Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial.

BACKGROUND: 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. OBJECTIVE: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection. DESIGN: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961). SETTING: National U.S. multicenter study. PARTICIPANTS: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection. INTERVENTION: 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. MEASUREMENTS: 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. RESULTS: 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]; P > 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; P = 0.026). LIMITATION: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days. CONCLUSION: 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. PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.

Differences in Vaginal Microbiota, Host Transcriptome, and Proteins in Women With Bacterial Vaginosis Are Associated With Metronidazole Treatment Response.

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.

Undisclosed Antiretroviral Therapy Use at Primary Health Care Clinics in Rural KwaZulu Natal South Africa: A DO-ART Trial Sub-study.

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.

Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.

BACKGROUND: Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. METHODS: We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. RESULTS: We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS: Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

Adherence to antiretroviral prophylaxis for HIV prevention: a substudy cohort within a clinical trial of serodiscordant couples in East Africa.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

Population health impact, cost-effectiveness, and affordability of community-based HIV treatment and monitoring in South Africa: A health economics modelling study.

Community-based delivery and monitoring of antiretroviral therapy (ART) for HIV has the potential to increase viral suppression for individual- and population-level health benefits. However, the cost-effectiveness and budget impact are needed for public health policy. We used a mathematical model of HIV transmission in KwaZulu-Natal, South Africa, to estimate population prevalence, incidence, mortality, and disability-adjusted life-years (DALYs) from 2020 to 2060 for two scenarios: 1) standard clinic-based HIV care and 2) five-yearly home testing campaigns with community ART for people not reached by clinic-based care. We parameterised model scenarios using observed community-based ART efficacy. Using a health system perspective, we evaluated incremental cost-effectiveness and net health benefits using a threshold of $750/DALY averted. In a sensitivity analysis, we varied the discount rate; time horizon; costs for clinic and community ART, hospitalisation, and testing; and the proportion of the population receiving community ART. Uncertainty ranges (URs) were estimated across 25 best-fitting parameter sets. By 2060, community ART following home testing averted 27.9% (UR: 24.3-31.5) of incident HIV infections, 27.8% (26.8-28.8) of HIV-related deaths, and 18.7% (17.9-19.7) of DALYs compared to standard of care. Adolescent girls and young women aged 15-24 years experienced the greatest reduction in incident HIV (30.7%, 27.1-34.7). In the first five years (2020-2024), community ART required an additional $44.9 million (35.8-50.1) annually, representing 14.3% (11.4-16.0) of the annual HIV budget. The cost per DALY averted was $102 (85-117) for community ART compared with standard of care. Providing six-monthly refills instead of quarterly refills further increased cost-effectiveness to $78.5 per DALY averted (62.9-92.8). Cost-effectiveness was robust to sensitivity analyses. In a high-prevalence setting, scale-up of decentralised ART dispensing and monitoring can provide large population health benefits and is cost-effective in preventing death and disability due to HIV.

A linked physiologically based pharmacokinetic model for hydroxychloroquine and metabolite desethylhydroxychloroquine in SARS-CoV-2(-)/(+) populations.

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.

Secondary Distribution of HIV Self-Testing Kits to Social and Sexual Networks of PLWH in KwaZulu-Natal, South Africa. A Brief Report.

Background: To reach 95% of persons living with HIV (PLWH) knowing their HIV status, alternative testing approaches such as HIV self-testing (HIVST) and secondary HIVST kit distribution are needed. We investigated if secondary HIVST kit distribution from male and female PLWH in South Africa would successfully lead to their contacts testing for HIV and linking to care if positive. Methods: Male and female PLWH participating in an HIV treatment trial between July and November 2018 in KwaZulu-Natal, South Africa were offered participation as "HIVST kit distributors" in a pilot of secondary distribution of HIVST kits to give to sexual partners and social networks. Univariate descriptive statistics were used to describe the characteristics of volunteer distributors, proportion of HIVST recipients who reported their results, and linkage to care among those who tested positive using HIVST were assessed. Results: Sixty-three participant kit distributors accepted kits to disperse to contacts, of whom 52% were female, median age was 34 years (IQR 26-42.5), 84% reported 1 sexual partner and 76% did not know their partner's HIV status. HIVST kit distributors took 218 kits, with 13/218 (6%) of kits reported to be intended to be given to a sexual partner. A total of 143 HIVST recipients reported their HIVST results; 92% reported their results were negative, 11 recipients reported positive results and 1 HIVST-positive recipient was linked to HIV care. Conclusion: Secondary distribution of HIVST to social networks and sexual partners from South African PLWH is feasible, with two thirds of contacts reporting use of the HIVST kits. Additional support is necessary to facilitate linkage to care.

