Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen.

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.

Genetic Diversity From Proviral DNA as a Proxy for Time Since HIV-1 Infection.

HIV-1 RNA genetic diversity predicts time since infection, which is important for clinical care and research. It is unclear, however, whether proviral DNA genetic diversity sampled under suppressive antiretroviral therapy can be used for this purpose. We tested whether proviral genetic diversity from next-generation sequencing predicts time since infection and recency in 221 people with HIV-1 with known infection time. Proviral diversity was significantly associated with time since infection (P < 5×10-7, R2 up to 25%) and predictive of treatment initiation during recent infection (area under the curve-receiver operating characteristic up to 0.85). This shows the utility of proviral genetic diversity as a proxy for time since infection.

Long-term quantitative hepatitis B surface antigen (HBsAg) trajectories in persons with and without HBsAg loss on tenofovir-containing antiretroviral therapy.

OBJECTIVES: Improving the understanding of the patterns of quantitative hepatitis B surface antigen (qHBsAg) trajectories associated with HBsAg loss is important in light of novel anti-hepatitis B virus agents being developed. We evaluated long-term qHBsAg trajectories in persons with HIV and HBV during tenofovir-containing antiretroviral therapy in the Swiss HIV Cohort Study. METHODS: We included 29 participants with and 29 without HBsAg loss, defined as qHBsAg <0.05 IU/mL. We assessed qHBsAg decline during therapy in both groups and used agglomerative hierarchical clustering to identify different qHBsAg trajectory profiles in persons with HBsAg loss. RESULTS: The median follow-up time was 11.9 years (IQR 8.4-14.1), and the median time to HBsAg loss was 48 months (IQR 12-96). Among participants with HBsAg loss, 79% had a qHBsAg decline ≥1 log10 IU/mL 2 years after starting tenofovir. The trajectories in qHBsAg levels during tenofovir therapy were heterogeneous, characterized by five distinct profiles. Among participants without HBsAg loss, only 7% had a qHBsAg decline ≥1 log10 IU/ml after 2 years. CONCLUSIONS: Most persons with HIV who experienced HBsAg loss had an early decline in qHBsAg levels, with diverse trajectories during long-term tenofovir therapy. In persons without HBsAg loss, qHBsAg levels remained remarkably stable over time.

Exploring group differences in the response to a sexual risk reduction intervention to prevent hepatitis C virus reinfection in HIV-infected MSM: a mixed-methods study.

To prevent hepatitis C virus (HCV) reinfection, within the Swiss HCVree Trial, a preventive risk reduction intervention was implemented alongside curative treatment. Formative qualitative research identified three response patterns to the intervention. This mixed-methods study's aim was to cross-validate group differences in (a) the content of sexual risk reduction goals set during intervention and (b) the extent of their behavioural change in condomless anal intercourse with non-steady partners (nsCAI), sexualised and intravenous drug use at start and six-month post-intervention. Qualitative thematic analysis was used to summarise goal setting domains. Quantitative descriptive analysis was used to evaluate group differences based on assumptions of the group descriptions. Results largely confirmed assumptions on inter-group response differences in goal setting and behaviour: as expected group 1 Avoid risks showed the lowest HCV risk profile with changes in nsCAI. Group 2 Minimize-risks and Group 3 Accept-risks showed unchanged nsCAI. Group 3 had the highest HCV risk profile. Differences in their goal preferences (1: condom use; 2 reduction blood exposure; 3 safer dating) highlight diversity in attitudes to behavioural change. Our results improve understanding of variability in intervention responses such as changes in attitudes and behaviour. This provides evidence for intervention tailoring and outcome measurement.

Hepatitis B Virus (HBV) Replication During Tenofovir Therapy Is Frequent in Human Immunodeficiency Virus/HBV Coinfection.

In the Swiss HIV Cohort Study, 61 of 222 (27%) HIV-suppressed persons with chronic hepatitis B virus (HBV) infection had HBV replication after 2 years on tenofovir, of whom 77% were suppressed thereafter. Self-reported adherence to therapy and HBV viral load at tenofovir initiation were predictors of persistent replication.

