Debika Bhattacharya

Review of Hepatitis B Therapeutics

Currently, there are 7 approved therapies for chronic hepatitis B virus (HBV) infection, an increase from just 3 agents 5 years ago. This review will focus on the pharmacology, potency, and adverse events associated with immunomodulatory agents and nucleos(t)ide analogues, with an emphasis on targets of therapy within the HBV life cycle. We will also offer guidelines for the use of available anti-HBV agents and review the emerging challenges in hepatitis B management, including HBV drug resistance, its management, and the potential role of combination therapy.

Safety and Antiviral Activity of the HCV Entry Inhibitor ITX5061 in Treatment-Naive HCV-Infected Adults: A Randomized, Double-Blind, Phase 1b Study

BACKGROUND Hepatitis C virus (HCV) entry involves scavenger receptor B1 (SRB1). In vitro, SRB1 inhibition by ITX5061 impedes HCV replication. METHODS Multicenter study to assess safety/activity of ITX5061 in previously untreated, noncirrhotic, HCV genotype 1 infected adults. Design included sequential cohorts of 10 subjects with ITX5061 (n = 8) or placebo (n = 2) to escalate duration (3 to 14 to 28 days) or deescalate dose (150 to 75 to 25 mg) based on predefined criteria for safety and activity (≥ 4 of 8 subjects with HCV RNA decline ≥ 1 log10 IU/mL). RESULTS Thirty subjects enrolled in 3 cohorts: ITX5061 150 mg/day by mouth for 3 (A150), 14 (B150), and 28 (C150) days. Six subjects had grade ≥ 3 adverse events (one in placebo); none were treatment related. One of the 7 C150 subjects (14.3%, 95% confidence interval [CI], .7%-55.4%) had ≥ 1 log10 IU/mL decline in HCV RNA (1.49 log10 IU/mL), whereas none of the 6 placebo, 8 A150 or 8 B150 subjects showed such decline. CONCLUSIONS Oral ITX5061 150 mg/day for up to 28 days was safe and well tolerated. In the 28-day cohort, 1 of 7 subjects showed antiviral activity; however, predefined criteria for antiviral activity were not met at the doses and durations studied.

Effectiveness of All-Oral Antiviral Regimens in 996 Human Immunodeficiency Virus/Hepatitis C Virus Genotype 1-Coinfected Patients Treated in Routine Practice

Background. Large cohorts are needed to assess human immunodeficiency virus (HIV)/hepatitis C virus (HCV) real-world treatment outcomes. We examined the effectiveness of ledipasvir/sofosbuvir with or without ribavirin (LDV/SOF ± RBV) and ombitasvir/ paritaprevir/ritonavir plus dasabuvir (OPrD) ± RBV in HIV/HCV genotype 1 (GT1)-coinfected patients initiating HCV therapy in clinical practice. Methods. Observational intent-to-treat cohort analysis using the Veterans Affairs Clinical Case Registry to identify HIV/HCV GT1-coinfected veterans initiating 12 weeks of LDV/SOF ± RBV or OPrD ± RBV. Multivariate models of sustained virologic response (SVR) included age, race, cirrhosis, proton pump inhibitor (PPI) prescription, prior HCV treatment, body mass index, genotype subtype, and HCV treatment regimen. Results. Nine hundred ninety-six HIV/HCV GT1-coinfected veterans initiated therapy: 757 LDV/SOF, 138 LDV/SOF + RBV, 28 OPrD, and 73 OPrD + RBV. Overall SVR was 90.9% (823/905); LDV/SOF 92.1% (631/685), LDV/SOF + RBV 86.3% (113/131), OPrD 88.9% (24/27), and OPrD + RBV 88.7% (55/62). SVR was 85.9% (176/205) and 92.4% (647/700) in those with and without cirrhosis (P = .006). SVR was similar between African Americans (90.5% [546/603]) and all others (91.7% [277/302]). PPI use with LDV/SOF ± RBV did not affect SVR (89.7% [131/146] with PPI and 91.5% [613/670] without PPI). Cirrhosis was predictive of reduced SVR (0.51 [95% confidence interval {CI}, .31-.87]; P = .01). Median creatinine change did not differ among patients receiving LDV/SOF and tenofovir disoproxil fumarate (TDF) without a protease inhibitor (PI) (0.18 [interquartile range {IQR}, 0.08-0.30]; n = 372), LDV/SOF and TDF/PI (0.17 [IQR, 0.04-0.30]; n = 100), and LDV/SOF without TDF (0.15 [IQR, 0.00-0.30]; n = 423). Conclusions. SVR rates in HIV/HCV GT1-coinfected patients were high. African American race or PPI use with LDV/SOF ± RBV was not associated with lower SVR rates, but cirrhosis was. Renal function did not worsen on LDV/SOF regimens with TDF.

