Risk of HCC With Hepatitis B Viremia Among HIV/HBV-Coinfected Persons in North America.

BACKGROUND AND AIMS: Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multicohort study of individuals coinfected with HIV/HBV. APPROACH AND RESULTS: We included persons coinfected with HIV/HBV within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995-2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted HRs (aHRs [95% CIs]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, HCV), or time-updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 individuals coinfected with HIV/HBV (median age, 43 years; 93% male; 52.4% non-White), 115 HCC cases were diagnosed over 65,392 person-years (incidence rate, 1.8 [95% CI, 1.5-2.1] events/1,000 person-years). Risk factors for HCC included age 40-49 years (aHR, 1.97 [1.22-3.17]), age ≥50 years (aHR, 2.55 [1.49-4.35]), HCV coinfection (aHR, 1.61 [1.07-2.40]), and heavy alcohol use (aHR, 1.52 [1.04-2.23]), while time-updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56-1.43]) and time-updated CD4+ percentage <14% (aHR, 1.03 [0.56-1.90]) were not. The risk of HCC was increased with time-updated HBV DNA >200 IU/mL (aHR, 2.22 [1.42-3.47]) and was higher with each 1.0 log10 IU/mL increase in time-updated HBV DNA (aHR, 1.18 [1.05-1.34]). HBV suppression with HBV-active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24-0.73]). CONCLUSION: Individuals coinfected with HIV/HBV on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary.

Intact Human Immunodeficiency Virus (HIV) Reservoir Estimated by the Intact Proviral DNA Assay Correlates With Levels of Total and Integrated DNA in the Blood During Suppressive Antiretroviral Therapy.

Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.

NK Response Correlates with HIV Decrease in Pegylated IFN-α2a-Treated Antiretroviral Therapy-Suppressed Subjects.

We previously reported that pegylated IFN-α2a (Peg-IFN-α2a) added to antiretroviral therapy (ART)-suppressed, HIV-infected subjects resulted in plasma HIV control and integrated HIV DNA decrease. We now evaluated whether innate NK cell activity or PBMC transcriptional profiles were associated with decreases in HIV measures. Human peripheral blood was analyzed prior to Peg-IFN-α2a administration (ART, baseline), after 5 wk of ART+Peg-IFN-α2a, and after 12 wk of Peg-IFN-α2a monotherapy (primary endpoint). After 5 wk of ART+Peg-IFN-α2a, immune subset frequencies were preserved, and induction of IFN-stimulated genes was noted in all subjects except for a subset in which the lack of IFN-stimulated gene induction was associated with increased expression of microRNAs. Viral control during Peg-IFN-α2a monotherapy was associated with 1) higher levels of NK cell activity and IFN-γ-induced protein 10 (IP-10) on ART (preimmunotherapy) and 2) downmodulation of NK cell KIR2DL1 and KIR2DL2/DL3 expression, transcriptional enrichment of expression of genes associated with NK cells in HIV controller subjects, and higher ex vivo IFN-α-induced NK cytotoxicity after 5 wk of ART+Peg-IFN-α2a. Integrated HIV DNA decline after immunotherapy was also associated with gene expression patterns indicative of cell-mediated activation and NK cytotoxicity. Overall, an increase in innate activity and NK cell cytotoxicity were identified as correlates of Peg-IFN-α2a-mediated HIV control.

Comparison of the prevalence, severity, and risk factors for hepatic steatosis in HIV-infected and uninfected people.

