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Comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) remains controversial. This individual patient data (IPD) meta-analysis aimed to compare HCC risk between the two drugs and identify any subgroup of patients who may benefit more from one treatment than the other.Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve CHB patients receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis, and diabetes status.We included 11 studies from Korea, Taiwan, and Hong Kong involving 42,939 patients receiving TDF (n=6,979) or ETV (n=35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk: adjusted HR 0.77 (95% CI 0.61-0.98; p=0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73, 95% CI 0.59-0.88; p0.01) and PSW (HR 0.83, 95% CI 0.67-1.03; p=0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76, 95% CI 0.58-1.00; p0.05), male (HR 0.74, 95% CI 0.58-0.96; p=0.02), HBeAg-positive (HR 0.69, 95% CI 0.49-0.97; p=0.03), and non-diabetic (HR 0.79, 95% CI 0.63-1.00; p0.05) subgroups.TDF was associated with significantly lower HCC risk than ETV in CHB patients, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups.Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in reducing hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan, and Hong Kong suggested that TDF-treated patients have a significantly lower HCC risk than ETV-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings may have to be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent.

The nucleos(t)ide analogues (NAs) entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are preferred treatment options for patients with chronic hepatitis B infection (CHB). However, resistance to ETV has been reported, especially with prior exposure to other NAs, and long-term TDF treatment has been associated with decline in renal function and loss of bone mineral density in some patients. Consequently, TAF may be preferable to ETV, TDF or other NAs in specific circumstances such as in patients with risk of bone or renal complications, elderly patients or those with previous NA experience.To provide a summary of the available efficacy and safety data following switch to TAF from other NAs in patients with CHB in clinical studies and real-world settings.Literature searches were performed on PubMed and abstracts from three major international liver congresses between 2019 and 2021. Studies that included efficacy and/or safety data for patients with CHB switching from any NA to TAF were selected.Thirty-six papers and abstracts were included in this narrative review. Switching from TDF to TAF maintained or improved virological and biochemical responses with improved bone and renal safety. Switching from ETV or other NAs to TAF maintained or improved virological and biochemical responses and varying results for bone and renal safety.Switching to TAF appears to maintain or improve virological, biochemical and bone- and renal-related safety outcomes. These data support the concept of switching to TAF in some patients with CHB based on their individual circumstances.

Background In a recent Phase 3 study (Study 4018) in HBV patients suppressed on TDF treatment, switching to TAF demonstrated non-inferior efficacy to continued TDF with superior bone and renal safety at Week 48. This study is to assess the safety and efficacy of switching to TAF from TDF in patients of Asian descent with risk factors for TDF toxicity as per current EASL and AASLD guidelines. Methods Virally suppressed patients (HBV DNA Results Among the 400 Asian patients enrolled, 288 (72%) had at least 1 TDF RF. At Week 48, similar proportions with ≥1 RF had HBV-DNA Conclusions Virally suppressed Asian patients with CHB and risk factors for TDF who switched to TAF showed improved bone and renal safety while efficacy was well-maintained.

BACKGROUND Efficacy trials have shown that antiviral therapy improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, prospective data regarding the effect of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), especially among patients without cirrhosis, are limited. The authors examined the impact of tenofovir disoproxil fumarate (TDF) on the incidence of HCC using a validated prediction model. METHODS The incidence of HCC in patients treated with TDF was obtained in the pivotal TDF registration studies after 384 weeks of follow-up. The predicted risk of HCC in individual patients was calculated using the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model, which estimates HCC incidence for up to 10 years based on age, sex, alanine aminotransferase level, hepatitis B e antigen status, and HBV-DNA. Standardized incidence ratios (SIRs) were calculated comparing the observed and predicted numbers of HCC cases in the study cohort. RESULTS Among 634 patients with evaluable baseline biopsies, 152 had cirrhosis (Ishak fibrosis score of 5 or 6) and 482 did not. During the 384 weeks of study, 14 cases of HCC were reported, with 4 occurring within the first year. The incidence of HCC was 0.37% per year in the study as a whole (0.28% among patients without cirrhosis and 0.65% among patients with cirrhosis). Among patients without cirrhosis, the observed incidence of HCC was significantly lower than predicted (SIR, 0.40; 95% confidence interval, 0.199-0.795). The last HCC case in a patient with cirrhosis occurred around week 192 with an SIR of 0.51 (95% confidence interval, 0.231-1.144) reported at week 384. CONCLUSIONS Based on the REACH-B risk calculator, long-term therapy with TDF was associated with a reduced incidence of HCC among patients without cirrhosis who met treatment criteria. Cancer 2015;121:3631–3638. © 2015 American Cancer Society.

Background & Aims We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA ≥9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment. Methods A total of 205 HBeAg-negative and HBeAg-positive self-described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA

