Effectiveness, safety and discontinuation rates of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in people with HIV using real-world data: a systematic review and meta-analysis.

BACKGROUND: The use of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is based on the results of robust clinical trials. OBJECTIVES: To assess the effectiveness and safety of BIC/FTC/TAF in treatment-naïve (TN) and treatment-experienced (TE) people with HIV using available real-world cohort studies. METHODS: Systematic review and meta-analysis of publications and communications identified via Boolean search in Medline, PubMed and Embase, and conference abstracts reporting retrospective real-world use of BIC/FTC/TAF, published until 31 January 2024. The primary endpoint was the proportion of TN and TE people with HIV with viral load (VL) < 50 copies/mL at 48 weeks while on treatment. RESULTS: Of the 38 identified publications and conference abstracts, for the present analysis we included 12 publications (comprising 792 TN and 6732 TE individuals). For the three publications including 507 TN participants reporting the primary outcome, VL suppression was 97% [95% confidence intervals (CI): 89-100]. For the nine publications including 4946 TE participants reporting the primary outcome, VL suppression was 95% (95% CI: 94-96), with suppression >93% in all studies. Total discontinuations at 48 weeks in TE individuals were 3% (95% CI: 2-5), 1% (95% CI: 0-2) due to side effects. A total of four publications with 151 TE individuals with previous presence of M184V substitution were identified, reporting a suppression rate at 48 weeks of 95% (95% CI: 88-100). CONCLUSIONS: Real-world studies demonstrate low discontinuation rates and high rates of virologic suppression in individuals treated with BIC/FTC/TAF, both TN and TE with and without previous detection of M184V substitution.

Rapid initiation of bictegravir/emtricitabine/tenofovir alafenamide as first-line therapy in HIV infection. A prospective study.

INTRODUCTION: Rapid initiation of ART after HIV diagnosis is recommended for individual and public health benefits. However, certain clinical and ART-related considerations hinder immediate initiation of therapy. METHODS: An open-label, single-arm, single-centre 48-week prospective clinical trial involving ART-naïve HIV-diagnosed adults who started bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) within a week from the first hospital visit, before the availability of baseline laboratory and genotype results. The primary aim was to determine the proportion of people with at least one condition that would hinder immediate initiation of any recommended ART regimen other than BIC/FTC/TAF. Clinicaltrials.gov: NCT04416906. RESULTS: We included 100 participants: 79% men, 64% from Latin America, median age 32 years. According to European AIDS Clinical Society (EACS) and US Department of Health and Human Services 2023 guidelines, 11% (95%CI 6; 19) of participants had at least one condition that made any ART different from BIC/FTC/TAF less appropriate for a rapid ART strategy. Seventy-nine percent of the people started BIC/FTC/TAF within the first 48 hours of their first hospital visit. There were 16 early discontinuations (11 lost to follow-up). By week 48, 92% (95%CI 86; 98) of the participants of the ITT population with observed data achieved viral suppression. Eight grade 3-4 adverse events (AEs), five serious AEs and six ART-related AEs were identified. Adherence remained high. CONCLUSIONS: BIC/FTC/TAF is an optimal treatment for rapid initiation of ART. However, additional strategies to improve retention in care must be implemented.

Efficacy and safety of raltegravir plus lamivudine maintenance therapy.