BACKGROUND: Hepatic steatosis is prevalent in Western countries, but few studies have evaluated whether the frequency and severity of steatosis are greater in the setting of HIV infection. We compared the prevalence and severity of hepatic steatosis between HIV-infected (HIV+) and uninfected persons and identified factors associated with greater steatosis severity within both groups. METHODS: We performed a cross-sectional study among participants without cardiovascular disease who participated in a substudy of the Veterans Aging Cohort Study. Hepatic steatosis was defined by noncontrast computed tomography (CT) liver-to-spleen (L/S) attenuation ratio < 1.0. Multivariable linear regression was used to: 1) evaluate the association between HIV infection and severity of hepatic steatosis, as measured by absolute liver attenuation, and 2) identify factors associated with greater severity of steatosis, by HIV status. RESULTS: Among 268 participants (median age, 55 years; 99% male; 79% black; 23% obese; 64% HIV+ [91% on antiretroviral therapy]), the overall prevalence of steatosis was 7.8% and was similar between HIV+ and uninfected individuals (13 [7.6%] versus 8 [8.2%], respectively; p = 0.85). Participants with HIV, the majority of whom received antiretroviral therapy, had a higher mean absolute liver attenuation (mean difference, 5.68 Hounsfield units; p < 0.001), correlating with lesser hepatic steatosis severity, compared to uninfected participants. After adjusting for covariates, only advanced hepatic fibrosis was associated with greater severity of steatosis in HIV+ persons (p = 0.03) and uninfected individuals (p < 0.001). CONCLUSIONS: In this sample of participants without cardiovascular disease, the prevalence of hepatic steatosis by noncontrast abdominal CT was not different by HIV status. Increasing severity of steatosis was independently associated with advanced hepatic fibrosis in both groups.

Risk of Acute Liver Injury After Statin Initiation by Human Immunodeficiency Virus and Chronic Hepatitis C Virus Infection Status.

BACKGROUND: Patients with human immunodeficiency virus (HIV) and/or chronic hepatitis C virus (HCV) infection may be prescribed statins as treatment for metabolic/cardiovascular disease, but it remains unclear if the risk of acute liver injury (ALI) is increased for statin initiators compared to nonusers in groups classified by HIV/HCV status. METHODS: We conducted a cohort study to compare rates of ALI in statin initiators vs nonusers among 7686 HIV/HCV-coinfected, 8155 HCV-monoinfected, 17739 HIV-monoinfected, and 36604 uninfected persons in the Veterans Aging Cohort Study (2000-2012). We determined development of (1) liver aminotransferases >200 U/L, (2) severe ALI (coagulopathy with hyperbilirubinemia), and (3) death, all within 18 months. Cox regression was used to determine propensity score-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of outcomes in statin initiators compared to nonusers across the groups. RESULTS: Among HIV/HCV-coinfected patients, statin initiators had lower risks of aminotransferase levels >200 U/L (HR, 0.66 [95% CI, .53-.83]), severe ALI (HR, 0.23 [95% CI, .12-.46]), and death (HR, 0.36 [95% CI, .28-.46]) compared with statin nonusers. In the setting of chronic HCV alone, statin initiators had reduced risks of aminotransferase elevations (HR, 0.57 [95% CI, .45-.72]), severe ALI (HR, 0.15 [95% CI, .06-.37]), and death (HR, 0.42 [95% CI, .32-.54]) than nonusers. Among HIV-monoinfected patients, statin initiators had lower risks of aminotransferase increases (HR, 0.52 [95% CI, .40-.66]), severe ALI (HR, 0.26 [95% CI, .13-.55]), and death (HR, 0.19 [95% CI, .16-.23]) compared with nonusers. Results were similar among uninfected persons. CONCLUSIONS: Regardless of HIV and/or chronic HCV status, statin initiators had a lower risk of ALI and death within 18 months compared with statin nonusers.

Risk of liver decompensation with cumulative use of mitochondrial toxic nucleoside analogues in HIV/hepatitis C virus coinfection.

PURPOSE: Among patients dually infected with human immunodeficiency virus (HIV) and chronic hepatitis C virus (HCV), use of antiretroviral therapy (ART) containing mitochondrial toxic nucleoside reverse transcriptase inhibitors (mtNRTIs) might induce chronic hepatic injury, which could accelerate HCV-associated liver fibrosis and increase the risk of hepatic decompensation and death. METHODS: We conducted a cohort study among 1747 HIV/HCV patients initiating NRTI-containing ART within the Veterans Aging Cohort Study (2002-2009) to determine if cumulative mtNRTI use increased the risk of hepatic decompensation and death among HIV-/HCV-coinfected patients. Separate marginal structural models were used to estimate hazard ratios (HRs) of each outcome associated with cumulative exposure to ART regimens that contain mtNRTIs versus regimens that contain other NRTIs. RESULTS: Over 7033 person-years, we observed 97 (5.6%) decompensation events (incidence rate, 13.8/1000 person-years) and 125 (7.2%) deaths (incidence rate, 17.8 events/1000 person-years). The risk of hepatic decompensation increased with cumulative mtNRTI use (1-11 mo: HR, 1.79 [95% confidence interval (CI), 0.74-4.31]; 12-35 mo: HR, 1.39 [95% CI, 0.68-2.87]; 36-71 mo: HR, 2.27 [95% CI, 0.92-5.60]; >71 mo: HR, 4.66 [95% CI, 1.04-20.83]; P = .045) versus nonuse. Cumulative mtNRTI use also increased risk of death (1-11 mo: HR, 2.24 [95% CI, 1.04-4.81]; 12-35 mo: HR, 2.05 [95% CI, 0.68-6.20]; 36-71 mo: HR, 3.04 [95% CI, 1.12-8.26]; >71 mo: HR, 3.93 [95% CI, 0.75-20.50]; P = .030). CONCLUSIONS: These findings suggest that cumulative mtNRTI use may increase the risk of hepatic decompensation and death in HIV/HCV coinfection. These drugs should be avoided when alternatives exist for HIV/HCV patients.

