To compare the gender distribution of clinical trial leadership in coronavirus disease 2019 (COVID-19) clinical trials.
We searched https://clinicaltrials.gov/ and retrieved all clinical trials on ...COVID-19 from 1 January 2020 to 26 June 2020. As a comparator group, we have chosen two fields that are not related to emerging infections and infectious diseases: and considered not directly affected by the pandemic: breast cancer and type 2 diabetes mellitus (T2DM) and included studies within the aforementioned study period as well as those registered in the preceding year (pre-study period: 1 January 2019 to 31 December 2019). Gender of the investigator was predicted using the genderize.io application programming interface. The repository of the data sets used to collect and analyse the data are available at https://osf.io/k2r57/.
Only 27.8% (430/1548) of principal investigators among COVID-19-related studies were women, which is significantly different compared with 54.9% (156/284) and 42.1% (56/133) for breast cancer (p < 0.005) and T2DM (p < 0.005) trials over the same period, respectively. During the pre-study period, the proportion of principal investigators who were predicted to be women were 49.7% (245/493) and 44.4% (148/333) for breast cancer and T2DM trials, respectively, and the difference was not statistically significant when compared with results from the study period (p > 0.05).
We demonstrate that less than one-third of COVID-19-related clinical trials are led by women, half the proportion observed in non-COVID-19 trials over the same period, which remained similar to the pre-study period. These gender disparities during the pandemic may not only indicate a lack of female leadership in international clinical trials and involvement in new projects but also reveal imbalances in women's access to research activities and funding during health emergencies.
We sought to identify factors associated with weight gain in randomized clinical trials of antiretroviral therapy (ART) switch.
We explored the effects of demographic factors, clinical ...characteristics, and ART on weight gain in a pooled analysis of 12 prospective clinical trials, wherein virologically suppressed people living with human immunodeficiency virus (PWH) were randomized to switch or remain on a stable baseline regimen (SBR).
Both PWH randomized to switch ART (n = 4166) and those remaining on SBR (n = 3150) gained weight. Median weight gain was greater in those who switched (1.6 kg, interquartile range IQR, -.05 to 4.0 vs 0.4 kg, IQR, -1.8 to 2.4 at 48 weeks, P < .0001), with most weight gain occurring in the first 24 weeks after switch. Among baseline demographic and clinical characteristics, only younger age and lower baseline body mass index were associated with any or ≥10% weight gain. By week 48, 4.6% gained ≥10% weight (6.4% of switch and 2.2% of SBR), the greatest risk was with switch from efavirenz (EFV) to rilpivirine (RPV) or elvitegravir/cobicistat and switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). Switch from abacavir to TAF was associated with less weight gain than switch from TDF to TAF and was not associated with increased risk for ≥10% weight gain.
Moderate weight gain after ART switch was common and usually plateaued by 48 weeks. Baseline ART was a predictor of post-switch weight gain; participants who switched off of EFV and TDF had the greatest weight gain. The biological mechanisms that underlie the differential effects of switching ART agents on weight and associated clinical implications require further study.
OBJECTIVE:Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, ...the comparative incidence of clinically significant renal events remains unclear.
DESIGN:We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes.
METHODS:We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios).
RESULTS:Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy.
CONCLUSION:These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.
In this randomized pilot clinical trial, dolutegravir plus lamivudine was noninferior to continuation of standard 3-drug maintenance antiretroviral therapy. There was no emergence of drug resistance ...in the participant who experienced virologic failure while receiving dolutegravir plus lamivudine.
Background. AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human ...immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥10⁵ copies/mL). Due to higher virologie failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients. Methods. Primary endpoints were times to virologie failure, regimen modification, and safety event. Results. In the low HIV RNA stratum, time to virologie failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio HR 1.25, 95% confidence interval CI 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologie failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14). Conclusions. In the low HIV RNA stratum, times to virologie failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologie failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.
In 2 double-blind phase 3 trials, 1733 antiretroviral-naive adults were randomized to tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), each coformulated with ...elvitegravir/cobicistat/emtricitabine (E/C/F). At 144 weeks, TAF was superior to TDF in virologic efficacy, with 84.2% vs 80.0% having HIV-1 RNA <50 copies/mL (difference 4.2%; 95% confidence interval0.6% to 7.8%). TAF had less impact than TDF on bone mineral density and renal biomarkers. No participants on TAF had renal-related discontinuations vs 12 on TDF (P < 0.001), with no cases of proximal tubulopathy for TAF vs 4 for TDF. There were greater increases in lipids with TAF vs TDF, with no difference in the total cholesterol to high-density lipoprotein ratio. For initial HIV therapy, E/C/F/TAF is superior to E/C/F/TDF in efficacy and bone and renal safety.