Background: Two receptor chains, IL-10RA and IL-10RB, are known to mediate the functions of interleukin-10 (IL-10), which has been shown to be involved in the progression of persistent hepatitis C virus (HCV) infection. Little information is available on the role of host genetic variation in IL-10 receptor genes and outcome of HCV infection. IL-22, an IL-10 homologue, shares the IL-10RB receptor chain with IL-10 and has antiviral properties. We investigated the possible role of polymorphisms in the IL-10RA and IL-22 genes in hepatitis C disease pathogenesis. Methods: This study population consisted of 631 HCV patients, recruited from several hepatology clinics across Europe. We genotyped four singlenucleotide polymorphisms (SNPs) in the IL-10RA and six SNPs in the IL-22 gene by ligation detection reaction or restriction fragment length polymorphism. Outcome of HCV infection was assessed according to viral clearance, treatment response, severity of fibrosis and overall inflammation. Conclusions: Variation in IL-10RA appeared to be correlated with response to treatment and inflammation. Two SNPs in IL-22 affected treatment response and viral clearance respectively. We furthermore report on allele and haplotype frequencies and linkage disequilibrium for IL-10RA and IL-22. Our results indicate that genetic variation in these genes may play a modulatory role in the outcome of hepatitis C infection. The prevalence of Hepatitis C is approximately 3% worldwide and an estimated 80% of individuals infected by the hepatitis C virus (HCV) suffer from persistent infection (1). The rate of disease progression is variable and the determinants of the clinical outcome of the disease long-term remain poorly understood. Multiple factors affect the outcome of infectious diseases, including environmental factors and interactions with both pathogens and host genetic factors. There is an increasing body of evidence for the involvement of polymorphic variation in the outcome of persistent HCV infection, influencing the degree of inflammation, severity of fibrosis and response to interferon (IFN) therapy (2‐6). HCV infection may be treated with IFN-a or in combination with ribavirin, but the response to current treatment is variable. Only approximately 20% of infected individuals spontaneously clear the virus (self-limiting infection), whereas the remaining 80% proceed to persistent HCV infection (7). These patients have varying degrees of hepatic inflammation and fibrosis at presentation. Long-term, up to 30% of carriers develop cirrhosis with annual risks of 1‐6% of developing hepatocellular carcinoma and 2‐5% of dying from liver disease (8). The investigation of host genetic factors should help us gain a better understanding of the possible molecular mechanisms underlying susceptibility and differences in disease outcome of HCV infection.

SUMMARY. In patients with chronic hepatitis C virus (HCV) infection, steatosis and fibrosis have been shown to be inversely associated with total cholesterol (TC) and low- density lipoprotein cholesterol. Steatosis and fibrosis have also been found to be associated with triglyceride (TG) levels; though, the direction of the relationship is inconsistent across studies. The objective of this study was to assess whether viral level and histological factors are associated with the serum lipid profile in a treatment-naive cohort with chronic HCV genotype 1 infection. Participants were from the prospective Study of Viral Resistance to Antiviral Ther- apy (Virahep-C). Fasting lipid profiles were analysed for 160 African Americans and 170 Caucasian Americans. Linear regression was used to evaluate associations of each lipid with viral load and liver disease. TG levels were significantly and directly associated with HCV levels (P = 0.0034) and steatosis (P < 0.0001). Other lipid parameters were signifi- cantly lower in those with fibrosis (HDLc (P = 0.001) and TC levels (P = 0.004)) than in those without fibrosis. In patients with HCV genotype 1 infection, more severe liver disease was associated with lower lipid levels, with the exception of TG levels that were directly related to steatosis. The direct relationship between viral load and TG levels is consistent with proposed the mechanisms of very low den- sity lipoprotein/HCV particle secretion. In contrast, the direct relationship between TG level and steatosis is inconsistent with posited mechanisms of HCV-induced steatosis, a possi- ble reflection of HCV genotype 1 infection and a metabolic aetiology of steatosis.

Approximately one half of patients who undergo antiviral therapy for chronic hepatitis C virus (HCV) genotype 1 infection do not respond to treatment. African Americans (AAs) are less responsive to treatment than Caucasian Americans (CAs), but the reasons for this disparity are largely unknown. Recent studies suggest that serum lipids may be associated with treatment response. The aims of this study were to evaluate baseline and changes in serum lipids during therapy, determine whether serum lipids are associated with virological response, and assess whether these measures explain the racial difference in efficacy. The study participants were from Virahep-C, a prospective study of treatment-naïve patients with genotype 1 HCV infection who received peginterferon (PEG-IN) alfa-2a plus ribavirin therapy for up to 48 weeks. Fasting serum lipids were analyzed at baseline and during and after therapy in 160 AAs and 170 CAs. A relative risk (RR) model was employed to evaluate characteristics associated with sustained virological response (SVR). Antiviral therapy was associated with changes in serum lipids during and after antiviral therapy, with the changes differing by race and the amount of PEG-IFN taken. Baseline lipid measures independently associated with higher rates of SVR were lower triglyceride and higher low-density lipoprotein cholesterol, with an interaction between high-density lipoprotein cholesterol (HDLc) and gender. Lipid measures did not contribute significantly to an explanation of the racial difference in SVR.Serum lipids are associated with SVR, although these paramaters did not explain the racial difference in treatment response. The results of this study are compatible with proposed biological mechanisms of HCV entry, replication, and secretion, and may underscore new potential therapeutic targets for HCV eradication.

Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-α-2a is successful in eradicating virus from only 30 to 80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to the therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) ((relative risk) RR=0.80; 95% CI: 0.66−0.98; P=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95% CI: 0.66–0.94; P=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95% CI: 0.66–0.94; P=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% CI: 0.62–1.0; P=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy.

The dynamics of the viral decline immediately after the start of therapy for chronic hepatitis C virus (HCV) infection may have prognostic potential for ultimate sustained virologic response. Considerable interindividual variability in the decline has been reported, including differences by race. The human major histocompatability complex (MHC) genes encode the human leukocyte antigens, which are important in the immune response to viral infections. We examined whether carriage of specific human MHC alleles are associated with the rate of the early viral decline. Longitudinal viral level data (baseline and days 1, 2, 7, 14, and 28 of treatment), medium resolution MHC genotyping, and random coefficients models were used to examine associations between MHC class I and class II allele carriage and the dynamics of the viral decline in 180 African-Americans (AAs) and 194 Caucasian Americans (CAs) with genotype-1 HCV infection over the first 28 days of treatment with peginterferon α2a plus ribavirin. Baseline viral levels were similar by race, irrespective of allele carriage. However, the rate of change in the viral decline was associated with both allele and race. Among the four subgroups defined by race and specific allele, the fastest rates of decline were observed (in terms of estimated mean viral declines log 10 IU/ml during the first four weeks) in CA noncarriers for A*03 (2.75; P = 0.018), in CA carriers for Cw*03 (2.99; P = 0.046), and in CA noncarriers for DQA1*04 (2.66; P = 0.018) or DQB1*0402 (2.65; P = 0.018). MHC alleles are associated with the viral decline during the first 28 days of peginterferon therapy.