Fee for home delivery and monitoring of antiretroviral therapy for HIV infection compared with standard clinic-based services in South Africa: a randomised controlled trial.

BACKGROUND: Home delivery and monitoring of antiretroviral therapy (ART) is convenient, overcomes logistical barriers, and could increase individual ART adherence and viral suppression. With client payment and sufficient health benefits, this strategy could be scalable. The aim of the Deliver Health Study was to test the acceptability and efficacy of a user fee for home ART monitoring and delivery. METHODS: We conducted a randomised trial, the Deliver Health Study, of a fee for home delivery of ART compared with free clinic ART delivery in South Africa. People with HIV who were 18 years or older and clinically stable (including CD4 count >100 cells per µL and WHO HIV stage 1-3) were randomly assigned to: (1) fee for home delivery and monitoring of ART, including community ART initiation if needed; or (2) clinic-based ART (standard of care). The one-time fee for home delivery (ZAR 30, 60, and 90; equivalent to US$2, 4, 6) was tiered on the basis of participant income. The primary outcomes were recorded fee payment and acceptability assessed via questionnaire. The key virological secondary outcome was viral suppression with the difference between study groups assessed through robust Poisson regression including participants with viral load measured at exit (modified intention-to-treat analysis). This trial is registered on ClinicalTrials.gov (NCT04027153) and is complete, with analyses ongoing. FINDINGS: From Oct 7, 2019, to Jan 30, 2020, 162 participants were enrolled; 82 were randomly assigned to the fee for home delivery group and 80 to the clinic-based group, with similar characteristics at baseline. Overall, 87 (54%) participants were men, 101 (62%) were on ART, and 98 (60%) were unemployed. In the home delivery group, 40 (49%), 33 (40%), and nine (11%) participants qualified for the ZAR 30, 60, and 90 fee, respectively. Median follow-up was 47 weeks (IQR 43-50) with 96% retention. 80 (98%) participants paid the user fee, with high acceptability and willingness to pay. In the modified intention-to-treat analysis of 155 (96%) participants who completed follow-up, fee for home delivery and monitoring statistically significantly increased viral suppression from 74% to 88% overall (RR 1·21, 95% CI 1·02-1·42); and from 64% to 84% among men (1·31, 1·01-1·71). INTERPRETATION: Among South African adults with HIV, a fee for home delivery and monitoring of ART significantly increased viral suppression compared with clinic-based ART. Clients' paying a fee for home delivery and monitoring of ART was highly acceptable in the context of low income and high unemployment, and improved health outcomes as a result. Home ART delivery and monitoring, potentially with a user fee to offset costs, should be evaluated as a differentiated service delivery strategy to increase access to care. FUNDING: National Institutes of Mental Health.

Comparison of Racial, Ethnic, and Geographic Location Diversity of Participants Enrolled in Clinic-Based vs 2 Remote COVID-19 Clinical Trials.

