A Randomized Trial of Dolutegravir Plus Darunavir/Cobicistat as a Switch Strategy in HIV-1-Infected Patients With Resistance to at Least 2 Antiretroviral Classes.

Background: Suppressed patients with drug-resistant HIV-1 require effective and simple antiretroviral therapy to maintain treatment adherence and viral suppression. Methods: This randomized, open-label, noninferiority, multicenter pilot study involved HIV-infected adults who met the following criteria: confirmed HIV-1 RNA <50 copies/mL for ≥6 months preceding the study randomization, treatment with at least 3 antiretroviral drugs, and a history of drug resistance mutations against at least 2 antiretroviral classes but remaining fully susceptible to darunavir (DRV) and integrase inhibitors. Participants were randomized 1:1 to switch to dolutegravir (DTG; 50 mg once per day) plus DRV boosted with cobicistat (DRV/c; 800/150 mg once per day; 2D group) or continue with their baseline regimen (standard-of-care [SOC] group). The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at week 48 relative to time to loss of virologic response, with a noninferiority margin set at -12.5%. Virologic failure was defined as confirmed HIV-1 RNA ≥50 copies/mL or a single determination of HIV-1 RNA >50 copies/mL followed by antiretroviral therapy discontinuation. Results: Forty-five participants were assigned to the 2D group and 44 to the SOC group. Time to loss of virologic response showed no difference in the proportion maintaining HIV-1 RNA <50 copies/mL at week 48: 39 of 45 (86.7%; 95% CI, 73.21%-94.95%) in the 2D group vs 42 of 44 (95.4%; 95% CI, 84.53%-99.44%) in the SOC group (log-rank P = .159) with an estimated difference of -8.7 (95% CI, -22.72 to 5.14). Only 2 (4.5%) in the SOC group experienced virologic failure, and 3 participants from the 2D group experienced adverse events leading to treatment discontinuation. Conclusions: In suppressed patients with at least 2 resistant antiretroviral classes, noninferiority could not be demonstrated by fully active DRV/c plus DTG. Nevertheless, there were no unexpected adverse events or virologic failure. DRV/c plus DTG may be considered a once-daily therapy option only for well-selected patients. Clinical Trials Registration. ClinicalTrials.gov (NCT03683524).

Impact of interferon-free therapies in HIV/HCV co-infected patients on real clinical practice: results from a multicenter region-wide cohort study (2014-2018).

BACKGROUND: Here, we assess the efficacy and safety of direct antiviral agents (DAAs) in a real-world cohort of co-infected individuals, and evaluate the consistency between clinical practice and guideline recommendations. METHODS: Multicenter, prospective cohort study of HIV/HCV co-infected patients followed-up in nine sites in Spain. All patients with detectable HCV-RNA naive to second-generation DAAs were enrolled. The primary endpoint was the assessment of sustained virological response at week 12 (SVR12). We performed intention-to-treat (ITT), per-protocol (PP), and multivariable analyses to identify factors associated with therapeutic failure. We compared the DAAs we administered to available guideline recommendations. Schemes not perfectly adjusted to the recommendations were defined as sub-optimal. RESULTS: Overall, 316 patients (82.1% male) received a total of 330 treatments. Of these, 43.9% were cirrhotic and 40.6% were treatment-experienced. In the ITT and PP analyses, SVR12 was achieved in 90.9% [95% confidence interval (CI) 87.3-93.6] and 93.7% (95% CI 90.5-95.6), respectively. Only alcohol abuse [odds ratio (OR): 0.33; 95% CI 0.138-0.789, P = 0.013] and a higher basal bilirubin level (OR: 0.595; 95% CI 0.416-0.851, P = 0.004) were independently associated to therapeutic failure. A progressive decrease in the proportion of sub-optimal treatments was observed over time, from 75% in 2014 to 0% in 2018. Being treated with a sub-optimal regimen was not associated with failure. CONCLUSION: Despite numerous difficulties in treatment access and in adaptation to the changing guidelines, we detected no differences among the DAAs used, nor did we detect a lower efficacy when the chosen treatment was not optimal.

Does fibrosis really regress in HIV/hepatitis C virus co-infected patients after treatment with direct antiviral agents?