BACKGROUND: Decreasing medication burden with raltegravir plus lamivudine in virologically suppressed persons with HIV (PWH) maintained efficacy and was well tolerated at 24 weeks, but more comprehensive data over longer follow-up are required. METHODS: Prospective 48 week extension phase of the raltegravir plus lamivudine arm from a previous 24 week pilot randomized clinical trial in which virologically suppressed PWH were randomized 2:1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. In this 48 week extension phase, raltegravir was dosed at 1200 mg/day and lamivudine 300 mg/day. Primary outcome was the proportion of PWH with treatment failure at Week 48. Secondary outcomes were changes in ultrasensitive plasma HIV RNA, HIV DNA in CD4 cells, serum IL-6, ultrasensitive C-reactive protein and sCD14, body composition, sleep quality, quality of life and adverse effects. RESULTS: Between May 2018 and June 2019, 33 PWH were enrolled. One participant experienced virological failure without resistance mutations and re-achieved sustained virological suppression without therapy discontinuation, and two others discontinued therapy due to adverse effects. Treatment failure was 9% (95% CI 2%-24%) and 3% (95% CI 0%-17%) in the ITT and on-treatment populations. There were significant changes between baseline and Week 48 in serum cytokines but not in other secondary outcomes. CONCLUSIONS: Switching to raltegravir and lamivudine in PWH with virological suppression maintains efficacy and is well tolerated. This maintenance regimen might be a cost-effective option for PWH at risk of drug-drug interactions or needing to avoid specific toxicities of certain antiretroviral drugs or their negative impact on comorbidities.

Epidemiological changes and outcomes of people living with HIV admitted to the intensive care unit: a 14-year retrospective study.

PURPOSES: Since 2016, the World Health Organization has recommended universal antiretroviral therapy (ART) for all people living with Human Immunodeficiency Virus (PLHIV). This recommendation may have influenced the characteristics and outcomes of PLHIV admitted to the Intensive Care Unit (ICU). This study aims to identify changes in the epidemiological and clinical characteristics of PLHIV admitted to the ICU, and their short- and medium-term outcomes before and after the implementation of universal ART (periods 2006-2015 and 2016-2019). METHODS: This retrospective, observational, single-center study included all adult PLHIV admitted to the ICU of a University Hospital in Barcelona from 2006 to 2019. RESULTS: The study included 502 admissions involving 428 patients, predominantly men (75%) with a median (P25-P75) age of 47.5 years (39.7-53.9). Ninety-one percent were diagnosed with HIV before admission, with 82% under ART and 60% admitted from the emergency department. In 2016-2019, there were more patients on ART pre-admission, reduced needs for invasive mechanical ventilation (IMV) and fewer in-ICU complications. ICU mortality was also lower (14% vs 7%). Predictors of in-ICU mortality included acquired immunodeficiency syndrome defining event (ADE)-related admissions, ICU complications, higher SOFA scores, IMV and renal replacement therapy (RRT) requirement. ART use during ICU admission was protective. Higher SOFA scores, admission from hospital wards, and more comorbidities predicted one-year mortality. CONCLUSIONS: The in-ICU mortality of critically ill PLHIV has decreased in recent years, likely due to changes in patient characteristics. Pre- and ICU admission features remain the primary predictors of short- and medium-term outcomes.

Tolerability of bictegravir/tenofovir alafenamide/emtricitabine versus dolutegravir/lamivudine as maintenance therapy in a real-life setting.

BACKGROUND: While both the burden of therapy and the individual drugs in bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) and dolutegravir/lamivudine differ, it is unclear whether their real-life tolerability may be also different. METHODS: Single-centre, clinical cohort analysis of all virologically suppressed persons with HIV (PWH) who were first prescribed bictegravir as BIC/TAF/FTC or dolutegravir as dolutegravir/lamivudine and had taken ≥1 dose of study medication. Major outcomes were discontinuations either for any reason or due to toxicity. Incidence was calculated as number of episodes per 100 person-years adjusted through propensity score analysis. RESULTS: Relative to persons treated with BIC/TAF/FTC (n = 1231), persons treated with dolutegravir/lamivudine (n = 821) were older and had more AIDS-defining conditions although better HIV control. After a median follow-up of 52 weeks, adjusted incidence rates for discontinuation were 6.68 (95% CI 5.18-8.19) and 8.44 (95% CI 6.29-10.60) episodes per 100 person-years for BIC/TAF/FTC and dolutegravir/lamivudine, respectively; adjusted incidence rate ratio for dolutegravir/lamivudine was 1.26 (95% CI 0.89-1.78) relative to BIC/TAF/FTC (P = 0.1847). Adjusted incidence rates for discontinuation due to toxicity were 3.88 (95% CI 2.70-5.06) and 4.62 (95% CI 3.05-6.19) episodes per 100 person-years for BIC/TAF/FTC and dolutegravir/lamivudine, respectively; adjusted incidence rate ratio for dolutegravir/lamivudine was 1.19 (95% CI 0.75-1.90) relative to BIC/TAF/FTC (P = 0. 4620). Adverse events leading to discontinuation were neuropsychiatric (n = 42; 2%), followed by gastrointestinal (n = 23; 1%), dermatological (n = 15; 1%) and weight increase (n = 15; 1%), without differences between regimens. CONCLUSIONS: Switching to BIC/TAF/FTC or dolutegravir/lamivudine showed no difference in the risks of overall or toxicity-related discontinuations or in the profile of adverse events leading to discontinuation.