Hepatic steatosis is the accumulation of fat in liver cells. Insulin resistance (IR) occurs when normal amounts of insulin do not stimulate insulin activity in cells. Both conditions have been described in hepatitis C virus (HCV) infection and are thought to be biologically related. This study examined the association of genetic variants with steatosis and IR among 167 African Americans and 184 Caucasian Americans with HCV genotype-1. Steatosis was defined as at least 5% of fat in cells on liver biopsy. IR was quantified as a score greater than 2 from the Homeostasis Model Assessment, version 2.2 (HOMA2-IR). Associations were investigated by estimating odds ratios separately by race. Statistically significant associations (p < 0.05) were observed for variants in interleukin-10 (IL10), leptin receptor (LEPR), interleukin-6 (IL6) and transforming growth factor beta-1 (TGF-β1) for both outcomes. Some significant interactions were observed between IL10,LEPR and TGF-β1 polymorphisms and HOMA2-IR scores when examining steatosis. The interaction of HOMA2-IR and IL10 was consistent in both races whereas for LEPR and TGF-β1 the interactions were statistically significant in only one of the racial groups.These results could imply that some IL10,LEPR and TGF-β1 polymorphisms may modify an association between steatosis and IR.

Background: In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG-IFN) for 48-weeks results in higher rates of hepatitis B surface antigen (HBsAg) loss than either monotherapy. Aim: To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. Methods: A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG-IFN (PI, 180 μg/week, subcutaneous) for 48 weeks (TDF/PI-48w); TDF plus PEG-IFN for 16 weeks, TDF for 32 weeks (TDF/PI-16w+TDF-32w); TDF for 120 weeks (TDF-120w) or PEG-IFN for 48 weeks (PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. Results: Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. Conclusions: HBsAg decline at Week 24 of TDF plus PEG-IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.

Health departments, community-based organizations (CBOs), and AIDS service organizations (ASOs) in the United States and abroad distribute large quantities of free condoms to sexually active individuals; however, little is known about where individuals who use condoms actually acquire them. This community-based participatory research (CBPR) study was designed to identify factors associated with the use of free condoms during most recent anal intercourse among self-identifying gay and bisexual men who reported condom use. Data were collected using targeted intercept interviewing during North Carolina Pride Festival events in Fall 2006, using the North Carolina Condom Acquisition and Preferences Assessment (NC-CAPA). Of the 606 participants who completed the assessment, 285 met the inclusion criteria. Mean age of participants was 33 (+/-10.8) years. The sample was predominantly white (80%), 50% reported being single or not dating anyone special, and 38% reported the use of free condoms during most recent anal intercourse. In multivariable analysis, participants who reported using free condoms during most recent anal sex were more likely to report increased age; dating someone special or being partnered; and having multiple male sexual partners in the past 3 months. These participants were less likely to report ever having had a sexually transmitted disease. Despite being in the third decade of the HIV epidemic, little is known about condom acquisition among, and condom preferences of, gay and bisexual men who use condoms. Although more research is needed, our findings illustrate the importance of free condom distribution.

Crystal methamphetamine is a highly addictive stimulant that initially gained popularity in the western region of the United States and has spread to all regions of the country. This study was designed to identify factors associated with methamphetamine use among men who have sex with men (MSM) in North Carolina. Participants were recruited in five gay bars and in five geographically defined Internet chat rooms concurrently in 2005 to complete a brief assessment of drug use and other risk behaviors. Of the 1189 MSM who completed the assessment, mean age was 29 years. Two thirds self-identified as black/African American or other minorities, and 25% as bisexual. Nearly 6% reported using methamphetamines during the past 30 days. In multivariable analysis, MSM who reported using methamphetamines were more likely to report higher education; health insurance coverage; inconsistent condom use during anal sex within the past 3 months; a history of sexually transmitted disease (STD) infection; positive HIV serostatus; and use of medications designed to treat erectile dysfunction. A lack of data exists on methamphetamine use among MSM in the southeastern United States, particularly in nonurban regions. Because the southeastern United States carries a disproportionate HIV, AIDS, and STD burden, our findings underscore the need for further research and intervention.

Chat room-based human immunodeficiency virus (HIV) prevention interventions are being implemented to reduce the risk of HIV exposure, infection and reinfection among men who have sex with men (MSM). However, little is known about how participants in chat room-based prevention interventions differ from their online non-participating peers. This analysis compared the baseline risk profiles of participants in an HIV prevention intervention ('active recruitment') to their chat room peers who did not participate in the intervention ('passive recruitment'). Data were collected using an online brief risk assessment from MSM (N = 448) who were recruited within Internet chat rooms. Mean age was 30 years. Half self-identified as Black or African American, 29% as White and 64% as gay. Compared with participants, non-participants were more likely to report: spending higher mean number of hours in online chat rooms; using condoms inconsistently during anal intercourse with a man met online during the past 3 months; having had an sexually transmitted disease; being HIV seropositive; using methamphetamines during the past 30 days and using drugs to enhance sexual satisfaction during the past 30 days. Although risk among MSM who use chat rooms remains high, those at greater risk may be those who are less likely to engage in online HIV prevention interventions.

