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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.)

Introduction: In 2019 38 million people were living with HIV worldwide, more than half of them girls and women. Knowledge about maternal HIV status enables HIV transmission prophylaxis, reducing mother-to-child transmission<1%. We aimed to investigate the implementation of the mandatory documentation of counseling and optional HIV testing in the maternity records as recommended in the German maternity guidelines., Methods: In the Obstetric Department of the University Hospital Bonn, maternity records were reviewed from June to October 2020, and pregnant women were interviewed regarding the patients' recall of counseling and HIV testing as well as their attitude towards a universal screening strategy using an anonymous questionnaire., Results: Documentation was incomplete in 11% of maternal records: in 8% there was neither documentation of counseling nor of HIV testing, in 3% documentation of counseling only. In 291 questionnaires 47% of pregnant women could not recall counselling. 90% of pregnant women were in favor of universal HIV testing in pregnancy, 9% were undecided, and 1% opposed it. 55% would support change from an "opt-in" to an "opt-out" screening policy in pregnancy., Summary: Documentation of counseling and HIV testing was incomplete in 11% of cases, and nearly half of the women could not recall counselling. New strategies from midwives and obstetricians need to be developed to achieve universal HIV testing in pregnant women leading to zero HIV mother-to-child transmissions., Competing Interests: C.B. hat Honorare für Vorträge oder Beratungstätigkeiten erhalten von AbbVie, Gilead, Janssen, MSD, ViiV, weiterhin Drittmittelunterstützung durch Dt. Leberstiftung, DZIF, Hector Stiftung, NEAT ID. J.R. hat Honorare für Vorträge oder Beratungstätigkeiten erhalten von Gilead, Janssen, Merck und ViiV., (Thieme. All rights reserved.)

We compared the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific antibodies to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in patients with natural infection and vaccinated persons. Analyzing plasma samples from 39 coronavirus disease 2019 (COVID-19) patients and 11 vaccinated individuals, significant induction of ADCC could be observed over a period of more than 3 months in both vaccinated and recovered individuals. Although plasma antibody concentrations were lower in recovered patients, we found antibodies elicited by natural infection induced a significantly stronger ADCC response compared to those induced by vaccination, which may affect protection conferred by vaccination., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Prior to direct-acting antivirals (DAAs), HCV incidence rose among men who have sex with men (MSM) living with HIV infection in Germany despite high hepatitis C virus (HCV) treatment rates. We establish a HCV elimination modeling framework to evaluate whether existing treatment rates can achieve the World Health Organization (WHO) incidence target among MSM living with HIV in Germany., Methods: To evaluate progress towards HCV elimination in Germany, we adapted a previously published HCV transmission model among MSM living with diagnosed HIV. We modelled HCV incidence and prevalence until 2030 (relative to 2015) under existing treatment and DAA scale-up and explored potential impacts of disruptions in treatment and behavioral risk reduction due to the COVID-19 pandemic., Results: Continuing current treatment rates will result in stable HCV incidence among MSM living with HIV in Germany between 2015-2030. The WHO HCV incidence target is achievable under DAA scale-up to 100% treatment combined with treatment of those previously diagnosed and untreated (at a rate of 15%/year) and would result in greater reductions with early treatment (3 vs 6 months) reducing incidence from 4.0/100person-years to 0.8/100person-years by 2030. A 12-month disruption to HCV treatment (20% reduction) and risk behaviors (25%,50%,75% reduction) during the COVID-19 pandemic would result in a 15% relative increase in total HCV incidence in 2030 compared to that expected under the status quo., Conclusions: HCV elimination among MSM living with HIV in Germany requires further DAA scale-up among those newly diagnosed combined with efforts to treat those previously diagnosed but untreated. Prospective monitoring will establish whether Germany is on track for HCV microelimination., Competing Interests: NKM has received unrestricted research grants and honoraria from Gilead and Merck. CB reports personal fees from AbbVie, Gilead, Johnson & Johnson, Merck Sharp & Dohme (MSD), and ViiV and grants from DZIF (German Center for Infection Research), Deutsche Leberstiftung, and Hector Stiftung. TL reports grants from AbbVie, Gilead Sciences, ViiV, Janssen-Cilag, MSD, Deutsche Leberstiftung, and DAGNÄ for scientific work. SC reports personal fees from Gilead, AbbVie, ViiV, MSD, and Indivior. SM reports personal fees from AbbVie, Gilead, and MSD. JKR reports personal fees from Abivax, AbbVie, Gilead, Janssen, Merck, and ViiV, outside the submitted work. PI has received unrestricted research grants from Gilead (IN-DE-987-4637 and IN-FR-980-6332), a research grant from Abott Laboratories, and speaker fees from Gilead, AbbVie, ViiV, MSD, and Bristol-Myers Squibb. JOW receives funding from CDC via contracts to his institution. LKM, FH and SJ have no conflicts to declare.] This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: People living with human immunodeficiency virus (PLHIV) have a similar prevalence of psoriasis as the general population, though incidence and severity correlate with HIV viral load. Adequately treating HIV early renders the infection a chronic medical condition and allows PLHIV with a suppressed viral load (PLHIV-s) to live normal lives. Despite this, safety concerns and a lack of high-level data have hindered the use of systemic psoriasis therapies in PLHIV-s., Objectives: We aim to provide a structured framework that supports healthcare professionals and patients discussing the risks and benefits of systemic psoriasis therapy in PLHIV-s. Our goal was to address the primary question, are responses to systemic therapies for the treatment of psoriasis in PLHIV-s similar to those in the non-HIV population?, Methods: We implemented an inference-based approach relying on indirect evidence when direct clinical trial data were absent. In this instance, we reviewed indirect evidence supporting inferences on the status of immune function in PLHIV. Recommendations on systemic treatment for psoriasis in PLHIV were derived using an inferential heuristic., Results: We identified seven indirect indicators of immune function informed by largely independent bodies of evidence: (1) functional assays, (2) vaccine response, (3) life expectancy, (4) psoriasis manifestations, (5) rate of infections, (6) rate of malignancies, and (7) organ transplant outcomes., Conclusions: Drug-related benefits and risks when treating a patient with systemic psoriasis therapies are similar for non-HIV patients and PLHIV with a suppressed viral load and normalized CD4 counts. Prior to initiating psoriasis treatment in PLHIV, HIV replication should be addressed by an HIV specialist. Exercise additional caution for patients with a suppressed viral load and discordant CD4 responses on antiretroviral therapy., (© 2022. The Author(s).)

Background: Sarcopenia and spontaneous portosystemic shunts (SPSSs) are common complications of liver cirrhosis, and both are associated with higher rates of hepatic encephalopathy (HE) development in these patients. This study aimed to evaluate the simultaneous impact of skeletal muscle mass and spontaneous portosystemic shunting, measured from routine diagnostic CT on outcomes in patients with liver cirrhosis., Methods: Retrospective analysis of patients with cirrhosis. Skeletal muscle mass [including fat-free muscle index (FFMI) as a surrogate for sarcopenia] and total cross-sectional spontaneous portosystemic shunt area (TSA) were quantified from CT scans. The primary endpoint was the development of HE, while the secondary endpoint was 1-year mortality., Results: One hundred fifty-six patients with liver cirrhosis were included. Patients with low (L-) FFMI and large (L-)TSA showed higher rates of HE development. In multivariable analysis, L-FFMI and L-TSA were independent predictors of HE development (L-FFMI HR = 2.69, CI 1.22-5.93; L-TSA, HR = 2.50, CI = 1.24-4.72) and 1-year mortality (L-FFMI, HR = 7.68, CI 1.75-33.74; L-TSA, HR = 3.05, CI 1.32-7.04). The simultaneous presence of L-FFMI and L-TSA exponentially increased the risk of HE development (HR 12.79, CI 2.93-55.86) and 1-year mortality (HR 13.66, CI 1.75-106.50). An easy sequential algorithm including FFMI and TSA identified patients with good, intermediate, and poor prognoses., Conclusion: This study indicates synergy between low skeletal muscle mass and large TSA to predict exponentially increased risk of HE development and mortality in liver cirrhosis. Simultaneous screening for sarcopenia and TSA from routine diagnostic CT may help to improve the identification of high-risk patients using an easy-to-apply algorithm., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT03584204]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Faron, Abu-Omar, Chang, Böhling, Sprinkart, Attenberger, Rockstroh, Luu, Jansen, Strassburg, Trebicka, Luetkens and Praktiknjo.)

