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.

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.

Background. Although liver disease commonly causes morbidity and mortality among human immunodeficiency virus (HIV)–infected individuals, data are limited on its prevalence in HIV monoinfection. We used the aspartate aminotransferase-to-platelet ratio index (APRI) as a surrogate marker of hepatic fibrosis to characterize liver disease in the Multicenter AIDS Cohort Study.

Methods. Men were categorized based on their HIV and viral hepatitis status: uninfected (n = 1170), HIV monoinfected (n = 509), viral hepatitis monoinfected (n = 74), and HIV–viral hepatitis coinfected (n = 66).

Results. The median APRI in the HIV-monoinfected group was similar to that in the hepatitis-monoinfected group (0.42 vs 0.43; P > .05), higher than in the uninfected group (0.42 vs 0.27; P < .001) but lower than in the coinfected group (0.42 vs 1.0; P < .001). On multivariable analysis, HIV infection (1.39-fold increase [FI]; P < .001), viral hepatitis infection (1.52-FI; P < .001), and the interaction between HIV and viral hepatitis infections were independently associated with a higher APRI (1.57-FI; P < .001). Among the HIV-infected men, viral hepatitis coinfection (2.34-FI; P < .001), HIV RNA ≥100 000 copies/mL (1.26-FI; P = .007), and CD4 count ≤200 cells/mL (1.23-FI; P = .022) were independently associated with a higher APRI.

Conclusions. HIV and viral hepatitis are independently associated with an increased APRI. Further studies are needed to understand the biological basis for the association between HIV and liver disease.

(See the editorial commentary by Peters and Marston, on pages 166–8.)

Background. Understanding the impact of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) coinfection has been limited by heterogeneity of HIV disease. We evaluated HBV coinfection and HIV-related disease progression in a cohort of HIV seroconverters.

Methods. Participants with HIV diagnosis seroconversion window of ≤3 years and serologically confirmed HBV infection (HB) status were classified at baseline into 4 HB groups. The risk of clinical AIDS/death in HIV seroconverters was calculated by HB status.

Results. Of 2352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. Unadjusted rates (95% confidence intervals [CIs]) of clinical AIDS/death for the HB-negative, resolved HB, isolated HBcAb, and chronic HB groups were 2.43 (2.15–2.71); 3.27 (2.71–3.84); 3.75 (2.25–5.25); and 5.41 (3.41–7.42), respectively. The multivariable risk of clinical AIDS/death was significantly higher in the chronic HB group compared to the HB-negative group (hazard ratio [HR], 1.80; 95% CI, 1.20–2.69); while the HRs were increased but nonsignificant for those with resolved HB (HR, 1.17; 95% CI, .94–1.46) and isolated HBcAb (HR, 1.14; 95% CI, .75–1.75).

Conclusions. HBV coinfection has a significant impact on HIV outcomes. The hazard for an AIDS or death event is almost double for those with chronic HB compared, with HIV-monoinfected persons.

The −1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (−1G) from the guanine rich homopolymer sequence located at nts 2,085–2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at 64Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B “e” antigen (HBeAg), and the core protein which forms the viral nucleocapsid. However, the replication phenotype of the −1G mutant HBV is unknown. An in vitro cell culture model in which hepatoma cells were transiently transfected with infectious cDNAs was used to show that the −1G mutant HBV is incapable of autonomous replication and, as expected, replication was restored to wild-type (wt) levels by supplying HBV core protein in trans. Although the −1G mutation had no deleterious effect on intracellular HBV-DNA levels, high levels of −1G mutant HBV relative to wt HBV reduced virus secretion and HBeAg secretion relative to empty vector controls. Importantly, the −1G mutant HBV also caused intracellular retention of truncated precore protein in the endoplasmic reticulum (ER) and Golgi apparatus. Together, these effects may be contributing to the increased pathology observed in the setting of HIV/HBV co-infection.

Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3′ untranslated regions (3′UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3′UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3′UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.

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.

Screening with hepatitis B surface antigen (HBsAg) is highly recommended for at-risk individuals. Mutations in the HBsAg can result in an inability to detect the virus during routine screening. We describe a hemodialysis patient found to have high levels of hepatitis B virus (HBV) DNA and HBV antibody but negative HBsAg on two routine assays.

Objectives

Since 2003, U.S. organizations have recommended universal screening, rather than targeted screening, of HIV-infected persons for gonorrhea (NG) and Chlamydia (CT). Our objective was to determine whether wider testing resulting from these guidelines would produce an increase in NG/CT diagnoses.

