Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. ...Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.
To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.
Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).
National U.S. multicenter study.
Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.
Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.
Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.
Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 95% CI, 0.73 to 1.66;
> 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 16.2% versus 46 10.9%, respectively;
= 0.026).
The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.
This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.
Bill & Melinda Gates Foundation.
Randomized clinical trials of oral antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention have widely divergent efficacy estimates, ranging from 0% to 75%. These discrepancies are likely ...due to differences in adherence. To our knowledge, no studies to date have examined the impact of improving adherence through monitoring and/or intervention, which may increase PrEP efficacy, or reported on objective behavioral measures of adherence, which can inform PrEP effectiveness and implementation.
Within the Partners PrEP Study (a randomized placebo-controlled trial of oral tenofovir and emtricitabine/tenofovir among HIV-uninfected members of serodiscordant couples in Kenya and Uganda), we collected objective measures of PrEP adherence using unannounced home-based pill counts and electronic pill bottle monitoring. Participants received individual and couples-based adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell to <80%. Participants were followed monthly to provide study medication, adherence counseling, and HIV testing. A total of 1,147 HIV-uninfected participants were enrolled: 53% were male, median age was 34 years, and median partnership duration was 8.5 years. Fourteen HIV infections occurred among adherence study participants--all of whom were assigned to placebo (PrEP efficacy = 100%, 95% confidence interval 83.7%-100%, p<0.001). Median adherence was 99.1% (interquartile range IQR 96.9%-100%) by unannounced pill counts and 97.2% (90.6%-100%) by electronic monitoring over 807 person-years. Report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use were associated with <80% adherence; the first 6 months of PrEP use and polygamous marriage were associated with >80% adherence. Study limitations include potential shortcomings of the adherence measures and use of a convenience sample within the substudy cohort.
The high PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high degree of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. Low PrEP adherence was associated with sexual behavior, alcohol use, younger age, and length of PrEP use. Please see later in the article for the Editors' Summary.
Community-based delivery of antiretroviral therapy (ART) for HIV, including ART initiation, clinical and laboratory monitoring, and refills, could reduce barriers to treatment and improve viral ...suppression, reducing the gap in access to care for individuals who have detectable HIV viral load, including men who are less likely than women to be virally suppressed. We aimed to test the effect of community-based ART delivery on viral suppression among people living with HIV not on ART.
We did a household-randomised, unblinded trial (DO ART) of delivery of ART in the community compared with the clinic in rural and peri-urban settings in KwaZulu-Natal, South Africa and the Sheema District, Uganda. After community-based HIV testing, people living with HIV were randomly assigned (1:1:1) with mobile phone software to community-based ART initiation with quarterly monitoring and ART refills through mobile vans; ART initiation at the clinic followed by mobile van monitoring and refills (hybrid approach); or standard clinic ART initiation and refills. The primary outcome was HIV viral suppression at 12 months. If the difference in viral suppression was not superior between study groups, an a-priori test for non-inferiority was done to test for a relative risk (RR) of more than 0·95. The cost per person virally suppressed was a co-primary outcome of the study. This study is registered with ClinicalTrials.gov, NCT02929992.
Between May 26, 2016, and March 28, 2019, of 2479 assessed for eligibility, 1315 people living with HIV and not on ART with detectable viral load at baseline were randomly assigned; 666 (51%) were men. Retention at the month 12 visit was 95% (n=1253). At 12 months, community-based ART increased viral suppression compared with the clinic group (306 74% vs 269 63%, RR 1·18, 95% CI 1·07–1·29; psuperiority=0·0005) and the hybrid approach was non-inferior (282 68% vs 269 63%, RR 1·08, 0·98–1·19; pnon-inferiority=0·0049). Community-based ART increased viral suppression among men (73%, RR 1·34, 95% CI 1·16–1·55; psuperiority<0·0001) as did the hybrid approach (66%, RR 1·19, 1·02–1·40; psuperiority=0·026), compared with clinic-based ART (54%). Viral suppression was similar for men (n=156 73%) and women (n=150 75%) in the community-based ART group. With efficient scale-up, community-based ART could cost US$275–452 per person reaching viral suppression. Community-based ART was considered safe, with few adverse events.