Disparities in Absolute Denial of Modern Hepatitis C Therapy by Type of Insurance.

BACKGROUND & AIMS: The high costs of direct-acting antiviral (DAA) agents to treat chronic hepatitis C virus (HCV) infection have resulted in denials of treatment, but it is not clear whether patients' access to these therapies differs with their type of insurance. METHODS: We conducted a prospective cohort study among all patients who had a DAA prescription submitted between November 1, 2014 and April 30, 2015 to Burman's Specialty Pharmacy, which provides HCV pharmacy services to patients in Delaware, Maryland, New Jersey, and Pennsylvania. We determined the incidence of absolute denial of DAA prescription, defined as a lack of approval of a prescription fill by the insurer, according to type of insurance (US Medicaid, US Medicare, or commercial insurance). Multivariable Poisson regression was used to estimate adjusted relative risks of absolute denial associated with patient characteristics. RESULTS: Among 2321 patients prescribed a DAA regimen (503 covered by Medicaid, 795 covered by Medicare, and 1023 covered by commercial insurance), 377 (16.2%) received an absolute denial. The most common reasons for absolute denial were insufficient information to assess medical need (134 [35.5%]) and lack of medical necessity (132 [35.0%]). A higher proportion of patients covered by Medicaid received an absolute denial (233 [46.3%]) than those covered by Medicare (40 [5.0%]; P < .001) or commercial insurance (104 [10.2%]; P < .001). Medicaid insurance (adjusted relative risk, 4.14; 95% confidence interval, 3.38-5.08) and absence of cirrhosis (adjusted relative risk, 1.96; 95% confidence interval, 1.53-2.50) were associated with absolute denial. CONCLUSIONS: There are significant disparities in access to DAA-based treatments for HCV infection among patients with different types of insurance. Nearly half of Medicaid beneficiaries in Delaware, Maryland, New Jersey, and Pennsylvania were denied access to these drugs for chronic HCV infection.

Shift in monocyte apoptosis with increasing viral load and change in apoptosis-related ISG/Bcl2 family gene expression in chronically HIV-1-infected subjects.

UNLABELLED: Although monocytes and macrophages are targets of HIV-1-mediated immunopathology, the impact of high viremia on activation-induced monocyte apoptosis relative to monocyte and macrophage activation changes remains undetermined. In this study, we determined constitutive and oxidative stress-induced monocyte apoptosis in uninfected and HIV(+) individuals across a spectrum of viral loads (n = 35; range, 2,243 to 1,355,998 HIV-1 RNA copies/ml) and CD4 counts (range, 26 to 801 cells/mm(3)). Both constitutive apoptosis and oxidative stress-induced apoptosis were positively associated with viral load and negatively associated with CD4, with an elevation in apoptosis occurring in patients with more than 40,000 (4.6 log) copies/ml. As expected, expression of Rb1 and interferon-stimulated genes (ISGs), plasma soluble CD163 (sCD163) concentration, and the proportion of CD14(++) CD16(+) intermediate monocytes were elevated in viremic patients compared to those in uninfected controls. Although CD14(++) CD16(+) frequencies, sCD14, sCD163, and most ISG expression were not directly associated with a change in apoptosis, sCD14 and ISG expression showed an association with increasing viral load. Multivariable analysis of clinical values and monocyte gene expression identified changes in IFI27, IFITM2, Rb1, and Bcl2 expression as determinants of constitutive apoptosis (P = 3.77 × 10(-5); adjusted R(2) = 0.5983), while changes in viral load, IFITM2, Rb1, and Bax expression were determinants of oxidative stress-induced apoptosis (P = 5.59 × 10(-5); adjusted R(2) = 0.5996). Our data demonstrate differential activation states in monocytes between levels of viremia in association with differences in apoptosis that may contribute to greater monocyte turnover with high viremia. IMPORTANCE: This study characterized differential monocyte activation, apoptosis, and apoptosis-related gene expression in low- versus high-level viremic HIV-1 patients, suggesting a shift in apoptosis regulation that may be associated with disease state. Using single and multivariable analysis of monocyte activation parameters and gene expression, we supported the hypothesis that monocyte apoptosis in HIV disease is a reflection of viremia and activation state with contributions from gene expression changes within the ISG and Bcl2 gene families. Understanding monocyte apoptosis response may inform HIV immunopathogenesis, retention of infected macrophages, and monocyte turnover in low- or high-viral-load states.

