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Background & Aims: Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF). Methods: Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.5 mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log10 IU/ml HBsAg decline at W24. Results: Sixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events. Most adverse events were grade 1. Alanine aminotransferase flares were not observed up to W48. Four patients experienced alanine aminotransferase and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. Mean HBsAg changes were -0.12, -0.16, and -0.12 log10 IU/ml in the selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo groups, respectively, at W48; HBV DNA declined in all groups by ≥2 log10 IU/ml as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU. Conclusions: Selgantolimod up to 3 mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies. Impact and implications: Novel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a TLR8) when administered with tenofovir alafenamide over 24 weeks in viremic patients with chronic HBV infection. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase levels greater than the upper limit of normal had significantly greater declines compared to those with normal alanine aminotransferase levels (-0.20 vs. -0.03 log10 IU/ml; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways. Clinical trial number: NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/.
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BACKGROUND: With the advent of efficacious oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV), identification of characteristics associated with adherence is critical to treatment success. We examined correlates of sub-optimal adherence to HCV therapy in a single-arm, multinational, clinical trial. METHODS: ACTG A5360 enrolled HCV treatment-naive persons without decompensated cirrhosis from 5 countries. All participants received a 12-weeks course of sofosbuvir/velpatasvir at entry. In-person visits occurred at initiation and week 24, sustained virologic response (SVR) assessment. Adherence at week 4 was collected remotely and was dichotomized optimal (100%, no missed doses) versus sub-optimal (<100%). Correlates of sub-optimal adherence were explored using logistic regression. RESULTS: In total, 400 participants enrolled; 399 initiated treatment; 395/397 (99%) reported completing at week 24. Median age was 47 years with 35% female. Among the 368 reporting optimal adherence at week 4 SVR was 96.5% (95% confidence interval [CI] [94.1%, 97.9%]) vs 77.8% (95% CI [59.2%, 89.4%]) P value < .001. In the multivariate model age <30 years and being a US participant were independently associated with early sub-optimal adherence. Participants <30 years were 7.1 times more likely to have early sub-optimal adherence compared to their older counterparts. CONCLUSIONS: Self-reported optimal adherence at week 4 was associated with SVR. Early self-reported adherence could be used to identify those at higher risk of treatment failure and may benefit from additional support. Younger individuals <30 years may also be prioritized for additional adherence support. Clinical Trials Registration. NCT03512210.
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Hepatitis C Crónica , Hepatitis C , Humanos , Femenino , Persona de Mediana Edad , Adulto , Masculino , Sofosbuvir/uso terapéutico , Hepatitis C Crónica/complicaciones , Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Resultado del Tratamiento , Respuesta Virológica Sostenida , Hepacivirus/genética , GenotipoRESUMEN
Outcomes for critically ill people living with human immunodeficiency virus (PLHIV) have changed with the use of antiretroviral therapy (ART). To identify these outcomes and correlates of mortality in a contemporary critically ill cohort in an urban academic medical center in Baltimore, a city with a high burden of HIV, we conducted a retrospective cohort study of individuals admitted to a medical intensive care unit (MICU) at a tertiary care center between 2009 and 2014. PLHIV who were at least 18 years of age with an index MICU admission of ≥24 hours during the 5-year study period were included in this analysis. Data were obtained for participants from the time of MICU admission until hospital discharge and up to 180 days after MICU admission. Logistic regression was used to identify independent predictors of hospital mortality. Between June 2009 and June 2014, 318 PLHIV admitted to the MICU met inclusion criteria. Eighty-six percent of the patients were non-Hispanic Blacks. Poorly controlled HIV was very common with 70.2% of patients having a CD4 cell count <200 cells/mm3 within 3 months prior to admission and only 34% of patients having an undetectable HIV viral load. Hospital mortality for the cohort was 17%. In a univariate model, mortality did not differ by demographic variables, CD4 cell count, HIV viral load, or ART use. Regression analysis adjusted by relevant covariates revealed that MICU patients admitted from the hospital ward were 6.4 times more likely to die in hospital than those admitted from emergency department. Other positive predictors were a diagnosis of end-stage liver disease, cardiac arrest, ventilator-dependent respiratory failure, vasopressor requirement, non-Hodgkin lymphoma, and symptomatic cytomegalovirus disease. In conclusion, in this critically ill cohort with HIV infection, most predictors of mortality were not directly related to HIV and were similar to those for the general population.