Clinical use and effectiveness of dolutegravir and lamivudine: a long-term, real-world, retrospective study.

BACKGROUND: The use of dolutegravir/lamivudine is based on solid clinical trials; however, real-world data remain limited. OBJECTIVES: To provide data on the clinical use and effectiveness of dolutegravir/lamivudine in persons with HIV in a real-world scenario. PATIENTS AND METHODS: Retrospective, single-centre and observational study. We included all adults starting dolutegravir/lamivudine since November 2014. We reported all demographic, virological and immunological variables at baseline and assessed effectiveness [on treatment (OT), modified ITT (mITT) and ITT in those persons who reached 6 and 12 month follow-ups (M6 and M12). RESULTS: Of the 1058 persons, 9 were treatment-naive; the final analysis included 1049 treatment-experienced people with HIV. Median (IQR) follow-up was 1 (0.3-1.6) years, with 81% and 63% persons reaching M6 and M12, respectively. The longest use of dolutegravir/lamivudine was 7.4 years. Per OT, mITT and ITT, HIV-RNA < 50 copies/mL was 97%, 92% and 81% (M6) and 98%, 90% and 80% (M12), respectively. Females [adjusted risk ratio, aRR (95% CI): 1.69 (1.19-2.40)]; immediate, previous PI-based regimen [aRR (95% CI): 1.67 (1.09-2.56)]; and viral load (VL) ≥ 50 copies/mL at dolutegravir/lamivudine initiation [aRR (95% CI): 3.36 (2.32-4.88)] were independently associated with lack of effectiveness at M12; other demographic, immunological and virological variables like previous M184V/I substitutions or virological failure, were unrelated. Of the total, 944 (90%) continued dolutegravir/lamivudine. The most frequent known reason for discontinuation was toxicity [48 (46%) cases]. CONCLUSIONS: In our real-world experience, virological suppression rates were high for treatment-experienced persons on dolutegravir/lamivudine; however, we identified subgroups with a higher risk of lack of effectiveness at M12, who may benefit from closer follow-ups.

Sex-based epidemiological and immunovirological characteristics of people living with HIV in current follow-up at a tertiary hospital: a comparative retrospective study, Catalonia, Spain, 1982 to 2020.

