Hepatocellular carcinoma among patients with chronic hepatitis B in the indeterminate phase.

Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an 'indeterminate phase' or 'grey zone'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.

Chronic hepatitis B baseline viral load and on-treatment liver cancer risk: A multinational cohort study of HBeAg-positive patients.

BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.

Atherosclerotic cardiovascular disease risk profile of patients with chronic hepatitis B treated with tenofovir alafenamide or tenofovir disoproxil fumarate for 96 weeks.

BACKGROUND: Patients with chronic hepatitis B (CHB) who switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) show changes in lipid profiles. AIM: To evaluate how these changes affect cardiovascular risk. METHODS: This pooled analysis, based on two large prospective studies, evaluated fasting lipid profiles of patients with CHB who were treated with TAF 25 mg/day or TDF 300 mg/day for 96 weeks. Patients who fulfilled the American College of Cardiology criteria (age 40-79 years, high-density lipoprotein [HDL] 20-100 mg/dL, total cholesterol [TC] 130-320 mg/dL and systolic blood pressure 90-200 mmHg) required to assess 10-year atherosclerotic cardiovascular disease (ASCVD) risk with baseline lipid data and at least one post-baseline measurement were included in the ASCVD-risk population. The 10-year ASCVD risk was calculated for patients in this population, and changes from baseline to Week 96 were assessed using intermediate- (≥7.5%) and high-risk (≥20%) cut-offs. RESULTS: Among 1632 patients, 620 (38%) met the criteria for the ASCVD-risk population. At Week 96, fasting levels of all lipids, except TC:HDL ratio, were lower with TDF than TAF. No significant increase was observed in overall ASCVD risk or in any ASCVD-risk categories during the 96-week treatment period compared with baseline. A similar proportion of patients in the TAF and TDF treatment groups (1.3% and 2.3%, respectively; p = 0.34) reported cardiovascular events. CONCLUSION: Despite on-treatment differences in lipid profiles with TAF and TDF, predicted cardiovascular risk and clinical events were similar for both groups after 96 weeks.

Tenofovir alafenamide and tenofovir disoproxil fumarate reduce incidence of hepatocellular carcinoma in patients with chronic hepatitis B.

Background & Aims: Antiviral therapy may attenuate the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to explore how tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) affect HCC risk in patients with CHB. Methods: The REACH-B, aMAP, and mPAGE-B models were utilized to assess HCC risk in patients with CHB from two global randomized-controlled trials evaluating the impact of TAF vs. TDF treatment. Standard incidence ratios (SIRs) were calculated using data from the REACH-B model as a ratio of observed HCC cases in the TAF- or TDF-treated patients vs. predicted HCC cases for untreated historical controls. Proportions of treated patients shifting aMAP and mPAGE-B risk categories between baseline and Week 240 were calculated. Results: Of the 1,632 patients (TAF, n = 1,093; TDF, n = 539) followed for up to 300 weeks, 22 HCC cases developed. Those receiving TAF had an SIR that was lower compared to the SIR of individuals receiving TDF: 0.32 (p <0.001) vs. 0.56 (p = 0.06). In the general study population, individuals without cirrhosis at baseline had an SIR that was lower compared to the SIR of individuals with cirrhosis at baseline: 0.37 (p <0.001) vs. 0.58 (p = 0.15). Of the patients at low risk of HCC at baseline, the majority (97%) remained low risk by mPAGE-B and aMAP scoring at Week 240. Among those at medium or high risk at baseline, substantial portions shifted to a lower risk category by Week 240 (mPAGE-B: 22% and 42%; aMAP: 39% and 63%, respectively). Conclusions: This evaluation provides evidence that treatment with TAF or TDF can reduce HCC risk in patients with CHB, particularly in patients without cirrhosis. Impact and implications: Despite the substantial impact of HCC on long-term outcomes of patients with CHB, the differential risk of HCC development among those receiving treatment with TAF vs. TDF has not been well elucidated. Using three validated risk prediction models, we found that TAF is at least as effective as TDF in reducing HCC risk in patients with CHB. While TDF is well-studied in the context of HCC risk reduction, our novel findings underscore the effectiveness of TAF as a treatment option for patients with CHB. Clinical trial numbers: NCT01940341; NCT02836249; NCT01940471; NCT02836236.