Background:� Althoughseekingsexualpartnersonthe� InternetisanidentifiedriskfactorforHIVandsexually� transmitteddiseaseinfectionamonggaymenandmenwho� havesexwithmen� (MSM),� themedicalliteraturelacks� descriptionsofthedevelopment,� implementation,� and� evaluationofinterventionsforreducinginfectionsamong� menwhoseeksexualpartnersonline. Objectives:�WesoughttofillthisgapbydescribingCyber- Based Education and Referral/Men for Men�(CyBER/M4M),� aninterventiondesignedtoreduceHIVexposureandtrans­ missionamonggaymenandMSMwhousegeographically� definedchatrooms. Methods:� CyBER/M4Mwasdevelopedbyacommunity- universitypartnershipthatincludedgaymenwhohad� experiencewithseekingsexualpartnersonline,�andrepre­ sentativesfromcommunity­basedorganizations,� thelocal� publichealthdepartment,� twouniversities,� andnational� organizationswithexpertiseincommunity­basedparticipatory� research�(CBPR)�andHIVprevention.� Results: Twoproductsemerged:� theCyBER/M4M Training Manual,� designedtofacilitatetrainingoflayhealthadvisors� knownasCyBER/M4MEducators,�andCyBER/M4M Resource Manual,�designedasareferencefortheEducators. Conclusions:�Furtherresearchisclearlyneeded,�butthiswork� providesinsightintothedevelopment,�implementation,�and� evaluationofachatroom­basedHIVpreventionintervention� usingCBPR.

While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients.Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up.In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy.APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy.

Phase 3 clinical studies have shown that long-term treatment with tenofovir disoproxil fumarate (TDF) can suppress hepatitis B viral load and promote significant fibrosis regression and cirrhosis reversal in a majority of treated chronic hepatitis B (CHB) patients. This retrospective analysis investigated the impact of baseline cirrhosis status on virologic, serologic, and histologic outcomes in patients treated with TDF. Patients enrolled in studies GS-US-174-0102 and GS-US-174-0103 who had baseline liver biopsy-diagnosed cirrhosis and entered the open-label phase of the studies were included in the virologic and serologic analyses. Patients (both HBeAg positive and negative) with paired liver biopsies at baseline and 5 years (N = 348) were included in a histologic analysis. After 5 years on study, comparing patients with and without baseline cirrhosis, respectively: 99.2 and 98.0 % achieved virologic response (hepatitis B viral load < 69 IU/ml) (p = 0.686); 79.7 and 81.9 % had normal serum levels of alanine aminotransferase (p = 0.586); 4.0 and 1.2 % developed hepatocellular carcinoma (p = 0.044). In HBeAg-positive patients with and without baseline cirrhosis, HBsAg loss occurred in 14.4 and 8.3 % of patients, respectively (p = 0.188). One HBeAg-negative patient had HBsAg loss. This represents the largest analyses to date of CHB patients with sequential liver biopsies demonstrating that treatment with TDF for up to 5 years is associated with favorable virologic, serologic, and histologic outcomes, regardless of baseline cirrhosis status. Notably, histologic improvement was observed in the majority of cirrhotic and noncirrhotic patients. Gilead Sciences Robert W. Storr bequest University of Sydney National Health and Medical Research Council (NHMRC) of Australia (1053206) Sydney West Translational Cancer Research Centre Partner Program - Cancer Institute NSW

Efficacy trials have shown that antiviral therapy improves the outcomes of patients with chronic hepatitis B virus (HBV) infection. However, prospective data regarding the effect of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), especially among patients without cirrhosis, are limited. The authors examined the impact of tenofovir disoproxil fumarate (TDF) on the incidence of HCC using a validated prediction model.The incidence of HCC in patients treated with TDF was obtained in the pivotal TDF registration studies after 384 weeks of follow-up. The predicted risk of HCC in individual patients was calculated using the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model, which estimates HCC incidence for up to 10 years based on age, sex, alanine aminotransferase level, hepatitis B e antigen status, and HBV-DNA. Standardized incidence ratios (SIRs) were calculated comparing the observed and predicted numbers of HCC cases in the study cohort.Among 634 patients with evaluable baseline biopsies, 152 had cirrhosis (Ishak fibrosis score of 5 or 6) and 482 did not. During the 384 weeks of study, 14 cases of HCC were reported, with 4 occurring within the first year. The incidence of HCC was 0.37% per year in the study as a whole (0.28% among patients without cirrhosis and 0.65% among patients with cirrhosis). Among patients without cirrhosis, the observed incidence of HCC was significantly lower than predicted (SIR, 0.40; 95% confidence interval, 0.199-0.795). The last HCC case in a patient with cirrhosis occurred around week 192 with an SIR of 0.51 (95% confidence interval, 0.231-1.144) reported at week 384.Based on the REACH-B risk calculator, long-term therapy with TDF was associated with a reduced incidence of HCC among patients without cirrhosis who met treatment criteria.

Because the southeastern USA is experiencing a disproportionate HIV infection rate compared to other regions of the country, we explored HIV behavioural risk disparities by race/ethnicity among self-identifying gay men. Conceived and implemented as a community-based participatory research (CBPR) study, this rapid assessment collected demographic and HIV risk-behaviour data from men in five gay bars in the northwestern part of the state of North Carolina, using an assessment available in English and Spanish. Of 719 participants, 34.8% reported inconsistent condom use during anal intercourse in the past three months, 11.4% reported ever having had a sexually transmitted disease (STD), 3.6% reported being HIV-seropositive and 26% reported illicit drug use during the past 30 days. Compared to white participants, African American/black and Hispanic/Latino participants were more likely to report inconsistent condom use during anal intercourse with multiple partners during the past three months. African American/black participants were more likely to report illicit drug use during the past 30 days. Hispanic/Latino participants were more likely to have never been tested for HIV. Rates of HIV risk behaviours among gay men remain high and racial/ethnic differences indicate the need for targeted and tailored prevention strategies.