Impact of Integrase Inhibitors on Cardiovascular Disease Events in People With Human Immunodeficiency Virus Starting Antiretroviral Therapy.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting INSTI-based antiretroviral therapy (ART) on CVD events among treatment-naïve people with human immunodeficiency virus using a target trial framework, which reduces the potential for confounding and selection bias. METHODS: We included Swiss HIV Cohort Study participants who were ART-naïve after May 2008, when INSTIs became available in Switzerland. Individuals were categorized according to their first ART regimen (INSTI vs other ART) and were followed from ART start until the first of CVD event (myocardial infarction, stroke, or invasive cardiovascular procedure), loss to follow-up, death, or last cohort visit. We calculated hazard ratios and risk differences using pooled logistic regression models with inverse probability of treatment and censoring weights. RESULTS: Of 5362 participants (median age 38 years, 21% women, 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART. Within 4.9 years (interquartile range, 2.4-7.4), 116 CVD events occurred. Starting INSTI-based ART was not associated with an increased risk for CVD events (adjusted hazard ratio, 0.80; 95% confidence interval [CI], .46-1.39). Adjusted risk differences between individuals who started INSTIs and those who started other ART were -0.17% (95% CI, -.37 to .19) after 1 year, -0.61% (-1.54 to 0.22) after 5 years, and -0.71% (-2.16 to 0.94) after 8 years. CONCLUSIONS: In this target trial emulation, we found no difference in short- or long-term risk for CVD events between treatment-naïve people with human immunodeficiency virus who started INSTI-based ART and those on other ART.

Increasing Frequency and Transmission of HIV-1 Non-B Subtypes Among Men Who Have Sex With Men in the Swiss HIV Cohort Study.

BACKGROUND: In Switzerland, HIV-1 transmission among men who have sex with men (MSM) has been dominated by subtype B, whilst non-B subtypes are commonly attributed to infections acquired abroad among heterosexuals. Here, we evaluated the temporal trends of non-B subtypes and the characteristics of molecular transmission clusters (MTCs) among MSM. METHODS: Sociodemographic and clinical data and partial pol sequences were obtained from participants enrolled in the Swiss HIV Cohort Study. For non-B subtypes, maximum likelihood trees were constructed, from which Swiss MTCs were identified and analyzed by transmission group. RESULTS: Non-B subtypes were identified in 8.1% (416/5116) of MSM participants. CRF01_AE was the most prevalent strain (3.5%), followed by subtype A (1.2%), F (1.1%), CRF02_AG (1.1%), C (0.9%), and G (0.3%). Between 1990 and 2019, an increase in the proportion of newly diagnosed individuals (0/123 [0%] to 11/32 [34%]) with non-B subtypes in MSM was found. Across all non-B subtypes, the majority of MSM MTCs were European. Larger MTCs were observed for MSM than heterosexuals. CONCLUSIONS: We found a substantial increase in HIV-1 non-B subtypes among MSM in Switzerland and the occurrence of large MTCs, highlighting the importance of molecular surveillance in guiding public health strategies targeting the HIV-1 epidemic.

Sustained Effect on Hepatitis C Elimination Among Men Who Have Sex With Men in the Swiss HIV Cohort Study: A Systematic Re-Screening for Hepatitis C RNA Two Years Following a Nation-Wide Elimination Program.

