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Background: Hepatitis C virus (HCV) reinfection rates are substantially higher than primary infection rates among men who have sex with men (MSM) with human immunodeficiency virus (HIV) in European cohorts. The behaviors mediating this high rate of transmission among MSM are poorly characterized., Methods: We performed a prospective cohort study in New York City (NYC) of MSM with HIV who cleared HCV to determine the incidence of and risk factors for HCV reinfection. We assessed the risk behaviors for primary HCV in NYC: receipt of semen in the rectum, and sexualized methamphetamine use, along with route of use. Multivariable analysis was performed with Andersen-Gill extension of the Cox proportional hazards model., Results: From 2000 through 2018, among 304 MSM with HIV who cleared HCV, 42 reinfections occurred over 898 person-years, for an incidence rate of 4.7 per 100 person-years. Assessing 1245 postclearance visits, only receipt of semen into the rectum was associated with reinfection (hazard ratio, 9.7 [95% confidence interval: 3.3-28.3], P < .001); methamphetamine use was not., Conclusions: The high HCV reinfection rate over almost 2 decades demonstrates that sexual transmission of HCV is not inefficient or unusual and that direct-acting antiviral treatment is not sufficient for HCV elimination among MSM in NYC. The contrasts between both the rates of and risk factors for primary and HCV reinfection suggest that HCV prevalence is highly heterogenous among sexual networks and that sexualized methamphetamine use, rather than mediating transmission, is instead a surrogate marker for the highest HCV prevalence networks. As neither condoms nor treatment have been successful strategies for HCV prevention in NYC, novel interventions are needed to stem this sexually transmitted HCV epidemic., Competing Interests: Potential conflicts of interest . D. S. F. reports research funding from Gilead Sciences and Merck, paid to his institution. R. C. reports being on the speakers bureau for Gilead. K. J. B. reports being a paid speaker for Gilead, ViiV, Janssen, and Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The benefits of direct-acting antivirals towards the elimination of hepatitis C virus (HCV) in people living with HIV are decreased when individuals are reinfected with HCV following treatment. We aimed to systematically review the existing evidence of HCV reinfection risk after treatment among people living with HIV, including people who inject drugs and men who have sex with men (MSM), and to identify the factors that explain heterogeneity in the incidence of HCV reinfection., Methods: For this systematic review and meta-analysis, we searched PubMed, Scopus, Web of Science, Cochrane, PsycINFO, and conference presentations from date of database inception to Jan 10, 2022, for clinical trials and cohort studies providing data that could be used to calculate the incidence of HCV reinfection following HCV treatment. Random-effect meta-analysis models were used to calculate rate estimates. Study-level factors contributing to heterogeneity of reinfection estimates were assessed using meta-regression. This study is registered with PROSPERO, CRD42019146973., Findings: 41 studies, predominantly conducted in Europe, were included, with a total of 9024 participants. The incidence of reinfection was 3·76 cases per 100 person-years of follow-up (95% CI 2·80-5·05; I 2 85·9%) among people living with HIV overall, 6·01 (4·54-7·95; 74·1%) among MSM, and 3·29 (2·01-5·39; 83·9%) among people who inject drugs. A similar incidence of reinfection was observed following interferon-based therapy (4·92 cases per 100 person-years of follow-up, 3·30-7·32; I 2 78·3%) and direct-acting antiviral therapy (3·88, 2·51-6·01; 85·4%). A higher proportion (≥85%) of MSM in the study population (adjusted rate ratio 2·66, 95% CI 1·37-5·15) and recent HCV infection (2·22, 1·09-4·55) were associated with an increased incidence of reinfection; a longer duration of follow-up after treatment (0·97, 0·96-0·99) was associated with a decreased incidence., Interpretation: Risk of HCV reinfection following treatment in people living with HIV was highest among MSM and those with recent HCV infection. Continued scale-up of HCV treatment and ongoing HCV screening and treatment of infection in this patient population should reduce viraemic burden and risk of reinfection., Funding: None., Competing Interests: Declaration of interests ML reports grants from Gilead Sciences, Janssen-Cilag, and ViiV Healthcare, outside the submitted work. DC reports personal fees from Merck; and non-financial support from Merck, Gilead, and GlaxoSmithKline–ViiV, outside the submitted work. JKR reports personal fees from Abivax, Galapagos, Gilead, Janssen, Merck, and ViiV, outside the submitted work. PI reports grants from Gilead and Abbott; and personal fees from Gilead, MYR Pharmaceuticals, AbbVie, and ViiV, outside the submitted work. C-CH reports grants and personal fees from Gilead Sciences and ViiV, outside the submitted work. GJD reports grants from Gilead Sciences, AbbVie, and Merck, outside the submitted work. GVM reports grants from Gilead and AbbVie, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The epidemic of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men (MSM) is in its second decade, but the routes of transmission remain poorly understood. We hypothesized that by pairing single genome sequencing (SGS), to enumerate infecting HCV genomes (viruses), with detailed sexual and drug histories, we could gain insight into the routes of transmission among MSM. We used SGS to analyze blood specimens from eight HIV-infected MSM who had 10 episodes of acute (seronegative) or early HCV infections. Seven of eight men reported condomless receptive anal intercourse (CRAI), six with rectal exposure to semen, and all eight denied rectal trauma or bleeding. Of the 10 HCV infections, eight resulted from transmission of a single virus; one infection resulted from transmission of either one or a few (three or four) closely-related viruses; and one infection resulted from transmission of >10 distinct viruses. The participant infected by >10 viruses reported sharing injection equipment for methamphetamine during sex. Two other participants also injected methamphetamine during sex but they did not share injection equipment and were infected by a single virus. Conclusions: Most HCV infections of HIV-infected MSM without a history of either rectal trauma or bleeding or shared injection equipment were caused by a single virus. Intra-rectal exposure to semen during CRAI is therefore likely sufficient for HCV transmission among MSM. Conversely, rectal trauma or bleeding or shared injection equipment are not necessary for HCV transmission among MSM. These results help clarify routes of HCV transmission among MSM and can therefore help guide the design of much-needed behavioral and other interventions to prevent HCV transmission among MSM., Competing Interests: I have read the journal's policy and the following authors of this manuscript have the following competing interests: Kristen M. Marks: reports research funding paid to her institution outside the submitted work from Gilead Sciences, Merck, and Bristol-Myers Squibb Andrew H. Talal: reports having served as a speaker, a consultant, and an advisory board member for Abbott Laboratories, and has received research funding from Merck Inc, Gilead, Abbott Laboratories, AbbVie, Intercept, Conatus, and Bristol-Myers-Squibb. Bisher Akil: reports receiving contract, consultant, and speaker fees from ViiV Healthcare Andrea D. Branch: reports having served as a consultant to Boehringer Ingelheim and receiving research funding paid to her institution from Gilead Sciences Daniel S. Fierer: reports research funding paid to his institution outside the submitted work from Gilead Sciences and Merck. The following authors have declared that no competing interests exist: Hui Li; Wouter O. van Seggelen; Asa Radix; Shirish Huprikar; Shuyi Wang; George M. Shaw. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection.

