Publications by authors named "Debika Bhattacharya"

39 Publications

T-cell Activation Is Correlated With Monocyte Activation in HCV/HIV Coinfection and Declines During HCV Direct-Acting Antiviral Therapy.

Open Forum Infect Dis 2021 Apr 18;8(4):ofab079. Epub 2021 Feb 18.

Department of Pathology, VA Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.

Background: Immune activation markers associate with morbidity and mortality in HIV and hepatitis C virus (HCV) infection. We investigated how T-cell and monocyte activation are related over the course of HCV direct-acting antiviral (DAA) therapy during HCV/HIV coinfection.

Methods: Peripheral blood mononuclear cells from AIDS Clinical Trials Group (ACTG) A5329 participants and a single-site separate cohort treated with DAAs were analyzed for central memory (CM)/effector memory (EM) T-cell subsets, monocyte subsets, and cell activation (CD38 and HLA-DR expression) before, during, and after therapy.

Results: Before therapy, classical and inflammatory monocyte subset HLA-DR expression positively correlated with absolute counts and frequencies of CD38HLA-DR-expressing CD4 and CD8 T cells and corresponding CM and EM subsets. After therapy initiation, CD38HLA-DR co-expression on CD4 and CD8 memory T cells decreased by 12 weeks and 36 weeks, and plasma sCD14 positively correlated with CD38HLA-DR CD4 and CD4CM T-cell frequencies. Monocyte subset activation remained similar over time.

Conclusions: During HCV/HIV coinfection, memory T-cell activation is associated with monocyte subset activation, consistent with related underlying mechanisms. Following therapy initiation, memory T-cell, but not monocyte, activation decreased. Residual CD4 T-cell activation after therapy completion is associated with sCD14, potentially linking the remaining CD4 T-cell activation to residual factors driving activation in antiretroviral therapy-controlled HIV.
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http://dx.doi.org/10.1093/ofid/ofab079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043262PMC
April 2021

Innovations in Hepatitis C Screening and Treatment.

Hepatol Commun 2021 Mar 7;5(3):371-386. Epub 2020 Dec 7.

Division of Liver Diseases Icahn School of Medicine at Mount Sinai New York NY USA.

New therapies offer hope for a cure to millions of persons living with hepatitis C virus (HCV) infection. HCV elimination is a global goal that will be difficult to achieve using the traditional paradigms of diagnosis and care. The current standard has evolved toward universal HCV screening and treatment, to achieve elimination goals. There are several steps between HCV diagnosis and cure with major barriers along the way. Innovative models of care can address barriers to better serve hardly reached populations and scale national efforts in the United States and abroad. Herein, we highlight innovative models of HCV care that aid in our progress toward HCV elimination.
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http://dx.doi.org/10.1002/hep4.1646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917266PMC
March 2021

Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.

Case Rep Womens Health 2021 Apr 12;30:e00299. Epub 2021 Feb 12.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of California Los Angeles, USA.

Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
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http://dx.doi.org/10.1016/j.crwh.2021.e00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905336PMC
April 2021

Unusual presentation of meningococcal meningitis in the elderly and utility of CSF PCR testing.

Access Microbiol 2020 12;2(10):acmi000158. Epub 2020 Aug 12.

Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, USA.

We present an unusual case of a previously healthy 74-year-old man who presented with diffuse weakness, severe myalgias, petechial palmar rash and hypotension, but without fever, altered mental status, nuchal rigidity or headache, who was ultimately found through PCR testing to have meningococcal meningitis.
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http://dx.doi.org/10.1099/acmi.0.000158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660242PMC
August 2020

Maternal HBV Viremia and Association With Adverse Infant Outcomes in Women Living With HIV and HBV.

Pediatr Infect Dis J 2021 Feb;40(2):e56-e61

From the Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.

Background: There is limited information on perinatal outcomes in HIV-hepatitis B virus (HBV) coinfection.

Methods: HIV Prevention Trials Network (HPTN) 046 was a randomized double-blind placebo-controlled trial of perinatal transmission that evaluated 6 months of infant nevirapine versus placebo among breast-fed infants. Women living with HIV and their infants enrolled in sub-Saharan Africa from 2007 to 2010; 78% received antiretroviral therapy (ART). Maternal samples were tested for hepatitis B surface antigen (HBsAg). High and low HBV viral load (VL) was defined as ≥106 IU/mL and <106 IU/mL. The association between HIV-HBV coinfection and maternal and infant outcomes was assessed using multivariate (MV) logistic and Cox regression.