Methods

We studied 3,283 patients receiving HIV care 1999–2007 in the Johns Hopkins Hospital HIV clinic. The two primary outcomes were: 1) the occurrence of any NG/CT testing in each year of care and 2) the occurrence of any positive result(s) in years of testing. The proportion of all patients in care who were diagnosed with NG/CT was defined as the number of patients with positive results divided by the number of patients in care. Trends were analyzed with repeated measures logistic regression.

Results

The proportion of patients tested for NG/CT increased steadily from 0.12 in 1999 to 0.33 in 2007 (OR per year for being tested, 1.17 [1.15, 1.19]). The proportion positive among those tested decreased significantly after 2003 (OR per year 0.67 [0.55, 0.81]). The proportion of all patients in care diagnosed with NG/CT therefore remained generally stable 1999–2007 (OR per year 0.97 [0.91, 1.04]).

Conclusions

Universal annual screening, as implemented, did not increase the proportion of all patients in care who were diagnosed with NG/CT. Similarly low implementation rates have been reported in cross-sectional studies. If future efforts to enhance implementation do not yield increases in diagnoses, then guidelines focusing on targeted screening of high risk groups rather than universal screening may be warranted.

Background. Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.

Methods. High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)–seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.

Results. DQB1*0301 was associated with low baseline HCV load (β = −.4; 95% confidence interval [CI], −.6 to −.3; P < .00001), as well as with low odds of FIB-4–defined (odds ratio [OR], .5; 95% CI, .2–.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3–1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0–3.7; P = .04).

Conclusions. HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.

We tested the hypothesis that a single nucleotide polymorphism (SNP) located near the interleukin-28B gene is associated with the control of hepatitis C virus and HIV-1 replication in elite controllers/suppressors. We show here that the protective genotype is not overrepresented in elite controllers/suppressors compared with HIV-1-seronegative patients and HIV-1-infected patients with viral loads more than 10 000 copies/ml. Thus, it appears that this SNP is not associated with the elite control of HIV-1 infection.

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.

Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART-era liver disease is now the most common non-AIDS related cause of death among HIV-infected patients, accounting for 14-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART-era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV-infected population in the ART-era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases.

Treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-γ3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFNγ3 upregulates interferon-stimulated genes (ISGs), similar to interferon-α and β, but via a different receptor. There is also evidence that IFNγ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated interferon-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFNγ3, the clinical implications of the genetic association, and areas of future research.

An IL28B haplotype strongly determines the outcome of natural and interferon-α treated hepatitis C virus (HCV) infection. To assess whether the polymorphism marking the haplotype (rs12979860) also affects other interferon-α responsive chronic viral illnesses, namely hepatitis B virus (HBV) and human immunodeficiency virus (HIV) type 1 infections, 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 (odds ratio, 0.99), resistance to HIV infection (odds ratio, 0.97), or HIV disease progression (P>.05). This IL28B single-nucleotide polymorphism affects the immune response to HCV but not to HBV or HIV.

There are currently seven approved therapies for chronic hepatitis B infection, an increase from just three agents five years ago. This review will focus on the pharmacology, potency, and adverse events associated with immunomodulatory agents and nucleos(t)ide analogs, with an emphasis on targets of therapy within the hepatitis B lifecycle. We will also offer guidelines for the use of available anti-HBV agents and review the emerging challenges in hepatitis B management, including HBV drug resistance, its management, and the potential role of combination therapy.

Objectives

Screening HIV-infected men for gonorrhea (GC) and Chlamydia (CT) may decrease HIV transmission and reduce the incidence of pelvic inflammatory disease in female partners. This study determined GC/CT testing rates in a clinical HIV cohort before and after 2003 when the U.S. Centers for Disease Control and Prevention issued guidelines for GC/CT screening.

Methods

First GC/CT testing episodes were identified for all men enrolling in a Baltimore HIV clinic 1999–2007. Multivariate Cox and logistic regression were used to assess clinical and demographic factors associated with being tested and with having a positive result.

Results

Among 1110 men, the rate of GC/CT testing upon clinic enrollment increased from 4.0% prior to 2003 to 16.5% afterward, and the rate of ever being tested increased from 34.2% to 49.1% (P <0.001 for both comparisons). Among men with same sex contact, 10% of first testing episodes included extragenital sites. Among the 342 men ever-tested, 5.2% had positive results on first testing. Predictors of testing included enrolling after 2003, younger age, frequent visits, and black race. Predictors of a positive test result included CD4 count ≥200 cells/mm3 and younger age.