Background: Direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) result in initial cure rates of 95% to 99% and re-treatment cure rates of 95%. Nevertheless, given the sheer magnitude of infected persons, some will ultimately fail multiple DAA therapies, and re-treatment of these persons has not been adequately studied., Methods: We evaluated treated an HIV-infected man with cirrhosis from genotype 1b HCV who had failed 3 DAA regimens., Results: We treated and cured our "particularly difficult-to-cure" patient with sofosbuvir plus glecaprevir/pibrentasvir plus ribavirin for 24 weeks. We discuss the literature on potential biological factors behind his treatment failures such as lack of HCV seroconversion during his infection course, and multiple failures of hepatitis B seroconversion after vaccination, and the rationale for choosing his curative salvage regimen., Discussion: There are no clinical trials-proven re-treatment regimens for "particularly difficult-to-cure" patients. Multiple patient- and virus-related factors that do not affect cure rates in treatment-naive patients may need to be considered in choosing a re-treatment regimen for these patients. These regimens may need to include combinations drugs that are not available in single-tablet form, addition of ribavirin, and longer durations of treatment than standard., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of anorectal infection with high-risk human papillomavirus and subsequent high-grade squamous intraepithelial lesions (HSIL), the putative precursor to anal cancer. Recently, an epidemic of sexually transmitted hepatitis C virus (HCV) has emerged that shares this anorectal route of transmission. We hypothesized that the prevalence of anal HSIL would be high in HIV-infected MSM with sexually acquired early HCV infection., Methods: High-resolution anoscopy (HRA) findings from a cohort of HIV-infected MSM with sexually acquired early HCV infection were compared with HRA findings from a contemporary cohort of HIV-infected MSM without HCV infection who underwent HRA due to abnormal anal cytology found during routine screening., Results: Sixty HIV-infected MSM with sexually acquired early HCV infection and the comparator group of 1150 HIV-infected MSM with abnormal anal cytology but without HCV underwent HRA. The HIV-infected MSM with sexually acquired early HCV had higher CD4 counts compared with the comparator group (656 and 541 cells/μL, respectively; P = .02). Despite this, the prevalence of anal dysplasia was as high among MSM with early HCV as in the comparator group of MSM with abnormal cytology (47 [78%] and 941 [82%], respectively; P = .50), as was the proportion with HSIL (25 [42%] and 379 [33%], respectively; P = .17)., Conclusions: The prevalence of anal dysplasia in HIV-infected MSM with sexually acquired early HCV infection was as high as that of HIV-infected MSM with abnormal anal cytology. These findings suggest that primary screening with HRA may be warranted for HIV-infected MSM with early HCV., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Current guidelines for the management of hepatitis C virus (HCV) infections provide varying recommendations for the optimal treatment of acute HCV infections. There are limited data from small cohort studies to provide guidance on the best approach to treatment of this important patient population., Methods: Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals is an open-label, 2-cohort, Phase 1 clinical trial in which the second cohort assessed the safety and efficacy of 8 weeks of ledipasvir/sofosbuvir for the treatment of acute HCV infections in participants with chronic human immunodeficiency virus (HIV)-1 infections. This final analysis of the second cohort had a planned accrual of 27 participants, based on non-inferiority criteria, compared to the study-defined, historical, sustained virologic response (SVR) of 60% with pegylated-interferon/ribavirin., Results: We enrolled 27 men (9 Hispanic; 11 White, non-Hispanic; 5 Black, non-Hispanic; 2 Asian or Pacific Islander; median age 46 years). Most (96%) had HCV genotype-1 infection and 59% had the favorable interleukin 28B CC genotype. The median baseline HCV RNA load was 6.17 log10 IU/mL (interquartile range 4.51 - 6.55). All participants (100%) achieved the primary outcome of a sustained virologic response 12 weeks after the date of the last dose of study treatment (90% confidence interval 90-100%), achieving non-inferiority versus the 60% historic benchmark. No treatment discontinuations occurred., Conclusions: This multicenter clinical trial, investigating 8 weeks of ledipasvir/sofosbuvir for acute HCV infections in men with HIV infections, reports a 100% SVR. This study provides the rationale for larger studies of shortened courses of direct-acting antiviral therapies in persons with HIV infections, including those with high baseline HCV RNA loads., Clinical Trials Registration: NCT02128217., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Sexually acquired hepatitis C virus (HCV) infections among human immunodeficiency virus (HIV)-uninfected men who have sex with men (MSM) have been rare. With the introduction of preexposure prophylaxis (PrEP) against HIV, we hypothesized that these infections would increase. Between 2013 and 2018, we diagnosed 15 likely sexually acquired HCV infections among 14 MSM using PrEP. Most (87%) were asymptomatic, detected by routine alanine transaminase (ALT) or HCV monitoring. Half reported increasing sex partners and drug use after starting PrEP; 5 reported injection of methamphetamine. Interventions are needed to prevent sexually acquired HCV infections by MSM using PrEP. Centers for Disease Control and Prevention guidelines for monitoring during PrEP should include regular ALT and HCV testing., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Treatment of HIV-infected men during early hepatitis C virus (HCV) infection with interferon results in a higher cure rate with a shorter duration of treatment than during chronic HCV infection. We recently demonstrated that this phenomenon applied to interferon-free treatment as well, curing most participants with short-course sofosbuvir and ribavirin. Due to the significantly higher potency of the ledipasvir/sofosbuvir (LDV/SOF) combination, we hypothesized that we would be more successful in curing early HCV infections using a shorter course of LDV/SOF than that used for treating chronic HCV infections., Methods: We performed a prospective, open-label, consecutive case series study of 8 weeks of LDV/SOF in HIV-infected men with early genotype 1 HCV infection. The primary end point was aviremia at least 12 weeks after completion of treatment., Results: We treated 25 HIV-infected men with early sexually acquired HCV infection with 8 weeks of LDV/SOF, and all 25 (100%) were cured. Twelve (48%) reported sexualized drug use with methamphetamine., Conclusions: Eight weeks of LDV/SOF cured all 25 HIV-infected men with early HCV infection, including those who were actively using drugs. Based on these results, we recommend treatment of newly HCV-infected men during early infection, regardless of drug use, to both take advantage of this 8-week treatment and to decrease further HCV transmission among this group of men.