Results: Among 2025 women, 88 (4.3%) had HBV. HIV-HBV women with high HBV VL had lower median CD4, versus HIV alone or HIV-HBV women with low HBV VL [320, 490 and 434 cells/mm3, respectively (P < 0.007)]. In MV analysis, adjusted for maternal CD4, age and maternal ART, infants born to women with high HBV VL were more likely to be low birth weight (LBW), versus HIV+/HBV- and low HBV VL women: [30% (3/10) vs. 10% (194/1953) vs. 6% (5/78), respectively, P = 0.03). High HBV VL was associated with HIV perinatal transmission [(hazard ratio 6.75 (95% confidence interval (CI): 1.86 - 24.50)]. There was no impact on infant mortality or maternal outcomes at 18 months.

Conclusions: In HIV-HBV women, high HBV viral loads increase the risk of LBW and potentially HIV perinatal transmission. Reduction of antepartum HBV viremia may have beneficial effects beyond the prevention of HBV perinatal transmission.
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http://dx.doi.org/10.1097/INF.0000000000002980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855346PMC
February 2021

Using Serologic Testing to Assess the Effectiveness of Outbreak Control Efforts, Serial PCR Testing, and Cohorting of Positive SARS-CoV-2 Patients in a Skilled Nursing Facility.

Clin Infect Dis 2020 Aug 28. Epub 2020 Aug 28.

Division of Infectious Diseases, David Geffen School of Medicine at University of California, Los Angeles. Los Angeles, California, USA.

We characterized serology following a nursing home outbreak where residents were serially tested by RT-PCR and positive residents were cohorted. When tested 46-76 days later, 24/26 RT-PCR-positive residents were seropositive; none of the 124 RT-PCR-negative residents had confirmed seropositivity, supporting serial SARS-CoV-2 RT-PCR testing and cohorting in nursing homes.
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http://dx.doi.org/10.1093/cid/ciaa1286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499538PMC
August 2020

Barriers to hepatitis C direct-acting antiviral therapy among HIV/hepatitis C virus-coinfected persons.

J Gastroenterol Hepatol 2021 Apr 8;36(4):1095-1102. Epub 2020 Sep 8.

Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

Background And Aim: Direct-acting antivirals (DAAs) have increased hepatitis C virus (HCV) treatment opportunities for vulnerable HIV/HCV coinfected persons. The aim of this study was to identify the frequency of and potential barriers to DAA prescription in HIV/HCV patients during the first few years of DAA availability in the United States.

Methods: The AIDS Healthcare Foundation electronic medical record system was queried to identify all HCV viremic HIV-infected patients in care at AIDS Healthcare Foundation Healthcare centers in January 2015-August 2017 and compare characteristics by receipt of a DAA prescription. Multivariate logistic regression analyses were conducted to examine factors associated with DAA prescription.

Results: Of 826 eligible patients, 355 (43%) were prescribed a DAA; among those not prescribed a DAA, 301 (64%) had well-controlled HIV (HIV RNA ≤ 200 copies per mL). In multivariate logistic regression analysis, patients with a history of substance use (odds ratio [OR], 0.51 [95% confidence interval 0.35-0.73]) or on select HIV antiretroviral regimens were less likely to be prescribed a DAA. Those who had well-controlled HIV (OR, 5.03 [3.06-8.27]), CD4 + T cell count >200 cells per mm (OR, 1.85 [1.04-3.30]), estimated glomerular filtration rate >60 mL/min/1.73 m (OR, 3.32 [1.08-10.15]), or established care prior to January 2015 (OR, 1.57 [1.08-2.29] were more likely to be prescribed a DAA.

Conclusions: In addition to lack of HIV suppression, select antiretroviral regimens, substance use, and kidney disease appeared to limit DAA prescription in the early interferon-free DAA era. Many were not prescribed DAAs despite HIV suppression. Further research is needed to determine if the observed associations persist today.
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http://dx.doi.org/10.1111/jgh.15228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904967PMC
April 2021

A Telephone and Mail Outreach Program Successfully Increases Uptake of Hepatocellular Carcinoma Surveillance.