BACKGROUND: The Swiss HCVree Trial (NCT02785666) was conducted in 2015-2017 with the goal of implementing a population-based systematic hepatitis C virus (HCV) micro-elimination program among men who have sex with men (MSM) with human immunodeficiency virus (HIV) enrolled in the Swiss HIV Cohort Study (SHCS). The trial led to a 91% and 77% decline of HCV prevalence and incidence, respectively. The long-term effect of this HCV micro-elimination program is yet to be explored. METHODS: All MSM enrolled in the SHCS were screened for HCV RNA using stored plasma samples obtained in 2019, termed "Swiss HCVree Post" screen. The incidence of HCV infection over time was assessed using additional information on HCV testing routinely collected in the SHCS. Characteristics of participants with replicating HCV infection were analyzed. RESULTS: The point-prevalence of "Swiss HCVree Post" (N = 4641) was 0.6%, reflecting a decline of 48% compared to the end of the Swiss HCVree Trial where the prevalence was 1.2%. Further, the incidence of HCV among MSM in the SHCS declined from 0.31/100 person-years (py) (95% confidence interval [CI] [.17, .55]) in 2017 to 0.19/100 py (95% CI [.09, .39]) in 2019. CONCLUSIONS: A systematic HCV RNA-based screening among MSM with HIV conducted 2 years after the Swiss HCVree Trial revealed a sustained effect and further decline of the prevalence and incidence of replicating HCV infection. This indicates that the Swiss HCVree Trial was successful in curbing the HCV epidemic among MSM with HIV in Switzerland. CLINICAL TRIALS REGISTRATION: NCT02785666.

Weight and Metabolic Changes After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People Living With HIV : A Cohort Study.

BACKGROUND: Tenofovir-based antiretroviral therapy (ART) has become first-line in all major HIV treatment guidelines. Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has a favorable renal and bone safety profile, but concerns about metabolic complications remain. OBJECTIVE: To assess weight changes, the development of overweight/obesity, and changes in lipid levels 18 months after replacing TDF with TAF. DESIGN: Cohort study. SETTING: 5 university hospitals, affiliated hospitals, and private physicians in Switzerland. PARTICIPANTS: 4375 adults living with HIV who received TDF-containing ART for 6 months or longer. MEASUREMENTS: Changes in weight and lipid levels were assessed using mixed-effect models. Differences in proportions of newly overweight/obese participants were calculated using 2-proportions Z tests. RESULTS: 4375 individuals were included, with follow-up between 1 January 2016 and 31 July 2019. Median age was 50 years (interquartile range, 43 to 56 years), 25.9% were female, and 51.7% had a normal body mass index (BMI); 3484 (79.6%) switched to TAF and 891 (20.4%) continued TDF. After 18 months, switching to TAF was associated with an adjusted mean weight increase of 1.7 kg (95% CI, 1.5 to 2.0 kg), compared with 0.7 kg (CI, 0.4 to 1.0 kg) with the continued use of TDF (between-group difference, 1.1 kg [CI, 0.7 to 1.4 kg]). Among individuals with a normal BMI, 13.8% who switched to TAF became overweight/obese, compared with 8.4% of those continuing TDF (difference, 5.4 percentage points [CI, 2.1 to 8.8 percentage points]). Switching to TAF led to increases in adjusted mean total cholesterol (0.25 mmol/L [9.5 mg/dL]), high-density lipoprotein cholesterol (0.05 mmol/L [1.9 mg/dL]), low-density lipoprotein cholesterol (0.12 mmol/L [4.7 mg/dL]), and triglyceride (0.18 mmol/L [16.1 mg/dL]) levels after 18 months. LIMITATION: Short follow-up, small subgroup analyses, and potential residual confounding. CONCLUSION: Replacing TDF with TAF is associated with adverse metabolic changes, including weight increase, development of obesity, and worsening serum lipid levels. PRIMARY FUNDING SOURCE: Swiss National Science Foundation.

Predictors of Virological Failure and Time to Viral Suppression of First-Line Integrase Inhibitor-Based Antiretroviral Treatment.

BACKGROUND: Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens. METHODS: We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations. RESULTS: We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio [mHR], 2.2; 95% confidence interval [CI], 1.3-3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1-3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3-.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2-.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6-.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0-1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome. CONCLUSIONS: Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts.

A Treatment-as-Prevention Trial to Eliminate Hepatitis C Among Men Who Have Sex With Men Living With Human Immunodeficiency Virus (HIV) in the Swiss HIV Cohort Study.