Background: Following the introduction of direct-acting antiviral therapy in 2013, WHO launched the first Global Health Sector Strategy on Viral Hepatitis. We describe a hepatitis C virus (HCV) cascade of care in people with HIV (PWH) across Europe in terms of reaching the WHO elimination targets of diagnosing 90% and treating 80% of HCV-infected individuals., Methods: HIV/HCV-coinfected participants in the EuroSIDA cohort under prospective follow-up at October 1, 2019, were described using a nine-stage cascade of care. Care cascades were constructed across Europe, on a regional (n = 5) and country (n = 21) level., Results: Of 4773 anti-HCV positive PWH, 4446 [93.1%, 95% confidence interval (CI) 92.4-93.9)] were ever tested for HCV RNA, and 19.0% (95% CI 16.4-21.6) were currently HCV RNA positive, with the highest prevalence in Eastern and Central-Eastern Europe (33.7 and 29.6%, respectively). In Eastern Europe, 78.1% of the estimated number of chronic infections have been diagnosed, whereas this proportion was above 95% in the other four regions. Overall, 3116 persons have ever started treatment (72.5% of the ever chronically infected, 95% CI 70.9-74.0) and 2404 individuals (55.9% of the ever chronically infected, 95% CI 53.9-57.9) were cured. Cure proportion ranged from 11.2% in Belarus to 87.2% in Austria., Conclusion: In all regions except Eastern Europe, more than 90% of the study participants have been tested for HCV-RNA. In Southern and Central-Western regions, more than 80% ever chronically HCV-infected PWH received treatment. The proportion with cured HCV infection did not exceed 80% in any region, with significant heterogeneity between countries., Summary: In a pan-European cohort of PWH, all regions except Eastern Europe achieved the WHO target of diagnosing 90% of chronic HCV infections, while the target of treating 80% of eligible persons was achieved in none of the five regions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Previous studies have shown that men with HIV and germ cell cancer (HIV-GCC) have inferior overall survival (OS) in comparison with their HIV-negative counterparts. However, little information is available on treatments and outcomes of HIV-GCC in the era of combination antiretroviral therapy (cART)., Methods: This study examined men living with HIV who were 18 years old or older and had a diagnosis of histologically proven germ cell cancer (GCC). The primary outcomes were OS and progression-free survival (PFS)., Results: Data for 89 men with a total of 92 HIV-GCCs (2 synchronous GCCs and 1 metachronous bilateral GCC) were analyzed; among them were 64 seminomas (70%) and 28 nonseminomas (30%). The median age was 36 years, the median CD4 T-cell count at GCC diagnosis was 420 cells/µL, and 77% of the patients on cART had an HIV RNA load < 500 copies/mL. Stage I disease was found in 44 of 79 gonadal GCCs (56%). Among 45 cases with primary disseminated GCC, 78%, 18%, and 4% were assigned to the good-, intermediate-, and poor-prognosis groups, respectively, of the International Germ Cell Cancer Collaborative Group. Relapses occurred in 14 patients. Overall, 12 of 89 patients (13%) died. The causes of death were refractory GCC (n = 5), an AIDS-defining illness (n = 3), and other causes (n = 4). After a median follow-up of 6.5 years, the 5- and 10-year PFS rates were 81% and 73%, respectively, and the 5- and 10-year OS rates were 91% and 85%, respectively., Conclusions: The 5- and 10-year PFS and OS rates of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients., Lay Summary: Men living with HIV are at increased risk for germ cell cancer (GCC). Previous studies have shown that the survival of men with HIV-associated germ cell cancer (HIV-GCC) is poorer than the survival of their HIV-negative counterparts. This study examined the characteristics, treatments, and outcomes of 89 men with HIV-GCC in the era of effective combination antiretroviral therapies. The long-term outcomes of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2., Design: Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks)., Methods: Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC., Results: At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA <50 copies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], -1.8% [-5.8, 2.1]), GEMINI-1 (-3.6% [-9.4, 2.1]), and GEMINI-2 (0.0% [-5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63-0.92]). Renal and bone biomarker changes favored DTG + 3TC., Conclusions: Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract)., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: We sought to identify factors associated with weight gain in randomized clinical trials of antiretroviral therapy (ART) switch., Methods: We explored the effects of demographic factors, clinical characteristics, and ART on weight gain in a pooled analysis of 12 prospective clinical trials, wherein virologically suppressed people living with human immunodeficiency virus (PWH) were randomized to switch or remain on a stable baseline regimen (SBR)., Results: Both PWH randomized to switch ART (n = 4166) and those remaining on SBR (n = 3150) gained weight. Median weight gain was greater in those who switched (1.6 kg, interquartile range [IQR], -.05 to 4.0 vs 0.4 kg, [IQR], -1.8 to 2.4 at 48 weeks, P < .0001), with most weight gain occurring in the first 24 weeks after switch. Among baseline demographic and clinical characteristics, only younger age and lower baseline body mass index were associated with any or ≥10% weight gain. By week 48, 4.6% gained ≥10% weight (6.4% of switch and 2.2% of SBR), the greatest risk was with switch from efavirenz (EFV) to rilpivirine (RPV) or elvitegravir/cobicistat and switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). Switch from abacavir to TAF was associated with less weight gain than switch from TDF to TAF and was not associated with increased risk for ≥10% weight gain., Conclusions: Moderate weight gain after ART switch was common and usually plateaued by 48 weeks. Baseline ART was a predictor of post-switch weight gain; participants who switched off of EFV and TDF had the greatest weight gain. The biological mechanisms that underlie the differential effects of switching ART agents on weight and associated clinical implications require further study., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: The CoSHeP study provides novel data on SARS-CoV-2 seroconversion rates in healthcare professionals (HP) at risk at the University Hospital Bonn, a maximum healthcare provider in a region of 900.000 inhabitants., Methods: Single-center, longitudinal observational study investigating rate of SARS-CoV-2 IgG seroconversion in HP at 2 time-points. SARS-CoV-2 IgG was measured with Roche Elecsys Anti-SARS-CoV-2 assay., Results: Overall, 150 HP were included. Median age was 35 (range: 19-68). Main operational areas were intensive care unit (53%, n = 80), emergency room (31%, n = 46), and infectious disease department (16%, n = 24). SARS-CoV-2-IgG was detected in 5 participants (3%) at inclusion in May/June 2020, and in another 11 participants at follow-up (December 2020/ January 2021). Of the 16 seropositive participants, 14 had already known their SARS-CoV-2 infection because they had performed a PCR-test previously triggered by symptoms. Trailing chains of infection by self-assessment, 31% (n = 5) of infections were acquired through private contacts, 25% (n = 4) most likely through semi-private contacts during work. 13% (n = 2) were assumed to result through contact with contagious patients, further trailing was unsuccessful in 31% (n = 5). All five participants positive for SARS-CoV-2 IgG at inclusion remained positive with a median of 7 months after infection., Discussion: Frontline HP caring for hospitalized patients with COVID-19 are at higher risk of SARS-CoV-2 infections. Noteworthy, based upon identified chains of infection most of the infections were acquired in private environment and semi-private contacts during work. The low rate of infection through infectious patients reveals that professional hygiene standards are effective in preventing SARS-CoV-2 infections in HP. Persisting SARS-CoV-2-IgG might indicate longer lasting immunity supporting prioritization of negative HP for vaccination., (© 2021. The Author(s).)