Hepatol Commun 2020 Jun 24;4(6):825-833. Epub 2020 Apr 24.

Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine University of California Los Angeles Los Angeles CA.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Society guidelines recommend surveillance with abdominal ultrasound with or without serum alpha-fetoprotein every 6 months for adults at increased risk of developing HCC. However, adherence is often suboptimal. We assessed the feasibility of a coordinated telephone outreach program for unscreened patients with cirrhosis within the Veteran's Affairs (VA) health care system. Using a patient care dashboard of advanced chronic liver disease in the VA Greater Los Angeles Healthcare System, we identified veterans with a diagnosis of cirrhosis, a platelet count ≤ 150,000/uL, and no documented HCC surveillance in the previous 8 months. Eligible veterans received a telephone call from a patient navigator to describe the risks and benefits of HCC surveillance. Orders for an abdominal ultrasound and alpha-fetoprotein were placed for veterans who agreed to surveillance. Veterans who were not reached by telephone received an informational letter by mail to encourage participation. Of the 129 veterans who met the eligibility criteria, most were male (96.9%). The most common etiology for cirrhosis was hepatitis C (64.3%), and most of the patients had compensated cirrhosis (68.2%). The patient navigators reached 32.5% of patients by phone. Patients in each group were similar across clinical and demographic characteristics. Patients who were called were more likely to undergo surveillance (adjusted odds ratio = 2.56, 95% confidence interval: 1.03-6.33). Most of the patients (72.1%) completed abdominal imaging when reached by phone. Targeted outreach increased uptake of HCC surveillance among patients with cirrhosis in a large, integrated, VA health care system.
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http://dx.doi.org/10.1002/hep4.1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262281PMC
June 2020

Hepatitis C Virus (HCV) Direct-Acting Antiviral Therapy in Persons With Human Immunodeficiency Virus-HCV Genotype 1 Coinfection Resulting in High Rate of Sustained Virologic Response and Variable in Normalization of Soluble Markers of Immune Activation.

J Infect Dis 2020 09;222(8):1334-1344

University of Colorado School of Medicine, Denver, Colorado, USA.

Background: Hepatitis C virus (HCV) direct-acting antivirals are highly effective. Less is known about changes in markers of immune activation in persons with human immunodeficiency virus (HIV) in whom a sustained virologic response (SVR) is achieved.

Methods: We conducted a nonrandomized clinical trial of 12 or 24 weeks of paritaprevir-ritonavir-ombitasvir plus dasabuvir (PrOD) with or without ribavirin in persons with HCV-1/HIV coinfection suppressed with antiretroviral therapy. Plasma HCV, soluble CD14 (sCD14), interferon-inducible protein 10, soluble CD163 (sCD163), interleukin 6 (IL-6), interleukin 18, monocyte chemoattractant protein (MCP-1), autotaxin (ATX), and Mac2-binding protein (Mac2BP) were measured over 48 weeks.

Results: Participants were treated with PrOD for 12 (n = 9) or 24 (n = 36) weeks; the SVR rate at 12 weeks was 93%. At baseline, cirrhosis was associated with higher ATX and MCP-1, female sex with higher ATX and IL-6, older age with higher Mac2BP, higher body mass index with higher ATX, and HIV-1 protease inhibitor use with higher sCD14 levels. In those with SVR, interferon-inducible protein 10, ATX, and Mac2BP levels declined by week 2, interleukin 18 levels declined by the end of treatment, sCD14 levels did not change, and sCD163, MCP-1, and IL-6 levels changed at a single time point.

Conclusions: During HIV/HCV coinfection, plasma immune activation marker heterogeneity is in part attributable to age, sex, cirrhosis, body mass index, and/or type of antiretroviral therapy. HCV treatment with paritaprevir-ritonavir-ombitasvir plus dasabuvir is highly effective and is associated with variable rate and magnitude of decline in markers of immune activation.

Clinical Trials Registration: NCT02194998.
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http://dx.doi.org/10.1093/infdis/jiaa254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749191PMC
September 2020

Hepatotoxicity and Liver-Related Mortality in Women of Childbearing Potential Living With Human Immunodeficiency Virus and High CD4 Cell Counts Initiating Efavirenz-Containing Regimens.

