Summary Background An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir ...(NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. Methods We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov , number NCT01581203. Findings This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85–94) patients in the treatment-naive cohort, 168 (82%, 77–87) in the non-responder cohort, and 192 (82%, 77–87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). Interpretation Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. Funding Bristol-Myers Squibb.
Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
We conducted a randomized, open-label, phase 3 ...trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).
BACKGROUND:It is unknown if a survival gap remains between HIV-infected and HIV-uninfected individuals with access to care.
METHODS:We conducted a cohort study within Kaiser Permanente California ...during 1996–2011, using abridged life tables to estimate the expected years of life remaining (“life expectancy”) at age 20.
RESULTS:Among 24,768 HIV-infected and 257,600 HIV-uninfected individuals, there were 2229 and 4970 deaths, with mortality rates of 1827 and 326 per 100,000 person-years, respectively. In 1996–1997, life expectancies at age 20 for HIV-infected and HIV-uninfected individuals were 19.1 and 63.4 years, respectively, corresponding with a gap of 44.3 years (95% confidence interval38.4 to 50.2). Life expectancy at age 20 for HIV-infected individuals increased to 47.1 years in 2008 and 53.1 years by 2011, narrowing the gap to 11.8 years (8.9–14.8 years) in 2011. In 2008–2011, life expectancies at age 20 for HIV-infected individuals ranged from a low of 45.8 years for blacks and 46.0 years for those with a history of injection drug use to a high of 52.2 years for Hispanics. HIV-infected individuals who initiated antiretroviral therapy with CD4 ≥500 cells per microliter had a life expectancy at age 20 of 54.5 years in 2008–2011, narrowing the gap relative to HIV-uninfected individuals to 7.9 years (5.1–10.6 years). For these HIV-infected individuals, the gap narrowed further in subgroups with no history of hepatitis B or C infection, smoking, drug/alcohol abuse, or any of these risk factors.
CONCLUSIONS:Even with early treatment and access to care, an 8-year gap in life expectancy remains for HIV-infected compared with HIV-uninfected individuals.
Few studies have compared cancer risk between HIV-infected individuals and a demographically similar HIV-uninfected internal comparison group, adjusting for cancer risk factors.
We followed 20,775 ...HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996 to 2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity.
We observed elevated RRs for Kaposi sarcoma (KS; RR = 199; P < 0.001), non-Hodgkin lymphoma (NHL; RR = 15; P < 0.001), anal cancer (RR = 55; P < 0.001), Hodgkin lymphoma (HL; RR = 19; P < 0.001), melanoma (RR = 1.8; P = 0.001), and liver cancer (RR = 1.8; P = 0.013), a reduced RR for prostate cancer (RR = 0.8; P = 0.012), and no increased risk for oral cavity/pharynx (RR = 1.4; P = 0.14), lung (RR = 1.2; P = 0.15), or colorectal (RR = 0.9; P = 0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P < 0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 < 200 cells/μL and for melanoma and liver cancer with CD4 < 500 cells/μL. Only KS and NHL were associated with HIV RNA.
Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors.
Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population.
Importance Antiretroviral therapy (ART) has improved life expectancy for individuals with HIV infection, but recent data comparing life span and comorbidity-free years by HIV status are lacking. ...Objective To quantify the gap in life span and comorbidity-free years by HIV status among adults with access to care. Design, Setting, and Participants This matched cohort study used data from insured adults with and without HIV infection (aged ≥21 years) matched 1:10 at medical centers of Kaiser Permanente in northern and southern California and the mid-Atlantic states of Washington DC, Maryland, and Virginia from January 1, 2000, through December 31, 2016. Data were analyzed from September 1, 2019, through March 31, 2020. Exposures HIV status and, for individuals with HIV infection, ART initiation at a CD4 cell count of 500/μL or greater. Main Outcomes and Measures Overall life expectancy and expected years free of major chronic comorbidities, including chronic liver disease, chronic kidney disease, chronic lung disease, diabetes, cancer, and cardiovascular disease. Results Of 39 000 individuals with HIV infection and 387 785 matched uninfected adults, 374 421 (87.7%) were male, with a mean (SD) age of 41.4 (10.8) years. Among 359 244 individuals with known race/ethnicity, 90 177 (25.1%) were non-Hispanic black and 87 191 (24.3%) were Hispanic. From 2000 to 2003, overall life expectancy at age 21 years of age was 37.6 years among individuals with HIV infection and 59.7 years among uninfected adults, (difference, 22.1 years; 95% CI, 20.2-24.0 years). From 2014 to 2016, overall life expectancy at 21 years of age among individuals with HIV infection increased to 56.0 years compared with 65.1 years among uninfected adults (difference, 9.1 years; 95% CI, 7.9-10.2 years). During 2011 to 2016, individuals with HIV infection who initiated ART with a CD4 cell count of 500/μL or greater had a life expectancy at 21 years of age of 57.4 years compared with 64.2 years among uninfected adults (difference, 6.8 years; 95% CI, 5.0-8.5 years). From 2000 to 2003, the expected number of comorbidity-free years remaining at 21 years of age was 11.3 for individuals with HIV infection and 26.6 years for uninfected adults (difference, 15.3 years; 95% CI, 13.9-16.6 years). This difference in comorbidity-free years persisted over time but decreased to 9.5 years (95% CI, 7.7-11.2 years) for individuals with HIV infection who initiated ART at a CD4 cell count of 500/μL or greater. Conclusions and Relevance The results suggest that life expectancy of adults with HIV infection may be near that of life expectancy of individuals without HIV infection, but greater attention is needed to prevention of comorbidities among individuals with HIV infection.