Background: The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions., Objectives: To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate., Methods: HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS., Results: Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment., Conclusions: These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.

Recent studies have reported higher rates of hepatocellular carcinoma (HCC) in individuals treated with direct-acting antivirals (DAAs). However, making definitive conclusions has been challenging because of the heterogeneous populations and methodologies of these reports. We investigated whether DAA use is associated with higher rates of incident HCC compared to treatment with interferon (IFN)-based regimens. We performed a retrospective, population-based cohort study using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database. In a cohort of 17,836 persons, sustained virological response (SVR) was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. Among all treated persons, risk of HCC was not higher in the DAA group compared to the IFN group (hazard ratio, 1.07; 95% confidence interval, 0.55, 2.08). Among persons with cirrhosis who achieved SVR, neither the HCC incidence rate nor HCC-free survival were significantly different in the DAA group compared to the IFN group (21.2 vs. 22.8 per 1,000 person-years; P = 0.78 and log-rank P = 0.17, respectively). Untreated persons with cirrhosis had a significantly higher HCC incidence rate (45.3 per 1,000 person-years) compared to those treated with either IFN or DAAs (P = 0.03). Both groups of treated persons had significantly lower probability of HCC development compared to untreated persons (log-rank, P = 0.0004)., Conclusion: DAA treatment is not associated with a higher risk of HCC in persons with cirrhosis with chronic HCV infection in the short term. Previously reported higher rates of HCC associated with DAA treatment may be explained by both the presence of relatively fewer baseline HCC risk factors in persons treated with IFN as well as selection bias, given that DAA regimens were used to treat persons at higher risk for developing HCC. (Hepatology 2018;67:2244-2253)., (© 2017 by the American Association for the Study of Liver Diseases.)