Importance: Racial and ethnic diversity among study participants is associated with improved generalizability of clinical trial results and may address inequities in evidence that informs public health strategies. Novel strategies are needed for equitable access and recruitment of diverse clinical trial populations. Objective: To investigate demographic and geographical location data for participants in 2 remote COVID-19 clinical trials with online recruitment and compare with those of a contemporaneous clinic-based COVID-19 study. Design, Setting, and Participants: This cohort study was conducted using data from 3 completed, prospective randomized clinical trials conducted at the same time: 2 remotely conducted studies (the Early Treatment Study and Hydroxychloroquine COVID-19 Postexposure Prophylaxis [PEP] Study) and 1 clinic-based study of convalescent plasma (the Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study). Data were collected from March to August 2020 with 1 to 28 days of participant follow-up. All studies had clinical sites in Seattle, Washington; the 2 remote trials also had collaborating sites in New York, New York; Syracuse, New York; Baltimore, Maryland; Boston, Massachusetts; Chicago, Illinois; New Orleans, Louisiana; and Los Angeles, California. Two remote trials with inclusive social media strategies enrolled 929 participants with recent SARS-CoV-2 exposure (Hydroxychloroquine COVID-19 PEP Trial) and 231 participants with COVID-19 infection (Early Treatment Study); the clinic-based Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study enrolled 250 participants with recent COVID-19 infection. Data were analyzed from April to August 2021. Interventions: Remote trials used inclusive social media strategies and clinician referral for recruitment and telehealth, courier deliveries, and self-collected nasal swabs for remotely conducted study visits. For the clinic-based study, participants were recruited via clinician referral and attended in-person visits. Main Outcomes and Measures: Google Analytics data were used to measure online participant engagement and recruitment. Participant demographics and geographical location data from remote trials were pooled and compared with those of the clinic-based study. Statistical comparison of demographic data was limited to participants with COVID infections (ie, those in the remotely conducted Early Treatment Study vs those in the clinic-based study) to improve accuracy of comparison given that the Hydroxychloroquine COVID-19 PEP Trial enrolled participants with COVID-19 exposures and thus had different enrollment criteria. Results: A total of 1410 participants were included. Among 1160 participants in remote trials and 250 participants in the clinic-based trial, the mean (range) age of participants was 39 (18-80) years vs 50 (19-79) years and 676 individuals (58.3%) vs 131 individuals (52.4%) reported female sex. The Early Treatment Study with inclusive social media strategies enrolled 231 participants in 41 US states with increased rates of racial, ethnic, and geographic diversity compared with participants in the clinic-based study. Among 228 participants in the remotely conducted Early Treatment Study with race data vs participants in the clinic-based study, 39 individuals (17.1%) vs 1 individual (0.4%) identified as Alaska Native or American Indian, 11 individuals (4.8%) vs 22 individuals (8.8%) identified as Asian, 26 individuals (11.4%) vs 4 individuals (1.6%) identified as Black, 3 individuals (1.3%) vs 1 individual identified as Native Hawaiian or Pacific Islander, 117 individuals (51.3%) vs 214 individuals (85.6%) identified as White, and 32 individuals (14.0%) vs 8 individuals (3.2%) identified as other race (P < .001). Among 230 individuals in the Early Treatment Study vs 236 individuals in the clinic-based trial with ethnicity data, 71 individuals (30.9%) vs 11 individuals (4.7%) identified as Hispanic or Latinx (P<.001). There were 29 individuals in the Early Treatment Study with nonurban residences (ie, rural, small town, or peri-urban; 12.6%) vs 6 of 248 individuals in the clinic-based trial with residence data (2.4%) (P < .001). In remote trial online recruitment, the highest engagement was with advertisements on social media platforms; among 125 147 unique users with age demographics who clicked on online recruitment advertisements, 84 188 individuals (67.3%) engaged via Facebook. Conclusions and Relevance: These findings suggest that remote clinical trials with online advertising may be considered as a strategy to improve diversity among clinical trial participants.

Implementation of HIV Self-Testing to Reach Men in Rural uMkhanyakude, KwaZulu-Natal, South Africa. a DO-ART Trial Sub Study.

Background: KwaZulu-Natal, South Africa has one of the highest HIV prevalence rates globally. Persons <35 years and men have lower rates of HIV testing. HIV self-testing (HIVST) may overcome many barriers of facility-based HIV testing in order to identify HIV positive young persons and men and link them to care. We investigated whether HIVST distribution was a feasible approach to reach men and assessed the proportion of participants who reported their HIVST results, tested positive and linked to care. Methods: Teams comprised of a nurse, clinic research assistant, and recruiters distributed HIVST kits in rural uMkhanyakude, KwaZulu-Natal from August-November 2018 with a focus on testing men. Workplaces (farms), social venues, taxi ranks, and homesteads were used as HIVST kit distribution points following community sensitisation through community advisory boards and community leaders. HIVST kits, demonstration of use, and small incentives to report testing outcomes were provided. The Department of Health provided confirmatory testing and HIV care at clinics. Results: Over 11 weeks in late 2018, we distributed 2,634 HIVST kits of which 2,113 (80%) were distributed to persons aged <35 years, 2,591 (98%) to men and 356 (14%) to first time testers. Of the HIVST distributed, 2,107 (80%) reported their results to the study team, and 157 (7%) tested positive. Of persons who tested positive, 107/130 (82%) reported having a confirmatory test of which 102/107 (95%) were positive and initiated on ART. No emergencies or social harms were reported. Conclusion: Large scale distribution of HIVST kits targeting men in rural KwaZulu-Natal is feasible and highly effective in reaching men, including those who had not previously tested for HIV. While two-thirds of persons who tested HIV positive initiated ART, additional linkage strategies are needed for those who do not link after HIVST. HIVST should be used as a tool to reach men in order to achieve 95% coverage in the UNAIDS testing and care cascade in KwaZulu-Natal.