Clin Infect Dis 2021 Apr;72(8):1342-1349

Johns Hopkins University, Baltimore, Maryland, USA.

Background: Severe hepatotoxicity in people with human immunodeficiency virus (HIV) receiving efavirenz (EFV) has been reported. We assessed the incidence and risk factors of hepatotoxicity in women of childbearing age initiating EFV-containing regimens.

Methods: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, ART-naive pregnant women with HIV and CD4 count ≥ 350 cells/μL and alanine aminotransferase ≤ 2.5 the upper limit of normal were randomized during the antepartum and postpartum periods to antiretroviral therapy (ART) strategies to assess HIV vertical transmission, safety, and maternal disease progression. Hepatotoxicity was defined per the Division of AIDS Toxicity Tables. Cox proportional hazards models were constructed with covariates including participant characteristics, ART regimens, and timing of EFV initiation.

Results: Among 3576 women, 2435 (68%) initiated EFV at a median 121.1 weeks post delivery. After EFV initiation, 2.5% (61/2435) had severe (grade 3 or higher) hepatotoxicity with an incidence of 2.3 (95% confidence interval [CI], 2.0-2.6) per 100 person-years. Events occurred between 1 and 132 weeks postpartum. Of those with severe hepatotoxicity, 8.2% (5/61) were symptomatic, and 3.3% (2/61) of those with severe hepatotoxicity died from EFV-related hepatotoxicity, 1 of whom was symptomatic. The incidence of liver-related mortality was 0.07 (95% CI, .06-.08) per 100 person-years. In multivariable analysis, older age was associated with severe hepatotoxicity (adjusted hazard ratio per 5 years, 1.35 [95% CI, 1.06-1.70]).

Conclusions: Severe hepatotoxicity after EFV initiation occurred in 2.5% of women and liver-related mortality occurred in 3% of those with severe hepatotoxicity. The occurrence of fatal events underscores the need for safer treatments for women of childbearing age.
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http://dx.doi.org/10.1093/cid/ciaa244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075031PMC
April 2021

Opiate Dependence: A Risk Factor for Hepatitis B Virus Exposure in Homeless Adults.

Fam Community Health 2020 Apr/Jun;43(2):161-169

Departments of Medicine, Division of Infectious Diseases (Drs Khouzam and Bhattacharya), Family Medicine (Dr Gelberg), and Biomathematics (Ms Guo and Dr Tseng), David Geffen School of Medicine, University of California, Los Angeles; and Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles (Dr Gelberg).

The prevalence of hepatitis B virus (HBV) in the homeless population is underestimated despite multiple behavioral risks. Data from a sample of 534 homeless adults from downtown Los Angeles were analyzed to examine the prevalence and predictors of HBV infection in this community. The prevalence of HBV was 7 to 10 times higher than in the US general population rate. Opiate dependence, injection and noninjection use, was an independent predictor of HBV exposure. Testing and counseling occurred at significantly lower rates for HBV than for human immunodeficiency virus. Findings emphasize the need to enhance screening and counseling in homeless communities and other populations with opiate use.
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http://dx.doi.org/10.1097/FCH.0000000000000246DOI Listing
November 2020

Editorial: HBV-the promise of a new era in therapeutics.

Aliment Pharmacol Ther 2020 02;51(4):479-480

Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

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http://dx.doi.org/10.1111/apt.15628DOI Listing
February 2020

High Rates of Hepatitis B Virus (HBV) Functional Cure Among Human Immunodeficiency Virus-HBV Coinfected Patients on Antiretroviral Therapy in Zambia.

J Infect Dis 2020 01;221(2):218-222

Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.

Among 284 human immunodeficiency virus (HIV)-hepatitis B virus (HBV) coinfected adults starting tenofovir-based antiretroviral therapy (ART) in Zambia, median baseline CD4+ count was 202 cells/mm3 and 41.6% were hepatitis B e-antigen positive. Within 2 years of therapy, 29 (10.2%) participants experienced HBV functional cure (confirmed loss of hepatitis B surface antigen). In multivariable analysis, baseline CD4 count <350 cells/mm3, female sex, and lower baseline HBV deoxyribonucleic acid were associated with increased odds of functional cure. Immune recovery during HIV-HBV treatment with ART may drive higher rates of functional cure than during HBV monoinfection treatment. Understanding the mechanisms underlying this phenomenon could inform immunomodulatory therapies for HBV cure.
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http://dx.doi.org/10.1093/infdis/jiz450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184905PMC
January 2020

Treating Hepatitis C in Homeless Veterans at the Greater Los Angeles Veterans' Affairs Medical Center.