BackgroundEpidemiological and immunovirological features of people living with HIV (PLWH) can vary by sex.AimTo investigate, particularly according to sex, characteristics of PLWH who consulted a tertiary hospital in Barcelona, Spain, in 1982-2020.MethodsPLWH, still in active follow-up in 2020 were retrospectively analysed by sex, age at diagnosis, age at data extraction (December 2020), birth place, CD4+ cell counts, and virological failure.ResultsIn total, 5,377 PLWH (comprising 828 women; 15%) were included. HIV diagnoses in women appeared to decrease from the 1990s, representing 7.4% (61/828) of new diagnoses in 2015-2020. From 1997, proportions of new HIV diagnoses from patients born in Latin America seemed to increase; moreover, for women born outside of Spain, the median age at diagnosis appeared to become younger than for those born in Spain, with significant differences observed in 2005-2009 and 2010-2014 (31 vs 39 years (p = 0.001), and 32 vs 42 years (p < 0.001) respectively), but not in 2015-2020 (35 vs 42 years; p = 0.254). Among women, proportions of late diagnoses (CD4+ cells/mm3 < 350) were higher than men (significantly in 2015-2020: 62% (32/52) vs 46% (300/656); p = 0.030). Initially, virological failure rates were higher in women than men, but they were similar in 2015-2020 (12% (6/52) vs 8% (55/659); p = 0.431). Women ≥ 50 years old represented 68% (564/828) of women actively followed up in 2020.ConclusionsWomen still have higher rates of late HIV diagnoses than men. Among currently-followed-up women, ≥ 50 year-olds, who need age-adapted care represent a high percentage. Stratifying PLWH by sex matters for HIV prevention and control interventions.

Simplification from tenofovir disoproxil fumarate plus lamivudine or emtricitabine plus ritonavir-boosted protease inhibitor to ritonavir-boosted atazanavir plus lamivudine in virologically suppressed HIV-infected adults with osteopenia: a pilot study.

BACKGROUND: Tenofovir disoproxil fumarate, particularly when given with a ritonavir-boosted PI, reduces bone mineral density (BMD) and increases bone turnover markers (BTMs). Ritonavir-boosted atazanavir plus lamivudine is a feasible simplified option. We evaluated whether switching from a triple ritonavir-boosted PI plus tenofovir disoproxil fumarate to a two-drug regimen of lamivudine plus ritonavir-boosted atazanavir would improve BMD. METHODS: Single-arm pilot study. Virologically suppressed patients on tenofovir disoproxil fumarate plus lamivudine or emtricitabine plus ritonavir-boosted PI with low BMD, without previous resistance mutations and/or virological failure to study drugs were switched to 100/300 mg of ritonavir-boosted atazanavir plus 300 mg of lamivudine once daily. The primary endpoint was BMD change by DXA at Week 48. RESULTS: There were 31 patients, 4 (13%) female, and median age was 40 years. Seven participants (22.5%) had osteoporosis. At 48 weeks, mean (SD) changes in spine and hip BMD were +0.01 (0.03) (P = 0.0239) and +0.013 (0.03) g/cm2 (P = 0.0046), respectively. Mean (SD) T-score changes were +0.1 (0.23) (P = 0.0089) and +0.25 (0.76) (P = 0.0197), respectively. N-telopeptide and urine tenofovir disoproxil fumarate toxicity markers showed significant improvements. One participant withdrew from the study and two were lost to follow-up. There were no virological failures, or serious or grade 3-4 adverse events. CONCLUSIONS: Switching from a tenofovir disoproxil fumarate plus ritonavir-boosted PI triple therapy to a lamivudine plus ritonavir-boosted atazanavir two-drug regimen in virologically suppressed HIV-infected adults with low BMD was safe, increased low BMD and reduced plasma markers of bone turnover and urine markers of tenofovir disoproxil fumarate toxicity over 48 weeks.

Real-life experience with bictegravir/emtricitabine/tenofovir alafenamide in a large reference clinical centre.