Direct-acting antivirals for hepatitis C virus infection may revolutionize treatment among persons with substance use disorders. Despite persons with substance use disorders having the highest hepatitis C virus prevalence and incidence, the vast majority have not engaged into care for the infection. Previously, interferon-based treatments, with substantial side effects and the propensity to exacerbate mental health conditions, were major disincentives to pursuit of care for the infection. Direct-acting antivirals with viral eradication rates of >90%, significantly improved side effect profiles, and shorter treatment duration are dramatic improvements over prior treatment regimens that should promote widespread hepatitis C virus care among persons with substance use disorders. The major unmet need is strategies to promote persons with substance use disorders engagement into care for hepatitis C virus. Although physical integration of treatment for substance use and co-occurring conditions has been widely advocated, it has been difficult to achieve. Telemedicine offers an opportunity for virtual integration of behavioral and medical treatments that could be supplemented by conventional interventions such as hepatitis C virus education, case management, and peer navigation. Furthermore, harm reduction and strategies to reduce viral transmission are important to cease reinfection among persons with substance use disorders. Widespread prescription of therapy for hepatitis C virus infection to substance users will be required to achieve the ultimate goal of global virus elimination. Combinations of medical and behavioral interventions should be used to promote persons with substance use disorders engagement into and adherence with direct-acting antiviral-based treatment approaches. Ultimately, either physical or virtual colocation of hepatitis C virus and substance use treatment has the potential to improve adherence and consequently treatment efficacy.

Background: Historically, acute hepatitis C virus (HCV) infection was treated with shorter durations of interferon-containing therapies. In the era of direct-acting antivirals (DAAs), it is unclear whether the efficacy of treatment achieved in chronic infection can be maintained with abbreviated courses of therapy during the acute phase., Methods: The sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals (SWIFT-C) is an open-label, 2-cohort clinical trial in which the first cohort assessed for the safety and efficacy of 12 weeks of sofosbuvir plus ribavirin for the treatment of acute HCV infection in participants with chronic human immunodeficiency virus type 1 (HIV-1) infection. This is a preplanned analysis of the first cohort, which had a planned accrual of 17 participants., Results: Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2 280 000 IU/mL (interquartile range, 272 000-4 230 000). Ten participants (59%) achieved the primary outcome of SVR12 (90% confidence interval, 36%-78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment., Conclusion: Sofosbuvir-ribavirin for 12 weeks for the treatment of acute HCV genotype-1 infection in HIV-1-infected persons results in a high relapse rate. Preliminary studies of DAA combination therapies suggest improved response rates, although the adequate duration of therapy remains unclear., Clinical Trials Registration: NCT02128217., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com)

Background: There is an international epidemic of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men. We previously showed that adding telaprevir to pegylated interferon (IFN) and ribavirin (RBV) both shortened treatment and increased the cure rate of early HCV in these men. Whether shortening treatment of early HCV using IFN-free regimens would be similarly successful has not yet been demonstrated., Methods: We performed a pilot study of treatment with sofosbuvir (SOF) + RBV for 12 weeks in early genotype 1 HCV infection in HIV-infected men. The primary endpoint was SVR 12., Results: Twelve men were treated with 12 weeks SOF + RBV and 11 (92%) achieved SVR 12. Most (63%) were actively using recreational drugs, mostly methamphetamine. The one man who failed had laboratory results more characteristic of chronic than of early HCV infection. The overall safety profile was similar to that known for SOF + RBV., Conclusions: The success of this short-duration IFN-free treatment in early HCV infection is proof in principle that enhanced treatment responsiveness is an inherent characteristic of early HCV infection and not a function of IFN treatment itself. Future studies should now be done with more potent regimens to try to further shorten therapy. In the mean time, in clinical practice early HCV infection should be treated immediately after detection to take advantage of short-duration treatments, as well as to decrease further HCV transmission among HIV-infected MSM.

HIV-1 viremic controllers (VC) spontaneously control infection without antiretroviral treatment. Several studies indicate that IgG Abs from VCs induce enhanced responses from immune effector cells. Since signaling through Fc-γ receptors (FCGRs) modulate these Ab-driven responses, here we examine if enhanced FCGR activation is a common feature of IgG from VCs. Using an infected cell-based system, we observed that VC IgG stimulated greater FCGR2A and FCGR3A activation as compared with noncontrollers, independent of the magnitude of HIV-specific Ab binding or virus neutralization activities. Multivariate regression analysis showed that enhanced FCGR signaling was a significant predictor of VC status as compared with chronically infected patients (CIP) on highly active antiretroviral therapy (HAART). Unsupervised hierarchical clustering of patient IgG functions primarily grouped VC IgG profiles by enhanced FCGR2A, FCGR3A, or dual signaling activity. Our findings demonstrate that enhanced FCGR signaling is a common and significant predictive feature of VC IgG, with VCs displaying a distinct spectrum of FCGR activation profiles. Thus, profiling FCGR activation may provide a useful method for screening and distinguishing protective anti-HIV IgG responses in HIV-infected patients and in monitoring HIV vaccination regimens., Competing Interests: Conflict of Interest: The authors have declared that no conflict of interest exists.