Structural Bone Deficits in HIV/HCV-Coinfected, HCV-Monoinfected, and HIV-Monoinfected Women.

BACKGROUND: Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is associated with reduced bone mineral density (BMD) and increased fracture rates, particularly in women. The structural underpinnings for skeletal fragility in coinfected women have not been characterized. We used tibial peripheral quantitative computed tomography to evaluate skeletal parameters in women, by HIV/HCV status. METHODS: We conducted a cross-sectional study among 50 HIV/HCV-coinfected, 51 HCV-monoinfected, and 50 HIV-monoinfected women. Tibial volumetric BMD and cortical dimensions were determined with peripheral quantitative computed tomography. Race-specific z scores for age were generated using 263 female reference participants without HIV infection or liver disease. RESULTS: Coinfected participants had lower mean z scores for trabecular volumetric BMD (-0.85), cortical volumetric BMD (-0.67), cortical area (-0.61), and cortical thickness (-0.77) than reference participants (all P < .001). The smaller cortical dimensions were due to greater mean z scores for endosteal circumference (+0.67; P < .001) and comparable z scores for periosteal circumference (+0.04; P = .87). Trabecular volumetric BMD was lower in coinfected than in HCV- or HIV-monoinfected participants. HCV-infected women with stage 3-4 liver fibrosis had lower mean z scores for trabecular volumetric BMD, cortical thickness, and total hip BMD those with stage 0-2 fibrosis. CONCLUSIONS: Compared with healthy reference patients, HIV/HCV-coinfected women had decreased tibial trabecular volumetric BMD, diminished cortical dimensions, and significant endocortical bone loss.

Access to Costly New Hepatitis C Drugs: Medicine, Money, and Advocacy.

Hepatitis C affects >3 million people in the United States, and often leads to end-stage liver disease or death. In 2014, several new drugs to treat hepatitic C virus received US Food and Drug Administration approval, with remarkable cure rates exceeding 90%. Medicaid, however, is rationing these drugs, and other insurers have restricted coverage due to their exorbitant costs and the large size of the population in need. These access barriers and disparities have resulted in national patient advocacy mobilization, US congressional inquiry, and legal challenges. The US Department of Health and Human Services has been urged to intervene. We propose the establishment of a federal program, analogous to AIDS Drug Assistance Programs, to reduce access barriers and facilitate focused price negotiations. The federal government may further undertake a nonvoluntary acquisition of the pharmaceutical patents pursuant to federal statutory authority and principles of eminent domain. Projections indicate this proposal could lower costs by 90% and eliminate rationing.

Plasmacytoid dendritic cell and functional HIV Gag p55-specific T cells before treatment interruption can inform set-point plasma HIV viral load after treatment interruption in chronically suppressed HIV-1(+) patients.