OBJECTIVE: To evaluate the progression of liver stiffness after treatment with direct antiviral agents (DAAs), to identify predictive factors of fibrosis regression and to analyze the changes of scores AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) after treatment. DESIGN: Multicenter prospective cohort study of HIV/HCV co-infected patients conducted within the GECMEI cohort, Spain. METHODS: Individuals were eligible if they were willing to start DAAs and underwent two transient elastographies: at baseline and after the end of treatment (EOT). All patients with detectable HCV RNA naïve to DAAs were consecutively enrolled from nine medical hospitals. Liver stiffness results were categorized in four Metavir stages (F1: <7.1; F2 : 7.1--9.5; F3 : 9.5--2.4; F4: >12.4 kPa). The APRI and FIB-4 scores were calculated at baseline, EOT and 12 weeks after EOT. RESULTS: One hundred and seventy-eight patients were examined throughout a follow-up of 16.3 months (IQR: 12.5-25). The median of liver stiffness decrease was 2.6 kPa (IQR: 0-6.3). A greater improvement was observed in F3-F4 compared with F1-F2, (6.4 vs. 0.91 kPa, P < 0.001; P = 0.001, respectively). A decline between baseline and EOT measures was observed in APRI and FIB-4 (P < 0.001). Sustained virological response (SVR12) achievement was the only predictor of fibrosis regression [OR:17.4 (95% CI: 1.8-164.6; P = 0.013)]. CONCLUSION: Most patients experienced a significant reduction of liver stiffness and APRI and FIB-4 scores. This improvement was greater in those with advanced liver disease. SVR12 was the only predictor of fibrosis regression. The significance of this reduction is unclear and could reflect a decline in inflammation rather than true fibrosis regression.

Clinical Impact of Virological Failure and Resistance Analysis Definitions used in Pivotal Clinical Trials of Initial Antiretroviral Treatment: A Systematic Review

There are no standardized criteria to characterize confirmed protocol-defined virological failure (PDVF) nor the inclusion criteria for the resistance analysis population (RAP) in Phase III randomized clinical trials (RCTs) of initial antiretroviral therapy (ART). We assessed the clinical impact of mismatching between virological non-response (HIV-1 RNA ≥50 copies/mL), confirmed PDVF (48 weeks), and RAP definition in studies with the newest first-line ART. A systematic review of all Phase III RCTs was performed, including preferred once-daily ART (EACS European AIDS guidelines) or recently approved by the US Food and Drug Administration. We identified 16 treatment arms (14 RCTs) with 6175 participants treated with dolutegravir, bictegravir, elvitegravir/cobicistat, raltegravir, darunavir/cobicistat, rilpivirine, or doravirine. Plasma HIV-1 RNA thresholds for PDVF or RAP ranged from 40 to 50, 200, 400, and 500 copies/mL. This led to discrepancies between trials regarding the participants defined as virological non-responders, PDVF, or included in RAP. Overall, 85/296 (29%) patients with PDVF were not genotyped. There was a linear correlation between the threshold of HIV RNA chosen to perform genotyping and rates of participants with PDVF but not genotyped. Only eight treatment arms genotyped all participants with PDVF. Most of the remaining eight arms genotyped roughly < 50% of those with PDVF. In summary, the absence of standardized definitions of VF and criteria for resistance testing in pivotal Phase III RCTs of the first-line ART leads to the possibility of underreporting of resistance mutations when genotypes are only performed at higher viral load cutoffs. Stringent homogeneous criteria should be defined to ensure that all participants with PDVF (e.g., confirmed HIV RNA ≥ 50 copies/mL and the second > 200 copies/mL) undergo genotyping.

Efectividad del tratamiento con agentes antivirales directos en pacientes con coinfección por VHC y VIH. Estudio de cohorte multicéntrico / Effectiveness of direct-acting antiviral therapy in patients with a HCV/HIV coinfection. A multicenter cohort study