In high and medium HIV prevalence settings in South Africa and Uganda, community-based delivery of ART significantly increased viral suppression compared with clinic-based ART, particularly among men, eliminating disparities in viral suppression by gender. Community-based ART should be implemented and evaluated in different contexts for people with detectable viral load.
The Bill & Melinda Gates Foundation; the University of Washington and Fred Hutch Center for AIDS Research; the Wellcome Trust; the University of Washington Royalty Research Fund; and the University of Washington King K Holmes Endowed Professorship in STDs and AIDS.
Abstract
Background
Bacterial vaginosis (BV) treatment failures and recurrences are common. To identify features associated with treatment response, we compared vaginal microbiota and host ...ectocervical transcriptome before and after oral metronidazole therapy.
Methods
Women with BV (Bronx, New York and Thika, Kenya) received 7 days of oral metronidazole at enrollment (day 0) and underwent genital tract sampling of microbiome (16S ribosomal RNA gene sequencing), transcriptome (RNAseq), and immune mediator concentrations on day 0, 15, and 35.
Results
Bronx participants were more likely than Thika participants to clinically respond to metronidazole (19/20 vs 10/18, respectively, P = .0067) and by changes in microbiota composition and diversity. After dichotomizing the cohort into responders and nonresponders by change in α-diversity between day 35 and day 0, we identified that transcription differences associated with chemokine signaling (q = 0.002) and immune system process (q = 2.5 × 10–8) that differentiated responders from nonresponders were present at enrollment. Responders had significantly lower levels of CXCL9 in cervicovaginal lavage on day 0 (P < .007), and concentrations of CXCL9, CXCL10, and monocyte chemoattractant protein 1 increased significantly between day 0 and day 35 in responders vs nonresponders.
Conclusions
Response to metronidazole is characterized by significant changes in chemokines and related transcripts, suggesting that treatments that promote these pathways may prove beneficial.
Clinical response to oral metronidazole treatment for bacterial vaginosis was more common among women in the Bronx, New York, compared to Thika, Kenya. Favorable response was characterized by microbiota changes, increases in chemokine signaling pathways, and chemokine concentrations in cervicovaginal secretions.
Since rapid cryptococcal antigen lateral flow assays (CrAg LFA) may expedite treatment of HIV-associated cryptococcal infections, we sought to validate clinic-based CrAg LFA testing. Among ...newly-diagnosed HIV-infected adults in South Africa, a trained nurse performed clinic-based testing of urine, fingerprick capillary and venous whole blood with rapid CrAg LFA (Immy Diagnostics, Norman, USA). We performed matched laboratory-based serum cryptococcal antigen testing with an enzyme immunoassay (EIA). We assessed diagnostic accuracy using EIA as the gold-standard, and performed additional validation testing on serum and among hospitalized adults with cryptococcal meningitis. Among 5,618 participants enrolled, 1,296 were HIV-infected and screened for cryptococcal antigenemia. Overall CrAg prevalence by serum EIA was 3.6% (95% CI 2.0-6.0%) for adults with CD4 < 200 cells/mm
, and 5.7% (95% CI 2.8-10.2%) for adults with CD4 < 100 cells/mm
. Using expanded screening guidelines (CD4 < 200 cells/mm
), CrAg LFA testing of venous whole blood, fingerprick capillary blood, and urine had diagnostic sensitivities of 46% (95% CI 19-75%), 38% (95% CI 14-68%), and 54% (95% CI 25-81%), and specificities of 97%, 97%, and 86%, respectively. When tested on serum samples, CrAg LFA had sensitivity of 93% (95% CI 66-100%) and specificity of 100% (95% CI 88-100%). All venous and fingerprick whole blood CrAg LFA tests were positive among 30 hospitalized adults with cryptococcal meningitis. Two independent readers had strong agreement for all LFA results (p < 0.0001). When performed at the point-of-care by trained nurses, CrAg LFA testing was feasible, had the highest accuracy on serum specimens, and may accelerate treatment of HIV-associated cryptococcal infections.
Cryptococcosis remains a leading cause of meningitis and mortality among people living with HIV (PLHIV) worldwide. We sought to evaluate laboratory-based cryptococcal antigen (CrAg) reflex testing ...and a clinic-based point-of-care (POC) CrAg screening intervention for preventing meningitis and mortality among PLHIV in South Africa.