Correlates of Adult Assault among Homeless Women

The purpose of this study was to assess predictors of sexual and physical assault among homeless women. A multivariate, correlation design was utilized to identify independent correlates of adult physical and sexual assault. The sample consisted of 202 homeless women residing in shelters or living on the street in the Skid Row area of Los Angeles. Respondents reporting a history of child sexual abuse were almost four times more likely to report being sexually assaulted as adults and were almost two and one third times more likely to report being physically assaulted as adults. A range of factors increase homeless womens risk of adult physical and sexual victimization, including child sexual abuse, substance use, lifetime sex trade activity, and previous incarceration. It is important for homeless service providers to develop an individual risk profile for homeless women and to intervene in order to decrease their risk of re-victimization.

The Effect of Hepatitis C Virologic Clearance on Cardiovascular Disease Biomarkers in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection

Background  Successful hepatitis C virus (HCV) treatment may reduce cardiovascular disease (CVD) risk and improve levels of CVD biomarkers produced outside the liver (nonhepatic biomarkers). Methods  Stored serum or plasma from before and 24 weeks after end of HCV treatment (EOT) from human immunodeficiency virus (HIV)/HCV-coinfected subjects who received up to 72 weeks of peginterferon/ribavirin, 27 with and 27 without sustained virologic response (SVR) matched by race, ethnicity and sex, were tested for nonhepatic (soluble intercellular adhesion molecule-1 [sICAM-1], soluble P-selectin [sP-selectin], interleukin [IL]-6, d-dimer, and lipoprotein-associated phospholipase A2 [Lp-PLA2]) and hepatic (cholesterol and high-sensitivity C-reactive protein) CVD and macrophage activation markers (soluble CD163 [sCD163] and soluble CD14). Changes in biomarkers and their association with SVR were examined by t tests or Wilcoxon tests and regression models. Results  Of the 54 subjects, 30 were white, 24 were black, and 44 were male. Pretreatment levels of nonhepatic biomarkers were high: sICAM-1 overall median, 439.2 ng/mL (interquartile range [IQR], 365.6–592.8]; sP-selectin, 146.7 ng/mL (IQR, 94.1–209.9), and IL-6, 2.32 pg/mL (IQR, 1.61–3.49). Thirty-seven of 52 (71%) subjects had Lp-PLA2 >235 ng/mL. Sustained virologic response was associated with decrease in sICAM-1 (P = .033) and sCD163 (P = .042); this result was attenuated after controlling for changes in the alanine aminotransferase level. At 24 weeks after EOT, 17 (63%) SVRs had Lp-PLA2 >235 ng/mL vs 25 (93%) non-SVRs (P = .021). Conclusions  Hepatitis C virus clearance may reduce hepatic and, subsequently, systemic inflammation and CVD risk in HIV/HCV coinfection.

Low prevalence of liver disease but regional differences in HBV treatment characteristics mark HIV/HBV co-infection in a South African HIV clinical trial

Background Hepatitis B virus (HBV) infection is endemic in South Africa however, there is limited data on the degree of liver disease and geographic variation in HIV/HBV coinfected individuals. In this study, we analysed data from the CIPRA-SA ‘Safeguard the household study’ in order to assess baseline HBV characteristics in HIV/HBV co-infection participants prior to antiretroviral therapy (ART) initiation. Methods 812 participants from two South African townships Soweto and Masiphumelele were enrolled in a randomized trial of ART (CIPRA-SA). Participants were tested for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA. FIB-4 scores were calculated at baseline. Results Forty-eight (5.9%) were HBsAg positive, of whom 28 (58.3%) were HBeAg positive. Of those with HBV, 29.8% had an HBV DNA<2000 IU/ml and ALT<40 IU/ml ; 83.0% had a FIB-4 score <1.45, consistent with absent or minimal liver disease. HBV prevalence was 8.5% in Masiphumelele compared to 3.8% in Soweto (relative risk 2.3; 95% CI: 1.3–4.0). More participants in Masiphumelele had HBeAg-negative disease (58% vs. 12%, p = 0.002) and HBV DNA levels ≤2000 IU/ml, (43% vs. 6% p<0.007). Conclusion One third of HIV/HBV co-infected subjects had low HBV DNA levels and ALT while the majority had indicators of only mild liver disease. There were substantial regional differences in HBsAg and HbeAg prevalence in HIV/HBV co-infection between two regions in South Africa. This study highlights the absence of severe liver disease and the marked regional differences in HIV/HBV co-infection in South Africa and will inform treatment decisions in these populations.