We examined correlates of antinuclear antibody (ANA) positivity (ANA+) in individuals with chronic hepatitis C virus (HCV) infection and the effect of positivity on clinical outcome of HCV. Pretreatment sera from 645 patients from three centres in Sweden (n = 225), the UK (n = 207) and Italy (n = 213) were evaluated by indirect immunofluorescence on Hep-2 cells for ANA pattern and titre by a single laboratory. Liver biopsies were all scored by one pathologist. A total of 258 patients were subsequently treated with interferon monotherapy. There was a significant difference in the prevalence of ANA (1:40) by geographic location: Lund 4.4%, London 8.7%, Padova 10.3% [odds ratio (OR) = 0.66; 95% CI: 0.46-0.94; P = 0.023]. Duration of HCV infection, age at infection, current age, route of infection, viral genotype, alcohol consumption, fibrosis stage and inflammatory score were not correlated with ANA+ or ANA pattern. Female gender was correlated with ANA+ and this association persisted in multivariable analyses (OR = 3.0; P = 0.002). Increased plasma cells were observed in the liver biopsies of ANA-positive individuals compared with ANA-negative individuals, while a trend towards decreased lymphoid aggregates was observed [hazard ratio (HR) = 9.0, P = 0.037; HR = 0.291, P = 0.118, respectively]. No correlations were observed between ANA positivity and nonresponse to therapy (OR = 1.4; P = 0.513), although ANA+ was correlated with faster rates of liver fibrosis, this was not statistically significant (OR = 1.8; P = 0.1452). Low titre ANA+ should not be a contraindication for interferon treatment. Our observation of increased plasma cells in ANA+ biopsies might suggest B-cell polyclonal activity with a secondary clinical manifestation of increased serum immunoglobulins.

Inducible nitric oxide synthase (iNOS) is an important molecule involved in the host defense against infectious agents. iNOS is encoded by the NOS2A gene and well-defined haplotypes exist with respect to this gene. We examined whether these haplotypes were associated with the outcome of hepatitis C virus (HCV) infection in 619 Caucasian patients from seven European liver centres. We observed five major haplotypes: (-277A)+(-1026G)+(-1659C): haplotype 1; (-277G)+(-1026T)+(-1659C): haplotype 2; (-277G)+(-1026G)+(-1659C): haplotype 3; (-277G)+(-1026T)+(-1659T): haplotype 4; and (-277A)+(-1026T)+(-1659C): haplotype 5. Distributions of these haplotypes are comparable with those of previous studies. Homozygotes for haplotype 2 or those with haplotypes 2/4 were more likely than those with the 1/1 (wild type) combination to have self-limiting infections (odds ratios (OR)=3.43; 95% confidence intervals (95% CI): 1.10-8.0; P=0.0206 and OR=5.15; 95% CI: 1.32-14.32; P=0.0018, respectively). Conversely, carriage of haplotype 1 was associated with the lack of self-limiting disease (OR=0.48; 95% CI: 0.27-0.83; P=0.009). The effect was mainly among males (OR=0.41; 95% CI: 0.182-0.942; P=0.031 for males, and OR=0.55; 95% CI: 0.24-1.37; P=0.136 for women). Carriage of haplotype 1 was not associated with initial response (P=0.268) or sustained response (P>0.171). Combinations of haplotypes 1/4 were more likely to respond to interferon monotherapy in comparison of initial responders to nonresponders (OR=2.25; 95% CI: 1.05-5.68; P=0.0275).

Using a bar-based sample, we identified factors associated with hepatitis B virus (HBV) vaccination among young African American men who have sex with men (MSM). The mean (+/- standard deviation [SD]) age of the 170 participants was 26 +/- 6.5 years. Nearly 40% reported at least one dose of vaccine; the remainder were completely unvaccinated. Approximately 22% (37) reported having never heard of HBV. Less than 7% of participants reported using condoms the majority of the time during oral intercourse within the past 3 months, and approximately 50% reported using condoms the majority of the time during anal intercourse within the past 3 months. In multivariable analysis, variables associated with vaccination were younger age (odds ratio [OR], 0.44 per 10-year increase in age; 95% confidence interval [CI]: 0.21-0.93, p = 0.032), higher educational attainment (OR, 4.6; 95% CI: 1.17-12.59, p = 0.003), homosexual as opposed to bisexual behavior (OR, 0.15; 95% CI: 0.06-0.41, p = 0.0001), and recent visits to a health care provider (OR, 4.31; 95% CI: 2.08-8.94, p = 0.0001). Our findings underscore the need to reach MSM for HBV vaccination. Innovative approaches are necessary to ensure the prevention of infection, transmission and disease among individuals with limited education, bisexual MSM, and men who have limited access to health care.

Objectives: Hepatitis B infection (HBV) is prevalent among men who have sex with men (MSM) and may lead to significant morbidity and death. Although an effective vaccine exists vaccination rates among MSM are low. We conducted a systematic review to synthesise the various findings from empirical correlational studies to understand HBV vaccination and series completion among MSM. Methods: We systematically searched the Medline, PubMed, EMBASE, CINAHL, ERIC, and Web of Science databases to identify the breadth of published studies pertaining to HBV vaccination among MSM and to synthesise findings from these studies to better identify common themes that may direct future research and intervention approaches. Results: Eight papers specifically addressed correlates of HBV vaccination among MSM. Six domains were identified as predictors of vaccination: (1) demographic variables such as younger age and higher education level; (2) knowledge of the vaccine; (3) access to health care; (4) level of "outness" regarding one's same sex sexual orientation; (5) behavioural factors including sexual and drug use behaviour; and (6) psychosocial variables. Three papers addressed predictors of vaccine series completion among MSM, observing two main domains: (1) demographic variables such as younger age and higher income level; and, (2) behavioural factors including sexual and health promotion behaviours. Conclusions: Continued educational efforts, creation of environments that facilitate proper risk factor evaluation, and access to low cost vaccine may facilitate vaccine uptake. Although we observed important trends in the studies we reviewed, there is a lack of empirical research regarding this important public health issue.