The identification of immune correlates of HIV control is important for the design of immunotherapies that could support cure or antiretroviral therapy (ART) intensification-related strategies. ART interruptions may facilitate this task through exposure of an ART partially reconstituted immune system to endogenous virus. We investigated the relationship between set-point plasma HIV viral load (VL) during an ART interruption and innate/adaptive parameters before or after interruption. Dendritic cell (DC), natural killer (NK) cell and HIV Gag p55-specific T-cell functional responses were measured in paired cryopreserved peripheral blood mononuclear cells obtained at the beginning (on ART) and at set-point of an open-ended interruption from 31 ART-suppressed chronically HIV-1(+) patients. Spearman correlation and linear regression modeling were used. Frequencies of plasmacytoid DC (pDC), and HIV Gag p55-specific CD3(+)  CD4(-)  perforin(+)  IFN-γ(+) cells at the beginning of interruption associated negatively with set-point plasma VL. Inclusion of both variables with interaction into a model resulted in the best fit (adjusted R(2)  = 0·6874). Frequencies of pDC or HIV Gag p55-specific CD3(+)  CD4(-)  CSFE(lo)  CD107a(+) cells at set-point associated negatively with set-point plasma VL. The dual contribution of pDC and anti-HIV T-cell responses to viral control, supported by our models, suggests that these variables may serve as immune correlates of viral control and could be integrated in cure or ART-intensification strategies.

Prevalence and risk factors for patient-reported joint pain among patients with HIV/hepatitis C coinfection, hepatitis C monoinfection, and HIV monoinfection.

BACKGROUND: To determine the prevalence of patient-reported joint pain among patients with human immunodeficiency virus (HIV)/chronic hepatitis C virus (HCV) coinfection, chronic HCV monoinfection, and HIV monoinfection followed in hepatology and infectious disease outpatient practices. METHODS: Standardized interviews were performed among 79 HIV/HCV-coinfected, 93 HCV-monoinfected, and 30 HIV-monoinfected patients in a cross-sectional study within hepatology and infectious disease clinics at three centers. The Multi-Dimensional Health Assessment Questionnaire was used to ascertain joint pain and associated symptoms. Information on potential risk factors for joint pain was obtained during the interview and by chart review. Logistic regression was used to determine adjusted odds ratios (aORs) with 95% confidence intervals (CIs) of joint pain associated with risk factors of interest among chronic HCV-infected and HIV-infected patients. RESULTS: Joint pain was more commonly reported in HCV-monoinfected than HIV/HCV-coinfected (71% versus 56%; p = 0.038) and HIV-monoinfected (71% versus 50%; p = 0.035) patients. A previous diagnosis of arthritis and current smoking were risk factors for joint pain among HCV-infected patients (arthritis: aOR, 4.25; 95% CI, 1.84-9.81; smoking: aOR, 5.02; 95% CI, 2.15-11.74) and HIV-infected (arthritis: aOR, 5.36; 95% CI, 2.01-14.25; smoking: aOR, 6.07; 95% CI, 2.30-16.00) patients. CONCLUSION: Patient-reported joint pain was prevalent among all three groups, but more common among chronic HCV-monoinfected than either HIV/HCV-coinfected or HIV-monoinfected patients. A prior diagnosis of arthritis and current smoking were risk factors for patient-reported joint pain among both HCV-infected and HIV-infected patients.

Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: a cohort study.

BACKGROUND: The incidence and determinants of hepatic decompensation have been incompletely examined among patients co-infected with HIV and hepatitis C virus (HCV) in the antiretroviral therapy (ART) era, and few studies have compared outcome rates with those of patients with chronic HCV alone. OBJECTIVE: To compare the incidence of hepatic decompensation between antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients and to evaluate factors associated with decompensation among co-infected patients receiving ART. DESIGN: Retrospective cohort study. SETTING: Veterans Health Administration. PATIENTS: 4280 co-infected patients who initiated ART and 6079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment-naive. MEASUREMENTS: Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage. RESULTS: The incidence of hepatic decompensation was greater among co-infected than monoinfected patients (7.4% vs. 4.8% at 10 years; P < 0.001). Compared with HCV-monoinfected patients, co-infected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% CI, 1.31 to 1.86]). Co-infected patients who maintained HIV RNA levels less than 1000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [CI, 1.05 to 1.99]). Baseline advanced hepatic fibrosis (FIB-4 score >3.25) (HR, 5.45 [CI, 3.79 to 7.84]), baseline hemoglobin level less than 100 g/L (HR, 2.24 [CI, 1.20 to 4.20]), diabetes mellitus (HR, 1.88 [CI, 1.38 to 2.56]), and nonblack race (HR, 2.12 [CI, 1.65 to 2.72]) were each associated with higher rates of decompensation among co-infected patients. LIMITATION: Observational study of predominantly male patients. CONCLUSION: Despite receiving ART, patients co-infected with HIV and HCV had higher rates of hepatic decompensation than HCV-monoinfected patients. Rates of decompensation were higher for co-infected patients with advanced liver fibrosis, severe anemia, diabetes, and nonblack race. PRIMARY FUNDING SOURCE: National Institutes of Health.