BACKGROUND: The use of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is mainly based on robust, pivotal clinical trials. OBJECTIVES: To provide data on clinical use of BIC/FTC/TAF in real life. PATIENTS AND METHODS: This was an observational, retrospective and single-centre study. We included all adult, treatment-naive (TN) and treatment-experienced (TE) people living with HIV (PLWH) starting BIC/FTC/TAF from 8 June 2018. We evaluated effectiveness [on treatment (OT), modified intention-to-treat (mITT) and intention-to-treat (ITT)], tolerability and safety in those patients who reached 6 months of follow-up (M6). RESULTS: We included 1584 PLWH [213 TN (13%) and 1371 TE (87%)]. The median (IQR) follow-up was 16 (7-21) months, with 81% and 53% of PLWH reaching M6 and M12, respectively. By OT, mITT and ITT, HIV-RNA <50 copies/mL was 77%, 70% and 62% at M6 and 92%, 77% and 63% at M12 for TN PLWH and 94%, 89% and 83% at M6 and 93%, 85% and 78% at M12 for TE PLWH, respectively. In PLWH carrying an M184V/I substitution, OT RNA <50 copies/mL was 89.5% at M6. The median CD4 cell count increased from 329 to 511/µL in TN PLWH and from 630 to 683/µL in TE PLWH at M6. Of the total, 1148 (88%) PLWH continued on BIC/FTC/TAF at M6. The most frequent known reason for discontinuation was toxicity [42 (69%) cases]; only 7 cases were considered virological failures (0.6% of the total OT cohort at M6), with no emerging resistance substitutions. CONCLUSIONS: In real life, BIC/FTC/TAF showed high rates of virological suppression and also in PLWH carrying lamivudine/emtricitabine resistance substitutions. The tolerability and safety of BIC/FTC/TAF were good, with high persistence observed for patients on this regimen at M6.

Chemsex Practices in PrEP: Beyond Addiction and Risk Toward a Healthy Sex Life-Baseline Experiences from a Hospital-Based PrEP Program in Barcelona, Spain.

Pre-exposure prophylaxis (PrEP) is a biomedical intervention that has demonstrated efficacy in HIV prevention in individuals at high-risk, among them chemsex users. Out of 190 PrEP users followed at Hospital Clinic of Barcelona until October 2020, 89% reported drug use, and 63% disclosed that they had engaged in chemsex practices, initiated in 64% of cases within the past year. Twenty-one percent used 3 or more drugs simultaneously, being GHB/GBL, nitrites, sildenafil, and methamphetamine the most prevalent combination. Eight percent reported slamming. Forty-one percent described having had negative experiences and 8% did not remember the last time they had sober sex. Methamphetamine, mephedrone, GHB/GBL, and having had open relationships, group sex, double penetration, and fisting were significantly more prevalent. Forty-nine percent admitted being worried about chemsex use, and 18% said they needed help. A comprehensive, interdisciplinary approach is mandatory to enable the attainment of a healthy approach to one's sex life.

RESUMEN: La PrEP es una intervención biomédica eficaz en la prevención del VIH en personas con alto riesgo, entre ellas las personas que practican chemsex. De los 190 usuarios de PrEP seguidos en el Hospital Clínic de Barcelona hasta octubre de 2020, el 89% refirió utilizar drogas y el 63% en contexto de chemsex, iniciando el consumo el 64% durante el último año. El 21% refería policonsumo, siendo GHB/GBL, nitritos, sildenafilo y metanfetamina la combinación más prevalente. El 8% reportó slamming. El 41% describió haber tenido experiencias negativas y el 8% no recordaba la última vez que tuvo sexo sobrio. Metanfetamina, mefedrona, GHB/GBL y haber tenido relaciones abiertas, sexo en grupo, doble penetración y fisting fueron significativamente más frecuentes. El 49% refirió estar preocupado por la práctica de chemsex y el 18% necesitar ayuda. Un abordaje integral e interdisciplinar mejoraría el acompañamiento global de la sexualidad en estas personas.

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy.

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response.

Factors associated with the use and composition of two-drug regimens in a large single-centre HIV cohort.