Hepatology 2019 09 28;70(3):1071-1073. Epub 2019 May 28.

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.

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http://dx.doi.org/10.1002/hep.30643DOI Listing
September 2019

Maternal health outcomes among HIV-infected breastfeeding women with high CD4 counts: results of a treatment strategy trial.

HIV Clin Trials 2018 12;19(6):209-224

a Division of Infectious Diseases, Department of Medicine , David Geffen School of Medicine at the University of California, Los Angeles , Los Angeles , CA , USA.

Background: IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery.

Methods: Women with pre-ART CD4+ cell counts ≥350 cells/mm who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat.

Findings: 1611 women were enrolled (June 2011-October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p = 0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p = 0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p = 0.61).

Interpretation: Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.
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http://dx.doi.org/10.1080/15284336.2018.1537327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428202PMC
December 2018

Chronic hepatitis B virus monoinfection at a university hospital in Zambia.

World J Hepatol 2018 Sep;10(9):622-628

Tropical Gastroenterology and Nutrition Group, School of Medicine, University of Zambia, Lusaka 50110, Zambia.

Aim: To characterize antiviral therapy eligibility among hepatitis B virus (HBV)-infected adults at a university hospital in Zambia.

Methods: Hepatitis B surface antigen-positive adults ( = 160) who were HIV-negative and referred to the hospital after a routine or clinically-driven HBV test were enrolled. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), platelet count, hepatitis B e-antigen, and HBV DNA were measured. Liver fibrosis/cirrhosis was assessed by physical examination, AST-to-platelet ratio index, and transient elastography. In antiviral therapy-naïve individuals, we described HBV stages and antiviral therapy eligibility per World Health Organization (WHO) and by HBV test (routine clinical). Elevated ALT was > 19 in women and > 30 U/L in men. Among treatment-experienced individuals, we described medication side effects, adherence, and viral suppression.

Results: The median age was 33 years, 71.9% were men, and 30.9% were diagnosed with HBV through a clinically-driven test with the remainder identified routine testing (at the blood bank, community events, .). Among 120 treatment-naïve individuals, 2.5% were categorized as immune tolerant, 11.7% were immune active, 35.6% were inactive carriers, and 46.7% had an indeterminate phenotype. Per WHO guidelines, 13 (10.8%) were eligible for immediate antiviral therapy. The odds of eligibility were eight times higher for those diagnosed at clinical routine settings (adjusted odds ratio, 8.33; 95%CI: 2.26-29.41). Among 40 treatment-experienced HBV patients, virtually all took tenofovir, and a history of mild side effects was reported in 20%. Though reported adherence was good, 12 of 29 (41.4%) had HBV DNA > 20 IU/mL.

Conclusion: Approximately one in ten HBV-monoinfected Zambians were eligible for antivirals. Many had indeterminate phenotype and needed clinical follow-up.
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http://dx.doi.org/10.4254/wjh.v10.i9.622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177566PMC
September 2018

Universal Screening of Pregnant Women for Hepatitis C: The Time Is Now.

Clin Infect Dis 2018 10;67(10):1493-1497

Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

The epidemiology of hepatitis C virus (HCV) has changed significantly over the last decade. Once most prevalent among older adults, the current burden has disproportionately affected young adults including women of childbearing age (WOCA). The Society for Maternal-Fetal Medicine recently issued guidelines that made no change in the recommendation to screen pregnant women based on risk factors. The current burden in young adults including WOCA supports a change in strategy away from risk-based screening to universal HCV screening in pregnancy. Universal screening offers several advantages that position us for a future where HCV treatment in pregnancy can happen and offers us progress toward the elimination of HCV.
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http://dx.doi.org/10.1093/cid/ciy586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927857PMC
October 2018

Treatment of Hepatitis C Virus (HCV) Genotype 1 Disease.

Curr Treat Options Infect Dis 2017 Jun 25;9(2):262-276. Epub 2017 May 25.