Risk of hip fracture associated with untreated and treated chronic hepatitis B virus infection.

BACKGROUND & AIMS: Chronic hepatitis B (CHB) infection is associated with reduced bone mineral density, but its association with fractures is unknown. Our objectives were to determine whether untreated or treated CHB-infected persons are at increased risk for hip fracture compared to uninfected persons. METHODS: We conducted a cohort study among 18,796 untreated CHB-infected, 7777 treated CHB-infected, and 979,751 randomly sampled uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999-2007). CHB infection was defined by two CHB diagnoses recorded >6 months apart and was classified as treated if a diagnosis was recorded and antiviral therapy was dispensed. After propensity score matching of CHB-infected and uninfected persons, Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident hip fracture in: (1) untreated CHB-infected vs. uninfected, and (2) treated CHB-infected vs. uninfected patients. RESULTS: Untreated CHB-infected patients of black race had a higher rate of hip fracture than uninfected black persons (HR, 2.55 [95% CI, 1.42-4.58]). Compared to uninfected persons, relative hazards of hip fracture were increased for untreated white (HR, 1.26 [95% CI, 0.98-1.62]) and Hispanic (HR, 1.36 [95% CI, 0.77-2.40]) CHB-infected patients, and treated black (HR, 3.09 [95% CI, 0.59-16.22]) and white (HR, 1.90 [95% CI, 0.81-4.47]) CHB-infected patients, but these associations were not statistically significant. CONCLUSIONS: Among U.S. Medicaid enrollees, untreated CHB-infected patients of black race had a higher risk of hip fracture than uninfected black persons.

Cloning and functional characterization of novel human neutralizing anti-interferon-alpha and anti-interferon-beta antibodies.

Type I interferons (IFNs) play a pivotal role in immune response modulation, yet dysregulation is implicated in various disorders. Therefore, it is crucial to develop tools that facilitate the understanding of their mechanism of action and enable the development of more effective anti-IFN therapeutic strategies. In this study, we isolated, cloned, and characterized anti-IFN-α and anti-IFN-ß antibodies (Abs) from peripheral blood mononuclear cells of individuals treated with IFN-α or IFN-ß, harboring confirmed neutralizing Abs. Clones AH07856 and AH07857 were identified as neutralizing anti-IFN-α-specific with inhibition against IFN-α2a, -α2b, and -αK subtypes. Clones AH07859 and AH07866 were identified as neutralizing anti-IFN-ß1a-specific signaling, and able to block Lipopolysaccharide or S100 calcium binding protein A14-induced IFN-ß signaling effects. Cloned Abs bind rhesus but not murine IFNs. The specificity of inhibition between IFN-α and IFN-ß suggests potential for diverse research and clinical applications.

Risk of hip fracture associated with hepatitis C virus infection and hepatitis C/human immunodeficiency virus coinfection.

UNLABELLED: Hepatitis C virus (HCV) infection has been associated with reduced bone mineral density, but its association with fracture rates is unknown, particularly in the setting of human immunodeficiency virus (HIV) coinfection. Our aims were to determine whether persons with HCV infection alone are at increased risk for hip fracture, compared to uninfected individuals, and to examine whether the risk of hip fracture is higher among HCV/HIV-coinfected persons, compared to those with HCV alone, those with HIV alone, and those uninfected with either virus. We conducted a cohort study in 36,950 HCV/HIV-coinfected, 276,901 HCV-monoinfected, 95,827 HIV-monoinfected, and 3,110,904 HCV/HIV-uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999-2005). Incidence rates of hip fracture were lowest among uninfected persons (1.29 events/1,000 person-years), increased with the presence of either HIV infection (1.95 events/1,000 person-years) or HCV infection (2.69 events/1,000 person-years), and were highest among HCV/HIV-coinfected individuals (3.06 events/1,000 person-years). HCV/HIV coinfection was associated with an increased relative hazard (adjusted hazard ratio [HR] [95% confidence interval; CI]) of hip fracture, compared to HCV-monoinfected (HR, 1.38; 95% CI: 1.25-1.53), HIV-monoinfected (females: HR, 1.76; 95% CI: 1.44-2.16; males: HR, 1.36; 95% CI: 1.20-1.55), and HCV/HIV-uninfected persons (females: HR, 2.65; 95% CI: 2.21-3.17; males: HR, 2.20; 95% CI: 1.97-2.47). HCV monoinfection was associated with an increased risk of hip fracture, compared to uninfected individuals, and the relative increase was highest in the youngest age groups (females, 18-39 years: HR, 3.56; 95% CI: 2.93-4.32; males, 18-39 years: HR, 2.40; 95% CI: 2.02-2.84). CONCLUSION: Among Medicaid enrollees, HCV/HIV coinfection was associated with increased rates of hip fracture, compared to HCV-monoinfected, HIV-monoinfected, and HCV/HIV-uninfected persons. HCV-monoinfected patients had an increased risk of hip fracture, compared to uninfected individuals.