Background: For over a decade we have known of an epidemic of sexually transmitted hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM), but there still remains significant controversy over which bodily fluid(s) are responsible for HCV transmission in these men., Methods: We enrolled HIV-infected MSM with recent and chronic HCV infection and quantified HCV from rectal fluid obtained by blind swab. We compared the rectal HCV viral load (VL) with paired blood HCV VL., Results: We found rectal HCV shedding in 20 (47%) of 43 men, only one (2%) of whom had visible bleeding. Detection of rectal HCV shedding was associated with blood VL > 5 log 10 IU/mL (p = .01), and 85% with blood VL > 5 log 10 IU/mL had rectal shedding. The HCV VL of the rectal fluid ranged from 2.6 to 5.5 log 10 IU/mL. Based on the median rectal fluid VL, the surface of an average human penis would be exposed to at least 2,300 IU of HCV for the duration of anal intercourse., Conclusion: This study provides the first direct evidence to our knowledge that a sufficient quantity of HCV is shed into the rectum in HIV-infected men with HCV infection to directly infect an inserted penis or be passed indirectly through fomite-like transmission to the rectum of sex partner. We must develop an appropriate public health campaign to educate MSM about these routes of HCV infection to reverse the HCV epidemic among HIV-infected MSM., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Mortality in patients with HIV infection is increasingly due to comorbid medical conditions. Research on how adherence to medications for comorbidities relates to antiretroviral (ARV) medication adherence and how interrelations between illness perceptions and medication beliefs about HIV and comorbidities affect medication adherence is needed to inform adherence interventions., Methods: HIV-infected adults with hypertension (HTN) (n = 151) or chronic kidney disease (CKD; n = 41) were recruited from ambulatory practices at an academic medical center. Illness perceptions and medication beliefs about HIV and HTN or CKD were assessed and adherence to one ARV medication and one medication for either HTN or CKD was electronically monitored for 10 weeks., Results: Rates of taking, dosing, and timing adherence to ARV medication did not differ from adherence to medication for HTN or CKD, with the exception that patients were more adherent to the timing of their ARV (78%) than to the timing of their antihypertensive (68%; P = 0.01). Patients viewed HIV as better understood, more chronic, having more negative consequences, and eliciting more emotions, compared with HTN. Patients viewed ARVs as more necessary than medication for HTN or CKD. Having a realistic view of the efficacy of ARVs (r = -0.20; P < 0.05) and a high level of perceived HIV understanding (r = 0.21; P < 0.05) correlated with better ARV adherence., Conclusions: Patients with HIV showed similar rates of adherence to ARVs as to medications for comorbidities, despite perceiving HIV as more threatening and ARVs as more important. This can be used in adapting existing interventions for ARV adherence to encompass adherence to medications for comorbid conditions.

Background: Patients with hepatitis C virus (HCV) with or without human immunodeficiency virus (HIV) achieve high sustained virological response (SVR) rates on sofosbuvir (SOF)-containing regimens in clinical trials. Real world data on patients coinfected with HCV and HIV treated with SOF-based regimens are lacking., Methods: This observational cohort study included HIV/HCV-coinfected adults with genotype 1 HCV who initiated treatment with a SOF-containing regimen between December 2013 and December 2014 (n = 89) at the Mount Sinai Hospital or the Brooklyn Hospital Center. The primary outcome was SVR at 12 weeks after the end of treatment. The secondary outcomes were risk factors for treatment failure, serious adverse events, and side effects. A post hoc per protocol analysis of SVR was performed on patients who completed treatment and follow-up., Results: In an intention-to-treat analysis, SVR rates were 76% (31/41) for simeprevir (SMV)/SOF, 94% (16/17) for SMV/SOF/ribavirin (RBV), and 52% (16/31) for SOF/RBV. The SVR rates of SMV/SOF/RBV and SMV/SOF did not differ significantly in this small study (P = .15). However the SVR rate of SMV/SOF/RBV was higher than that of SOF/RBV (P < .01). In a per protocol analysis, SMV/SOF/RBV had a higher SVR rate than SOF/RBV: 100% (16/16) vs 57% (16/28) (P < .01). The most commonly reported adverse effects were rash, pruritus, fatigue, and insomnia. One patient who had decompensated cirrhosis prior to treatment initiation died after receiving SMV/SOF., Conclusions: SMV/SOF ± RBV is an effective option with minimal adverse effects for most HIV-positive patients with genotype 1 HCV. SMV should be used with caution in patients with decompensated cirrhosis., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background & Aims: The host genetic environment contributes significantly to the outcomes of hepatitis C virus (HCV) infection and therapy response, but little is known about any effects of HCV infection on the host beyond any changes related to adaptive immune responses. HCV persistence is associated strongly with mitochondrial dysfunction, with liver mitochondrial DNA (mtDNA) genetic diversity linked to disease progression., Methods: We evaluated the genetic diversity of 2 mtDNA genomic regions (hypervariable segments 1 and 2) obtained from sera of 116 persons using next-generation sequencing., Results: Results were as follows: (1) the average diversity among cases with seronegative acute HCV infection was 4.2 times higher than among uninfected controls; (2) the diversity level among cases with chronic HCV infection was 96.1 times higher than among uninfected controls; and (3) the diversity was 23.1 times higher among chronic than acute cases. In 2 patients who were followed up during combined interferon and ribavirin therapy, mtDNA nucleotide diversity decreased dramatically after the completion of therapy in both patients: by 100% in patient A after 54 days and by 70.51% in patient B after 76 days., Conclusions: HCV infection strongly affects mtDNA genetic diversity. A rapid decrease in mtDNA genetic diversity observed after therapy-induced HCV clearance suggests that the effect is reversible, emphasizing dynamic genetic relationships between HCV and mitochondria. The level of mtDNA nucleotide diversity can be used to discriminate recent from past infections, which should facilitate the detection of recent transmission events and thus help identify modes of transmission.