Coronary Heart Disease Risk by Framingham Risk Score in Hepatitis C and HIV/Hepatitis C Coinfected Persons

Abstract We compared the Framingham risk score (FRS) for 10-year coronary heart disease (CHD) risk in age- and race-matched hepatitis C virus (HCV)-infected and HCV-uninfected persons: 114,073 HCV-infected (111,436 HCV-monoinfected and 2,637 HIV/HCV-coinfected) and 122,996 HCV-uninfected (121,380 HIV and HCV-uninfected and 1,616 HIV-monoinfected) males without cardiovascular disease, diabetes, or hepatitis B. In unadjusted analyses, FRS was similar between the HCV-infected and HCV-uninfected groups [median (interquartile range, IQR) risk points 13 (10–14) vs. 13 (10–14), p=0.192]. Cholesterol levels were lower and current smoking more prevalent in the HCV groups (both HCV and HIV/HCV) compared with the uninfected groups (p<0.001 for both). Prevalence of non-FRS CHD risk factors, such as substance abuse and chronic kidney disease, in the cohort was high, and differed by HCV and HIV status. Adjusting for age, race/ethnicity, body mass index, chronic kidney disease, drug and alcohol use, and HIV status, HCV ...We compared the Framingham risk score (FRS) for 10-year coronary heart disease (CHD) risk in age- and race-matched hepatitis C virus (HCV)-infected and HCV-uninfected persons: 114,073 HCV-infected (111,436 HCV-monoinfected and 2,637 HIV/HCV-coinfected) and 122,996 HCV-uninfected (121,380 HIV and HCV-uninfected and 1,616 HIV-monoinfected) males without cardiovascular disease, diabetes, or hepatitis B. In unadjusted analyses, FRS was similar between the HCV-infected and HCV-uninfected groups [median (interquartile range, IQR) risk points 13 (10-14) vs. 13 (10-14), p=0.192]. Cholesterol levels were lower and current smoking more prevalent in the HCV groups (both HCV and HIV/HCV) compared with the uninfected groups (p<0.001 for both). Prevalence of non-FRS CHD risk factors, such as substance abuse and chronic kidney disease, in the cohort was high, and differed by HCV and HIV status. Adjusting for age, race/ethnicity, body mass index, chronic kidney disease, drug and alcohol use, and HIV status, HCV infection was associated with minimally lower FRS (β=-0.095 risk points, p<0.001), suggesting a small but significant difference in 10-year CHD risk estimation in HCV-infected as compared to HCV-uninfected persons when measuring risk by FRS. Given the complex relationship between HCV, HIV, and CHD risk factors, some of which are not captured by the FRS, the FRS may underestimate CHD risk in HCV-monoinfected and HIV/HCV-coinfected persons. HCV- and HIV/HCV-specific risk scores may be needed to optimize CHD risk stratification.

Combination of allele-specific detection techniques to quantify minority resistance variants in hepatitis B infection: a novel approach.

Detection of minor variant viral quasispecies of the rtV173L+rtL180M+rtM204V combination mutation in the hepatitis B virus (HBV) polymerase mediating both lamivudine resistance and vaccine escape is potentially important for tracking the development and evolution of resistance within both individuals and populations. A highly sensitive and specific assay to quantitate HBV genomes was developed with this mutation combination directly from viral DNA in serum using allele-specific quantitative PCR with locked nucleic acid primers and a minor groove binder probe. This combination of primers and probe yields a linear detection range down to 150 copies. This strategy has 100% specificity even in mixtures of predominately wild type genomes. The assay accurately detected 3×10² copies of the triple mutant spiked into 3 × 10⁸ copies of the wild-type genomes (0.0001%), while maintaining 100% specificity. This approach was validated using serum from a subject infected with known lamivudine-resistant HBV. The triple mutant viral population was quantitated at 2.86 × 10⁸ copies/ml within a total viral concentration of 1.03 × 10¹⁰ copies/ml of serum (2.8%). This quantitative allele-specific PCR strategy therefore is a useful method for highly sensitive and specific detection of point mutation combinations that are clinically important in the pathogenesis of drug resistance and/or immune escape.