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global challenge that substantially risks reversing the progress in ending human immunodeficiency virus (HIV). At the same time, it may offer the opportunity for a new era of HIV management. This viewpoint presents the impact of COVID-19 on HIV care, including the Joint United Nations Programme on HIV/AIDS (UNAIDS) "three 90s" targets. It outlines how to enhance a patient-centered care approach, now known as the "fourth 90," by integrating face-to-face patient-physician and telemedicine encounters. It suggests a framework for prevention and treatment of multimorbidity and frailty, to achieve a good health-related quality of life, and to preserve intrinsic capacity in all people living with HIV., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: De novo steatosis is the main criteria for non-alcoholic fatty liver disease (NAFLD), which is becoming a clinically relevant comorbidity in HIV-infected patients. This may be due to the HIV virus itself, as well as long-term toxicities deriving from antiretroviral therapy. Therefore, HIV infected patients require prevention and monitoring regarding NAFLD., Methods: This study investigated the differential role of body mass index (BMI) and combination antiretroviral treatment (cART) drugs on NAFLD progression. This single center prospective longitudinal observational study enrolled HIV monoinfected individuals between August 2013 to December 2018 with yearly visits. Each visit included liver stiffness and steatosis [defined as controlled attenuation parameter (CAP)>237 dB/m] assessment by annually transient elastography using an M- or XL-probe of FibroScan, and calculation of the novel FibroScan-AST (FAST) score. Risk factors for denovo/progressed steatosis and tripling of FAST-score increase were investigated using Cox regression model with time-dependent covariates., Findings: 319 monoinfected HIV positive patients with at least two visits were included into the study, of which 301 patients had at least two valid CAP measurements. 51·5%(155) patients did not have steatosis at first assessment, of which 45%(69) developed steatosis during follow-up. A BMI>23 kg/m 2 (OR: 4·238, 95% CI: 2·078-8·938; p < 0·0001), tenofovir-alafenamid (TAF) (OR: 5·073, 95% CI: 2·362-10·899); p < 0·0001) and integrase strand transfer inhibitors (INSTI) (OR: 2·354, 95% CI: 1·370-4·048; p  = 0·002), as well as type 2 diabetes mellitus (OR: 7·605, 95% CI: 2·315-24·981; p < 0·0001) were independent predictors of de novo steatosis in multivariable analysis. Tenofovir disoproxilfumarate (TDF) was associated with a lower risk for weight gain and steatosis progression/onset using CAP value (HR: 0·28, 95% CI: 0·12-0·64; p  = 0·003) and FAST scores (HR: 0·31, 95% CI: 0·101-0·945; p  = 0·04)., Interpretation: Steatosis can develop despite non-obese BMI in patients with HIV monoinfection under cART, especially in male patients with BMI over 23 kg/m 2 . While TAF and INSTI increase the risk of progression of steatosis, TDF was found to be independently associated with a lower risk of a clinically significant weight gain and thereby, might slow down development and progression of steatosis., Funding: There was no additional funding received for this project. All funders mentioned in the 'declaration of interests' section had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript., Competing Interests: Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 to P18, CRC 1382AO9), European Union's Horizon 2020 Research and Innovation Programme (Galaxy, No. 668,031 and, MICROB-PREDICT, No. 825,694 and DECISION, No.847949), and Societal Challenges - Health, Demographic Change and Wellbeing (No. 731,875), and Cellex Foundation (PREDICT). Jürgen Rockstroh has received honoraria for consulting or speaking at educational events from Abivax, Galapagos, Gilead, Merck, Janssen, Theratechnologies and ViiV. Jenny Bischoff is supported by a scholarship of the BONFOR research support program for young scientists at the Rheinische Friedrich-Wilhelms-Universität (BONFOR Funding Instrument 1, Type A; Application number: 2020–1A-08). Christoph Boesecke has received honoraria for lectures from Abbvie, Gilead, ViiV, Janssen and MSD and was supported by a Grant from Hector-Stiftung for another HIV Study. Jan-Christian Wasmuth has received a travel grant from Gilead to attend a meeting. Wenyi Gu, Leona Dold, Carolynne Schwarze-Zander and Kathrin van Bremen have nothing to declare. All funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript., (© 2021 The Authors.)

Introduction: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment., Methods: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis)., Results: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred., Discussion: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Bictegravir (B)/emtricitabine (F)/tenofovir alafenamide (TAF) is guideline-recommended treatment for human immunodeficiency virus type 1 (HIV-1). We evaluated whether people receiving dolutegravir (DTG) plus F/TAF or F/TDF (tenofovir disoproxil fumarate) with viral suppression can switch to B/F/TAF without compromising safety or efficacy, regardless of preexisting nucleoside reverse transcriptase inhibitor (NRTI) resistance., Methods: In this multicenter, randomized, double-blinded, active-controlled, noninferiority trial, we enrolled adults who were virologically suppressed for ≥6 months before screening (with documented/suspected NRTI resistance) or ≥3 months before screening (with no documented/suspected NRTI resistance) on DTG plus either F/TDF or F/TAF. We randomly assigned (1:1) participants to switch to B/F/TAF or DTG + F/TAF once daily for 48 weeks, each with matching placebo. The primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm); the prespecified noninferiority margin was 4%., Results: Five hundred sixty-seven adults were randomized; 565 were treated (284 B/F/TAF, 281 DTG + F/TAF). At week 48, B/F/TAF was noninferior to DTG + F/TAF, as 0.4% (1/284) vs 1.1% (3/281) had HIV-1 RNA ≥50 copies/mL (difference, -0.7% [95.001% confidence interval {CI}, -2.8% to 1.0%]). There were no significant differences in efficacy among participants with suspected or confirmed prior NRTI resistance (n = 138). No participant had treatment-emergent drug resistance. Median weight change from baseline at week 48 was +1.3 kg (B/F/TAF) vs +1.1 kg (DTG + F/TAF) (P = .46). Weight change differed by baseline NRTIs (+2.2 kg [F/TDF] and +0.6 kg [F/TAF], P < .001), with no differences between B/F/TAF and DTG + F/TAF., Conclusions: The single-tablet regimen B/F/TAF is a safe, effective option for people virologically suppressed on DTG plus either F/TDF or F/TAF, including in individuals with preexisting resistance to NRTIs., Clinical Trials Registration: NCT03110380., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Acute-on-chronic liver failure (ACLF) is a syndrome associated with organ failure and high short-term mortality. Presence of ACLF at interventions, such as surgery or transjugular intrahepatic portosystemic shunt (TIPS), has been shown to determine outcome, but those interventions have also been attributed to precipitate ACLF in different studies. However, dedicated investigation for the risk of ACLF development in these interventions, especially in elective settings, has not been conducted. Patients with cirrhosis undergoing elective surgery were propensity score matched and compared to patients receiving TIPS. The primary endpoint was ACLF development within 28 days after the respective procedure. The secondary endpoint was 3-month and 1-year mortality. In total, 190 patients were included. Within 28 days, ACLF developed in 24% of the surgery and 3% of the TIPS cohorts, with the highest ACLF incidence between 3 and 8 days. By day 28 after the procedure, ACLF improved in the TIPS cohort. In both cohorts, patients developing ACLF within 28 days after surgery or TIPS placement showed significantly worse survival than patients without ACLF development at follow-up. After 12 months, mortality was significantly higher in the surgery cohort compared to the TIPS cohort (40% vs. 23%, respectively; P  = 0.031). Regression analysis showed a European Foundation Chronic Liver Failure Consortium acute decompensation (CLIF-C AD) score ≥50 and surgical procedure as independent predictors of ACLF development. CLIF-C AD score ≥50, C-reactive protein, and ACLF development within 28 days independently predicted 1-year mortality. Conclusion: Elective surgical interventions in patients with cirrhosis precipitate ACLF development and ultimately death, but TIPS plays a negligible role in the development of ACLF. Elective surgery in patients with CLIF-C AD ≥50 should be avoided, while the window of opportunity would be CLIF-C AD <50., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Rabies post-exposure prophylaxis (R-PEP) including wound treatment, vaccination and application of rabies immunoglobulin (RIG) is essential in preventing rabies mortality. Today, Germany is officially declared free from terrestrial rabies and rabies is only found in bats. However, physicians in A&E Departments are frequently consulted on the need for R-PEP. We retrospectively analysed patients who received R-PEP at the A&E Department of the University Hospital Bonn between 01.01.2013 and 30.06.2019. Demographic data, travel history, clinical and laboratory findings, previous rabies vaccinations and R-PEP vaccination regimen were recorded. During the study period, 90 patients received R-PEP at the University Hospital Bonn, in 10 cases without indication for R-PEP. Altogether, we found deviations from R-PEP guidelines in 51% (n = 41/80). Infiltration of RIG was missed in 12 patients and incorrectly administrated in 24 patients. Furthermore, vaccination scheme was incorrect in 11 patients. Correct wound washing and documentation of tetanus status was missing in 14% and 63% of patients, respectively. Despite rabies elimination in Germany patients frequently seek advice for R-PEP, the majority returning from foreign travel. Our data show that there is a high need for education on indication for R-PEP before and after travel and for implementation of precise R-PEP guidelines in daily clinical practice.