OBJECTIVES: We aimed to assess the clinical characteristics associated with the use of two-drug regimens (2DRs) and the factors associated with specific antiretrovirals in 2DRs in a large single-centre HIV cohort. METHODS: Retrospective analysis of demographics, HIV characteristics and AIDS events, antiretroviral prescription, virological failure and genotypic resistance testing, and laboratory results from all adult people with HIV (PWH) prospectively followed at the Hospital Clinic of Barcelona who were receiving a 3DR or a 2DR in January 2020. We assessed factors associated with the probability of receiving 2DRs relative to three-drug regimens (3DRs) using a logistic regression model, controlling for age, sex and year of HIV diagnosis. The same methodology was applied to identify factors associated with the prescription of integrase inhibitor-based regimens or PI-based regimens among PWH receiving 2DRs. RESULTS: There were 3432 (88%) PWH receiving 3DRs and 463 (12%) receiving 2DRs. In the final adjusted model, ≥2 previous virological failures, previous resistance mutations, previous AIDS diagnosis, longer time on current regimen, higher total cholesterol or triglycerides and lower baseline haemoglobin were independent factors associated with 2DRs. The majority of 2DRs included an integrase inhibitor or/and a PI. We identified independent factors associated with the inclusion of integrase inhibitors (lower HDL cholesterol) or PIs (prior AIDS, prior genotypic resistance mutations and lower CD4/CD8 ratio) in the 2DR. CONCLUSIONS: In this large single-centre HIV cohort, a worse cardiometabolic status or more archived resistance were key factors associated with inclusion of integrase inhibitors or PIs, respectively, in 2DRs.

Efficacy of Elbasvir/Grazoprevir in Early Chronic G1/G4 Hepatitis C infection in HIV/HCV co-infected patients with mild fibrosis.

BACKGROUND: Acute hepatitis C virus (AHC) infection is increasingly common among HIV+ men who have sex with men (MSM). Until 2017, the guidelines recommended therapy with pegylated-interferon plus ribavirin with a mild sustained virological response (SVR). This prompted many patients to reject that treatment, at that time, waiting to be treated with better and safer options with new Direct-Acting-Antivirals (DAA). OBJECTIVES: Assess the efficacy and safety of Elbasvir/Grazoprevir to treat recent chronic hepatitis C infection, genotype 1 or 4, in HIV+ MSM patients. METHODS: Prospective, open-labeled, two center, pilot study. SVR is analyzed for treatment with Elbasvir/Grazoprevir (8 weeks in GT1b or 12 in GT1a or GT4) in patients with a recent chronic HCV infection, defined as HCV infection lasting less than 4 years and mild liver fibrosis (liver stiffness <8kPa). RESULTS: Forty-eight patients were included (May 2017-March 2018): 2 GT1b, 24 GT1a and 22 GT4. HCV-RNA>800000UI in 63% and medium liver stiffness 4.9kPa. The SVR was 98%, one patient failed due to poor adherence. 67% of patients had adverse effects, but only 16% treatment related. The most frequent side effects were gastrointestinal (19%), related with the central nervous system (18%), respiratory (16%) and systemic symptoms (15%). During one year of follow-up post-therapy, 4 AHC and 18 patients with sexually transmitted diseases (STD) were diagnosed. CONCLUSIONS: Treatment with Elbasvir/Grazoprevir in this scenario is highly effective and safe. Patients with risky sexual practices must remain linked to the medical care system to detect new STD and HCV reinfection.

Quality of life in patients with hepatitis C. Importance of treatment. / Calidad de vida en los pacientes con hepatitis C. Importancia del tratamiento.

Chronic hepatitis C virus infection is a systemic disease that impairs the quality of life of affected individuals. The impairment is not only due to physiological factors, such as the non-hepatic manifestations of the disease or certain symptoms such as fatigue, weakness and nausea, but is also due to the substantial psychological impact of the infection. Treatment with direct-acting antivirals (DAA) has been demonstrated to substantially improve patient's quality of life, starting in the initial phases. Supplement information: This article is part of a supplement entitled "The value of simplicity in hepatitis C treatment", which is sponsored by Gilead. © 2019 Elsevier España, S.L.U. All rights reserved.

Elimination of hepatitis C virus infection from a hemodialysis unit and impact of treatment on the control of anemia.