The landscape of therapeutic options for HCV infection has dramatically changed with the approval of all-oral direct-acting antiviral (DAA) regimens. DAAs target important steps in the HCV viral life cycle, resulting in higher response rates and fewer adverse events than were afforded with interferon and ribavirin, the prior standard of care. The achievement of sustained virologic response (SVR) rates in excess of 90% with use of DAA regimens has not only translated into HCV eradication for the hundreds of thousands treated but is also anticipated to decrease the incidence of major complications associated with chronic HCV infection. Additionally, the favorable side effect profile of DAAs has made HCV therapy feasible in difficult-to-treat populations, including those with previous exposure to interferon and ribavirin, cirrhosis, decompensated liver disease, HIV and HCV co-infection, and severe renal dysfunction/end stage renal disease. Given this tremendous progress, all patients infected with HCV infection should be treated.
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http://dx.doi.org/10.1007/s40506-017-0124-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966038PMC
June 2017

Significance and Management of Isolated Hepatitis B Core Antibody (Anti-HBc) in HIV and HCV: Strategies in the DAA Era.

Curr HIV/AIDS Rep 2018 04;15(2):172-181

UCLA CARE Center, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, 37-121 CHS, Los Angeles, CA, 90095, USA.

Purpose Of Review: The purpose of this review is to summarize the prevalence and clinical implications of the isolated anti-HBc serologic profile in HIV-infected individuals. We highlight the rare but important issue of HBV reactivation in the setting of HCV therapy and describe an approach to management.

Recent Findings: The isolated anti-HBc pattern, a profile that most often indicates past exposure to HBV with waning anti-HBs immunity, is found commonly in HIV-infected individuals, particularly those with HCV. Some large cohort studies demonstrate an association with advanced liver disease, while others do not. Conversely, meta-analyses have found an association between occult HBV infection (a component of the isolated anti-HBc pattern) and advanced liver disease and hepatocellular carcinoma in HIV-uninfected individuals. In HIV-uninfected individuals with anti-HBc positivity, HBV reactivation has been reported in patients receiving HCV therapy. This phenomenon is likely the result of disinhibition of HBV with HCV eradication. In HIV-infected patients, the long-term liver outcomes associated with the isolated anti-HBc pattern remain to be fully elucidated, supporting the need for large cohort studies with longitudinal follow-up. HBV reactivation during HCV DAA therapy has been well-described in HIV-uninfected cohorts and can inform algorithms for the screening and management of the isolated anti-HBc pattern in this population.
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http://dx.doi.org/10.1007/s11904-018-0379-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039383PMC
April 2018

Race affects SVR12 in a large and ethnically diverse hepatitis C-infected patient population following treatment with direct-acting antivirals: Analysis of a single-center Department of Veterans Affairs cohort.

Pharmacol Res Perspect 2018 04 22;6(2):e00379. Epub 2018 Feb 22.

Division of Gastroenterology, Hepatology and Parenteral Nutrition Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA USA.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. HCV cure has been linked to improved patient outcomes. In the era of direct-acting antivirals (DAAs), HCV cure has become the goal, as defined by sustained virological response 12 weeks (SVR12) after completion of therapy. Historically, African-Americans have had lower SVR12 rates compared to White people in the interferon era, which had been attributed to the high prevalence of non-CC interleukin 28B (IL28B) type. Less is known about the association between race/ethnicity and SVR12 in DAA-treated era. The aim of the study is to evaluate the predictors of SVR12 in a diverse, single-center Veterans Affairs population. We conducted a retrospective study of patients undergoing HCV therapy with DAAs from 2014 to 2016 at the VA Greater Los Angeles Healthcare System. We performed a multivariable logistic regression analysis to determine predictors of SVR12, adjusting for age, HCV genotype, DAA regimen and duration, human immunodeficiency virus (HIV) status, fibrosis, nonalcoholic fatty liver disease (NAFLD) fibrosis score, homelessness, mental health, and adherence. Our cohort included 1068 patients, out of which 401 (37.5%) were White people and 400 (37.5%) were African-American. Genotype 1 was the most common genotype (83.9%, N = 896). In the adjusted models, race/ethnicity and the presence of fibrosis were statistically significant predictors of non-SVR. African-Americans had 57% lower odds for reaching SVR12 (adj.OR = 0.43, 95% CI = 1.5-4.1) compared to White people. Advanced fibrosis (adj.OR = 0.40, 95% CI = 0.26-0.68) was also a significant predictor of non-SVR. In a single-center VA population on DAAs, African-Americans were less likely than White people to reach SVR12 when adjusting for covariates.
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http://dx.doi.org/10.1002/prp2.379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821896PMC
April 2018

Quantifying perinatal transmission of Hepatitis B viral quasispecies by tag linkage deep sequencing.