HLA-B*57 affects the course of HIV infection. Under antiretroviral therapy, its effects cannot be explained by outstandingly efficient T cell responses alone but may also involve cells of innate immunity. Studying in vitro stimulation with Pam3CSK4, E. coli LPS-B5 and CpG-ODN-2216, we observed greater induction of IL-6/IL-1beta double-positive CD14 + CD16 ++ monocytes as well as IFN-gamma-positive cytotoxic CD56 high CD16 neg NK cells in HLA-B*57- versus HLA-B*44-positive HIV patients, while TNF-alpha induction remained unchanged. Differences were not seen in the other monocyte and NK cell subsets or in HLA-matched healthy controls. Our findings show that, in virally suppressed HIV infection, HLA-B*57 is associated with enhanced responsiveness of inflammatory innate immune cells to TLR ligands, possibly contributing to increased vulnerability in sepsis. KEY MESSAGES: • HLA-B*57 is a host factor affecting clinical outcomes of HIV infection. • HLA-B*57 modifies inflammatory subsets of NK cells and monocytes in HIV infection. • In HLA-B*57-positive HIV patients TLR agonists induce enhanced IL-6/IL-1beta in monocytes. • NK cells from HLA-B*57 HIV patients release more IFN-gamma upon TLR costimulation. • HLA-B*57 is linked to enhanced inflammatory responsiveness to TLR ligands.

Background: The ongoing global SARS-CoV-2 pandemic has caused over 4.7 million infections greatly challenging healthcare workers (HCW) and medical institutions worldwide. The SARS-CoV-2 pandemic has shown to significantly impact mental and physical health of HCW. Thus, implementation of testing facilities supporting HCW are urgently needed., Methods: A low-threshold SARS-CoV-2 testing facility was introduced at the University Hospital Bonn, Germany, in March 2020. Irrespective of clinical symptoms employees were offered a voluntary and free SARS-CoV-2 test. Furthermore, employees returning from SARS-CoV-2 risk regions and employees after risk contact with SARS-CoV-2 infected patients or employees were tested for SARS-CoV-2 infection. Pharyngeal swabs were taken and reverse transcription polymerase chain reaction for detection of SARS-CoV-2 was performed, test results being available within 24 h. Profession, symptoms and reason for SARS-CoV-2 testing of employees were recorded., Results: Between 9th March and April 30, 2020, a total of 1510 employees were tested for SARS-CoV-2 infection. 1185 employees took advantage of the low-threshold testing facility. One percent (n = 11) were tested positive for SARS-CoV-2 infection, 18% being asymptomatic, 36% showing mild and 36% moderate/severe symptoms (missing 10%). Furthermore, of 56 employees returning from SARS-CoV-2 risk regions, 18% (10/56) were tested SARS-CoV-2 positive. After risk contact tracking by the hospital hygiene 6 patient-to-employee transmissions were identified in 163 employees with contact to 55 SARS-CoV-2 positive patients., Conclusion: In the absence of easily accessible public SARS-CoV-2 testing facilities low-threshold SARS-CoV-2 testing facilities in hospitals with rapid testing resources help to identify SARS-CoV-2 infected employees with absent or mild symptoms, thus stopping the spread of infection in vulnerable hospital environments. High levels of professional infection prevention training and implementation of specialized wards as well as a perfectly working hospital hygiene network identifying and tracking risk contacts are of great importance in a pandemic setting., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Objective: To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted darunavir, or efavirenz., Design: Post-hoc analysis of pooled data from three randomized controlled trials., Methods: We evaluated weight change from baseline, weight gain at least 10%, and increase in BMI after 48 and 96 weeks of treatment with doravirine, ritonavir-boosted darunavir, or efavirenz-based regimens. Risk factors for weight gain and metabolic outcomes associated with weight gain were also examined., Results: Mean (and median) weight changes were similar for doravirine [1.7 (1.0) kg] and ritonavir-boosted darunavir [1.4 (0.6) kg] and were lower for efavirenz [0.6 (0.0) kg] at week 48 but were similar across all treatment groups at week 96 [2.4 (1.5), 1.8 (0.7), and 1.6 (1.0) kg, respectively]. No significant differences between treatment groups were found in the proportion of participants with at least 10% weight gain or the proportion with BMI class increase at either time point. Low CD4 T-cell count and high HIV-1 RNA at baseline were associated with at least 10% weight gain and BMI class increase at both timepoints, but treatment group, age, sex, and race were not., Conclusion: Weight gains over 96 weeks were low in all treatment groups and were similar to the average yearly change in adults without HIV-1. Significant weight gain and BMI class increase were similar across the treatment groups and were predicted by low baseline CD4 T-cell count and high baseline HIV-1 RNA.