Laboratory Reflex and Clinic-Based Point-of-Care Cryptococcal Antigen Screening for Preventing Meningitis and Mortality Among People Living With HIV.

INTRODUCTION: 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. METHODS: We conducted a prospective pre-post intervention study of adults presenting for HIV testing in Umlazi township, South Africa, over a 6-year period (2013-2019). Participants were enrolled during 3 phases of CrAg testing: CrAg testing ordered by a clinician (clinician-directed testing, 2013-2015); routine laboratory-based CrAg reflex testing for blood samples with CD4 ≤100 cells/mm3 (laboratory 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 laboratory 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, OK). We followed up participants for up to 14 months to compare associations between baseline CrAg positivity, antiretroviral therapy and fluconazole treatment initiation, and outcomes of cryptococcal meningitis, hospitalization, and mortality. RESULTS: Three thousand one hundred five (39.4%) of 7877 people screened were HIV-positive, of whom 908 had CD4 ≤200 cells/mm3 and were included in the analyses. Laboratory reflex and clinic-based testing increased CrAg screening (P < 0.001) and diagnosis of CrAg-positive PLHIV (P = 0.011). When compared with clinician-directed testing, clinic-based CrAg testing showed an increase in the number of PLHIV diagnosed with cryptococcal meningitis (4.5% vs. 1.5%; P = 0.059), initiation of fluconazole preemptive therapy (7.2% vs. 2.5%; P = 0.010), and initiation of antiretroviral therapy (96.8% vs. 91.3%; P = 0.012). Comparing clinic-based testing with laboratory reflex testing, there was no significant difference in the cumulative incidence of cryptococcal meningitis (4.5% vs. 4.1%; P = 0.836) or mortality (8.1% vs. 9.9%; P = 0.557). CONCLUSIONS: Laboratory reflex and clinic-based CrAg testing facilitated the diagnosis of HIV-associated cryptococcosis and fluconazole initiation but did not reduce cryptococcal meningitis or mortality. In this nonrandomized cohort, clinical outcomes were similar between laboratory reflex testing and clinic-based POC CrAg testing.

Implementation of a fully remote randomized clinical trial with cardiac monitoring.

Background: The coronavirus disease 2019 (COVID-19) pandemic has challenged researchers performing clinical trials to develop innovative approaches to mitigate infectious risk while maintaining rigorous safety monitoring. Methods: In this report we describe the implementation of a novel exclusively remote randomized clinical trial (ClinicalTrials.gov NCT04354428) of hydroxychloroquine and azithromycin for the treatment of the SARS-CoV-2-mediated COVID-19 disease which included cardiovascular safety monitoring. All study activities were conducted remotely. Self-collected vital signs (temperature, respiratory rate, heart rate, and oxygen saturation) and electrocardiographic (ECG) measurements were transmitted digitally to investigators while mid-nasal swabs for SARS-CoV-2 testing were shipped. ECG collection relied on a consumer device (KardiaMobile 6L, AliveCor Inc.) that recorded and transmitted six-lead ECGs via participants' internet-enabled devices to a central core laboratory, which measured and reported QTc intervals that were then used to monitor safety. Results: Two hundred and thirty-one participants uploaded 3245 ECGs. Mean daily adherence to the ECG protocol was 85.2% and was similar to the survey and mid-nasal swab elements of the study. Adherence rates did not differ by age or sex assigned at birth and were high across all reported race and ethnicities. QTc prolongation meeting criteria for an adverse event occurred in 28 (12.1%) participants, with 2 occurring in the placebo group, 19 in the hydroxychloroquine group, and 7 in the hydroxychloroquine + azithromycin group. Conclusions: Our report demonstrates that digital health technologies can be leveraged to conduct rigorous, safe, and entirely remote clinical trials.