INTRODUCTION: In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes. PATIENTS AND METHODS: This is a prospective, interventional, single-center study at Hospital Clínic de Barcelona. All HCV-RNA positive patients who received antiviral therapy with DAAs within a 3-year period (2014-2017) were analyzed (n=20). Data on virologic response, adverse events, and biochemical and hematological parameters during and after DAA therapy were analyzed. RESULTS: All patients achieved sustained virologic response (SVR) and only 40% of patients presented with mild AEs. None of the patients presented with HCV reinfection after a 1-year follow-up period, and thus HCV was eliminated from our HD unit. SVR was associated with a significant increase in hemoglobin and hematocrit, and a tendency toward the need for lower doses of iron supplementation with no changes in darbepoetin dose. CONCLUSION: HCV infection can be safely eliminated from HD units with the use of DAAs, preventing new infections in patients and healthcare staff. In the short term, the achievement of SVR is associated with an improvement in the control of anemia.

Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial.

Background: No controlled comparisons between dolutegravir/lamivudine or dolutegravir maintenance therapy have been done. We hypothesized that these options would have similar efficacy to triple ART. Methods: We used an open-label non-inferiority randomized controlled trial comprising two phases: phase A was established to test that experimental arms did not have an unacceptable (≥5%) failure rate; phase B was intended to include the full number of patients followed for 48 weeks. Treated HIV-1-infected adults with viral load <50 copies/mL for ≥12 months, no prior viral failure or resistance mutations to study drugs, nadir CD4 >200 cells/mm3, and hepatitis B virus surface antigen negative were randomized 1:1:1 to maintain triple therapy (control arm), or to switch to dolutegravir/lamivudine, or to dolutegravir monotherapy stratifying by anchor drug. Premature discontinuation was considered if viral failure or therapy interruption due to adverse events, concurrent illness, protocol deviation or patient's wish occurred. Blips were registered. Planned phase A results at 24 weeks are reported here. The study is registered at EudraCT: 201500027435. Results: Ninety-one (control, n = 31; dual therapy, n = 29; monotherapy, n = 31) patients were randomized. Three patients (none previously exposed to integrase inhibitors) prematurely discontinued treatment due to viral failure: dolutegravir/lamivudine (n = 1), no resistance mutations (subject A); dolutegravir (n = 2), N155H, S147G and Q148R resistance mutations (subject B), and E138K, G140S and N155H resistance mutations (subject C). There were no discontinuations for other reasons. One patient (dolutegravir/lamivudine) experienced a blip in viral load. The Data Safety Monitoring Board recommended stopping the dolutegravir monotherapy arm. Conclusions: In contrast to dolutegravir/lamivudine, a higher than expected risk of viral failure with development of cross-resistance integrase mutations occurred with dolutegravir maintenance monotherapy.

Eradication of hepatitis C virus and non-liver-related non-acquired immune deficiency syndrome-related events in human immunodeficiency virus/hepatitis C virus coinfection.

We assessed non-liver-related non-acquired immunodeficiency syndrome (AIDS)-related (NLR-NAR) events and mortality in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients treated with interferon (IFN) and ribavirin (RBV), between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and nonresponders. Fine and Gray regression analysis was conducted to determine the adjusted subhazard rate (sHR) of NLR deaths and NLR-NAR events considering death as the competing risk. The NLR-NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR-NAR cancer, bone events, and non-AIDS-related infections. The variables for adjustment were age, sex, past AIDS, HIV transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV RNA, liver fibrosis, HCV genotype, and exposure to specific anti-HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median 5-year follow-up, SVR was found to be associated with a significant decrease in the hazard of diabetes mellitus (sHR, 0.57; 95% confidence interval [CI], 0.35-0.93; P = 0.024) and decline in the hazard of chronic renal failure close to the threshold of significance (sHR, 0.43; 95% CI, 0.17-1.09; P = 0.075). CONCLUSION: Our data suggest that eradication of HCV in coinfected patients is associated not only with a reduction in the frequency of death, HIV progression, and liver-related events, but also with a reduced hazard of diabetes mellitus and possibly of chronic renal failure. These findings argue for the prescription of HCV therapy in coinfected patients regardless of fibrosis stage. (Hepatology 2017;66:344-356).