Several cohorts have shown that long-term tenofovir-containing combination antiretroviral therapy (cART) leads to higher HBsAg seroclearance rates in HIV/HBV coinfected patients vs HBV-monoinfected patients under tenofovir disoproxil fumarate (TDF)-based therapy. We have analysed data on determinants of HBsAg loss in a retrospective multicentric cohort of 359 HIV/HBV coinfected patients. Median CD4 T-cell count at baseline was 359/ul (321-404), CDC stage was C in 20% (n = 70). Most patients (68%) were ART-naïve when TDF- or tenofovir alafenamide (TAF)-containing cART was initiated (baseline). After a median follow-up of 11 years HBsAg loss had occurred in 66/359 (18%) patients. However, patients with stage CDC C (P ≤ .001), lower CD4 gain (P = .043) and not receiving TDF/FTC (P = .008) were less likely to lose HBsAg. Long-term TDF-containing cART appears to achieve higher rates of HBsAg seroclearance compared to published data for HBV monoinfected subjects. However, late presentation for HIV and poor immune recovery significantly impair HBV seroconversion rates., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

Since 2002, a global epidemic of acute hepatitis C virus (HCV) infection has been noted in men who have sex with men (MSM). Transmission of HCV, particularly in the context of traumatic sex practices that increase the risk of blood-blood contacts (eg, anal sex and fisting), was initially found in human immunodeficiency virus (HIV)-coinfected and more recently in HIV-uninfected MSM, especially those receiving pre-exposure prophylaxis (PrEP). Early HCV treatment with all-oral direct-acting antiviral combination therapy has been associated with very high HCV cure rates of up to 100%. Indeed, immediate treatment of recently acquired HCV directly after new HCV diagnosis, or after 4 weeks if no 2-log10 drop in HCV RNA level occurs, promises rapid HCV elimination. Reports from the Netherlands, Switzerland, and the United Kingdom all show that with increased treatment uptake in this particular patient group, dramatic reductions in new HCV infections can be achieved. A general consensus on how to best screen for and manage acute HCV infections, along with broad access to rapid HCV therapy initiation, is crucial to attaining HCV elimination, a goal that is challenged by high HCV reinfection rates among MSM., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The role of hepatitis C virus (HCV) coinfection and HCV-RNA in the development of diabetes mellitus (DM) in HIV-positive persons remains unclear., Methods: Poisson regression was used to compare incidence rates of DM (blood glucose >11.1 mmol/L, HbA1C >6.5% or >48 mmol/mol, starting antidiabetic medicine or physician reported date of DM onset) between current HIV/HCV groups (anti-HCV-negative, spontaneously cleared HCV, chronic untreated HCV, successfully treated HCV, HCV-RNA-positive after HCV treatment)., Results: A total of 16 099 persons were included; at baseline 10 091 (62.7%) were HCV-Ab-negative, 722 (4.5%) were spontaneous clearers, 3614 (22.4%) were chronically infected, 912 (5.7%) had been successfully treated, and 760 (4.7%) were HCV-RNA-positive after treatment. During 136 084 person-years of follow-up (PYFU; median [interquartile range], 6.9 [3.6-13.2]), 1108 (6.9%) developed DM (crude incidence rate, 8.1/1000 PYFU; 95% CI, 7.7-8.6). After adjustment, there was no difference between the 5 HCV strata in incidence of DM (global P  = .33). Hypertension (22.2%; 95% CI, 17.5%-26.2%) and body mass index >25 (22.0%; 95% CI, 10.4%-29.7%) had the largest population-attributable fractions for DM., Conclusions: HCV coinfection and HCV cure were not associated with DM in this large study. The biggest modifiable risk factors were hypertension and obesity, and continued efforts to manage such comorbidities should be prioritized., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation., Methods: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation., Results: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine., Conclusions: Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Micro-elimination of the hepatitis C virus (HCV) includes treatment in populations at risk of ongoing HCV transmission, such as men who have sex with men (MSM) or people who inject drugs (PWID). We analyzed the HCV reinfection incidence rates of participants in the German hepatitis C cohort (GECCO) and compared our data to previous findings from the interferon era., Methods: Patients with HCV reinfections in the multi-centric GECCO cohort were compared to patients in whom no reinfection occurred. The HCV reinfection incidence rate in MSM was also compared to the incidence rate in the interferon era (using data from the European Acquired Immunodeficiency Syndrome Treatment Network [NEAT])., Results: Between January 2014 and April 2018, 48 HCV reinfections occurred in 2298 individuals (2%), with 2346 cured HCV episodes. The median time to reinfection was 500 days (range 16-1160) and the overall HCV reinfection incidence rate was 1.89 per 100 person-years (py; 95% confidence interval [CI], 1.41-2.48). In a multivariate analysis, the transmission risk in MSM was the only independent risk factor of HCV reinfection (odds ratio, 39.3; 95% CI, 4.57-334.40; P = .001). The incidence rate in MSM was 9.02 (95% CI, 6.48-12.26) per 100 py, compared to 1.14 per 100 py in PWID (95% CI, .56-2.09). The incidence rate for a first HCV reinfection in MSM was similar in the direct-acting antiviral era, compared to the interferon era, with a hazard ratio of 1.05 (95% CI, .64-1.74; P = .831)., Conclusions: HCV reinfection remains a frequent finding among MSM in Germany. In addition to behavioral interventions, early HCV treatment and retreatment should be implemented for this subgroup to prevent HCV transmission., (© 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.)

Direct-acting antivirals (DAAs) have tremendously improved the treatment of hepatitis C virus (HCV) infections also in human immunodeficiency virus (HIV)-positive individuals. Curing HCV infection is of particular importance in HIV-positive individuals as liver disease progression is accelerated in the course of concomitant HIV infection. Former challenges, such as safety and tolerability as well as reduced treatment uptake of pegylated interferon and ribavirin-based treatments, have been overcome with the approval of DAAs. Indeed, rates of discontinuation under modern all-oral DAA therapy in HIV/HCV coinfection have been reported to be <1%. Rates of sustained virological response (SVR) following treatment have aligned with those seen in HCV monoinfected patients, resulting in an equalisation of treatment recommendations for HCV monoinfected and HIV/HCV coinfected patients. Nevertheless, coinfection with HIV has been associated with slightly higher relapse rates in some real-world cohorts, arousing discussion regarding more individualised treatment once again. Moreover, an ongoing epidemic of acute HCV infections in HIV-positive men who have sex with men with high re-infection rates challenges physicians and researchers. The present review gives a concise summary of the remaining challenges in HCV treatment of HIV-positive individuals., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Background: A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear., Methods: People living with HIV from EuroSIDA with a known HCV status after January 2001 were classified into strata based on time-updated HCV RNA measurements and HCV treatment, as either HCV antibody-negative; spontaneously resolved HCV; chronic, untreated HCV; cured HCV (HCV RNA-negative); or HCV treatment failures (HCV RNA-positive). Poisson regression was used to compare incidence rates between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non-acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD)., Results: There were 16 618 persons included (median follow-up 8.3 years, interquartile range 3.1-13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0-6.9) for CVD, 6.5 (95% CI 6.1-6.9) for NADM, and 3.1 (95% CI 2.8-3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14-0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36-1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02-2.13) or treatment failure (aIRR 1.80, 95% CI 1.22-2.66) had significantly raised rates of ESLD, compared to those who were cured., Conclusions: Incidences of NADM or CVD were independent of HCV group, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD., (© 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.)

