Summary Background Influenza continues to have a significant socioeconomic and health impact despite a long established vaccine program and approved antivirals. Preclinical data suggest combination antivirals might be more effective than oseltamivir alone in the treatment of influenza. Methods We conducted a randomized, double-blinded, multicenter phase 2 trial of combination antivirals versus monotherapy for the treatment of influenza. Participants ≥18 years with influenza at increased risk of complications from influenza were randomized by an online computer-generated randomization system to receive either oseltamivir, amantadine, and ribavirin or oseltamivir alone for 5 days, and followed for 28 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at Day 3. Among the secondary outcomes, there were safety and time to alleviation of influenza clinical symptoms. ClinicalTrials.gov Identifier: NCT01227967. Findings Between March 2011 and April 2016 we randomized 633 participants. Seven participants were excluded from analysis: 3 were given treatment without randomization, 3 withdrew before taking any medication, and 1 was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 of 200 (40.0%) participants in the combination arm had virus detectable at Day 3 compared to 97 of 194 (50.0%) (95%C.I. 0.2–19.8%, p=0.046) in the control arm. There was no benefit, however, in multiple clinical secondary endpoints, such as median duration of symptoms (4.5 days in the combination arm vs 4.0 days in the oseltamivir arm; p = 0.21). Interpretation Although oseltamivir, amantadine, and ribavirin showed a statistically significant decrease in viral shedding at Day 3 relative to oseltamivir, this difference was not associated with improved clinical benefit. More work is needed to understand the lack of clinical benefit when a difference in virologic outcome was identified. Funding National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States.

Objective: Cardiovascular events are a significant cause of mortality in HIV/AIDS patients. The objective is to determine the correlation between kidney function and the risk of cardiovascular events in the HIV-infected population. Design: Nested, matched, case-control study design was employed. Methods: We performed a single-center study of 315 HIV-infected patients (63 cases who had cardiovascular events and 252 controls). Estimated glomerular filtration rate (eGFR), calculated by the CKD-EPI and the MDRD equation, and proteinuria were the primary exposures of interest. Results: Mean eGFR was significantly lower in the cases compared to controls (68·4 vs. 103·2 ml/min/1·73m2, p<0·001 by CKD-Epi and 69·0 vs. 103·1 ml/min/1·73m2, p<0·001 by MDRD). In univariate analysis, an eGFR of <60 ml/min/1·73m2 was associated with a 15·9 fold increased odds of a cardiovascular event compared to an eGFR ≥ 60 ml/min/1·73m2 (p<0·001). In multivariate analysis, a 10 ml/min/1·73m2 decrease in eGFR was associated with a 20% increased odds of a cardiovascular event (odds ratio 1·2, 95% CI 1·1–1·4). The prevalence of proteinuria in the cases was approximately twice that of controls (51% vs. 25%, p<0·001). Proteinuria was associated with cardiovascular events both in univariate and multivariate analyses (OR of 3·6, 95% CI 1·9–7·0 and 2·2, 95% CI 1·1–4·8 respectively). Traditional cardiovascular risk factors like history of previous cardiovascular events, diabetes mellitus, and dyslipidemia along with low CD4 counts were also found as significant predictors of risk of cardiovascular events. Conclusion: Our study shows a significant independent association between decreased kidney function and increased risk of CVE in HIV-1-infected patients.

Background Gay and bisexual men (GBM) are a key population affected by HIV and hepatitis C (HCV) co-infection. Providing HCV treatment scale-up across specialist and non-hepatitis specialist settings may eliminate HCV in this population. We aimed to (1) deliver and measure HCV treatment effectiveness, and (2) determine the population impact of treatment on HCV prevalence and incidence longitudinally. Methods The co-EC Study (Enhancing care and treatment among HCV/HIV co-infected individuals to Eliminate Hepatitis C transmission) was an implementation trial providing HCV direct-acting antiviral treatment in Melbourne, Australia, from 2016-2018. Individuals with HCV/HIV co-infection were prospectively enrolled from primary and tertiary-care services providing care for 85% of GBM with HIV in our jurisdiction. HCV-viraemic prevalence and HCV-antibody/viraemic incidence were measured using a state-wide, individually-linked, electronic surveillance system. Results Among 200 participants recruited, 186 initiated treatment during the study period. Sustained virological response among primary care participants (98%, 95%CI:93-100%) was not different to tertiary care (98%, 95%CI:86-100%). From 2012-2019, between 2434 and 3476 GBM with HIV-infection attended our primary-care sites annually providing 13,801 person-years of follow-up; 50-60% received an HCV test annually, 10-14% were anti-HCV positive. Among those anti-HCV positive, viraemic prevalence declined 83% during the study (54% to 9%; 2016 to 2019). HCV incidence decreased 25% annually from 1.7/100 person-years in 2012 to 0.5/100 person-years in 2019 (incidence rate ratio 0.75; CI:0.68-0.83;p&lt;0.001). Conclusion High treatment effectiveness by non-specialists demonstrates the feasibility of treatment scale-up in this population. Substantial declines in HCV incidence and prevalence among GBM with HIV-infection provides proof-of-concept for HCV micro-elimination. Registration ClinicalTrials.gov (Identifier: NCT02786758).

The albumin to creatinine ratio (ACR) can be used to measure urine albumin excretion rates, but is inconvenient and expensive. More rapid and less expensive screening methods estimate only albumin concentration and are subject to errors caused by variation in urine volume. We examined whether urine specific gravity could be used in place of urine creatinine to correct albumin concentration for differences in urine volume in 50 patients. Urine specific gravity accurately estimated urine creatinine concentration (r = 0.79, P < 0.001). The albumin estimated-creatinine ratio (ACestR) in random spot urine sample correlated with urine albumin excretion measured in a 24-hour urine collection (r = 0.98, P < 0.001), as did the ACR (r = 0.95, P < 0.001). For determining microalbuminuria, the sensitivity (0.88) and specificity (0.93) of the ACestR were similar to those of ACR (0.89 and 0.93, respectively). Unfortunately, the sensitivity (0.63) of the Micral-Test was relatively poor, and was only slightly improved by correcting for urine specific gravity (0.69) in this small sample of patients. Nevertheless, these results suggest that as rapid methods for measuring urine albumin concentration improve, combining them with urine specific gravity might produce a less expensive and more convenient alternative to the ACR.