Background. Recommended human immunodeficiency virus (HIV) treatment regimens in the United States contain 3 antiretroviral agents, costing >$30 000/person/year. Pilot studies are evaluating the ...efficacy of dual therapy with dolutegravir (DTG) and lamivudine (3TC). We examined the potential cost-effectiveness and budget impact of DTG + 3TC regimens in the United States. Methods. Using a mathematical model, we projected the clinical and economic outcomes of antiretroviral therapy (ART)–naive patients under 4 strategies: (1) no ART (for modeling comparison); (2) 2-drug: initial regimen of DTG + 3TC; (3) induction-maintenance: 48-week induction regimen of 3 drugs (DTG/abacavir ABC/3TC), followed by DTG + 3TC maintenance if virologically suppressed; and (4) standard of care: 3-drug regimen of DTG/ABC/3TC. Strategy-dependent model inputs, varied widely in sensitivity analyses, included 48-week virologic suppression (88%–93%), subsequent virologic failure (0.1%–0.6%/month), and Medicaid-discounted ART costs ($15 200–$39 600/year). A strategy was considered cost-effective if its incremental cost-effectiveness ratio (ICER) was <$100 000/quality-adjusted life-year (QALY). Results. The 3 ART strategies had the same 5-year survival rates (90%). The ICER was $22 500/QALY for induction-maintenance and >$500 000/QALY for standard of care. Two-drug was the preferred strategy only when DTG + 3TC 48-week virologic suppression rate exceeded 90%. With 50% uptake of either induction-maintenance or 2-drug for ART-naive patients, cost savings totaled $550 million and $800 million, respectively, within 5 years; savings reached >$3 billion if 25% of currently suppressed patients were switched to DTG + 3TC maintenance. Conclusions. Should DTG + 3TC demonstrate high rates of virologic suppression, this regimen will be cost-effective and would save >$500 million in ART costs in the United States over 5 years.
The relationship between efavirenz use and suicidality is not well-defined.
To compare time to suicidality with efavirenz-containing versus efavirenz-free antiretroviral regimens for initial ...treatment of HIV.
Participant-level data were analyzed from 4 AIDS Clinical Trials Group, antiretroviral-naive studies conducted from 2001 to 2010. Within each study, participants were randomly assigned to an efavirenz-containing (n = 3241) or efavirenz-free (n = 2091) regimen. (ClinicalTrials.gov: NCT00013520 A5095, NCT00050895 A5142, NCT00084136 A5175, and NCT00118898 A5202).
AIDS Clinical Trials Group sites; 74% of participants enrolled in the United States.
Antiretroviral-naive participants.
Efavirenz versus efavirenz-free regimens.
Suicidality was defined as suicidal ideation or attempted or completed suicide. Groups were compared with a hazard ratio and 95% CI estimated from a Cox model, stratified by study.
Seventy-three percent of participants were men, the median age was 37 years, and 32% had documented psychiatric history or received psychoactive medication within 30 days before entering the study. Median follow-up was 96 weeks. Suicidality incidence per 1000 person-years was 8.08 (47 events) in the efavirenz group and 3.66 (15 events) in the efavirenz-free group (hazard ratio, 2.28 95% CI, 1.27 to 4.10; P = 0.006). Incidence of attempted or completed suicide was 2.90 (17 events) and 1.22 (5 events) in the efavirenz and efavirenz-free groups, respectively (hazard ratio, 2.58 CI, 0.94 to 7.06; P = 0.065). Eight suicides in the efavirenz group and 1 in the efavirenz-free group were reported.
There was not a standardized questionnaire about suicidal ideation or attempt. Efavirenz was open-label in 3 of 4 studies.
Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a 2-fold increased hazard of suicidality compared with a regimen without efavirenz.
National Institutes of Health.
Limited data exist on initial human immunodeficiency virus type 1 (HIV-1) treatment with dolutegravir plus lamivudine.
A5353 is a phase 2, single-arm, pilot study of once-daily dolutegravir (50 mg) ...plus lamivudine (300 mg) in treatment-naive participants with HIV-1 RNA ≥1000 and <500000 copies/mL. Exclusion criteria included active hepatitis B or major protease, reverse transcriptase, or integrase resistance. The primary efficacy measure was the proportion with HIV-1 RNA <50 copies/mL (FDA US Food and Drug Administration Snapshot) at week 24. Virologic failure (VF) was confirmed HIV-1 RNA >400 copies/mL at week 16/20 or >200 copies/mL at or after week 24. Dolutegravir levels and drug resistance testing were performed at VF.
One hundred and twenty participants (87% male, median age 30 years, 37 (31%) HIV-1 RNA >100000 copies/mL) initiated study treatment. Median entry HIV-1 RNA and CD4 count were 4.61 log10 copies/mL and 387 cells/mm3. Virologic efficacy at week 24 was 108/120 (90%, confidence interval 83%, 95%), with comparable results in the >100000 copies/mL and ≤100000 copies/mL strata, that is, 89% (75%, 97%) and 90% (82%, 96%), respectively. Three participants with VF, had undetected plasma dolutegravir at ≥1 time points; the M184V and R263R/K mutations developed in 1 participant. Two participants experienced grade 3 possible/probable treatment-related adverse events; none discontinued treatment due to adverse events.
Dolutegravir plus lamivudine demonstrated efficacy in individuals with pretreatment HIV-1 RNA up to 500000 copies/mL in this pilot trial, but a participant developed resistance mutations.
NCT02582684.
PDF
