Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Hepatic steatosis in people older and younger than fifty who are living with HIV and HIV-negative controls: A cross-sectional study nested within the POPPY cohort.

BACKGROUND: Hepatic steatosis is a major cause of chronic liver disease associated with several negative health outcomes. We compared the prevalence of and factors associated with steatosis in people living with and without HIV. METHODS: Older (>50 years) and younger (<50 years) people with HIV and older HIV-negative controls (>50 years) underwent liver transient elastography examination with controlled attenuation parameter (steatosis ≥238 dB/m, moderate/severe steatosis ≥280 dB/m, liver fibrosis ≥7.1 kPa). We compared groups using logistic regression/Chi-squared/Fisher's exact/Kruskal-Wallis tests. RESULTS: In total, 317 participants (109 older people with HIV; 101 younger people with HIV; 107 HIV-negative controls) were predominantly white (86%) and male (76%), and 21% were living with obesity (body mass index ≥30 kg/m2 ). Most (97%) people with HIV had undetectable HIV RNA. The prevalence of fibrosis was 8.4%, 3.0%, and 6.5% in the three groups, respectively (p = 0.26). Fibrosis was predominately (>65%) mild. The prevalence of steatosis was the same in older people with HIV (66.4%) and controls (66.4%) but lower in younger people with HIV (37.4%; p < 0.001). After adjustment, younger people with HIV were less likely to have steatosis (odds ratio [OR] 0.26; 95% confidence interval [CI] 0.14-0.52) than controls, but male sex (OR 2.45; 95% CI 1.20-4.50) and high waist-to-hip ratio (OR 3.04; 95% CI 1.74-5.33) were associated with an increased odds of steatosis. We found no association between steatosis and HIV-related variables. CONCLUSIONS: The prevalence of hepatic steatosis and fibrosis was similar between older participants regardless of HIV status. Age, sex, and abdominal obesity, but not HIV-related variables, were associated with steatosis. Interventions for controlling obesity should be integrated into routine HIV care.

No overall impact on rate of weight gain with integrase inhibitor-containing regimens in antiretroviral-naïve adults.

OBJECTIVES: Integrase strand transfer inhibitors (INSTIs) are commonplace in modern antiretroviral therapy (ART). Increased weight gain with their use is increasingly scrutinized. We evaluated weight changes in treatment-naïve adults with HIV-1 attending a UK centre who started regimens including raltegravir or dolutegravir. METHODS: A retrospective cohort study of adults prescribed an INSTI between January 2015 and March 2020 were categorized as having started an ART regimen containing raltegravir, dolutegravir, a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Individuals with one or more weight measurement ≤ 5 years both pre- and post-ART initiation, who started a three-drug regimen with ≥ 6 months duration and achieved virological suppression (< 50 copies/mL) within 6 months were included. A random effects model with linear slope pre- and post-ART was used, adjusting for age, gender, ethnicity, ART regimen, backbone and year of initiation. RESULTS: The cohort included 390 adults; 88.7% were male, 66.4% were of white ethnicity, their median age was 40 years, there was a median of six weight measurements, 2.2 years from diagnosis to ART initiation, 2.9 years from ART to the last weight measurement, and weight and body mass index at initiation were 75 kg and 24.1 kg/m2 respectively. Of these, 254 (65%) started an INSTI. The average pre-ART rate of weight gain was 0.44 kg/year [95% confidence interval (CI): 0.19-0.70], increasing to 0.88 kg/year (0.63-1.10, p = 0.04) after ART initiation. Our adjusted model found no evidence of an association between ART regimen and rate of weight gain. CONCLUSIONS: Weight increased in the cohort both pre- and post-ART. We found no evidence of a higher rate of weight gain following ART initiation with an INSTI compared with other regimens.

Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa.

BACKGROUND: In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%. METHODS: In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality. RESULTS: A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups. CONCLUSIONS: Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374 .).

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial.

Background: In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity. Methods: Participants started ART with a CD4 count <100 cells/µL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non-mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown. Results: Median pre-ART CD4 count was 37 cells/µL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2). Conclusions: Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease. Clinical Trials Registration: ISRCTN43622374.

Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial.

BACKGROUND: In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. METHODS AND FINDINGS: In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82-1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76-1.28], p = 0.91); in serious (aHR = 0.99 [0.81-1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71-1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63-1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76-1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. CONCLUSIONS: Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT01825031. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number ISRCTN 43622374.

Bone turnover change after randomized switch from tenofovir disoproxil to tenofovir alafenamide fumarate in men with HIV.

OBJECTIVE: Bone loss in people with HIV (PWH) is poorly understood. Switching tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has yielded bone mineral density (BMD) increases. PETRAM (NCT#:03405012) investigated whether BMD and bone turnover changes correlate. DESIGN: Open-label, randomized controlled trial. SETTING: Single-site, outpatient, secondary care. PARTICIPANTS: Nonosteoporotic, virologically suppressed, cis-male PWH taking TDF/emtricitabine (FTC)/rilpivirine (RPV) for more than 24 weeks. INTERVENTION: Continuing TDF/FTC/RPV versus switching to TAF/FTC/RPV (1 : 1 randomization). MAIN OUTCOME MEASURES: :[ 18 F]NaF-PET/CT for bone turnover (standardized uptake values, SUV mean ) and dual-energy x-ray absorptiometry for lumbar spine and total hip BMD. RESULTS: Thirty-two men, median age 51 years, 76% white, median duration TDF/FTC/RPV 49 months, were randomized between 31 August 2018 and 09 March 2020. Sixteen TAF:11 TDF were analyzed. Baseline-final scan range was 23-103 (median 55) weeks. LS-SUV mean decreased for both groups (TAF -7.9% [95% confidence interval -14.4, -1.5], TDF -5.3% [-12.1,1.5], P  = 0.57). TH-SUV mean showed minimal changes (TAF +0.3% [-12.2,12.8], TDF +2.9% [-11.1,16.9], P  = 0.77). LS-BMD changes were slightly more favorable with TAF but failed to reach significance (TAF +1.7% [0.3,3.1], TDF -0.3 [-1.8,1.2], P  = 0.06). Bone turnover markers decreased more with TAF ([CTX -35.3% [-45.7, -24.9], P1NP -17.6% [-26.2, -8.5]) than TDF (-11.6% [-28.8, +5.6] and -6.9% [-19.2, +5.4] respectively); statistical significance was only observed for CTX ( P  = 0.02, P1NP, P  = 0.17). CONCLUSION: Contrary to our hypothesis, lumbar spine and total hip regional bone formation (SUV mean ) and BMD did not differ postswitch to TAF. However, improved LS-BMD and CTX echo other TAF-switch studies. The lack of difference in SUV mean may be due to inadequate power.

MAVMET trial: maraviroc and/or metformin for metabolic dysfunction-associated fatty liver disease(MAFLD) in adults with suppressed HIV.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) is over-represented in people living with HIV (PLWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism. DESIGN: Open-label, 48-week randomised trial with a 2x2 factorial design. SETTING: Multicentre HIV clinics. PARTICIPANTS: Nondiabetic, virologically-suppressed PLWH, aged ≥35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features). INTERVENTION: Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone. PRIMARY OUTCOME: Change in liver fat fraction (LFF) between baseline and week-48 using Magnetic Resonance Proton Density Fat Fraction (MR PDFF). RESULTS: Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between 19-Mar-2018 and 11-November-2019. 70% had imaging/biopsy plus ≥1 MAFLD criteria. The analysis included 82/90 with week-0 and -48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40%, 38%, 8%, and 14% had grade zero, one, two, and three steatosis respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% CI 2.97, 5.48], P  < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53-0.68, P  = 0.45]), MET (-0.62 [-1.81-0.56, P  = 0.30]), and MVC+MET (-1.04 [-2.74-0.65, P  = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%. CONCLUSIONS: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced MR PDFF compared to ART alone.

Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study.