BACKGROUND: In 2016, the World Health Organization (WHO) introduced global targets for the elimination of hepatitis C virus (HCV) by 2030. We conducted a nationwide HCV micro-elimination program among men who have sex with men (MSM) living with human immunodeficiency virus (HIV) from the Swiss HIV Cohort Study (SHCS) to test whether the WHO goals are achievable in this population. METHODS: During phase A (10/2015-06/2016), we performed a population-based and systematic screening for HCV-RNA among MSM from the SHCS. During phase B (06/2016-02/2017) we offered treatment with HCV direct-acting antiviral (DAA) agents to MSM identified with a replicating HCV infection. During phase C (03/2017-11/2017), we offered rescreening to all MSM for HCV-RNA and initiated DAA treatment in MSM with replicating infections. RESULTS: We screened 3715/4640 (80%) MSM and identified 177 with replicating HCV infections (4.8%); 150 (85%) of whom started DAA treatment and 149 (99.3%) were cured. We rescreened 2930/3538 (83%) MSM with a prior negative HCV-RNA and identified 13 (0.4%) with a new HCV infection. At the end of the micro-elimination program, 176/190 MSM (93%) were cured, and the HCV incidence rate declined from .53 per 100 patient-years (95% CI, .35-.83) prior to the intervention to .12 (95% CI, .03-.49) by the end of 2019. CONCLUSIONS: A systematic, population-based HCV micro-elimination program among MSM living with HIV was feasible and resulted in a strong decline in HCV incidence and prevalence. Our study can serve as a model for other countries aiming to achieve the WHO HCV elimination targets. CLINICAL TRIALS REGISTRATION: NCT02785666.

Changes in Renal Function After Switching From TDF to TAF in HIV-Infected Individuals: A Prospective Cohort Study.

BACKGROUND: Replacing tenofovir disoproxil fumarate (TDF) with tenofovir alafenamide (TAF) improves renal tubular markers in HIV-infected individuals but the impact on estimated glomerular filtration rate (eGFR) remains unclear. METHODS: In all participants from the Swiss HIV Cohort Study who switched from TDF to TAF-containing antiretroviral regimen or continued TDF, we estimated changes in eGFR and urine protein-to-creatinine ratio (UPCR) after 18 months using mixed-effect models. RESULTS: Of 3520 participants (26.6% women, median age 50 years), 2404 (68.5%) switched to TAF. Overall, 1664 (47.3%) had an eGFR <90 mL/min and 1087 (30.9%) an UPCR ≥15 mg/mmol. In patients with baseline eGFR ≥90 mL/min, eGFR decreased with the use of TDF and TAF (-1.7 mL/min). Switching to TAF was associated with increases in eGFR of 1.5 mL/min (95% confidence interval [CI], .5-2.5) if the baseline eGFR was 60-89 mL/min, and 4.1 mL/min (95% CI, 1.6-6.6) if <60 mL/min. In contrast, eGFR decreased by 5.8 mL/min (95% CI, 2.3-9.3) with continued use of TDF in individuals with baseline eGFR <60 mL/min. UPCR decreased after replacing TDF by TAF, independent of baseline eGFR. CONCLUSIONS: Switching from TDF to TAF improves eGFR and proteinuria in patients with renal dysfunction.

High Cure Rates With Grazoprevir-Elbasvir With or Without Ribavirin Guided by Genotypic Resistance Testing Among Human Immunodeficiency Virus/Hepatitis C Virus-coinfected Men Who Have Sex With Men.

Background: This study was performed to investigate the efficacy and safety of grazoprevir-elbasvir guided by baseline resistance-associated substitutions (RASs) in the Swiss HCVree Trial. Methods: We performed hepatitis C virus (HCV) RNA screening among all men who have sex with men (MSM) enrolled in the Swiss HIV Cohort Study. Individuals with replicating HCV genotype 1 or 4 infection were eligible for grazoprevir-elbasvir treatment. Genotype 1a-infected individuals with baseline RASs and genotype 4-infected individuals with prior failure of HCV treatment received 16 weeks of grazoprevir-elbasvir combined with ribavirin. All other individuals received 12 weeks of grazoprevir-elbasvir alone. Patients reporting unprotected sex with occasional partners were offered a HCV risk reduction-oriented behavioral intervention. Results: We screened 3722 MSM and identified 177 (4.8%) with replicating infection. A total of 122 individuals (3.3%) were eligible for study treatment. Six of 76 patients infected with genotype 1a (7.3%) harbored baseline RASs. Sustained virological response after 12 weeks of follow-up was achieved in 121 patients (99%), including all with genotype 1a infection. Overall, 8 serious adverse events occurred, none of which was related to the study drug. Seventy-five percent of eligible MSM participated in the risk counseling program. Conclusions: Grazoprevir-elbasvir for 12 or 16 weeks, with or without ribavirin, achieved high cure rates and had an excellent safety profile. Unique to other studies, the treatment duration was guided by the presence of baseline RASs among genotype 1a-infected individuals, and the treatment phase was accompanied by an HCV risk reduction-oriented behavioral intervention. This successful population-wide treatment approach lays the groundwork to achieve HCV elimination in coinfected MSM. Clinical Trials Registration: NCT02785666.