COVID-19 (coronavirus disease 2019) is associated with heightened risks of venous and arterial thrombosis and hospitalization due to respiratory failure. To assess whether prophylactic ...anticoagulation can safely reduce the frequency of venous and arterial thrombosis, hospitalization, and death in nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor, we conducted the PREVENT-HD double-blind, placebo-controlled randomized trial (A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic COVID-19 Infection).
PREVENT-HD was conducted between August 2020 and April 2022 at 14 US integrated health care delivery networks. A virtual trial design used remote informed consent and clinical monitoring and facilitated data collection through electronic health record integration with a cloud-based research platform. Nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor were enrolled and randomly assigned to either 10 mg of oral rivaroxaban or placebo daily for 35 days. The primary efficacy outcome was time to first occurrence of a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic arterial embolism, hospitalization, or death through day 35. The principal safety end point was International Society on Thrombosis and Hemostasis critical-site or fatal bleeding. The last study visit was on day 49.
The study was terminated prematurely because of enrollment challenges and a lower-than-expected blinded pooled event rate. A total of 1284 patients underwent randomization with complete accrual of primary events through May 2022. No patients were lost to follow-up. The primary efficacy outcome occurred in 22 of 641 in the rivaroxaban group and 19 of 643 in the placebo group (3.4% versus 3.0%; hazard ratio, 1.16 95% CI, 0.63-2.15;
=0.63). No patient in either group experienced critical-site or fatal bleeding. One patient receiving rivaroxaban had a major bleed.
The study was terminated prematurely after enrollment of 32% of planned accrual because of recruitment challenges and lower-than-expected event rate. Rivaroxaban prescribed for 35 days in nonhospitalized patients with symptomatic COVID-19 at risk for thrombosis did not appear to reduce a composite end point of venous and arterial thrombotic events, hospitalization, and death.
URL: https://www.
gov; Unique identifier: NCT04508023.
Concerns remain for an increased myocardial infarction (MI) risk among individuals infected with human immunodeficiency virus (HIV). We conducted a cohort study evaluating MI risk from 1996 to 2011 ...by HIV status. The adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (95% confidence interval, .7–1.4) in 2010–2011, the most recent study period.
Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need.
We conducted a multicenter, single-group, ...open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval CI, 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events.
Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).
The incidence of certain non-AIDS-defining cancers (NADCs) in HIV patients has been reported to have increased in the combination antiretroviral therapy (ART) era. Studies are needed to directly ...evaluate the effect of ART use on cancer risk.
We followed 12 872 HIV-infected Kaiser Permanente members whose complete ART history was known for incident cancers between 1996 and 2008.
Cancers, identified from Surveillance, Epidemiology, and End Results (SEER)-based cancer registries, were grouped as ADCs, infection-related NADCs, or infection-unrelated NADCs. We also evaluated the most common individual cancer types. Rate ratios for ART use (yes/no) and cumulative duration of any ART, protease inhibitor, and nonnucleotide reverse transcriptase inhibitor (NNRTI) therapy were obtained from Poisson models adjusting for demographics, pretreatment or recent CD4 cell count and HIV RNA levels, years known HIV-infected, prior antiretroviral use, HIV risk, smoking, alcohol/drug abuse, overweight/obesity, and calendar year.
The cohort experienced 32 368 person-years of ART, 21 249 person-years of protease inhibitor therapy, and 15 643 person-years of NNRTI therapy. The mean follow-up duration was 4.5 years. ADC rates decrease with increased duration of ART use rate ratio per year = 0.61 (95% confidence interval 0.56-0.66); the effect was similar by therapy class. ART, protease inhibitor, or NNRTI therapy duration was not associated with infection-related or infection-unrelated NADC rate ratio per year ART = 1.00 (0.91-1.11) and 0.96 (0.90-1.01), respectively, except a higher anal cancer risk with longer protease inhibitor therapy rate ratio per year = 1.16 (1.02-1.31).
No therapy class-specific effect was found for ADC. ART exposure was generally not associated with NADC risk, except for long-term use of protease inhibitor, which might be associated with increased anal cancer risk.
To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons.
Retrospective cohort study.
Adult HIV-infected and matched HIV-uninfected members of Kaiser ...Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkin's lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs).
We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 95% confidence interval (CI): 31.7-44.8, with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7-11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkin's lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2-1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007).
In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.
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