BACKGROUND: Untreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals. PURPOSE: In this article, we outline the rationale and methods of the Strategic Timing of AntiRetroviral Treatment (START) study, an ongoing multicenter international trial designed to assess the risks and benefits of initiating ART earlier than is currently practiced. We also describe some of the challenges encountered in the design and implementation of the study and how these challenges were addressed. METHODS: A total of 4000 study participants who are HIV type 1 (HIV-1) infected, ART naïve with CD4 count > 500 cells/µL are to be randomly allocated in a 1:1 ratio to start ART immediately (early ART) or defer treatment until CD4 count is <350 cells/µL (deferred ART) and followed for a minimum of 3 years. The primary outcome is time to AIDS, SNA, or death. The study had a pilot phase to establish feasibility of accrual, which was set as the enrollment of at least 900 participants in the first year. RESULTS: Challenges encountered in the design and implementation of the study included the limited amount of data on the risk of a major component of the primary endpoint (SNA) in the study population, changes in treatment guidelines when the pilot phase was well underway, and the complexities of conducting the trial in a geographically wide population with diverse regulatory requirements. With the successful completion of the pilot phase, more than 1000 participants from 100 sites in 23 countries have been enrolled. The study will expand to include 237 sites in 36 countries to reach the target accrual of 4000 participants. CONCLUSIONS: START is addressing one of the most important questions in the clinical management of ART. The randomization provided a platform for the conduct of several substudies aimed at increasing our understanding of HIV disease and the effects of antiretroviral therapy beyond the primary question of the trial. The lessons learned from its design and implementation will hopefully be of use to future publicly funded international trials.

Utility of a buccal swab point-of-care test for the IFNL4 genotype in the era of direct acting antivirals for hepatitis C virus.

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy.

Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study.

Background: World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods: Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28. Results: Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels. Conclusions: Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment. Funding: Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).

Hepatitis C is a blood-borne virus that causes thousands of deaths from liver cirrhosis and liver cancer each year. Antiviral therapies can cure most cases of infection in 12 weeks. Unfortunately, treatment is expensive, and sticking with the regimen for 12 weeks can be difficult. It may be especially challenging for unhoused people or those who use injection drugs and who have high rates of hepatitis C infection. Shorter durations of therapy may make it more accessible, especially for high-risk populations. But studies of shorter antiviral treatment durations have yet to produce high enough cure rates. Finding ways to identify patients who would benefit from shorter therapy is a key goal of the World Health Organization. Potential characteristics that may predict a faster treatment response include low virus levels before initiating treatment, patient genetics, drug resistance mutations in the virus, and higher drug levels in the patient's blood during treatment. For example, previous research showed that a rapid decrease in virus levels in a patient's blood two days after starting antiviral therapy with three drugs predicted patient cures after three weeks of treatment. To test if high cure rates could be achieved in just four weeks of treatment, Flower et al. enrolled 52 patients with hepatitis C in a study to receive the most widely accessible dual antiviral treatment (sofosbuvir and daclatasvir). Participants received four or eight weeks of treatment, depending on the amount of viral RNA in their blood after two days of treatment. The results indicate that a rapid decrease in virus levels in the blood does not adequately predict cure rates with four weeks of two-drug combination therapy. However, eight weeks may be highly effective, regardless of viral levels early in treatment. Thirty-four individuals with low virus levels on the second day of treatment received four weeks of therapy, which cured 21 or 62% of them. All seventeen individuals with higher viral levels on day two were cured after eight weeks of treatment. Twelve weeks of retreatment was sufficient to cure the 13 individuals who did not achieve cure with four weeks of therapy. Even patients with drug resistance genes after the first round of therapy responded to a longer second round. Flower et al. show that patient genetics, virus subtype, drug levels in the patient's blood, and viral drug resistance genes before therapy, were not associated with patient cures after four weeks of treatment. Given that retreatment is safe and effective, larger studies are now needed to determine whether eight weeks of therapy with sofosbuvir and daclatasvir may be enough to cure patients with mild liver disease. More studies are also necessary to identify patients that may benefit from shorter therapy durations. Finding ways to shorten antiviral therapy for hepatitis C could help make treatment more accessible and reduce therapy costs for both individuals and governments.

SARS-CoV-2 immunity and vaccine strategies in people with HIV.