This study compared the demographics and risk behaviors of two samples of men who have sex with men (MSM), using cross-sectional data that were collected via the Internet and through conventional bar-based outreach. The Internet sample was significantly older, more likely to identify as "bisexual," and less educated than the bar sample. After controlling for age and education, few differences were observed between the samples. However, three variables that markedly differentiated the samples were history of sexually transmitted disease infection, HIV serostatus, and sources utilized to obtain health information. No difference in Internet use was found. Based on the possible decreased social desirability promoted by the use of electronic data collection methodologies, these findings provide preliminary evidence that Internet and bar respondents are similar and that the Internet may serve as an expedient as well as reliable methodology to increase understanding of risk among MSM.

We explored the influence of the major CCR5 promoter or coding region variants as haplotypes and genotypes in a cohort of 250 chronically infected HCV patients receiving combined interferon/ ribavirin therapy. No haplotype, including the D32-bearing haplotype (G*2) reportedly associated in homozygotes with high HCV viral load (VL), showed a similar effect. Patients with genotype C/G*2 showed slightly lower median VL (p = 0.05). Neither the G*2 haplotype nor the C/G*2 genotype influenced viral dynamics during the initial 12 wk of treatment (p = 0.53). The genotype E/E was more frequent among sustained responders (15.5%) than non-responders (7.8%), and VL declined further among E/E homozygotes during the initial 12 wk of treatment, particularly those with HCV genotype 1 (p = 0.016). Differential receptor expression due to E/E homozygosity in HCV infection remains to be confirmed.

Background Perinatal or mother-to-child transmission of hepatitis B virus (HBV) results in a high frequency of chronic infection. Risk of mother-to-child transmission is associated with maternal viral factors including hepatitis B e antigen (HBeAg) positivity and viral load. Aim To investigate associations between age, HBeAg status, HBV DNA levels and genotype in female patients screened for inclusion into two contemporary, randomized HBV trials. Methods Retrospective analyses focused on differences between women of childbearing age (≤44 years) and older women. Female patients (N = 355; 18–69 years) were included in the analysis: 41.7% of patients were Asian. In total, 44.4% were HBeAg-positive. Results Significantly more women aged ≤44 years were HBeAg-positive compared to women ≥45 years (57.2% versus 27.5%, respectively, p108 copies mL: ≤44 years 46.0% vs ≥45 years 25.5%, respectively; p

Background: Nearly 4 million individuals in the United States (1.8%) have been infected with hepatitis C virus, yet few are aware of their infection. Goal: To identify correlates associated with hepatitis C virus testing among a sample of men who have sex with men. Study Design: Internet communications were used for solicitation and collection of data, using a 31-question survey. Results: When the study was restricted to men who have sex with men in the United States (n = 381), 95% of the respondents (n = 361) reported at least one risk factor for hepatitis C virus transmission, 39% of these respondents (n = 140) reported having been tested for hepatitis C virus. Testing was associated with a history of nonsexual risk behavior, increased knowledge of the hepatitis C virus, and healthcare provider communication. Conclusion: A significant proportion of at-risk respondents had not been tested. Interventions are needed to increase hepatitis C virus knowledge in the community of men who have sex with men, and to encourage providers to communicate about hepatitis to the men in this group who screen as high risk on the basis of their risk behaviors.

Host genetic factors have been reported to influence the natural history of hepatitis C virus (HCV) infection. We examined whether variation in interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha) genes would predict the likelihood of sustained response to antiviral therapy. Single nucleotide polymorphisms (SNPs) and microsatellites at two loci encoding the cytokines IL-10 and TNF-alpha were determined by polymerase chain reaction (PCR)-based techniques. Their relationship to the outcome of antiviral therapy for chronic HCV infection was studied in 49 white patients who had a virologically sustained response (SR) and in 55 white nonresponders (NR) to a combination of interferon alfa-2b and ribavirin (IFN + R). Several IL-10 variants were more frequent among SRs compared with NRs. Carriage of the -592A or the -819T SNP was associated with SR (odds ratio [OR] = 2.2; P =.016). The -592A/A and the exclusively linked -819T/T genotypes were also associated with SR (OR = 16.6; P =.013 for either). The haplotype consisting of the 108-bp IL-10.R microsatellite and -3575T, -2763C, -1082A, -819T, -592A was also associated with SR (OR = 2.65; P =.01). Stratification for viral genotype, baseline viral RNA concentration, and histologic status identified homozygosity for the haplotype as the principal determinant: all 5 homozygous individuals achieved SR (OR(crude) = 13.7; P =.025; stratified ORs = 1.9-7.0), whereas heterozygotes differed only slightly from wild-type carriers. In contrast, TNF alleles defined by promoter sequences -238G/A and -308G/A were approximately equally distributed among SR and NR. In conclusion, homozygosity for -592A, -819T or the extended haplotype (108bp) - (-2575T) - (-2763C) - (-1082A) - (-819T) - (-592A) is associated with SR to IFN + R.