We conducted a prospective pre-post intervention study of adults presenting for HIV testing in Umlazi Township, South Africa over a six-year period (2013-2019). Participants were enrolled during three phases of CrAg testing - CrAg testing ordered by a clinician ("Clinician-directed testing"; 2013-2015); routine lab-based CrAg reflex testing for blood samples with CD4 ≤100 cells/mm3 ("Lab reflex testing"; 2015-2017), and a clinic-based intervention with POC CD4 testing and POC CrAg testing for PLHIV with CD4 ≤200 cells/mm3 with continued standard-of-care routine lab-reflex testing among those with CD4 ≤100 cells/mm3 ("Clinic-based testing"; 2017-2019). The laboratory and clinical teams performed serum CrAg by enzyme immunoassay and lateral flow assay (Immy Diagnostics, Norman, USA). We followed participants for up to 14 months to compare associations between baseline CrAg positivity, ART and fluconazole treatment initiation, and outcomes of cryptococcal meningitis, hospitalization and mortality.
3,105 (39.4%) of 7,877 people screened were HIV-positive, of whom 908 had CD4 ≤200 cells/mm3 and were included in analyses. Lab reflex and clinic-based testing increased CrAg screening (p<0.001) and diagnosis of CrAg-positive PLHIV (p=0.011). As compared to clinician-directed testing, clinic-based CrAg testing increased the number of PLHIV diagnosed with cryptococcal meningitis (4.5% compared to 1.5%; p=0.059), initiation of fluconazole pre-emptive therapy (7.2% compared to 2.5%; p=0.010), and initiation of ART (96.8% compared to 91.3%; p=0.012). Comparing clinic-based testing to lab reflex testing, there was no significant difference in the cumulative incidence of cryptococcal meningitis (4.5% compared to 4.1%; p=0.836) or mortality (8.1% compared to 9.9%; p=0.557).
Lab reflex and clinic-based CrAg testing facilitated diagnosis of HIV-associated cryptococcosis and fluconazole initiation, but did not reduce cryptococcal meningitis or mortality. In this non-randomized cohort, clinical outcomes were similar between lab reflex testing and clinic-based point-of-care CrAg testing.
Accurate reporting of antiretroviral therapy (ART) uptake is crucial for measuring the success of epidemic control. Programs without linked electronic medical records are susceptible to duplicating ...ART initiation events. We assessed the prevalence of undisclosed ART use at the time of treatment initiation and explored its correlates among people presenting to public ambulatory clinics in South Africa. Data were analyzed from the community-based delivery of ART (DO ART) clinical trial, which recruited people living with HIV who presented for ART initiation at two clinics in rural South Africa. We collected data on socioeconomic factors, clinical factors, and collected blood as part of study screening procedures. We estimated the proportion of individuals presenting for ART initiation with viral load suppression (< 20 copies/mL) and fitted regression models to identify social and clinical correlates of non-disclosure of ART use. We also explored clinical and national databases to identify records of ART use. Finally, to confirm surreptitious ART use, we measured tenofovir (TDF) and emtricitabine (FTC) levels in dried blood spots. A total of 193 people were screened at the two clinics. Approximately 60% (n = 114) were female, 40% (n = 78) reported a prior HIV test, 23% (n = 44) had disclosed to a partner, and 31% (n = 61) had a partner with HIV. We found that 32% (n = 62) of individuals presenting for ART initiation or re-initiation had an undetectable viral load. In multivariable regression models, female sex (AOR 2.16, 95% CI 1.08–4.30), having a prior HIV test and having disclosed their HIV status (AOR 2.48, 95% CI 1.13–5.46), and having a partner with HIV (AOR 1.94, 95% CI 0.95–3.96) were associated with having an undetectable viral load. In records we reviewed, we found evidence of ART use from either clinical or laboratory databases in 68% (42/62) and detected either TDF or FTC in 60% (37/62) of individuals with an undetectable viral load. Undisclosed ART use was present in approximately one in three individuals presenting for ART initiation or re-initiation at ambulatory HIV clinics in South Africa. These results have important implications for ART resource use and planning in the region. A better understanding of reasons for non-disclosure of ART at primary health care clinics in such settings is needed.