An implementation study of oral and blood-based HIV self-testing and linkage to care among men in rural and peri-urban KwaZulu-Natal, South Africa.

INTRODUCTION: In South Africa, HIV-infected men are less likely than women to test and know their status (the first UNAIDS "90-90-90" target), and men have worse outcomes across the HIV care cascade. HIV self-testing (HIVST) may address this testing disparity but questions remain over the most effective distribution strategy and linkage following a positive test result. We implemented a men-focused HIVST distribution programme to evaluate components contributing to participation and retention. METHODS: We conducted an implementation study of multi-venue HIVST kit distribution in rural and peri-urban KwaZulu-Natal (KZN), South Africa. We distributed HIVST kits at community points, workplaces and social venues for on site or take-home use. Clients could choose blood-based or oral-fluid-based HIVST kits and elect to watch an in-person or video demonstration. We provided a USD2 incentive to facilitate reporting test results by phone or SMS. Persons with reactive HIVST results were provided immediate confirmatory tests (if used HIVST on site) or were referred for confirmatory testing (if took HIVST off site) and linkage to care for ART initiation. We describe the testing and linkage cascade in this sample and describe predictors of reactive HIVST results and linkage. RESULTS: Between July and November 2018, we distributed 4496 HIVST kits in two regions of KZN (96% to men, median age 28 (IQR 23 to 35). Most participants (58%) chose blood-based HIVST and 42% chose oral-swab kits. 11% of men were testing for the first time. A total of 3902 (83%) of testers reported their test result to the study team, with 314 (8%) screening positive for HIV. Among 274 men with reactive HIVST results, 68% linked to ART; no significant predictors of linkage were identified. 10% of kit users reported they would prefer a different type (oral vs. blood) of kit for repeat testing than the type they used. CONCLUSIONS: HIVST is acceptable to men and rapid distribution with optional testing support is feasible in rural and peri-urban settings. HIVST kits successfully reached younger men and identified undetected infections. Both oral and blood-based HIVST were selected. Scaling up HIVST distribution and guidance may increase the number of first-time testers among men and help achieve the first UNAIDS "90" for men in South Africa.

Lottery incentives have short-term impact on ART initiation among men: results from a randomized pilot study.

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.

Community-based antiretroviral therapy versus standard clinic-based services for HIV in South Africa and Uganda (DO ART): a randomised trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: 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.

Validation of clinic-based cryptococcal antigen lateral flow assay screening in HIV-infected adults in South Africa.

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/mm3, and 5.7% (95% CI 2.8-10.2%) for adults with CD4 < 100 cells/mm3. Using expanded screening guidelines (CD4 < 200 cells/mm3), 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.

Integrating hypertension screening at the time of voluntary HIV testing among adults in South Africa.

BACKGROUND: Guidelines recommend integrating hypertension screening for HIV-infected adults, but blood pressure measurements may be dynamic around the time of HIV testing. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Factors predictive of significant hepatic fibrosis in adults with chronic hepatitis B and normal serum ALT.

GOAL: This study examines the prevalence and correlates of significant liver fibrosis among patients with immunotolerant hepatitis B. BACKGROUND: Adults with chronic hepatitis B infection acquired early in life often have normal serum alanine aminotransferase (ALT) activity and high serum hepatitis B virus deoxyribonucleic acid loads (HBV DNA), known as "immunotolerant" hepatitis B. STUDY: We conducted a cross-sectional study of 28 hepatitis B patients with serum HBV DNA titer >10 copies/mL, positive hepatitis B envelope antigen, and persistently normal serum ALT in a tertiary care setting. Liver biopsies were reviewed by a single pathologist who was blinded to other data. The prevalence of significant hepatic fibrosis was determined using the hospital-defined upper limit of normal for ALT and 2 more stringent criteria proposed by recent studies. Statistical analyses were conducted to identify factors associated with hepatic fibrosis. RESULTS: The prevalence of stage 2 fibrosis using the hospital laboratory, more stringent, and most stringent definitions of normal serum ALT, was 32%, 32%, and 13%, respectively, corresponding to negative predictive values of 68%, 68%, and 88%, respectively. Age greater than 30 years (P=0.035), grade 2 liver inflammation (P=0.005), and lower serum HBV DNA level (mean 7.45 vs. 8.42 log10 copies/mL, P<0.001) were independently associated with stage 2 fibrosis on liver biopsy. CONCLUSIONS: These results highlight the need to use stringent definitions of normal serum ALT when making clinical decisions for patients with chronic hepatitis B. Older age and lower serum HBV DNA level predict significant hepatic fibrosis on biopsy. Our findings may guide decisions regarding liver biopsy among patients with immunotolerant hepatitis B.