Background.  The epidemic of sexually transmitted hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) has been documented for over a decade. Despite this, there is no consensus as to the risk factors for sexual acquisition of HCV in these men. Methods.  We obtained paired semen and blood samples at 2-week intervals from HIV-infected MSM with recent and chronic HCV infection and quantified HCV in semen. Results.  Hepatitis C virus was quantified in 59 semen specimens from 33 men. Hepatitis C virus was shed in 16 (27%) of semen specimens from 11 (33%) of the men. Median HCV viral load (VL) in semen was 1.49 log10 IU/mL. Hepatitis C virus VL in blood was significantly higher at the time of HCV shedding in semen than when HCV shedding in semen was not detected (P = .002). Furthermore, there was a significant correlation between the HCV VL in blood and semen overall (rs = 0.41; P = .001), and in the subgroup with recent HCV infection (rs = 0.37; P = .02), but not in the subgroup with chronic HCV infection (rs = 0.34; P = .1). Conclusions.  One third of HIV-infected MSM coinfected with HCV shed HCV into their semen. Based on the HCV VL in semen in this study, an average ejaculate would deliver up to 6630 IU of virus into the rectum of the receptive partner. Therefore, our data strongly support that condoms should be used during anal intercourse among MSM to prevent transmission of HCV.

Unlabelled: Despite the recent development of highly effective anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and development of an effective vaccine. A precise molecular identification of transmitted/founder (T/F) HCV genomes that lead to productive clinical infection could play a critical role in vaccine research, as it has for HIV-1. However, the replication schema of these two RNA viruses differ substantially, as do viral responses to innate and adaptive host defenses. These differences raise questions as to the certainty of T/F HCV genome inferences, particularly in cases where multiple closely related sequence lineages have been observed. To clarify these issues and distinguish between competing models of early HCV diversification, we examined seven cases of acute HCV infection in humans and chimpanzees, including three examples of virus transmission between linked donors and recipients. Using single-genome sequencing (SGS) of plasma vRNA, we found that inferred T/F sequences in recipients were identical to viral sequences in their respective donors. Early in infection, HCV genomes generally evolved according to a simple model of random evolution where the coalescent corresponded to the T/F sequence. Closely related sequence lineages could be explained by high multiplicity infection from a donor whose viral sequences had undergone a pretransmission bottleneck due to treatment, immune selection, or recent infection. These findings validate SGS, together with mathematical modeling and phylogenetic analysis, as a novel strategy to infer T/F HCV genome sequences., Importance: Despite the recent development of highly effective, interferon-sparing anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and the development of an effective vaccine, which could be facilitated by a precise molecular identification of transmitted/founder (T/F) viral genomes and their progeny. We used single-genome sequencing to show that inferred HCV T/F sequences in recipients were identical to viral sequences in their respective donors and that viral genomes generally evolved early in infection according to a simple model of random sequence evolution. Altogether, the findings validate T/F genome inferences and illustrate how T/F sequence identification can illuminate studies of HCV transmission, immunopathogenesis, drug resistance development, and vaccine protection, including sieving effects on breakthrough virus strains., (Copyright © 2015 Li et al.)

Hepatitis C virus (HCV) is not considered to be efficiently transmitted sexually, but since the early 2000s, HCV infection of HIV-infected men who have sex with men has emerged as an epidemic worldwide. In this review, we discuss the epidemiology of sexually transmitted acute HCV, the growing body of literature regarding risk factors for acquisition, and possible mechanisms of transmission. We also discuss the progression of liver disease in these men and the advances in therapy of acute HCV with interferon-free regimens and put forth our current approach of evaluating and treating these men in New York City.

Unlabelled: The type I interferon-inducible factor tetherin retains virus particles on the surfaces of cells infected with vpu-deficient human immunodeficiency virus type 1 (HIV-1). While this mechanism inhibits cell-free viral spread, the immunological implications of tethered virus have not been investigated. We found that surface tetherin expression increased the antibody opsonization of vpu-deficient HIV-infected cells. The absence of Vpu also stimulated NK cell-activating FcγRIIIa signaling and enhanced NK cell degranulation and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). The deletion of vpu in HIV-1-infected primary CD4(+) T cells enhanced the levels of antibody binding and Fc receptor signaling mediated by HIV-positive-patient-derived antibodies. The magnitudes of antibody binding and Fc signaling were both highly correlated to the levels of tetherin on the surfaces of infected primary CD4 T cells. The affinity of antibody binding to FcγRIIIa was also found to be critical in mediating efficient Fc activation. These studies implicate Vpu antagonism of tetherin as an ADCC evasion mechanism that prevents antibody-mediated clearance of virally infected cells., Importance: The ability of the HIV-1 accessory factor to antagonize tetherin has been considered to primarily function by limiting the spread of virus by preventing the release of cell-free virus. This study supports the hypothesis that a major function of Vpu is to decrease the recognition of infected cells by anti-HIV antibodies at the cell surface, thereby reducing recognition by antibody-dependent clearance by natural killer cells.