Sci Rep 2017 08 31;7(1):10168. Epub 2017 Aug 31.

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.

Despite full immunoprophylaxis, mother-to-child transmission (MTCT) of Hepatitis B Virus still occurs in approximately 2-5% of HBsAg positive mothers. Little is known about the bottleneck of HBV transmission and the evolution of viral quasispecies in the context of MTCT. Here we adopted a newly developed tag linkage deep sequencing method and analyzed the quasispecies of four MTCT pairs that broke through immunoprophylaxis. By assigning unique tags to individual viral sequences, we accurately reconstructed HBV haplotypes in a region of 836 bp, which contains the major immune epitopes and drug resistance mutations. The detection limit of minor viral haplotypes reached 0.1% for individual patient sample. Dominance of "a determinant" polymorphisms were observed in two children, which pre-existed as minor quasispecies in maternal samples. In all four pairs of MTCT samples, we consistently observed a significant overlap of viral haplotypes shared between mother and child. We also demonstrate that the data can be potentially useful to estimate the bottleneck effect during HBV MTCT, which provides information to optimize treatment for reducing the frequency of MTCT.
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http://dx.doi.org/10.1038/s41598-017-10591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578979PMC
August 2017

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

Clin Infect Dis 2017 Jun;64(12):1711-1720

3Population Health Services, Department of Veterans Affairs, Palo Alto Health Care System, California.

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.
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http://dx.doi.org/10.1093/cid/cix111DOI Listing
June 2017

Virologic and immunologic aspects of HIV-hepatitis C virus coinfection.

AIDS 2016 10;30(16):2395-2404

David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

HIV/hepatitis C virus (HCV) coinfection is estimated to affect 2 million individuals globally. The acceleration of HCV-associated complications, particularly hepatic fibrosis, because of HIV coinfection has been well established, whereas the impact of HCV on HIV progression remains unclear. In this review, we summarize the current evidence on the impact of coinfection on the transmission and clinical progression of each infection. We focus on the virological and immunological alterations that contribute to HIV and HCV pathogenesis in coinfection and also review the disease-modifying effects of antiretroviral therapy as they pertain to HCV.
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http://dx.doi.org/10.1097/QAD.0000000000001203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039386PMC
October 2016

Isolated Hepatitis B Core Antibody is Associated With Advanced Hepatic Fibrosis in HIV/HCV Infection But Not in HIV Infection Alone.

J Acquir Immune Defic Syndr 2016 May;72(1):e14-7

*VA Greater Los Angeles Healthcare System, Los Angeles, CA †David Geffen School of Medicine, UCLA, Los Angeles, CA ‡VA Connecticut Healthcare System, West Haven, CT §Yale University School of Medicine, New Haven, CT ‖Philadelphia VA Medical Center, Philadelphia, PA ¶Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA #Washington DC VA Medical Center, Washington, DC **George Washington University Medical Center, Washington, DC ††Hamad Healthcare Quality Institute and Hamad Medical Corporation, Doha, Qatar ‡‡VA Pittsburgh Healthcare System, Pittsburgh, PA §§James J. Peters VA Medical Center, Bronx, NY ‖‖Icahn School of Medicine at Mt. Sinai, New York, NY ¶¶Michael E. DeBakey VA Medical Center, Houston, TX ##Baylor College of Medicine, Houston, TX ***Atlanta VA Medical Center, Atlanta, GA †††Emory University School of Medicine, Atlanta, GA ‡‡‡Saint Louis University School of Medicine, Saint Louis, MO.

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http://dx.doi.org/10.1097/QAI.0000000000000941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837046PMC
May 2016

Low prevalence of hepatitis C co-infection in recently HIV-infected minority men who have sex with men in Los Angeles: a cross-sectional study.