Guidelines recommend integrating hypertension screening for HIV-infected adults, but blood pressure measurements may be dynamic around the time of HIV testing.
We measured a seated resting blood ...pressure in adults (≥18 years) prior to HIV testing, and again after receiving HIV test results, in an ambulatory HIV clinic in KwaZulu-Natal, South Africa. We assessed sociodemographics, smoking, body mass index, diabetes, substance abuse, and anxiety/depression. We used blood pressure categories defined by the Seventh Joint National Committee (JNC 7) classifications, which includes normal, pre-hypertension, stage 1 hypertension, and stage 2 hypertension.
Among 5,428 adults, mean age was 31 years, 51% were male, and 35% tested HIV-positive. Before HIV testing, 47% (2,634) had a normal blood pressure, 40% (2,225) had prehypertension, and 10% (569) had stage 1 or 2 hypertension. HIV-infected adults had significantly lower blood pressure measurements and less hypertension, as compared to HIV-negative adults before HIV testing; while also having significantly elevated blood pressures after HIV testing. In a multivariable model, HIV-infected adults had a 30% lower odds of hypertension, compared to HIV-uninfected adults (aOR = 0.70, 95% CI: 0.57-0.85). In a separate multivariable model, HIV-infected adults with CD4 ≤200 cells/mm3 had a 44% lower odds of hypertension (aOR = 0.56, 95% CI: 0.38-0.83), as compared to adults with CD4 >200 cells/mm3. The mean arterial blood pressure was 6.5 mmHg higher among HIV-infected adults after HIV testing (p <0.001).
HIV-infected adults experienced a transient blood pressure increase after receiving HIV results. Blood pressure measurements may be more accurate before HIV testing and repeated blood pressure measurements are recommended after ART initiation before formally diagnosing hypertension in HIV-infected adults.
Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)‐approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal ...mechanism of action and a well‐established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID‐19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease‐related consequences of SARS‐CoV‐2 infection/COVID‐19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS‐CoV‐2 infection/COVID‐19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS‐CoV‐2(−)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS‐CoV‐2(−)/(+)participants, and incorporating COVID‐19‐associated changes in cytochrome P450 activity did not further improve model performance for the SARS‐CoV‐2(+) population.
Introduction
Among people living with HIV in South Africa, viral suppression is lower among men than women. The study aim was to test the impact of lottery incentives, which reward positive health ...choice (e.g. antiretroviral therapy (ART) linkage) with a chance to win a prize, on strengthening the HIV care continuum including ART initiation and viral suppression for men.
Methods
We conducted a randomized, prospective trial of lottery incentives in the context of HIV testing and linkage to ART in rural KwaZulu‐Natal, South Africa. Men living with HIV were randomly allocated to: lottery incentives and motivational text messages or motivational text messages only. Lottery prize eligibility was conditional on clinic registration, ART initiation, or viral suppression by one, three and six months respectively. After completing each continuum step, participants in the lottery group were notified whether they had won and were encouraged to continue in care. Lottery prizes were either a mobile phone, data or a gift card (valued at R1000/$100). Kaplan–Meier curves were plotted to determine time to ART initiation by study group. The primary outcome was viral suppression at six months.
Results
Between November 2017 and December 2018, we tested 740 men for HIV and enrolled 131 HIV‐positive men who reported not being on ART. At baseline, 100 (76%) participants were 30 years and older, 95 (73%) were unemployed and the median CD4 count was 472 cells/μL. At study exit, 84% (110/131) of participants had visited a clinic and 62% (81/131) were virally suppressed. Compared to motivational text messages, lottery incentives decreased the median time to ART initiation from 126 to 66 days (p = 0.0043, age‐adjusted Cox regression) among all participants, and, from 134 days to 20 days (p = 0.0077) among participants who were not virally suppressed at baseline. Lottery incentives had an inconclusive effect on clinic registration (RR = 1.21, 95% CI: 0.83 to 1.76) and on viral suppression at six months (RR = 1.13, 95% CI: 0.73 to 1.75) compared to motivational text messages.
Conclusions
Conditional lottery incentives shortened the time to ART initiation among South African men. Behavioural economics strategies strengthen linkage to ART, but the study power was limited to see an impact on viral suppression.
Clinical Trial Number
NCT03808194.
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