Background: The 2-drug regimen dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL in treatment-naive adults in the 48-week primary analysis of the GEMINI trials. We present results from the prespecified 96-week secondary analyses., Setting: One hundred eighty-seven centers in 21 countries., Methods: GEMINI-1 and GEMINI-2 are identical, double-blind phase III studies. Participants with screening HIV-1 RNA ≤500,000 copies/mL were randomized 1:1 to once-daily dolutegravir + lamivudine or dolutegravir + tenofovir disoproxil fumarate/emtricitabine., Results: At week 96, dolutegravir + lamivudine (N = 716) was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (N = 717) in achieving HIV-1 RNA <50 copies/mL (Snapshot algorithm; -10% noninferiority margin) in the pooled analysis (proportion of responders, 86.0% vs 89.5%, respectively; adjusted treatment difference [95% CI], -3.4% [-6.7 to 0.0007]), GEMINI-1 (-4.9% [-9.8 to 0.03]), and GEMINI-2 (-1.8% [-6.4 to 2.7]). Proportions of participants in the HIV-1 RNA ≥50 copies/mL Snapshot category were largely unchanged from week 48 to 96. Eleven participants taking dolutegravir + lamivudine and 7 taking dolutegravir + tenofovir disoproxil fumarate/emtricitabine met confirmed virologic withdrawal criteria through week 96; none had treatment-emergent resistance mutations. Dolutegravir + lamivudine had a lower rate of drug-related adverse events than dolutegravir + tenofovir disoproxil fumarate/emtricitabine (19.6% vs 25.0%; relative risk ratio, 0.78; 95% CI: 0.64 to 0.95). Renal and bone biomarker changes favored dolutegravir + lamivudine., Conclusions: Consistent with 48-week data, dolutegravir + lamivudine demonstrated long-term, noninferior efficacy vs dolutegravir + tenofovir disoproxil fumarate/emtricitabine without increased risk of treatment-emergent resistance, supporting its use in treatment-naive HIV-1-infected individuals.

Goals and Background: International guidelines recommend prioritized treatment initiation in hepatitis C virus (HCV)-infected patients with advanced liver disease. We aimed to evaluate whether the widespread usage of direct acting antivirals (DAAs) has led to a decrease in late presentation for care., Study: Data derived from the multicenter German Hepatitis C Cohort (GECCO) was analyzed. Treatment naive HCV-infected patients initiating DAA-based treatment between January 2014 and September 2017 were included. Advanced liver disease was defined by aspartate aminotransferase to platelet ratio index score ≥1.5, METAVIR≥F3, or FibroScan ≥9.5 kPa. Period prevalence and risk factors for late presentation were evaluated., Results: Six hundred fifty-three HCV-monoinfected and 210 HIV/HCV-coinfected patients (mean age, 48.6±12.7 y; 65.5% male) were included. Overall 32.5% of patients had advanced liver disease. In 2014 39.4% of patients presented with advanced liver disease, decreasing to 30.1%, 34.4%, and 26.4% in the years 2015, 2016, and 2017 (P=0.057), respectively. Patients with and without advanced liver disease differed in age (P<0.0001), CD4 ≤350/µL (P=0.027), genotype (P=0.005), transmission route (P=0.047), body mass index (P<0.001), and time since diagnosis (P=0.007). In the multivariable binary logistic regression analysis GT3, age above 45 years and being diagnosed >2 years ago were positively and HCV transmission through men who have sex with men was negatively associated with advanced liver disease., Conclusions: Overall 32.5% of patients presented with advanced liver disease. We observed a trend toward a lower proportion of patients starting treatment late.GT3, age, years since HCV diagnosis and HCV transmission route were identified as risk factors for presentation with advanced liver disease.

There is an ongoing global hepatitis C virus (HCV) epidemic mainly related to high-risk behaviour in persons who inject drugs (PWID) and in HIV-infected men who have sex with men (MSM) which continues to fuel the HCV epidemic. Treatment of HCV infection with direct antiviral therapy (DAA) has been very successful in the last decade. Main obstacles for HCV elimination are HCV reinfections observed in PWID and HIV-infected MSM. We present here an HIV-infected MSM patient who has been reinfected thrice with HCV. The virus which was investigated from his last reinfection episode reveals transmission of a newly acquired HCV protease inhibitor (PI) resistance, despite not having been exposed to HCV-PIs during his last DAA therapy., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Despite high hepatitis C virus (HCV) treatment rates, HCV incidence among human immunodeficiency virus (HIV)-infected men who have sex with men (HIV-infected MSM) in Germany rose before HCV direct-acting antivirals (DAAs). We model what intervention can achieve the World Health Organization (WHO) elimination target of an 80% reduction in HCV incidence by 2030 among HIV-infected MSM in Berlin., Methods: An HCV transmission model among HIV-diagnosed MSM was calibrated to Berlin (rising HCV incidence and high rates of HCV testing and treatment). We modeled the HCV incidence among HIV-diagnosed MSM in Berlin until 2030 (relative to 2015 WHO baseline) under scenarios of DAA scale-up with or without behavior change (among HIV-diagnosed MSM and/or all MSM)., Results: Continuing current treatment rates will marginally reduce the HCV incidence among HIV-diagnosed MSM in Berlin by 2030. Scaling up DAA treatment rates, beginning in 2018, to 100% of newly diagnosed HCV infections within 3 months of diagnosis and 25% each year of previously diagnosed and untreated HCV infections could reduce the HCV incidence by 61% (95% confidence interval, 55.4%-66.7%) by 2030. The WHO target would likely be achieved by combining DAA scale-up with a 40% reduction in HCV transmission among HIV-diagnosed MSM and a 20% reduction among HIV-undiagnosed or HIV-uninfected MSM., Discussion: HCV elimination among HIV-infected MSM in Berlin likely requires combining DAA scale-up with moderately effective behavioral interventions to reduce risk among all MSM., (© 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.)

HIV/HCV infection is supposed to substantially reduce survival as compared to HIV mono-infection. Here, we compared longtime-survival and causes of death in a cohort of HIV- and HIV/HCV-co-infected patients on combined antiretroviral therapy (cART), before introduction of HCV direct acting antivirals (DAA). 322 Caucasian patients with HIV (n = 176) and HIV/HCV-infection (n = 146) were enrolled into this study. All patients were recruited between 2003 and 2004 and followed until 01.01.2014. We compared overall survival between the two groups by the Kaplan-Meyer method and identified independent factors associated with long-time survival by conditional Cox regression analysis. In total 46 (14.3%) patients died during the observation period (HIV infection: n = 23 (13.1%), HIV/HCV infection: n = 23 (15.8%) but overall-survival did not differ significantly between HIV/HCV-infected and HIV mono-infected patients (p = 0.619). Survival was substantially better in patients with complete suppression of HIV replication below the level of detection than in those with residual viremia (p = 0.001). Age (p = 0.008), γ-glutamyltranspeptidase (p < 0.0001) and bilirubin (p = 0.008) were significant predictors of survival irrespective from HCV co-infection. Complete repression of HIV replication on cART is the key factor determining survival both in HIV- and HIV/HCV-co-infected patients, while HCV co-infection and therapy without DAAs seem to affect survival to a lesser extent. Thus, patients with HIV/HCV co-infection require particularly intensive cART.