Background: There is an international epidemic of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men. Sustained virologic response (SVR) rates with pegylated interferon and ribavirin treatment are higher in these men during acute HCV than during chronic HCV, but treatment is still lengthy and SVR rates are suboptimal., Methods: We performed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute genotype 1 HCV infection in HIV-infected men. Men who were treated prior to the availability of, or ineligible for, telaprevir were the comparator group. The primary endpoint was SVR12, defined as an HCV viral load <5 IU/mL at least 12 weeks after completing treatment., Results: In the telaprevir group, 84% (16/19) of men achieved SVR12 vs 63% (30/48) in the comparator group. Among men with SVR, median time to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and 94% vs 53% had undetectable viral loads at week 4. Most patients (81%) who achieved SVR in the telaprevir group received ≤12 weeks of treatment and there were no relapses after treatment. The overall safety profile was similar to that known for telaprevir-based regimens., Conclusions: Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV-infected men halved the treatment duration and increased the SVR rate. Larger studies should be done to confirm these findings. Clinicians should be alert to detect acute HCV infection of HIV-infected men to take advantage of this effective therapy and decrease further transmission in this epidemic.

Background: We and others have shown that primary hepatitis C (HCV) infection in men infected with human immunodeficiency virus (HIV) causes early-onset liver fibrosis; however, little is known about the long-term natural history of the liver disease in these HIV-infected men., Methods: We followed a cohort of HIV-infected men with primary HCV infection in New York City., Results: Four men who were not cured after their primary HCV infection developed decompensated cirrhosis within 17 months to 6 years after primary HCV infection. Three died within 8 years of primary HCV infection, and 1 survived after liver transplant done 2 years after primary HCV infection. Three of the 4 men had AIDS at the time of primary HCV infection, and the most rapid progression occurred in the 2 men with the lowest CD4 counts at the time of HCV infection. Liver histopathology was most consistent with HCV-induced damage even though some had exposures to other potential hepatotoxins., Conclusions: Primary HCV infection resulted in decompensated cirrhosis and death within 2-8 years in 4 HIV-infected men. The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign. The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.

Sexual contact is thought to be an inefficient mode of hepatitis C virus (HCV) transmission. However, reports of sexually transmitted HCV infection among HIV-infected men who have sex with men (MSM) began to appear in 2004. The patients were of early middle age with well-controlled HIV infection, participated in unprotected receptive sex, and frequently used noninjection recreational drugs. Molecular studies showed evidence of clusters of transmission between patients in different countries in Europe. Spontaneous clearance was relatively rare, but treatment with pegylated interferon and ribavirin resulted in cure in about two thirds of patients. Of concern was the finding of moderately advanced fibrosis during the early stages of HCV infection. HIV-infected MSM are a new risk group for HCV infection and so should be screened regularly for HCV infection.

Outbreaks of acute hepatitis C virus (HCV) infection are occurring in HIV-infected men who have sex with men. We evaluated risk factors and liver histopathology in 11 consecutively enrolled men with newly acquired HCV infection that was diagnosed on the basis of antibody seroconversion, new elevations in alanine aminotransferase level, and wide fluctuations in HCV RNA level. Ten patients reported unprotected anal intercourse, and 7 reported "club-drug" use, including methamphetamine. Liver biopsy showed moderately advanced fibrosis (Scheuer stage 2) in 9 patients (82%). No cause of liver damage other than acute HCV infection was identified. The specific pathways leading to periportal fibrosis in HIV-infected men with newly acquired HCV infection require investigation.

A recent study found high levels of human immunodeficiency virus type 1 (HIV-1) bound to erythrocytes in HIV-1-infected patients with long-term undetectable plasma HIV-1 loads, potentially representing a novel and important reservoir of HIV-1 infection. To attempt to confirm this finding, we purified erythrocytes from 13 HIV-1-infected patients with long-term undetectable plasma viral load and depleted contaminating CD3(+)CD4(+) lymphocytes using magnetic beads. HIV-1 load of the purified erythrocyte fraction was <20 copies/mL in 11 of 13 patients and 42 and 52 copies/mL in 2 patients. Contrary to the prior report, therefore, erythrocytes do not represent a novel reservoir of HIV-1 infection in these patients.