Tropomodulin is a globular protein that caps the pointed end of actin filaments by complexing with the N-terminus of a tropomyosin (TM) molecule. TM consists of coiled coils except for the N-terminus, which may be globular. Here we report that human TM isoform 5 (hTM5) lacking the N-terminal 18 residues lost its binding activity toward tropomodulin. We further characterized the tropomodulin-binding site by creating a series of deletion and missense mutations within this region, followed by a solid-phase binding assay. I 7 , V 10 , and I 14 , hydrophobic residues located at the a and d positions of N-terminal heptad repeats involving intertwine, are essential for tropomodulin binding. R 12 , a positively charged residue at the f position, is also involved in recognition. In contrast, A2R and G3Y mutations, each creating a bulky N-terminus, did not alter the binding. In addition, rat TM5b, which differs from hTM5 in residues 4–6, exhibits a similar binding affinity. The tropomodulin-binding site, therefore, is mapped to residues 7–14 at the beginning of the long heptad repeats. Column chromatography revealed that hTM5 mutants remained capable of dimerization. Results also suggest tropomodulin has a groove-type, rather than a cavity-type, binding site for hTM5. We also mapped the epitope of monoclonal antibody LC1 to residues 4–10 of hTM5 and showed the competition between mAb LC1 and tropomodulin in hTM5 binding. Since the N-terminal residues need to overlap with the C-terminus of TM in their head-to-tail association, this investigation elucidates the mechanisms by which the tropomodulin–hTM5 complex is formed and functions in regulating the actin filaments.

The human erythrocyte membrane skeleton consists of hexagonal lattices with junctional complexes containing F-actin protofilaments of approximately 33-37 nm in length. We hypothesize that complexes formed by tropomodulin, a globular capping protein at the pointed end of actin filaments, and tropomyosin (TM), a rod-like molecule of approximately 33-35 nm, may contribute to the formation of protofilaments. We have previously cloned the human tropomodulin complementary DNA and identified human TM isoform 5 (hTM5), a product of theγ-TM gene, as one of the major TM isoforms in erythrocytes. We now identify TM5b, a product of the -TM gene, to be the second major TM isoform. TM5a, the alternatively spliced isoform of the-TM gene, which differs by 1 exon and has a weaker actin-binding affinity, however, is not present. TM4, encoded by the δ-TM gene, is not present either. In sodium dodecyl sulfate–polyacrylamide gel electrophoresis, hTM5 comigrated with the slower TM major species in erythrocyte membranes, and hTM5b comigrated with the faster TM major species. TM5b, like TM5, binds strongly to tropomodulin, more so than other TM isoforms. The 2 major TM isoforms, therefore, share several common features: They have 248 residues, are approximately 33-35 nm long, and have high affinities toward F-actin and tropomodulin. These common features may be the key to the mechanism by which protofilaments are formed. Tropomodulin-TM5 or tropomodulin-TM5b complexes may stabilize F-actin in segments of approximately 33-37 nm during erythroid terminal differentiation and may, therefore, function as a molecular ruler. TM5 and TM5b further define the hexagonal geometry of the skeletal network and allow actin-regulatory functions of TMs to be modulated by tropomodulin.

Chronic hepatitis B (CHB) patients with high pretreatment viral load (HVL) represent a clinical challenge. Higher levels of hepatitis B virus (HBV) DNA are associated with an increased risk for hepatocellular carcinoma (HCC) and cirrhosis.1 In addition, available evidence suggests that CHB patients with HVL are less likely to respond to interferon (IFN)-based regimens than those with lower viral load. In hepatitis B e antigen (HBeAg)-positive patients, having baseline HBV DNA

The outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are heterogeneous, ranging from an asymptomatic self-limiting infection to cirrhosis and hepatocellular carcinoma. Several viral environmental and demographic variables have been identified as determinants of disease outcome, but these fail to explain a large proportion of the variability. Evidence from twin studies suggests that the host genetic background is an important contributor to disease outcome. Identification of genes that influence the outcome of infection has been attempted using a wide spectrum of approaches including candidate gene disease association studies, genome-wide scanning in affected sibling pairs and most recently genome-wide association studies. We summarize the main findings from a large number of studies in this review. Many studies have focused on the MHC loci from which several reproducible disease associations have been identified. More recently, genome-wide association studies have identified an important locus within the IL-28 - Il-29 region on chromosome 29, which appears to be a major determinant of the treatment response in patients infected with HCV and also a determinant of spontaneous resolution of infection. Translation of the genetic architecture of chronic viral hepatitis into therapeutic opportunities has been slow to proceed. One clinical trial and one drug development program have been based on genetic discoveries. The use of IL-28B genotyping to predict the response to pegylated interferon and ribavirin may also find its way into clinical practice. Indeed, stratification of clinical trial populations based on IL-28B genotype is already considered mandatory.

Little is known about the intersections of immigration, masculinity, and sexual risk behaviours among recently arrived Latino men in the United States (USA). Nine immigrant Latino men from three urban housing communities in the South-eastern USA used photovoice to identify and explore their lived experiences. From the participants’ photographs and words, thirteen themes emerged within four domains. The immigration experience and sociocultural norms and expectations of masculinity were factors identified decreasing Latino men’s sense of power and increasing stress, which lead to sexual risk. Latino community strengths and general community strengths were factors that participants identified as promoting health and preventing risk. These themes influenced the development of a conceptual model to explain risk among immigrant Latino men. This model requires further exploration and may prove useful in intervention development.