Conclusions

GC/CT testing rates among men increased substantially after the 2003 guidelines but remain low. Disseminating existing evidence for GC/CT screening and promoting operational interventions to facilitate it are warranted.

Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection.

Author Summary

Hepatitis C virus (HCV) and human T-cell leukemia virus (HTLV-I) infect millions of people worldwide. Some HCV-infected individuals spontaneously clear the virus and many HTLV-1-infected people remain asymptomatic; however, in both cases the infection can lead to serious illness such as cancer. The factors which determine outcome are still elusive. We have found that a gene that encodes a receptor (KIR2DL2) enhances both protective and detrimental HLA class I-mediated immunity to HCV and HTLV-1. Strikingly, although KIRs are primarily associated with innate immunity, our observations suggest that they also have a major impact on the efficiency of the adaptive immune response. This work helps to explain why one individual infected with a virus remains healthy but another, infected with the same virus develops disease; it also helps to explain why particular HLA class I molecules do not always protect or cause susceptibility as expected. Interestingly, the impact of the KIR is entirely context dependent: if an HLA class I molecule is protective then protection is enhanced, but in the context of a detrimental HLA then susceptibility is enhanced. This study reveals a novel role for inhibitory KIRs in adaptive immunity.

HIV infection has a significant impact on the natural progression of hepatitis B virus (HBV) related liver disease. In HIV-HBV co-infected patients, little is known about mutations in the HBV genome, which can influence severity of liver disease. The aim of this study was to characterize and to determine the frequency of known clinically-significant mutations in the HBV genomes from HIV-HBV co-infected patients and from HBV mono-infected patients. To accomplish this, genomic length HBV sequencing was performed in highly-active anti-retroviral therapy (HAART) –naïve HIV-HBV co-infected patients (n= 74) and in anti-HBV therapy-naïve HBV mono-infected patients (n=55).

The frequency of HBV mutations differed between the co-infected and mono-infected patients when comparing patients with the same genotype. BCP mutations A1762T and G1764A were significantly more frequent in HBV genotype C mono-infection and the −1G frameshift was significantly more frequent in co- infection and was only observed in HBV genotype A co-infection. PreS2 deletions were observed more frequently in the setting of co-infection. Further work is needed to determine if these mutational patterns influence the differences in liver disease progression in HIV-HBV co-infected and HBV mono-infected patients.

Hepatitis C virus (HCV) infection is the most common blood borne infection in the U.S. with estimates of 4 million HCV-infected individuals in the U.S. and 170 million worldwide1. The majority (70%–80%) of HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral, and host factors have been associated with the differences in HCV clearance or persistence and studies have demonstrated that a strong host immune response against HCV favors viral clearance3,4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3kb upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a 2-fold difference in response to HCV drug treatment5. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (N = 388) or had persistent infection (N = 620). We show that the C/C genotype strongly enhances resolution of HCV infection amongst individuals of both European and African ancestry (European: OR = 0.38, p = 10−7; African: OR = 0.32, p = 10−4; combined: OR = 0.33, p <10−12). To date, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multi-racial cohort of US women with high prevalence of HCV and HIV. Our primary analyses evaluated associations between twelve HLA alleles identified through a critical review of the literature and HCV viremia in 758 HCV-seropositive women. Other alleles with >5% prevalence were also assessed; previously unreported associations were corrected for multiple comparisons. DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1–2.6), B*5701 (PR=2.0; 95% CI = 1.0–3.1), B*5703 (PR = 1.7; 95% CI = 1.0–2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0–3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), while DRB1*0301 (PR = 0.4; 95% CI = 0.2–0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2–11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles with HCV infection (serostatus) in women at high risk of HCV from injection drug use (IDU; N=838), but no significant relationships were observed.

Conclusion

HLA genotype influences host capacity to clear HCV viremia. The specific HLA associations observed in the current study are unlikely to be due to chance since they were a priori hypothesized.

Summary

We show that entecavir, an FDA-approved drug used to treat chronic hepatitis B, potently inhibits HIV replication in vitro and leads to a 1 log decline in HIV RNA in vivo. Detailed analysis of two HIV-HBV co-infected patients receiving up to seven months of entecavir monotherapy demonstrated accumulation of HIV variants with the lamivudine-resistance mutation, M184V, in one of them. In vitro experiments demonstrated that M184V confers resistance to entecavir. Thus, entecavir has clinically relevant anti-HIV activity and can select for variants resistant to anti-HIV drugs. Until more is known about HIV resistance patterns and their selection by entecavir, caution is needed when using entecavir in HIV-HBV co-infected individuals not receiving fully suppressive antiretroviral regimens.

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.