Evidence for Benefits of Early Treatment Initiation for Chronic Hepatitis B.

Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Antiviral treatment reduces the risk of HCC and mortality; nonetheless, globally in 2019, only 2.2% of CHB patients received treatment. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage. This contrasts with hepatitis C or HIV where early treatment is recommended in all infected patients, regardless of end-organ damage. This narrative review aims to provide an overview of data on the early initiation of antiviral treatment and its related potential economic impact. Literature searches were performed using PubMed and abstracts from international liver congresses (2019-2021). Data on risk of disease progression and HCC and the impact of antiviral treatment in currently ineligible patients were summarized. Cost-effectiveness data on early antiviral treatment initiation were also collated. Accumulating molecular, clinical, and economic data suggest that early initiation of antiviral treatment could save many lives through HCC prevention in a highly cost-effective manner. In light of these data, we consider several alternative expanded treatment strategies that might further a simplified 'treatment as prevention' approach.

Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis.

BACKGROUND & AIMS: The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other. METHODS: 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 patients with CHB 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. RESULTS: 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 hazard ratio [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; p <0.01) 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; p <0.05), 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; p <0.05) subgroups. CONCLUSION: TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups. IMPACT AND IMPLICATIONS: Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma 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 tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should 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.

Review article: switching patients with chronic hepatitis B to tenofovir alafenamide-a review of current data.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study.

BACKGROUND & AIMS: Long-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB). METHODS: LAM-R CHB patients were randomised 1:1 to receive TDF 300mg or FTC 200mg and TDF 300mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA<69IU/ml (<400copies/ml) at week 96 (primary efficacy endpoint) was reported previously. Here we present week 240 follow-up data. RESULTS: Overall, 280 patients were randomised to receive TDF (n=141) or FTC/TDF (n=139), and 85.4% completed 240weeks of treatment. At week 240, 83.0% of patients in the TDF arm, and 82.7% of patients in the FTC/TDF treatment arm had HBV DNA<69IU/ml (p=0.96). Rates of normal alanine aminotransferase (ALT) and normalised ALT were similar between groups (p=0.41 and p=0.97 respectively). Hepatitis B e antigen loss and seroconversion at week 240 were similar between groups, (p=0.41 and p=0.67 respectively). Overall, six patients achieved hepatitis B surface antigen (HBsAg) loss and one patient (FTC/TDF arm) had HBsAg seroconversion by week 240. No TDF resistance was observed up to week 240. Treatment was generally well tolerated, and renal events were mild and infrequent (∼8.6%). The mean change in bone mineral density at week 240 was -0.98% and -2.54% at the spine and hip, respectively. CONCLUSIONS: TDF monotherapy was effective and well tolerated in LAM-R CHB patients for up to 240weeks. LAY SUMMARY: The goal of oral antiviral treatment for chronic hepatitis B (CHB) is to achieve and maintain undetectable HBV DNA levels. Treatment options with enhanced potency, and low risk of resistance development for patients infected with lamivudine resistant (LAM-R) HBV are required. Tenofovir disoproxil fumarate (TDF) monotherapy was effective and well tolerated without TDF resistance development in CHB patients with LAM-R, for up to 240weeks. Clinical trial number: NCT00737568.

Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); 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. CONCLUSIONS: 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.

Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B.

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.

Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Tenofovir disoproxil fumarate in Asian or Pacific Islander chronic hepatitis B patients with high viral load (≥ 9 log10 copies/ml).

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 <400 copies/ml were compared. Mean declines in HBV DNA were evaluated in API vs. non-API patients. RESULTS: Throughout the first 72 weeks of treatment, a smaller proportion of HVL API patients reached HBV DNA <400 copies/ml than non-HVL API patients. However, after this timepoint similar proportions of HVL and non-HVL API patients achieved HBV DNA <400 copies/ml (100% vs. 97%, respectively), which was maintained through week 288, where 92% of HVL patients and 99% of non-HVL API patients on treatment had HBV DNA <400 copies/ml. During the 288 weeks of treatment, API patients had similar mean HBV DNA declines as non-API patients, regardless of whether patients were HVL or non-HVL. No API HVL patient had persistent viremia at week 288. No resistance was detected among HVL or non-HVL patients. CONCLUSIONS: API patients with HVL CHB achieve HBV DNA <400 copies/ml with long-term TDF treatment; however, achieving viral suppression may take longer for HVL patients relative to non-HVL API patients.

Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load.

UNLABELLED: We evaluated the antiviral response of patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA ≥ 9 log10 copies/mL, after 240 weeks of tenofovir disoproxil fumarate (TDF) treatment. A total of 641 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients (129 with HVL) received 48 weeks of TDF 300 mg (HVL n = 82) or adefovir dipivoxil (ADV) 10 mg (HVL n = 47), followed by open-label TDF for an additional 192 weeks. Patients with confirmed HBV DNA ≥ 400 copies/mL on or after week 72 had the option of adding emtricitabine (FTC). By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL. Both groups had similar rates of histologic regression between baseline and week 240. Patients with HVL generally took longer to achieve HBV DNA <400 copies/mL than non-HVL patients, but by week 96, the percentages of patients with HBV DNA <400 copies/mL were similar in both groups. Among HVL patients, time to achieving HBV DNA <400 copies/mL was shorter among those initially receiving TDF, compared to ADV. No patient with baseline HVL had persistent viremia at week 240 or amino acid substitutions associated with TDF resistance. CONCLUSION: CHB patients with HVL can achieve HBV DNA negativity with long-term TDF treatment, although time to HBV DNA <400 copies/mL may be longer, relative to patients with non-HVL.

Associations between serum lipids and hepatitis C antiviral treatment efficacy.

UNLABELLED: 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. CONCLUSION: 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.

Host genetics, steatosis and insulin resistance among African Americans and Caucasian Americans with hepatitis C virus genotype-1 infection.

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-beta1) for both outcomes. Some significant interactions were observed between IL10,LEPR and TGF-beta1 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-beta1 the interactions were statistically significant in only one of the racial groups.These results could imply that some IL10,LEPR and TGF-beta1 polymorphisms may modify an association between steatosis and IR.

Sexual and alcohol risk behaviours of immigrant Latino men in the South-eastern USA.

Little is known about the intersections of immigration, masculinity and sexual risk behaviours among recently arrived Latino men in the 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.

Polymorphism in the human major histocompatibility complex and early viral decline during treatment of chronic hepatitis C.

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 alpha2a 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.

Association of single nucleotide polymorphisms in interferon signaling pathway genes and interferon-stimulated genes with the response to interferon therapy for chronic hepatitis C.

BACKGROUND/AIMS: Interferon signaling pathway genes (IPGs) and interferon-stimulated genes (ISGs) are associated with the host response to hepatitis C virus (HCV) infection. We studied single nucleotide polymorphisms (SNPs) in IPGs and ISGs for their associations with response to pegylated interferon alpha-2a (Peg-IFN-alpha) plus ribavirin therapy in HCV genotype-1 infected patients. METHODS: A two-stage study design was used. First, out of 118 SNPs selected, 91 SNPs from 5 IPGs and 12 ISGs were genotyped in a cohort of 374 treatment-naïve HCV patients and assessed for association with sustained virologic response (SVR). Next, 14 potentially functional SNPs from the OASL gene were studied in this cohort. RESULTS: Three OASL SNPs (rs3213545 and rs1169279 from stage I, and rs2859398 from stage II), were significantly associated with SVR [rs3213545: p=0.03, RR=1.27 (1.03-1.58); rs1169279: p=0.02, RR=1.32 (1.05-1.65) p=0.02; rs2859398: p=0.02, RR=1.29 (1.04-1.61)] after adjusting for other covariates. Further analysis showed that these three SNPs independently associated with SVR. Additionally, a similar trend towards the associations of these three SNPs with SVR was observed in a smaller, independent HCV cohort consisting of subjects from a number of clinical practice settings. CONCLUSIONS: Our study suggests that OASL variants are involved in the host response to IFN-based therapy in HCV patients.

Comparing MSM in the southeastern United States who participated in an HIV prevention chat room-based outreach intervention and those who did not: how different are the baseline HIV-risk profiles?

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.