Willingness to undergo a repeat liver biopsy among HIV/hepatitis C virus-coinfected and hepatitis C virus-monoinfected patients.

BACKGROUND: Guidelines for chronic hepatitis C virus (HCV) management have recommended that a liver biopsy be repeated at 3-year intervals for HIV/HCV-coinfected patients and 5-year intervals for those with HCV monoinfection to assess fibrosis progression. However, it is unclear if patients are willing to repeat this procedure. OBJECTIVE: To determine the prevalence and factors, particularly HIV coinfection, associated with willingness to repeat a liver biopsy. METHODS: A questionnaire was administered to 235 HCV-infected patients (113 with HIV coinfection) between January 2008 and June 2011 who previously underwent liver biopsy. The main outcome was self-reported willingness to repeat the biopsy. The questionnaire collected data on other hypothesized determinants of willingness to repeat the biopsy. These were evaluated by logistic regression. RESULTS: Among 235 subjects who completed the questionnaire, 32 (14%) reported unwillingness to repeat the biopsy, most commonly because of a perception that it was unimportant for care [13(41%)], concerns regarding pain [12(38%)], and a poor experience with the prior biopsy [7(21%)]. Considering biopsy to be safe [odds ratio (OR), 4.45; 95% CI, 1.50-13.27], important (OR, 4.87; 95% CI, 1.83-12.95), and knowing a person who underwent liver biopsy (OR, 3.45; 95% CI, 1.16-10.23) were associated with willingness to repeat the biopsy. HIV was not associated with willingness to repeat the biopsy (OR, 1.42; 95% CI, 0.67-3.03). CONCLUSIONS: Eighty-six percent of chronic HCV-infected patients were willing to repeat a liver biopsy. HIV was not associated with unwillingness. In patients in whom a repeat liver biopsy is indicated, education on the utility and safety of the biopsy is important to its acceptance.

Susceptibility to 3BNC117 and 10-1074 in ART suppressed chronically infected persons.

OBJECTIVE: The aim of this study was to assess the susceptibility of HIV to two HIV monoclonal antibodies (bnAbs), 3BNC117 and 10-1074, in individuals with chronically antiretroviral therapy (ART) suppressed HIV infection. DESIGN: The susceptibility of bnAbs was determined using the PhenoSense mAb Assay, which is a cell-based infectivity assay designed to assess the susceptibility of luciferase-reporter pseudovirions. This assay is the only Clinical Laboratory Improvement Ammendment (CLIA)/College of American Pathologist (CAP) compliant screening test specifically developed for evaluating bnAb susceptibility in people with HIV infection. METHOD: The susceptibility of luciferase-reporter pseudovirions, derived from HIV-1 envelope proteins obtained from peripheral bloodmononuclear cells of 61 ART-suppressed individuals, to 3BNC117 and 10-1074 bnAbs was assessed using the PhenoSense mAb assay. Susceptibility was defined as an IC 90 of <2.0 µg/ml and 1.5 µg/ml for 3BNC117 and 10-1074, respectively. RESULTS: About half of the individuals who were chronically infected and virologically suppressed were found to harbor virus with reduced susceptibility to one or both of the tested bnAbs. CONCLUSIONS: The reduced combined susceptibility of 3BNC117 and 10-1074 highlights a potential limitation of using only two bnAbs for pre-exposure prophylaxis or treatment. Further studies are needed to define and validate the clinical correlates of bnAb susceptibility.