High Number of Potential Transmitters Revealed in a Population-based Systematic Hepatitis C Virus RNA Screening Among Human Immunodeficiency Virus-infected Men Who Have Sex With Men.

Background: The proportion of undiagnosed hepatitis C virus (HCV) infections in high-risk populations, such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) is unclear. Identification of potential HCV transmitters is important to reach World Health Organization HCV elimination targets. Methods: Between October 2015 and May 2016, we performed a systematic HCV RNA-based screening among HIV-infected MSM participating in the Swiss HIV Cohort Study (SHCS). HCV antibodies were measured from all HCV RNA-positive samples. Results: Of 4257 MSM recorded in the SHCS database, we screened 3722 (87%) by HCV polymerase chain reaction, and 177 (4.8%) harbored a replicating HCV infection. We identified 24 individuals (14%) with incident HCV infection; one-third of them had a negative HCV antibody result at the time of HCV RNA positivity. In a multivariable model, elevated liver enzyme values (odds ratio, 14.52; 95% confidence interval, 9.92-21.26), unprotected sex with occasional partners (2.01; 1.36-2.98), intravenous drug use (7.13; 4.36-11.64), noninjectable drug use (1.94; 1.3-2.88), and previous syphilis diagnosis (2.56; 1.74-3.76) were associated with HCV RNA positivity. Conclusions: A systematic HCV RNA-based screening among HIV-infected MSM revealed a high number of potential transmitters. A substantial subpopulation of MSM had incident infection, one-third of whom had a negative HCV antibody test result at the time of the HCV RNA positivity. These data reveal that one-time RNA testing of a high-risk population for HCV RNA might identify more infected persons than routine testing for HCV antibodies and liver enzymes. Clinical Trials Registration: NCT02785666.

Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort.

BACKGROUND: Tenofovir alafenamide (TAF)-containing combinations were introduced in Switzerland after October 2016 and are recommended over tenofovir disoproxil fumarate (TDF) in patients with osteoporosis or impaired renal function. METHODS: We included all participants of the Swiss HIV Cohort Study on TDF-containing antiretroviral therapy with follow-up visits after January 2016. We determined the proportion of switches from TDF to TAF overall, and among patients with risk factors for TDF toxicity, including osteoporosis, impaired renal function or marked proteinuria. We used multivariable logistic regression to explore predictors of switching from TDF to TAF. RESULTS: We included 5'012 patients, of whom 652 (13.0%) had risk factors for TDF toxicity. A switch from TDF to TAF was undertaken in 2'796 (55.8%) individuals overall, and in 465 (71.3%) with risk factors. Predictors of switching to TAF were male sex (adjusted odds ratio 1.27, 95% confidence interval 1.07-1.50), age > 50 years (1.43, 1.23-1.66) and the presence of risk factors for TDF toxicity (2.21, 1.77-2.75). In contrast, patients with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-pill regimen (0.11, 0.09-0.13), those treated in non-tertiary care centers (0.56, 0.46-0.70), as well as those with CD4 cell counts below 500/µL (0.77, 0.66-0.90) and with chronic hepatitis C infection (0.66, 0.54-0.80) were most likely to stay on TDF. CONCLUSIONS: Over 50% of patients on TDF-containing therapy, including the majority of patients at risk for TDF toxicity, were switched to TAF within two years of its introduction in Switzerland. Individuals on NNRTI-based single-pill regimens were most likely to remain on TDF.