Effects of pegylated interferon/ribavirin on bone turnover markers in HIV/Hepatitis C virus-coinfected patients

Abstract HIV/hepatitis C virus (HCV) patients have a 3-fold increased fracture incidence compared to uninfected patients. The impact of HCV therapy on bone health is unclear. We evaluated bone turnover markers (BTM) in well-controlled (HIV RNA <50 copies/ml) HIV/HCV-coinfected patients who received pegylated interferon-α and ribavirin (PEG-IFN/RBV) in ACTG trial A5178. Early virologic responders (EVR: ≥2 log HCV RNA drop at week 12) continued PEG-IFN/RBV and non-EVRs were randomized to continuation of PEG-IFN alone or observation. We assessed changes in C-terminal telopeptide of type 1 collagen (CTX; bone resorption marker) and procollagen type I intact N-terminal propeptide (P1NP; bone formation marker), and whether BTM changes were associated with EVR, complete early virologic response (cEVR: HCV RNA <600 IU/ml at week 12), or PEG-IFN treatment. A total of 192 subjects were included. After 12 weeks of PEG-IFN/RBV, CTX and P1NP decreased: −120 pg/ml and −8.48 μg/liter, respectively (both p < 0.0001). CTX declines were greater in cEVR (N = 91; vs. non-cEVR (N = 101; p = 0.003). From week 12 to 24, CTX declines were sustained among EVR patients who continued PEG-IFN/RBV (p = 0.027 vs. non-EVR) and among non-EVR patients who continued PEG-IFN alone (p = 0.022 vs. Observation). Median decreases of P1NP in EVR vs. non-EVR were similar at weeks 12 and 24. PEG-IFN-based therapy for chronic HCV markedly reduces bone turnover. It is unclear whether this is a direct IFN effect or a result of HCV viral clearance, or whether they will result in improved bone mineral density. Further studies with IFN-free regimens should explore these questions.

Performance of the Pooled Cohort atherosclerotic cardiovascular disease risk score in hepatitis C virus-infected persons

Chronic hepatitis C virus (HCV) infection has been associated with an increased risk for cardiovascular disease (CVD). The recommended Pooled Cohort atherosclerotic cardiovascular disease (ASCVD) risk equation for estimation of 10‐year CVD risk has not been validated in HCV‐infected populations. We examined the performance of the ASCVD risk score in HCV‐infected persons, using the national Electronically Retrieved Cohort of HCV Infected Veterans to derive a cohort of HCV‐infected and uninfected subjects without baseline ASCVD, hepatitis B, or HIV infection, and with low‐density lipoprotein cholesterol level<190 mg/dL. Performance of the ASCVD risk equation was assessed by Cox proportional hazard regression, C‐statistics and Hosmer‐Lemeshow statistic. The cohort included 70 490 HCV‐infected and 97 766 HCV‐uninfected men with mean age of 55 years, 56% White and 29% Black. Incident CVD event rates were similar between the two groups (13.2 and 13.4 events/1000 person‐years), with a higher incidence of coronary heart disease events in the HCV‐uninfected group and of stroke events in the HCV‐infected group. Adjusting for ASCVD risk score, HCV infection was associated with higher risk for an ASCVD event in the subgroup with baseline ASCVD risk ≥7.5% (HR: 1.19, P<.0001). C‐statistics were poor in both the HCV‐infected and uninfected groups (0.60 and 0.61, respectively). By Hosmer‐Lemeshow test, the ASCVD risk equation overestimated risk amongst lower risk patients and underestimated risk amongst higher risk patients in both the HCV‐infected and uninfected groups. Further investigation is needed to determine whether a modified equation to accurately predict ASCVD risk in HCV‐infected persons is warranted.