Current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines, based on the ancestral Wuhan strain, were developed rapidly to meet the needs of a devastating global pandemic. People living with Human Immunodeficiency Virus (PLWH) have been designated as a priority group for SARS-CoV-2 vaccination in most regions and varying primary courses (two- or three-dose schedule) and additional boosters are recommended depending on current CD4+ T cell count and/or detectable HIV viraemia. From the current published data, licensed vaccines are safe for PLWH, and stimulate robust responses to vaccination in those well controlled on antiretroviral therapy and with high CD4+ T cell counts. Data on vaccine efficacy and immunogenicity remain, however, scarce in PLWH, especially in people with advanced disease. A greater concern is a potentially diminished immune response to the primary course and subsequent boosters, as well as an attenuated magnitude and durability of protective immune responses. A detailed understanding of the breadth and durability of humoral and T cell responses to vaccination, and the boosting effects of natural immunity to SARS-CoV-2, in more diverse populations of PLWH with a spectrum of HIV-related immunosuppression is therefore critical. This article summarizes focused studies of humoral and cellular responses to SARS-CoV-2 infection in PLWH and provides a comprehensive review of the emerging literature on SARS-CoV-2 vaccine responses. Emphasis is placed on the potential effect of HIV-related factors and presence of co-morbidities modulating responses to SARS-CoV-2 vaccination, and the remaining challenges informing the optimal vaccination strategy to elicit enduring responses against existing and emerging variants in PLWH.

Enfuvirtide injection site reactions: a clinical and histopathological appraisal.

BACKGROUND/OBJECTIVES: Enfuvirtide was the first of a new class of antiretroviral agents termed 'fusion inhibitors' used for the treatment of HIV-1 infection. Enfuvirtide is administered subcutaneously and injection site reactions (ISR) are commonplace (98%). The aim of this study was to analyse in detail the histopathological changes associated with striking ISR seen in four patients. METHODS: Biopsies were obtained at various times post-injection and were reviewed histologically. The changes in epidermal, dermal and subcutaneous connective tissue and the presence and nature of the inflammatory cellular infiltrate were noted. An immunohistochemical assessment was undertaken. RESULTS: All biopsy specimens demonstrated striking changes in the dermal connective tissue. Alteration in collagen was the most prominent feature and resembled a morphoea/scleroderma-like process. These changes persisted well beyond cessation of enfuvirtide (>1 year). The relative populations of dermal dendritic cells (DDC) (types 1 (Factor XIIIa) and 2 (CD34+)) were analysed and a reciprocal relationship between DDC subpopulations was observed akin to that observed in other sclerosing and fibrosing conditions. CONCLUSION: This study details histopathological changes associated with enfuvirtide ISR. We postulate that changes in DDC populations may contribute to the pathogenesis of the sclerotic process observed with enfuvirtide ISR.

Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection.

BACKGROUND: Human immunodeficiency virus (HIV) replication and immune activation may increase inflammation and coagulation biomarkers. Limited data exist comparing such biomarkers in persons with and without HIV infection. METHODS: For persons 45-76 years of age, levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, D-dimer, and cystatin C were compared in 494 HIV-infected individuals in the Strategies for Management of Anti-Retroviral Therapy (SMART) study and 5386 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study. For persons 33-44 years of age, hsCRP and IL-6 levels were compared in 287 participants in the SMART study and 3231 participants in the Coronary Artery Development in Young Adults (CARDIA) study. RESULTS: hsCRP and IL-6 levels were 55% (P < . 001) and 62 (P < . 001) higher among HIV-infected participants than among CARDIA study participants. Compared with levels noted in MESA study participants, hsCRP, IL-6, D-dimer, and cystatin C levels were 50%, 152%, 94%, and 27% higher, respectively (P < . 001, for each), among HIV-infected participants. HIV-infected participants receiving antiretroviral therapy who had HIV RNA levels 400 copies/mL had levels higher (by 21% to 60%) (P < . 001) than those in the general population, for all biomarkers. CONCLUSIONS: hsCRP, IL-6, D-dimer, and cystatin C levels are elevated in persons with HIV infection and remain so even after HIV RNA levels are suppressed with antiretroviral therapy. Additional research is needed on the pathophysiology of HIV-induced activation of inflammatory and coagulation pathways, to guide potential interventions.