Screening HIV-positive men who have sex with men for hepatitis C re-infection risk: is a single question on condom-use enough? A sensitivity analysis.

BACKGROUND: Hepatitis C virus (HCV) is common in men who have sex with men (MSM) with HIV. The Swiss HCVree Trial targeted a micro-elimination by using a treat and counsel strategy. Self-reported condomless anal intercourse with non-steady partners was used as the selection criterion for participation in a counselling intervention designed to prevent HCV re-infection. The purpose of this study was to assess the ability of this criterion to identify men who engaged in other sexual risk behaviours associated with HCV re-infection. METHODS: Men who disclosed their sexual and drug- use behaviours during the prior 6 months, at study baseline, were included in the current study. Using a descriptive comparative study design, we explored self-reported sexual and drug-use risk behaviours, compared the odds of reporting each behaviour in men who reported and denied condomless anal intercourse with non-steady partners during the prior year and calculated the sensitivity/specificity (95% CI) of the screening question in relation to the other at-risk behaviours. RESULTS: Seventy-two (61%) of the 118 men meeting eligibity criteria reported condomless anal intercourse with non-steady partners during the prior year. Many also engaged in other potential HCV transmission risk behaviours, e.g., 52 (44%) had used drugs. In participants disclosing drug use, 44 (37%) reported sexualised drug use and 17 (14%) injected drugs. Unadjusted odds ratios (95% CI) for two well-known risk behaviours were 2.02 (0.80, 5.62) for fisting and 5.66 (1.49, 37.12) for injecting drug use. The odds ratio for sexualised drug use - a potential mediator for increased sexual risk taking - was 5.90 (2.44, 16.05). Condomless anal intercourse with non-steady partners showed varying sensitivity in relation to the other risk behaviours examined (66.7-88.2%). CONCLUSIONS: Although condomless anal intercourse with non-steady partners was fairly sensitive in detecting other HCV relevant risk behaviours, using it as the only screening criterion could lead to missing a proportion of HIV-positive men at risk for HCV re-infection due to other behaviours. This work also points to the importance of providing access to behavioral interventions addressing other sexual and drug use practices as part of HCV treatment. TRIAL REGISTRATION: Clinical Trial Number: NCT02785666 , 30.05.2016.

No Effect of Pegylated Interferon-α on Total HIV-1 DNA Load in HIV-1/HCV Coinfected Patients.

Pegylated interferon-alpha (pIFN-α) is suggested to lower human immunodeficiency virus type-1 (HIV-1) DNA load in antiretroviral therapy (ART)-treated patients. We studied kinetics of HIV-1 DNA levels in 40 HIV-1/hepatitis C virus (HCV) coinfected patients, treated with pIFN-α for HCV and categorized into 3 groups according to start of ART: chronic HIV-1 infection (n = 22), acute HIV-1 infection (n = 8), no-ART (n = 10). Total HIV-1 DNA levels in 247 peripheral blood mononuclear cell samples were stable before, during, and after pIFN-α treatment in all groups. Our results question the benefit of pIFN-α as an immunotherapeutic agent for reducing the HIV-1 reservoir.

Hepatitis C Infection and the Risk of Non-Liver-Related Morbidity and Mortality in HIV-Infected Persons in the Swiss HIV Cohort Study.