The human major histocompatability complex (MHC) genes encode the human leukocyte antigens, which are important in antigen presentation and regulation of CD8+ and CD4+ T cells. Response to therapies in hepatitis C virus (HCV) infection is highly variable (30-80%) and lower response rates have been reported among African Americans (AA; approximately 30%) compared to Caucasian Americans (CA; approximately 50%) infected with genotype-1 viruses. We evaluated whether MHC gene variants were associated with response to therapy and racial differences in AA and CA sustained virologic response (SVR) rates. We genotyped alleles at 8 MHC loci: 3 class I (A, B and C) and 5 class II (DRB1, DQA1, DQB1, DPA1 and DPB1) loci in 373 individuals (179 AA and 194 CA) with genotype-1 HCV infections, who were treated with peginterferon-alpha-2a and ribavirin. We observed carriage of A(*)02 (RR=1.33(1.08-1.64); P=0.008), B(*)58 (RR=1.84(1.24-2.73); P=0.002) and DPB1(*)1701 (RR=1.57(1.09-2.26); P=0.015) to be associated with SVR after adjustment for other predictors of response. In analysis of AA and CA subgroups separately, we observed potential, though not statistically significant, differences in these MHC associations. Variation in the immunogenetic background of HCV-infected individuals might account for some observed variation in viral-specific immunity and courses of disease. In this regard, future studies examining broader patient populations are warranted.

This chapter examines the epidemiology of hepatitis A, hepatitis B, and hepatitis C within the U.S. male population and within various samples of men-who-have-sex-with-men. Vaccine strategies for the prevention of hepatitis A and B are discussed, including relevant information about vaccine uptake among MSM. The chapter concludes with a review of promising strategies for resolving disparities in hepatitis infection (especially HBV) among MSM. These include both clinic and community-based interventions.

Candidate genes, including myxovirus resistance-1 (Mx1), protein kinase (PKR), transforming growth factor-β1 (TGF-β), interleukin-10 (IL-10), and interferon-gamma (IFN-γ), were evaluated for associations with liver fibrosis in 374 treatment-naive patients with genotype-1 chronic HCV infection [194 Caucasian Americans (CAs) and 180 African Americans (AAs)], using a genetic haplotype approach. Among the 18 haplotypes that occurred with a frequency ≥5% in the cohort overall, the Mx1-(-123C)-(+6886A)-(+19820G(379V))-(+38645T) (abbreviated Mx1-CAGT), and PKR-(+110T)-(+7949G)-(+13846A)-(+22937T)-(+40342T) (abbreviated PKR-TGATT) haplotypes were independently associated with less severe hepatic fibrosis (Ishak ≥ 3 versus

P0644 HCC RISK SCORES: APPLICATION OF THE CU-HCC, GAG-HCC AND PAGE-B SCORES TO CHRONIC HEPATITIS B (CHB) PATIENTS TREATED WITH TENOFOVIR DISOPROXIL FUMARATE (TDF) W.R. Kim, R. Loomba, T. Berg, R. Aguilar Schall, L. Yee, P. Dinh, J.F. Flaherty, E.B. Martins, I. Jacobson, S. Fung, S. Gurel, M. Buti, P. Marcellin. Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, Division of Gastroenterology, and Epidemiology, University of California at San Diego, La Jolla, United States; Department of Internal Medicine, Division of Gastroenterology and Rheumatology, Section of Heptology, Universitatsklinikum Leipzig, Leipzig, Germany; Gilead Sciences, Foster City, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, United States; Department of Gastroenterology, University of Toronto, Toronto, Canada; Department of Gastroenterology, University of Uludag, Bursa, Turkey; Department of Hepatology, Hospital General Universitari Vall d’Hebron, Barcelona, Spain; Department of Hepatology, Hopital Beaujon, University of Paris, Clichy, France E-mail: Leland.yee@gilead.com

Background: An understanding of vaccine acceptance and uptake is imperative for successful vaccination of populations that will be primary targets for vaccination after a vaccine against HIV is developed and ready for dissemination. Experiences with vaccination against vaccine-preventable hepatitis (VPH) among men who have sex with men (MSM) may offer key insights to inform future HIV vaccination strategies. The purpose of this analysis was to explore what is known currently about vaccination among MSM, using knowledge gained from vaccination against VPH, and to identify important considerations from these experiences that must be explored further as a vaccine against HIV is promoted among MSM. Because cultural and political differences make it difficult to extrapolate findings from studies in one country to another, we have focused our analyses on studies conducted in the USA. Methods: Through a qualitative systematic review of published reports, we identified eight studies that reported correlates of VPH among MSM in the USA. Results: Six major domains of variables associated with vaccination against VPH were identified, including: demographics (e.g. younger age, higher educational attainment); increased vaccine knowledge; increased access to health care; provider recommendation; behaviours (e.g. same-sex behaviour, health-promoting and disease-preventing behaviours); and psychosocial factors (e.g. openness about one’s sexual orientation, reduced barriers to being vaccinated, self-efficacy). Conclusions: Further research is needed to understand vaccination behaviour among MSM and to maximise acceptance and uptake after a vaccine exists. Experiences with VPH provide a real-world model on which to base preliminary assumptions about acceptance and uptake of a vaccine against HIV.

In addition to viral and environmental/behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in hepatitis C virus (HCV) infection. This paper reviews the literature with respect to studies of host genetic determinants of HCV outcome and attempts to highlight trends and synthesise findings. With respect to the susceptibility to HCV infection, several studies have replicated associations of the HLA class II alleles DQB1(*)0301 and DRB1(*)11 with self-limiting infection predominantly in Caucasian populations. Meta-analyses yielded summary estimates of 3.0 (95% CI: 1.8-4.8) and 2.5 (95% CI: 1.7-3.7) for the effects of DQB1(*)0301 and DRB1(*)11 on self-limiting HCV, respectively. Studies of genetics and the response to interferon-based therapies have largely concerned single-nucleotide polymorphisms and have been inconsistent. Regarding studies of genetics and the progression of HCV-related disease, there is a trend with DRB1(*)11 alleles and less severe disease. Studies of extrahepatic manifestations of chronic HCV have shown an association between DQB1(*)11 and DR3 with the formation of cryoglobulins. Some important initial observations have been made with respect to genetic determinants of HCV outcome. Replication studies are needed for many of these associations, as well as biological data on the function of many of these polymorphisms.