Tolerability of integrase inhibitors in a real-life setting.

Background: Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them. Aims: We compared rates and reasons for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients. Methods: Retrospective analysis of a prospectively followed cohort including all antiretroviral-naive and all virologically suppressed antiretroviral-experienced patients prescribed a first regimen containing raltegravir, elvitegravir or dolutegravir with at least one follow-up visit. Major outcomes were early discontinuation (≤1 year) due to any reason and more specifically due to toxicity. Incidence was calculated as number of episodes per 1000 person-years. Risk factors for discontinuation were assessed by multivariate Cox models. Results: Early discontinuations due to any reason were 271 (raltegravir), 168 (elvitegravir) and 264 (dolutegravir) per 1000 patient-years ( P = 0.0821). Early discontinuations due to toxicity were 76 (raltegravir), 103 (elvitegravir) and 81 (dolutegravir) per 1000 patient-years ( P = 0.6792). Overall, the most common toxicities leading to discontinuation were neuropsychiatric, osteomuscular or digestive. Most frequent neuropsychiatric manifestations reported at discontinuation were insomnia, dizziness, headache and anxiety irrespective of the integrase inhibitor. Among discontinuations due to toxicity, neuropsychiatric effects were more common with dolutegravir than with raltegravir or elvitegravir ( P = 0.0046). Age (HR 1.04, 95% CI 1.02-1.07, P = 0.0007) was the only independent risk factor for early discontinuation due to toxicity. Conclusions: Discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations due to toxicity did not differ among integrase inhibitors. Neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir.

Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial.

BACKGROUND: Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. METHODS: The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326. FINDINGS: 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93-98% in mono-infected and 87-97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88-100; 43/44) and 87% (95% CI 69-96; 26/30), respectively, and with ribavirin were 93% (95% CI 85-97; 79/85) and 97% (95% CI 82-100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61-92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). INTERPRETATION: Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87-98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. FUNDING: Merck & Co, Inc.

A randomized clinical trial comparing ritonavir-boosted lopinavir versus raltegravir each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection.

OBJECTIVES: The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28, comparing two regimens. METHODS: A prospective, open, randomized clinical trial was conducted at a tertiary hospital in Barcelona, Spain. Individuals attending the emergency room because of potential sexual exposure to HIV were randomized to tenofovir disoproxil/emtricitabine (245/200 mg) plus either ritonavir-boosted lopinavir (400/100 mg) or raltegravir (400 mg). The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov: NCT01576731. RESULTS: One-hundred-and-twenty-one individuals were randomized to receive ritonavir-boosted lopinavir and 122 to raltegravir (n = 243). PEP non-completion at day 28 was 43% with no significant difference between arms. We performed a modified ITT analysis including only those patients who attended on day 1 (n = 191). PEP non-completion in this subgroup was higher in the ritonavir-boosted lopinavir arm than in the raltegravir arm (34.6% versus 20.4%, P = 0.04), as was the number of patients lost to follow-up at day 28 (32.6% versus 21.6%, P = 0.08) and the proportion of patients with low adherence (49.2% versus 30.8%, P = 0.03). Adverse events were significantly more common in the ritonavir-boosted lopinavir arm (73.4% versus 60.2%, P = 0.007). There was an HIV seroconversion at day 90 in the raltegravir arm in a patient who had multiple potential sexual risk exposures before and after receiving PEP. CONCLUSIONS: Although we found no differences between arms regarding PEP non-completion, poor adherence and adverse events were significantly higher in patients allocated to tenofovir disoproxil/emtricitabine plus ritonavir-boosted lopinavir. These data support the use of raltegravir as the preferred third drug in current PEP recommendations.