Background: It is cost-effective to perform an HIV test in people with specific indicator conditions (IC) with an undiagnosed HIV prevalence of at least 0.1%. Our aim was to determine the HIV prevalence for 14 different conditions across 20 European countries., Methods: Individuals aged 18-65 years presenting for care with one of 14 ICs between January 2012 and June 2014 were included and routinely offered an HIV test. Logistic regression assessed factors associated with testing HIV positive. Patients presenting with infectious mononucleosis-like syndrome (IMS) were recruited up until September 2015., Results: Of 10,877 patients presenting with an IC and included in the analysis, 303 tested positive (2.8%; 95% CI 2.5-3.1%). People presenting with an IC in Southern and Eastern Europe were more likely to test HIV positive as were people presenting with IMS, lymphadenopathy and leukocytopenia/ thrombocytopenia. One third of people diagnosed with HIV after presenting with IMS reported a negative HIV test in the preceding 12 months. Of patients newly diagnosed with HIV where data was available, 92.6% were promptly linked to care; of these 10.4% were reported lost to follow up or dead 12 months after diagnosis., Conclusion: The study showed that 10 conditions had HIV prevalences > 0.1%. These 10 ICs should be adopted into HIV testing and IC specialty guidelines. As IMS presentation can mimic acute HIV sero-conversion and has the highest positivity rate, this IC in particular affords opportunities for earlier diagnosis and public health benefit., Competing Interests: The HIDES study was funded by the HIV in Europe initiative which has received unrestricted funding from Gilead Sciences, ViiV Healthcare, Merck, Tibotec, Pfizer, Schering-Plough, Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline. This does not alter our adherence to PLOS ONE policies on sharing data and materials. AM has received honoraria and consultancy fee from Gilead Sciences and ViiV Healthcare. JG has received honoraria and grants from ViiV Healthcare, MSD, Gilead Sciences and Janssen and is by 1 May 2018 employed by ViiV Healthcare. JR has received honoraria and consultancy fee from ViiV Healthcare, Merck/MSD, Gilead Sciences, Abbott, Abbvie, Abivax, Janssen. YY has received speaker and consultancy fee from Abbott, BMS, Gilead Sciences, MSD, Roche, Tibotec and ViiV Healthcare. KC has received consultancy and speaker fee from Gilead. All other authors declare no conflict of interest.

Background: Severe hepatic steatosis shows a high prevalence and contributes to morbidity and mortality in human immunodeficiency virus (HIV) infected patients. Known risk factors include obesity, dyslipidaemia and features of metabolic syndrome. Fibroblast growth factor 21 (FGF-21) is involved with hepatic glucose and lipid metabolism. This study aimed to evaluate FGF-21 as a biomarker for severe hepatic steatosis in non-obese HIV-infected patients., Methods: This is a prospective, cross-sectional, monocentric study including HIV-infected out-patients. Hepatic steatosis was measured via controlled attenuation parameter (CAP) using FibroScan 502 touch (ECHOSENS, France). Severe hepatic steatosis was defined at CAP ≥ 253 dB/m. Peripheral blood samples were collected and plasma was analysed for FGF-21. Demographic and clinical characteristics were collected from patient's health records., Results: In total, 73 non-obese HIV-monoinfected patients were included in this study. Prevalence of severe hepatic steatosis was 41%. Patients with severe hepatic steatosis showed significantly higher levels of FGF-21. Univariate analysis revealed FGF-21, BMI, hyperlipidaemia, ALT levels and arterial hypertension as significant, while multivariate analysis showed only FGF-21, arterial hypertension and ALT levels as significant independent risk factors for severe hepatic steatosis., Conclusion: This study presents FGF-21 as an independent and stronger predictor of severe hepatic steatosis than blood lipids in HIV-infected patients. Moreover, arterial hypertension and ALT levels predict severe steatosis even in non-obese HIV-monoinfected patients. Furthermore, this study supports existing metabolic risk factors and expands them to non-obese HIV-infected patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

Objective: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear., Design: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes., Methods: We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios)., Results: Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy., Conclusion: These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

Background and Aims: Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies showed that circulating levels of extracellular matrix (ECM) fragments might reflect degree of portal hypertension and fibrosis stage in liver disease. In this study, we analyzed the correlation between liver fibrosis assessed by Fibroscan and levels of the formation and degradation markers of type III and IV collagen in HIV positive patients receiving cART., Methods: 116 HIV positive patients (82.7% male, median age 47 years) were enrolled into the study. Liver stiffness and liver fat content were determined using a Fibroscan with integrated CAP function. We quantified ECM formation and degradation fragments of collagen III and IV: PRO-C3, PRO-C4, C3M and C4M. These fragments were measured in peripheral serum by using specific ELISAs., Results: Fifteen (12.9%) out of the 116 HIV positive patients had relevant fibrosis with a liver stiffness ≥ 7.1 kPa, and 79 patients had relevant steatosis with a CAP value > 248 dB/m. Circulating PRO-C3 levels significantly correlated with increasing degree of liver fibrosis assessed by Fibroscan (p = 0.0005), as well as with APRI score (p = 0.015). Interestingly, circulating PRO-C3 levels were significantly correlated with bilirubin (p = 0.022), reduced platelet count (p = 0.0008) and low albumin levels (p = 0.001), suggesting the association of type III collagen deposition with impaired liver function. None of the other measured ECM components significantly correlated with fibrosis or steatosis., Conclusion: The formation marker of type III collagen, PRO-C3 not only reflects liver fibrosis, but might also mirror liver dysfunction in HIV positive patients receiving cART. Therefore, the circulating levels of PRO-C3 might be suitable to monitor progression of liver fibrosis and deterioration of liver function in HIV positive patients receiving cART., Competing Interests: Leona Dold has received funding for another project from GILEAD and a stipend from the German center for infection research (DZIF). Jürgen Kurt Rockstroh has received honoraria for speaking at educational events or consulting from Abbvie, Abivax, Gilead, Janssen, merck and ViiV. JKR is president of the European Clinical AIDS Society and member of the IAS executive committee. Christoph Boesecke: Honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD, ViiV. Funding from Dt. Leberstiftung, DZIF, Hector Stiftung, NEAT ID. Diana J. Leeming, Morten A. Karsdal, and Mette J Nielsen are employees of Nordic Bioscience, a company engaged in the development of biochemical markers. Morten A. Karsdal and Diana J. Leeming are stockholders of Nordic Bioscience. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. All other authors declare no conflict of interest.

Objectives: The aim of the study was to establish a methodology for evaluating the hepatitis C continuum of care in HIV/hepatitis C virus (HCV)-coinfected individuals and to characterize the continuum in Europe on 1 January 2015, prior to widespread access to direct-acting antiviral (DAA) therapy., Methods: Stages included in the continuum were as follows: anti-HCV antibody positive, HCV RNA tested, currently HCV RNA positive, ever HCV RNA positive, ever received HCV treatment, completed HCV treatment, follow-up HCV RNA test, and cure. Sustained virological response (SVR) could only be assessed for those with a follow-up HCV RNA test and was defined as a negative HCV RNA result measured > 12 or 24 weeks after stopping treatment., Results: Numbers and percentages for the stages of the HCV continuum of care were as follows: anti-HCV positive (n = 5173), HCV RNA tested (4207 of 5173; 81.3%), currently HCV RNA positive (3179 of 5173; 61.5%), ever HCV RNA positive (n = 3876), initiated HCV treatment (1693 of 3876; 43.7%), completed HCV treatment (1598 of 3876; 41.2%), follow-up HCV RNA test to allow SVR assessment (1195 of 3876; 30.8%), and cure (629 of 3876; 16.2%). The proportion that achieved SVR was 52.6% (629 of 1195). There were significant differences between regions at each stage of the continuum (P < 0.0001)., Conclusions: In the proposed HCV continuum of care for HIV/HCV-coinfected individuals, we found major gaps at all stages, with almost 20% of anti-HCV-positive individuals having no documented HCV RNA test and a low proportion achieving SVR, in the pre-DAA era., (© 2019 British HIV Association.)