Introducción: la eficacia de los agentes antivirales directos (AAD) ha quedado demostrada en ensayos clínicos tanto en mono como en coinfectados. Nuestro objetivo es analizar la efectividad y toxicidad de este tratamiento en vida real en pacientes con coinfección por VIH y VHC así como determinar variables asociadas a una evolución desfavorable. Métodos: estudio ambispectivo multicéntrico en una cohorte de pacientes coinfectados. Los datos fueron recogidos en ocho centros de Castilla-La Mancha entre 2014 y 2016. Se realizó un análisis por intención de tratamiento en el que cualquier pérdida de seguimiento, abandono de tratamiento o toxicidad terapéutica se consideró fracaso. Resultados: se estudiaron 229 pacientes con una mediana de edad de 49,6 años con predominio masculino (83%). Menos de un 10% presentaba carga viral (CV) detectable para el VIH. El genotipo de VHC más prevalente fue el 1 (65,1%). Un 50% tenía hepatopatía en grado de cirrosis. El 65% presentaba más de 800.000 copias/ml de CV de VHC. La respuesta viral sostenida (RVS) se alcanzó globalmente en el 91,7%. La estrategia de AAD más utilizada fue sofosbuvir/ ledipasvir. Un 52% de las pautas incluyeron ribavirina. El 65,9% completó pautas de 12 semanas y un 30%, de 24 semanas. Hubo 19 fracasos terapéuticos. No existen diferencias entre las distintas estrategias de AAD utilizadas. No se observó ningún factor predictor independiente de RVS. Conclusiones: el tratamiento del VHC en pacientes coinfectados presenta tasas de RVS muy elevadas también en vida real. La toxicidad es excepcional. No hemos identificado factores predictores específicos de evolución desfavorable (AU)

ntroduction: The effectiveness of direct-acting antiviral (DAA) agents has been demonstrated in clinical trials both in patients with mono and coinfections. The goal of the study was to analyze the effectiveness and toxicity of this therapy in real-life patients with a HIV/HCV coinfection and to identify variables that are associated with an unfavorable outcome. Methods: This was a multicenter ambispective study in a cohort of coinfected patients. Data were collected from eight centers in Castilla-La Mancha from 2014 to 2016. An intent-to-treat analysis was performed and any loss to follow-up, treatment withdrawal or toxicity was considered as a failure. Results: A total of 229 patients were included with a median age of 49.6 years and the majority were male (83%). Fewer than 10% had a detectable HIV-related viral load (VL). The most prevalent HCV genotype was 1 (65.1%). Fifty percent had cirrhotic liver disease and 65% had over 800,000 copies/ml of HCV VL. The global sustained viral response (SVR) was reached by 91.7% of cases. The most commonly used DAA regimen was sofosbuvir/ledipasvir. Ribavirin was included in 52% of regimens, 65.9% of cases completed 12-week regimens and 30% completed 24-week schemes. There were 19 therapy failures. No differences were observed between the various DAA strategies used. No independent predictor was found for SVR. Conclusions: HCV treatment in coinfected patients is highly successful in terms of SVR rate in the real-life setting and toxicity is exceptional. We identified no specific predictors of an unfavorable outcome (AU)

Effectiveness of direct-acting antiviral therapy in patients with a HCV/HIV coinfection. A multicenter cohort study.

INTRODUCTION: The effectiveness of direct-acting antiviral (DAA) agents has been demonstrated in clinical trials both in patients with mono and coinfections. The goal of the study was to analyze the effectiveness and toxicity of this therapy in real-life patients with a HIV/HCV coinfection and to identify variables that are associated with an unfavorable outcome. METHODS: This was a multicenter ambispective study in a cohort of coinfected patients. Data were collected from eight centers in Castilla-La Mancha from 2014 to 2016. An intent-to-treat analysis was performed and any loss to follow-up, treatment withdrawal or toxicity was considered as a failure. RESULTS: A total of 229 patients were included with a median age of 49.6 years and the majority were male (83%). Fewer than 10% had a detectable HIV-related viral load (VL). The most prevalent HCV genotype was 1 (65.1%). Fifty percent had cirrhotic liver disease and 65% had over 800,000 copies/ml of HCV VL. The global sustained viral response (SVR) was reached by 91.7% of cases. The most commonly used DAA regimen was sofosbuvir/ledipasvir. Ribavirin was included in 52% of regimens, 65.9% of cases completed 12-week regimens and 30% completed 24-week schemes. There were 19 therapy failures. No differences were observed between the various DAA strategies used. No independent predictor was found for SVR. CONCLUSIONS: HCV treatment in coinfected patients is highly successful in terms of SVR rate in the real-life setting and toxicity is exceptional. We identified no specific predictors of an unfavorable outcome.