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Enfermedad Crítica , Infecciones por VIH , Estudios de Cohortes , Enfermedad Crítica/terapia , Infecciones por VIH/tratamiento farmacológico , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment. METHODS: ACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA >1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210. FINDINGS: Between Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment. INTERPRETATION: In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda. FUNDING: US National Institutes of Health and Gilead Sciences.
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Hepatitis C Crónica , Hepatitis C , Adolescente , Antivirales/efectos adversos , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , ARN/uso terapéutico , Sofosbuvir/efectos adversos , Resultado del Tratamiento , Estados UnidosRESUMEN
In 2016, the World Health Organization developed a plan for viral hepatitis elimination by 2030. Globally, control of hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most challenging aspects of viral hepatitis elimination. In many developed countries elimination of HBV could be targeted to special populations mostly immigrants from low resource settings. Elimination of HCV, however, remains a challenge globally. Barriers to HCV elimination include high cost of medications and the ability to engage specific at-risk populations as well as individuals who are out of medical care. In the context of the coronavirus disease 2019 (COVID-19) pandemic, treatment access and screening have been further negatively impacted by social distancing rules and COVID-19-related anxieties. This threatens to throw most countries off course in their elimination efforts. Before the pandemic, some states in the United States had scaled up their elimination efforts with plans to ramp up testing and treatment using Netflix-like payment models for HCV direct acting antiviral drugs. Most of these efforts have stalled on account of the health system's focus on COVID-19 control. To prevent further delays in achieving elimination targets, programs would need to explore new models of care that address COVID-19-related access hurdles. Systems that leverage technologies such as telemedicine and self-testing could help maintain treatment levels. Mathematical models estimate that COVID-19-related delays in 2020 could lead to 44,800 hepatocellular cancers and 72,300 liver-related deaths for the next decade.
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COVID-19/epidemiología , Erradicación de la Enfermedad/estadística & datos numéricos , Hepatitis Viral Humana/epidemiología , Antivirales/uso terapéutico , Objetivos , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepatitis Viral Humana/diagnóstico , Hepatitis Viral Humana/tratamiento farmacológico , Humanos , Pandemias , SARS-CoV-2 , Factores de TiempoRESUMEN
People living with HIV are at high risk for anal cancer (AC); however, the impact of screening for and treatment of precancerous anal lesions on AC incidence remains uncertain. In 2013, we conducted a survey of HIV providers evaluating the perceived need for an institutional AC screening program. Based on an overwhelmingly positive response, we established a dedicated AC screening clinic (including provision of high-resolution anoscopies) embedded within the institutional HIV clinic. Here, we describe that referral of high-risk patients in the first 3 years was lower than expected. Referral patterns suggest that screening practices vary widely among HIV providers within the institution. Anal cancer clinic patients who completed a perception survey rated the value of AC screening as high, with perceived positive health impact, and identified their providers as the main source of information on AC and AC screening. Our findings imply remaining provider-related barriers to AC screening.