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naïve persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI > 0.5 or FIB-4 > 1.45), significant fibrosis (APRI > 1.5 or FIB-4 > 3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis B and/or C, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651, and 5.3% had HIV RNA ≤ 200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.57-0.78; P < 0.001) and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; P < 0.001). Conclusions: Significant liver fibrosis was rare among ART-naïve HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis., (© 2018 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Objectives: The aim of the study was to assess the regression of liver stiffness after successful direct-acting antiviral (DAA) treatment in patients with hepatitis C virus (HCV) monoinfection and HCV/-HIV coinfection. In addition, we aimed to identify factors associated with liver stiffness regression., Methods: We studied patients treated with interferon-free DAA regimens with a sustained virological response at week 12 (SVR 12 ) or 24 (SVR 24 ) post-treatment. Liver stiffness was assessed by transient elastography (TE) before the initiation and after the end of treatment (median 12 weeks)., Results: Of 214 enrolled patients, 85 (40%) were HCV monoinfected and 129 (60%) HCV/HIV coinfected. Baseline median TE values were 7.8 kPa [interquartile range (IQR) 5.9-12.0 kPa] in mono-infected patients and 10.7 kPa (IQR 7.8-17.0 kPa) in coinfected patients. Overall, the median TE value decreased from 10.1 to 6.8 kPa (n = 214; P < 0.0001). There was no difference between mono- and coinfected patients (-2.2 versus -3.3 kPa, respectively; P = 0.88), which was verified by an analysis of covariance (ANCOVA) adjusting for baseline TE values. Significant (≥ 30%) regression of liver stiffness was achieved by 45% of patients (54% with baseline TE ≥ 7.1 kPa). In multivariate analysis, a prior HCV treatment was a negative predictor of liver stiffness regression [odds ratio (OR) 0.31; P = 0.001]. A higher baseline TE value was positively associated with achieving a significant regression (OR 1.06; P = 0.02). HIV coinfection status, HCV genotype, age, sex, treatment duration, controlled attenuation parameter value, bilirubin concentration, platelet count and aspartate aminotransferase concentration were not associated with liver stiffness regression., Conclusions: Regression of liver stiffness after successful DAA treatment did not differ in patients with HCV monoinfection and those with HCV/HIV coinfection. Half of all patients achieved a significant (≥ 30%) regression. Prior treatment for HCV was a negative predictor for this endpoint, while a higher baseline TE value was positively associated with regression., (© 2019 British HIV Association.)

Introduction: Worldwide, 37 million people are infected with HIV; more than 50% are women. Currently, MTCT (mother-to-child transmission) can be reduced to<1%. The intention of the present study was to analyze the development of (1) the course of pregnancy of HIV-infected women, (2) the mode of delivery and (3) the post-exposure prophylaxis of the newborn over the last decade., Methodology: In this retrospective study, data from HIV-infected women who between 2005 and 2016 received care at the HIV outpatient department and gave birth at the Department of Obstetrics at University Hospital Bonn was analyzed. Furthermore, neonatal data was collected and HIV-MTCT was evaluated., Results: In the 2005-2016 study period, 87 pregnancies in 61 women were identified. Seventy babies were born alive at the Department of Obstetrics, University Hospital Bonn. 53% of these women were of African origin. The median of CD4 + cell count was 510 cells/ml (IQR 444); however, 32 women (52%) had more than 500 cells/ml. During the antenatal period, the HI viral load had been suppressed completely in 77% of women (<50 HIV-1-RNA copies/ml) and was<400 HIV-1-RNA copies/ml in 92% of women. The elective cesarean section rate fell significantly from 77% in the years 2005-2011 to 58% in 2012-2016. The proportion of deliveries after 37 weeks of gestation increased markedly from 60% to 69% after 2012. Additionally, while between 2005-2011 the birth weight of 78% of the newborns was between the 10 th and 90 th percentile, this proportion increased to 92% after 2012. Fifty-four of 70 newborns (77%) were classified as having low to normal HIV transmission risk. A vertical HIV transmission from mother to child did not occur (0/70)., Conclusions: Between 2005 and 2016 no vertical HIV transmission from mother to child occurred (0/70). Due to the change in treatment strategy, the elective cesarean section rate fell significantly as well the rate of premature births. An optimal interdisciplinary collaboration builds the basis for successful treatment of HIV in pregnancy., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Vacc-4x, a therapeutic HIV vaccine candidate has previously induced a significant reduction in viral load (VL) set-point compared to placebo upon interruption of combination anti-retroviral therapy (ART) (2007/1 study). This study, (2012/1), explored the potential to maintain Vacc-4x effect by re-boosting eligible 2007/1 study participants., Methods: Participant inclusion required 2007/1 participants to have completed all Vacc-4x immunizations and interrupted ART for up to 26 weeks. At weeks (wk)0 and 2, participants received intradermal (i.d.) Vacc-4x booster immunizations (1.2mg) on ART with GM-CSF (60μg) i.d. as a local adjuvant. ART was interrupted for up to 16 weeks (wk12-wk28). Participants were then followed on ART until wk36. VL set-point, total proviral DNA (pvDNA) and immunogenicity assessed by IFN-γ ELISPOT, T-cell proliferation and delayed type hypersensitivity (DTH) reactions were compared to participants' values in the 2007/1 study where available., Results: This open, multicenter, clinical study enrolled 33 participants from 9 clinical trial sites in the US and Europe. In the per-protocol (PP) population, the VL set-point geometric mean (GM) 18162 copies/mL was not significantly changed compared to the 2007/1 study (GM VL 22035 copies/mL), (p = 0.453, n = 18). For participants with available preART VL values, the VL set-point (GM 26279 copies/mL) remained significantly lower than the preART VL set-point (GM 74048 copies/mL, p = 0.021, n = 13). A statistically significant reduction in pvDNA (49%) from baseline to wk4 was observed (p = 0.03, n = 26). DTH responses (wk4) increased significantly from baseline (p = 0.006, n = 30) and compared to the 2007/1 study (p = 0.022, n = 29) whilst the proportion of participants with ELISPOT and T-cell proliferation responses was similar between the two studies., Conclusions: Vacc-4x booster immunizations safely maintained the mean VL set-point at that established following primary Vacc-4x therapeutic immunization. The reduction in pvDNA during ART supports the potential for Vacc-4x immunization to reduce HIV reservoirs and thereby contribute to combination HIV cure strategies., Competing Interests: We have the following interests: This study was funded in part by the sponsor Bionor Immuno AS. During the course of the study Jürgen K Rockstroh, Giuseppe Pantaleo and Barry Peters were members of Bionor Immuno’s Clinical Advisory Board. Mats Ökvist (MO) and Maja A. Sommerfelt (MAS) were employees of Bionor Immuno and had shares in the company. Currently, MO and MAS are no longer employed at Bionor Immuno and do not have shares in the company. Darren Jolliffe (DJ) is employed by S-Cubed Biometrics Ltd., Kim Krogsgaard (KK) is employed by KLIFO. Neither S-Cubed nor KLIFO provided funding for the study. The remaining co-authors have no competing interests. The following patents related to this study are owned by Bionor Immuno AS: HIV PEPTIDES, ANTIGENS, VACCINE COMPOSITIONS, IMMUNOASSAYS KIT AND A METHOD OF DETECTING ANTIBODIES INDUCED BY HIV WO00/52040 and METHOD FOR REDUCING AND/OR DELAYING PATHOLOGICAL EFFECTS OF HUMAN IMMUNODEFICIENCY VIRUS I (HIV) OR FOR REDUCING THE RISK OF DEVELOPING ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) WO2016/005508. There are no further patents, products in development or marketed products to declare related to this study. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.