Purpose of Review: To summarize recent investigations into the establishment and maintenance of the kidney and central nervous system as reservoirs of HIV infection and the resultant pathogenesis of HIV infection in these organs., Recent Findings: Significant progress has been made in understanding the pathogenesis of HIV-associated nephropathy with the demonstration that HIV gene expression within podocytes was sufficient to recapitulate HIV-associated nephropathy -like renal disease in mouse models. Little progress has been made, however, in understanding how the HIV reservoir in the kidney is established and maintained. Studies of the central nervous system reservoir have further characterized the compartmentalization of HIV between the central nervous system and lymphoid organs and within brain regions. The relationship between HIV in the cerebrospinal fluid and in the brain and the utility of cerebrospinal fluid as a surrogate for the brain have been reevaluated in patients receiving antiretroviral medication and in patients at different stages of HIV infection and neurologic impairment. Finally, nonproductive infection of astrocytes in vivo has been demonstrated and mechanisms to explain viral entry and the block to productive infection of these cells have been described., Summary: Although much progress has been made in the understanding of the pathogenesis of HIV-associated nephropathy, much work remains to be done to better understand the establishment and maintenance of the HIV reservoir in both the kidney and the brain, and in particular, the mechanisms of neurologic dysfunction resulting from HIV infection of the brain.

A double-blind, placebo-controlled trial of efficacy and safety of thalidomide in AIDS-associated wasting was carried out. Ninety-nine of 103 male patients had at least one on-study measurement (intent-to-treat [ITT] cohort). Patients were randomized to thalidomide at 100 mg/day (T100) or 200 mg/day (T200), or placebo for 8 weeks. By ITT analysis, the mean change in body weight of the placebo, T100, and T200 treatment groups was 0.3 kg (0.4%), 2.0 kg (3.0%), and 0.9 kg (1.4%), respectively (p = 0.021 for T100 versus placebo; p = 0.53 for T200 versus placebo). Of the 64 patients who completed the 8 weeks of study treatment, significant weight gain was observed in both the T100 group (2.2 kg, [33%]; p = 0.008 versus placebo) and the T200 group (1.5 kg [2.5%]; p = 0.019 versus placebo). Approximately half the weight gain was fat-free mass (bioimpedance analysis). Patients in the T100 or T200 groups had no significant change in CD4+ cell counts, neutrophil counts, or TNF-alpha levels, compared with placebo. HIV viral load measured as log10 copies/ml decreased by a median of 0.07 in the placebo group, and increased by a median of 0.29 (T100 group) and 0.23 (T200 group) (p = 0.024 andp = 0.018 versus placebo, respectively). Thalidomide therapy was associated with mild to moderate rashes and fevers, but not peripheral neuropathy. Although the anabolic benefits of high-dose thalidomide are limited by drug intolerance, 8 weeks of low-dose thalidomide results in significant weight gain in patients with AIDS-associated wasting.

A number of studies have demonstrated that the herpes simplex virus type 1 (HSV-1) UL9 protein, which is a homodimer in solution, binds to two high affinity binding sites in each origin of replication. Interaction between the proteins bound at the two sites leads to the formation of a complex nucleoprotein structure. The simplest models for this binding interaction predict two possible binding stoichiometries: 1) one UL9 dimer is bound at each site; or 2) one UL9 monomer is bound at each site so that one UL9 dimer occupies both sites. Two recent papers have addressed this issue by using indirect methods to measure the binding stoichiometry. Martin et al. (Martin, D. W., Muñoz, R. M., Oliver, D., Subler, M. A., and Deb, S. (1994) Virology 198, 71-80) reported that a monomer of UL9 binds to a single high affinity site, and Stabell and Olivo (Stabell, E. C., and Olivo, P.D. (1993) Nucleic Acids Res. 21, 5203-5211) concluded that a dimer of UL9 binds to a single high affinity site. We have directly measured the stoichiometry of binding of the carboxyl-terminal DNA binding domain of UL9 (t-UL9) to the origin of replication using a double-label gel shift assay. Using a short synthetic double-stranded oligonucleotide containing a single UL9 binding site, one protein-DNA complex was detected in the gel shift assay, and the molar ratio of UL9 DNA binding domains to DNA binding sites in this complex was determined to be 2.0 +/- 0.1 (n = 13). Using the minimal origin sequence excised from plasmid DNA, two protein-DNA complexes were detected. The binding stoichiometry of the faster migrating complex was 1.8 +/- 0.1 (n = 15), and the stoichiometry of the more slowly migrating band was 3.7 +/- 0.4 (n = 15). The simplest explanation for these data is that UL9 binds to the origin of replication as a homodimer with one dimer bound at both high affinity sites.

UL9, the origin-binding protein of herpes simplex virus type 1 (HSV-1), has been overexpressed in an insect cell overexpression system and purified to homogeneity. In this report, we confirm and extend recent findings on the physical properties, enzymatic activities, and binding properties of UL9. We demonstrate that UL9 exists primarily as a homodimer in solution and that these dimers associate to form a complex nucleoprotein structure when bound to the HSV origin of replication. We also show that UL9 is an ATP-dependent helicase, capable of unwinding partially duplex DNA in a sequence-independent manner. Although the helicase activity of UL9 is demonstrable on short duplex substrates in the absence of single-stranded DNA-binding proteins, the HSV single-stranded DNA-binding protein ICP8 (but not heterologous binding proteins) stimulates UL9 to unwind long DNA sequences of over 500 bases. We were not able to demonstrate unwinding of fully duplex DNA sequences containing the HSV origin of replication. However, in experiments designed to detect origin-dependent unwinding, we did find that UL9 wraps supercoiled DNA independent of sequence or ATP hydrolysis.