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Neoplasias del Ano/diagnóstico , Detección Precoz del Cáncer/psicología , Infecciones por VIH/complicaciones , Implementación de Plan de Salud , Pacientes Ambulatorios/psicología , Derivación y Consulta/estadística & datos numéricos , Adulto , Instituciones de Atención Ambulatoria , Canal Anal/patología , Neoplasias del Ano/virología , Detección Precoz del Cáncer/métodos , Femenino , Homosexualidad Masculina , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios/estadística & datos numéricos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Estudios Prospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
In this article, we sought to understand the perceptions and practice of providers on anal cancer screening in HIV-infected patients. Providers in an academic outpatient HIV practice were surveyed. Data were analyzed to determine the acceptability and perceptions of providers on anal Papanicolaou tests. Survey response rate was 55.3% (60.7% among male and 47.4% among female providers). One-third of the providers had received screening requests from patients. Female providers had higher self-rated comfort with anal Papanicolaou tests, with a mean score of 7.1 (95% confidence interval [CI] 4.7-9.5) compared to 3.6 (95% CI 1.5-5.7) for male providers, P = .02. Sixty-seven percent of male providers and 37.5% of female providers would like to refer their patients for screening rather than perform the test themselves. Only 54.2% of our providers have ever performed anal cytology examination. Our survey revealed that not all providers were comfortable performing anal cancer screening for their patients.
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Neoplasias del Ano/diagnóstico , Infecciones por VIH/complicaciones , Médicos/psicología , Pautas de la Práctica en Medicina , Adulto , Neoplasias del Ano/etiología , Neoplasias del Ano/psicología , Detección Precoz del Cáncer , Femenino , Infecciones por VIH/psicología , Conocimientos, Actitudes y Práctica en Salud , Encuestas Epidemiológicas , Homosexualidad Masculina , Humanos , Masculino , Persona de Mediana Edad , Servicio Ambulatorio en Hospital , Percepción , Salud UrbanaRESUMEN
BACKGROUND: With improved access to antiretroviral therapy in resource-constrained settings, long-term retention in HIV clinics has become an important means of reducing costs and improving outcomes. Published data on retention in HIV clinics beyond 24 months are, however, limited. In our clinic in rural Haiti, we hypothesized that individuals residing in locations with higher transportation costs to clinic would have poorer retention than those who had lower costs. METHODS: We used a retrospective cohort design to evaluate potential predictors of HIV clinic retention. Patient information was abstracted from the electronic medical records. Cox proportional hazards regression was used to identify independent predictors of 4-year clinic retention. RESULTS: There were 410 patients in our cohort, 266 (64.9%) females and 144 (35.1%) males. Forty-five (11%) patients lived in locations with transportation costs >$2. Males were 1.5 times more likely to live in municipalities with transportation costs to clinic of >$2. Multivariate analysis suggested that age <30 years, male gender, and transportation cost were independent predictors of loss to follow-up (LTFU): risk ratio of 2.98, 95% confidence interval (CI): 1.73 to 4.96, P < 0.001; 1.71, CI: 1.08 to 2.70, P = 0.02; and 1.91, CI: 1.08 to 3.36, P = 0.02, respectively. CONCLUSIONS: Patients with transportation costs greater than $2 were 1.9 times more likely to be lost to care compared with those who paid less for transportation. HIV treatment programs in resource-constrained settings may need to pay closer attention to issues related to transportation cost to improve patient retention.
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Costos y Análisis de Costo/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Transportes/economía , Adolescente , Adulto , Femenino , Haití/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Población Rural/estadística & datos numéricos , Transportes/estadística & datos numéricos , Adulto JovenRESUMEN
Tobacco use in the U.S. has declined significantly since the 1960s, but differentially by socioeconomic status. Current HIV (human immunodeficiency virus) infection rates in the United States are higher in minorities and underprivileged individuals. Effective highly active anti-retroviral therapy (HAART) has changed HIV into a chronic infection. Mortality among HIV patients is now as likely to be due to heart disease and cancers as HIV-related infections. In the current situation, one would expect public insurance plans to focus on interventions targeting lifestyle-associated behaviors such as tobacco use that have been found to be associated with increased risk for heart disease and cancers. Review of the AIDS Drug Assistance Program formularies and the Medicaid Programs of 50 states and the District of Columbia, however, revealed that coverage for smoking cessation is inadequate in most instances. To reduce health disparities, publicly funded programs that serve the nation's most vulnerable should provide coverage for effective tobacco cessation.