Background: Hepatitis C virus (HCV) infection has been associated with increased non-liver-related morbidity and mortality. However, studies have yielded inconsistent results. Methods: The incidence of clinical events in human immunodeficiency virus (HIV)­infected HCV-seropositive and incidence density­matched HCV-seronegative participants of the Swiss HIV Cohort Study from August 1994 to December 2014 was studied. We compared (1) HCV-seropositive with HCV-seronegative participants and (2) HCV-viremic with successfully treated nonviremic patients. Poisson regression was used to assess differences between these groups. Results: We included 2503 HCV-seropositive participants (540 with spontaneous HCV clearance, 1294 untreated HCV RNA positive, 345 treated with sustained virologic response [SVR], 43 during treatment, and 281 treated without SVR), and 2503 HCV-seronegative controls. After a mean follow-up of 8.2 years, we observed (HCV seropositive and HCV seronegative, respectively) 107 and 18 liver events, 41 and 14 kidney events, 230 and 121 osteoporosis/fractures, 82 and 94 diabetes mellitus, 114 and 129 cardiovascular events, 119 and 147 non-AIDS malignancies, 162 and 126 Centers for Disease Control and Prevention HIV category B/C events, 106 and 10 liver-related deaths, and 227 and 218 non-liver-related deaths. Compared with HCV-negative controls, HCV-seropositive participants had an increased risk of liver events (incidence rate ratio [IRR], 6.29 [95% confidence interval {CI}, 3.52­11.22]), liver-related death (IRR, 8.24 [95% CI, 3.61­18.83]), kidney events (IRR, 2.43 [95% CI, 1.11­5.33]), and osteoporosis/fracture (IRR, 1.43 [95% CI, 1.03­2.01]). Among HCV-seropositive individuals, treated participants without SVR vs those with SVR had a higher risk of liver events (IRR, 6.79 [95% CI, 2.33­19.81]), liver-related death (IRR, 3.29 [95% CI, 1.35­8.05]), and diabetes mellitus (IRR, 4.62 [95% CI, 1.53­13.96]). Similar but not statistically significant differences were found between untreated HCV RNA­positive patients and those with SVR. Conclusions: While HCV exposure was associated with an increased risk of kidney disease and osteoporosis/fracture, this risk did not seem to be dependent of persistent HCV RNA. Successful HCV treatment was associated with a lower incidence of liver disease, liver-related death, and diabetes mellitus, whereas the other conditions studied were less affected.

High hepatic and extrahepatic mortality and low treatment uptake in HCV-coinfected persons in the Swiss HIV cohort study between 2001 and 2013.

BACKGROUND & AIMS: The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS: We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS: Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV-infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS: Over the last 13 years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver-related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.

Comparative effectiveness of tenofovir in treatment-naïve HIV-infected patients: systematic review and meta-analysis.

INTRODUCTION: Benefits and harms of tenofovir disoproxil fumarate (TDF) in HIV-infected, antiretroviral treatment (ART)-naïve patients of any age have not been systematically reviewed since recent milestone trials were published. METHODS: We searched MEDLINE, EMBASE, CENTRAL, SCI, LILACS, WHO GHL, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing TDF-based treatments with any other ART-regimen (last search 01/2015). Trial characteristics and results were extracted, risks of bias systematically assessed, and treatment effects synthesized in meta-analyses using random-effects models. RESULTS: We included 22 RCTs (8297 patients). We found no differences between groups for mortality, AIDS, fractures, CD4 cell count, and virological failure; and inconclusive information due to inadequate reporting for cardiovascular events, renal failure, proteinuria, rash, and quality of life. Tenofovir disoproxil fumarate-based regimens significantly reduced total cholesterol (mean difference -18.42 mg/dl; 95% confidence interval [CI] -22.80 to -14.0), LDL-cholesterol (-9.53 mg/dl; -12.16 to -6.89), HDL-cholesterol (-2.97 mg/dl; -4.41 to -1.53), and triglycerides (-29.77 mg/dl; -38.61 to -20.92), bone mineral density (BMD) (hip: -1.41%; -1.87 to -0.94), and glomerular filtration rate (eGFR) (-3.47 ml/minute; -5.89 to -1.06) over 48 weeks of follow-up. Effects were similar in trials comparing fixed-dose TDF/FTC-based regimens with ABC/3TC-based regimens. We found no influence of baseline viral load on virological failure. DISCUSSION: Moderate-quality evidence suggests similar effects of TDF-based treatment regimens and other ART on virological failure. Tenofovir disoproxil fumarate-based regimens are associated with a more favorable lipid profile, but with increased risk of reduced BMD and eGFR. Improved reporting quality is vital to allow assessment of clinical outcomes in future trials.