BMC Infect Dis 2015 Nov 20;15:538. Epub 2015 Nov 20.

Department of Epidemiology, UCLA Fielding School of Public Health, 71-235E CHS, Los Angeles, CA, 90095, USA.

Background: Geographic and sociodemographic characterization of hepatitis C virus (HCV) transmission amongst men who have sex with men (MSM) has been limited. Our aim was to characterize HCV prevalence, risk factors for HCV co-infection, and patterns of HIV and HCV co-transmission and transmitted drug resistance mutations (DRMs) in newly HIV-diagnosed Los Angeles MSM.

Methods: Viral RNA was extracted from stored plasma samples from a Los Angeles cohort of newly diagnosed HIV-infected MSM with well-characterized substance use and sexual behavioral characteristics via computer-assisted self-interviewing surveys. Samples were screened for HCV by qPCR. HCV E1, E2, core, NS3 protease and NS5B polymerase and HIV-1 protease and reverse transcriptase regions were amplified and sequenced. Phylogenetic analysis was used to determine relatedness of HCV and HIV-1 isolates within the cohort and viral sequences were examined for DRMs.

Results: Of 185 newly HIV-diagnosed MSM, the majority (65%) were of minority race/ethnicity and recently infected (57.8%), with median age of 28.3 years. A minority (6.6%) reported injection drug use (IDU), whereas 96 (52.8%) reported recent substance use, primarily cannabis or stimulant use. High risk sexual behaviors included 132 (74.6%) with unprotected receptive anal intercourse, 60 (33.3%) with group sex, and 10 (5.7%) with fisting. Forty-five (24.3%) had acute gonorrhea or chlamydia infection. Only 3 (1.6%) subjects had detectable HCV RNA. Amongst these subjects, HIV and HCV isolates were unrelated by phylogenetic analysis and none possessed clinically relevant NS3 or NS5B HCV DRMs.

Conclusions: Prevalence of HCV co-infection was low and there was no evidence of HIV-HCV co-transmission in this cohort of relatively young, predominantly minority, newly HIV-diagnosed MSM, most with early HIV infection, with high rates of high risk sexual behaviors, STI, and non-IDU. The low HCV prevalence in a group with high-risk behaviors for non-IDU HCV acquisition suggests an opportune time for targeted HCV prevention measures.
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http://dx.doi.org/10.1186/s12879-015-1279-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654841PMC
November 2015

Effects of Pegylated Interferon/Ribavirin on Bone Turnover Markers in HIV/Hepatitis C Virus-Coinfected Patients.

AIDS Res Hum Retroviruses 2016 Apr 24;32(4):325-8. Epub 2015 Nov 24.

9 Northwestern University , Chicago, Illinois.

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.
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http://dx.doi.org/10.1089/AID.2015.0204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817562PMC
April 2016

Short Communication: Coronary Heart Disease Risk by Framingham Risk Score in Hepatitis C and HIV/Hepatitis C-Coinfected Persons.

AIDS Res Hum Retroviruses 2015 Jul 11;31(7):718-22. Epub 2015 May 11.

2 VA Pittsburgh Healthcare System , Pittsburgh, Pennsylvania.

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.
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http://dx.doi.org/10.1089/AID.2014.0284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505770PMC
July 2015

The effect of hepatitis C virologic clearance on cardiovascular disease biomarkers in human immunodeficiency virus/hepatitis C virus coinfection.

Open Forum Infect Dis 2014 Dec 3;1(3):ofu104. Epub 2014 Dec 3.

Department of Medicine , David Geffen School of Medicine at University of California, Los Angeles.

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.
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http://dx.doi.org/10.1093/ofid/ofu104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324212PMC
December 2014

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

PLoS One 2013 6;8(12):e74900. Epub 2013 Dec 6.

Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074900PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855615PMC
September 2014

Safety and antiviral activity of the HCV entry inhibitor ITX5061 in treatment-naive HCV-infected adults: a randomized, double-blind, phase 1b study.

J Infect Dis 2014 Mar 16;209(5):658-67. Epub 2013 Sep 16.

Johns Hopkins University, Baltimore, Maryland.

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.
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http://dx.doi.org/10.1093/infdis/jit503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923538PMC
March 2014