Prevalence of HIV/hepatitis B and HIV/hepatitis C coinfection among people of East, South, Central and West African ancestry in the United Kingdom.

Regional variability in the prevalence of hepatitis B (HBV) and C (HCV) is reported in sub-Saharan Africa, although data for people with HIV are sparse. We determined the prevalence of HBV/HCV in 2473 people of African ancestry with HIV in the UK. Overall, 6.2% were co-infected with HBV and 1.3% with HCV. Central [adjusted odds ratio (aOR) 2.40 (95% confidence interval (CI) 1.23--4.67) and West [2.10 (1.29-3.41)] African ancestry was associated with HBV and Central [6.98 (2.00-24.43)] African ancestry with HCV.

Benefits of enhanced infection prophylaxis at antiretroviral therapy initiation by cryptococcal antigen status.

OBJECTIVES: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. DESIGN: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/µl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). METHODS: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity. RESULTS: Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratio = 0.36 (95% confidence interval 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratio = 0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneity = 0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneity > 0.3). CONCLUSION: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.

High Cure Rates for Hepatitis C Virus Genotype 6 in Advanced Liver Fibrosis With 12 Weeks Sofosbuvir and Daclatasvir: The Vietnam SEARCH Study.

BACKGROUND: Genotype 6 is the most genetically diverse lineage of hepatitis C virus, and it predominates in Vietnam. It can be treated with sofosbuvir with daclatasvir (SOF/DCV), the least expensive treatment combination globally. In regional guidelines, longer treatment durations of SOF/DCV (24 weeks) are recommended for cirrhotic individuals, compared with other pangenotypic regimens (12 weeks), based on sparse data. Early on-treatment virological response may offer means of reducing length and cost of therapy in patients with liver fibrosis. METHODS: In this prospective trial in Vietnam, genotype 6-infected adults with advanced liver fibrosis or compensated cirrhosis were treated with SOF/DCV. Day 14 viral load was used to guide duration of therapy: participants with viral load <500 IU/mL at day 14 were treated with 12 weeks of SOF/DCV and those ≥500 IU/mL received 24 weeks. Primary endpoint was sustained virological response (SVR). RESULTS: Of 41 individuals with advanced fibrosis or compensated cirrhosis who commenced treatment, 51% had genotype 6a and 34% had 6e. The remainder had 6h, 6k, 6l, or 6o. One hundred percent had viral load <500 IU/mL by day 14, meaning that all received 12 weeks of SOF/DCV. One hundred percent achieved SVR12 despite a high frequency of putative NS5A inhibitor resistance-associated substitutions at baseline. CONCLUSIONS: Prescribing 12 weeks of SOF/DCV results in excellent cure rates in this population. These data support the removal of costly genotyping in countries where genotype 3 prevalence is <5%, in keeping with World Health Organization guidelines. NS5A resistance-associated mutations in isolation do not affect efficacy of SOF/DCV therapy. Wider evaluation of response-guided therapy is warranted.

Adaptive platform trials using multi-arm, multi-stage protocols: getting fast answers in pandemic settings.

Global health pandemics, such as coronavirus disease 2019 (COVID-19), require efficient and well-conducted trials to determine effective interventions, such as treatments and vaccinations. Early work focused on rapid sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), subsequent in-vitro and in-silico work, along with greater understanding of the different clinical phases of the infection, have helped identify a catalogue of potential therapeutic agents requiring assessment. In a pandemic, there is a need to quickly identify efficacious treatments, and reject those that are non-beneficial or even harmful, using randomised clinical trials. Whilst each potential treatment could be investigated across multiple, separate, competing two-arm trials, this is a very inefficient process. Despite the very large numbers of interventional trials for COVID-19, the vast majority have not used efficient trial designs. Well conducted, adaptive platform trials utilising a multi-arm multi-stage (MAMS) approach provide a solution to overcome limitations of traditional designs. The multi-arm element allows multiple different treatments to be investigated simultaneously against a shared, standard-of-care control arm. The multi-stage element uses interim analyses to assess accumulating data from the trial and ensure that only treatments showing promise continue to recruitment during the next stage of the trial. The ability to test many treatments at once and drop insufficiently active interventions significantly speeds up the rate at which answers can be achieved. This article provides an overview of the benefits of MAMS designs and successes of trials, which have used this approach to COVID-19. We also discuss international collaboration between trial teams, including prospective agreement to synthesise trial results, and identify the most effective interventions. We believe that international collaboration will help provide faster answers for patients, clinicians, and health care systems around the world, including for each further wave of COVID-19, and enable preparedness for future global health pandemics.

