cohort had fatty liver, which was more common in the HIV-uninfected compared with the HIV-infected men (19 vs. 13 %, P= 0.02). In multivariable analysis, HIV infection was associated with a lower prevalence of fatty liver (odds ratio (OR) = 0.44, P= 0.002), whereas a higher prevalence of fatty liver was seen in participants with PNPLA3 (rs738409) non-CC genotype (OR = 2.06, P= 0.005), more abdominal visceral adipose tissue (OR = 1.08 per 10 cm2, P< 0.001), and homeostatic model assessment of insulin resistance (HOMA-IR) ≥ 4.9 (OR = 2.50, P= 0.001). Among HIV-infected men, PNPLA3 (rs738409) non-CC genotype was associated with a higher prevalence of fatty liver (OR = 3.30, P= 0.001) and cumulative dideoxynucleoside exposure (OR = 1.44 per 5 years, P= 0.02).
CONCLUSIONS
CT-defined fatty liver is common among men at risk for HIV infection and is associated with greater visceral adiposity, HOMA-IR, and PNPLA3 (rs738409). Although treated HIV infection was associated with a lower prevalence of fatty liver, prolonged exposure to dideoxynucleo side analogs is associated with higher prevalence.
doi:10.1038/ajg.2014.32
PMCID: PMC4133993  PMID: 24642579
24.  Reply to Tsai et al 
doi:10.1093/infdis/jit300
PMCID: PMC3762385  PMID: 23840048
25.  Patterns and Causes of Suboptimal Response to Tenofovir-Based Therapy in Individuals Coinfected With HIV and Hepatitis B Virus 
In this international prospective cohort of 165 individuals coinfected with HIV and hepatitis B virus (HBV), 3 patterns of suboptimal response to tenofovir therapy were identified: persistent viremia, viral rebound, and viral blips. Suboptimal adherence was associated with detectable HBV DNA, even when HIV was undetectable.
Background. Tenofovir (TDF) is effective for treatment of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) infection; however, some individuals have ongoing HBV viremia, the reasons for which are unclear. We determined the patterns and factors associated with detectable HBV DNA in HIV-HBV–coinfected subjects on highly active antiretroviral therapy (HAART).
Methods. One hundred sixty-five HIV-HBV–coinfected individuals from the United States, Australia, and Thailand, the majority of whom were on HAART at study entry, were prospectively followed semiannually for a median of 2.8 years. Logistic regression was used to determine factors associated with detectable HBV DNA.
Results. Anti-HBV regimens were TDF/emtricitabine (57%), lamivudine or emtricitabine (19%), or TDF monotherapy (13%). During follow-up, HBV DNA was detected at 21% of study visits and was independently associated with hepatitis B e antigen (HBeAg), HAART <2 years, CD4 <200 cells/mm3, detectable HIV RNA, reporting <95% adherence, and anti-HBV regimen. TDF/emtricitabine was less likely to be associated with detectable HBV than other regimens, including TDF monotherapy (odds ratio, 2.79; P = .02). In subjects on optimal anti-HBV therapy (TDF/emtricitabine) and with undetectable HIV RNA, HBeAg, CD4 <200 mm3, and reporting <95% adherence remained associated with detectable HBV DNA. Three main patterns of HBV viremia were observed: persistent HBV viremia, viral rebound (>1 log from nadir), and viral blips. No TDF resistance was identified.
Conclusions. Tenofovir/emtricitabine was superior to other anti-HBV regimens in long-term HBV suppression. HBV viremia on therapy was identified in 1 of 3 main patterns. Suboptimal adherence was associated with detectable HBV DNA during therapy, even when HIV was undetectable.
doi:10.1093/cid/cit002
PMCID: PMC3693490  PMID: 23315316
HIV; hepatitis B; antiretroviral therapy; adherence

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