The design and statistical aspects of VIETNARMS: a strategic post-licensing trial of multiple oral direct-acting antiviral hepatitis C treatment strategies in Vietnam.

BACKGROUND: Eliminating hepatitis C is hampered by the costs of direct-acting antiviral treatment and the need to treat hard-to-reach populations. Access could be widened by shortening or simplifying treatment, but limited research means it is unclear which approaches could achieve sufficiently high cure rates to be acceptable. We present the statistical aspects of a multi-arm trial designed to test multiple strategies simultaneously and a monitoring mechanism to detect and stop individual randomly assigned groups with unacceptably low cure rates quickly. METHODS: The VIETNARMS trial will factorially randomly assign patients to two drug regimens, three treatment-shortening strategies or control, and adjunctive ribavirin or no adjunctive ribavirin with shortening strategies (14 randomly assigned groups). We will use Bayesian monitoring at interim analyses to detect and stop recruitment into unsuccessful strategies, defined by more than 0.95 posterior probability that the true cure rate is less than 90% for the individual randomly assigned group (non-comparative). Final comparisons will be non-inferiority for regimens (margin 5%) and strategies (margin 10%) and superiority for adjunctive ribavirin. Here, we tested the operating characteristics of the stopping guideline for individual randomly assigned groups, planned interim analysis timings and explored power at the final analysis. RESULTS: A beta (4.5, 0.5) prior for the true cure rate produces less than 0.05 probability of incorrectly stopping an individual randomly assigned group with a true cure rate of more than 90%. Groups with very low cure rates (<60%) are very likely (>0.9 probability) to stop after about 25% of patients are recruited. Groups with moderately low cure rates (80%) are likely to stop (0.7 probability) before overall recruitment finishes. Interim analyses 7, 10, 13 and 18 months after recruitment commences provide good probabilities of stopping inferior individual randomly assigned groups. For an overall true cure rate of 95%, power is more than 90% to confirm non-inferiority in the regimen and strategy comparisons, regardless of the control cure rate, and to detect a 5% absolute difference in the ribavirin comparison. CONCLUSIONS: The operating characteristics of the stopping guideline are appropriate, and interim analyses can be timed to detect individual randomly assigned groups that are highly likely to have suboptimal performance at various stages. Therefore, our design is suitable for evaluating treatment-shortening or -simplifying strategies. TRIAL REGISTRATION: ISRCTN registry: ISRCTN61522291. Registered on 4 October 2019.

No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV.

OBJECTIVE: Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy. DESIGN: Retrospective single-centre cohort. METHODS: Adults who switched to RAL or DTG before or between January 2015 and October 2017 were identified. Virologically suppressed, treatment-experienced (≥2 years) individuals, at least 6 months on INSTI, with weight measurements 2 years or less pre and postswitch were included. Our analysis used a random effects model with linear slope pre and post-INSTI with adjustment for age, sex, ethnicity, preswitch-regimen (protease inhibitor vs. nonprotease inhibitor), and RAL vs. DTG use. RESULTS: A total of 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and BMI at switch of 76.6 kg and 25.3 kg/m, respectively, were included. Weight increased by an average of 0.63 kg/year (95% confidence interval 0.17-1.09) preswitch with no overall change in rate of weight gain postswitch [+0.05 kg/year (-0.61-0.71, P = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain postswitch was isolated to older individuals though this lacked statistical significance [e.g., +1.59 kg/year (-0.26-3.45) if aged 65 years]. Our findings did not differ by sex, ethnicity, preswitch regimen, or RAL vs. DTG. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone. CONCLUSION: We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically suppressed individuals.