Uptake of antiretroviral therapy and male circumcision after community-based HIV testing and strategies for linkage to care versus standard clinic referral: a multisite, open-label, randomised controlled trial in South Africa and Uganda.

BACKGROUND: Male circumcision decreases HIV acquisition by 60%, and antiretroviral therapy (ART) almost eliminates HIV transmission from HIV-positive people who are virally suppressed; however, coverage of these interventions has lagged behind targets. We aimed to assess whether community-based HIV testing with counsellor support and point-of-care CD4 cell count testing would increase uptake of ART and male circumcision. METHODS: We did this multisite, open-label, randomised controlled trial in six research-naive communities in rural South Africa and Uganda. Eligible HIV-positive participants (aged ≥16 years) were randomly assigned (1:1:1) in a factorial design to receive lay counsellor clinic linkage facilitation, lay counsellor follow-up home visits, or standard-of-care clinic referral, and then (1:1) either point-of-care CD4 cell count testing or referral for CD4 testing. HIV-negative uncircumcised men (aged 16-49 years) who could receive secure mobile phone text messages were randomly assigned (1:1:1) to receive text message reminders, lay counsellor visits, or standard clinic referral. The study biostatistician generated the randomisation schedule via a computer-generated random number program with varying block sizes (multiples of six or three) stratified by country. Primary outcomes for HIV-positive people were obtaining a CD4 cell count, linkage to an HIV clinic, ART initiation, and viral suppression at 9 months, and for HIV-negative uncircumcised men were visiting a circumcision facility and uptake of male circumcision at 3 months. We assessed social harms as a safety outcome throughout the study. We did the primary analyses by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02038582. FINDINGS: Between June 6, 2013, and March 11, 2015, 15 332 participants were tested. 2339 (15%) participants tested HIV positive, of whom 1325 (57%) were randomly assigned to receive lay counsellor clinic linkage facilitation (n=437), lay counsellor follow-up home visits (n=449), or standard clinic referral (n=439), and then point-of-care CD4 cell testing (n=206, n=220, and n=213, respectively) or referral for CD4 testing (n=231, n=229, and n=226, respectively). 12 993 (85%) participants tested HIV negative, of whom 750 (6%) uncircumcised men were randomly assigned to receive clinic referral (n=230), text message reminders (n=288), or lay counsellor follow-up visits (n=232). 1218 (93%) of 1303 HIV-positive participants were linked to care, but only 488 (37%) participants initiated ART. Overall, 635 (50%) of 1272 HIV-positive individuals achieved viral suppression at 9 months: 219 (52%) of 419 participants in the clinic facilitation group, 202 (47%) of 431 participants in the lay counsellor follow-up group, and 214 (51%) of 422 participants in the clinic referral group, with no significant differences between groups (p=0·668 for clinic facilitation and p=0·273 for lay counsellor follow-up vs clinic referral). 523 (72%) of 734 HIV-negative men visited a circumcision facility, with no difference between groups. 62 (28%) of 224 men were circumcised in the male circumcision clinic referral group compared with 137 (48%) of 284 men in the text message reminder group (relative risk 1·72, 95% CI 1·36-2·17; p<0·0001) and 106 (47%) of 226 men in the lay counsellor follow-up group (1·67, 1·29-2·14; p=0·0001). No cases of study-related social harm were reported, including probing about partnership separation, unintended disclosure, gender-based violence, and stigma. INTERPRETATION: All the community-based strategies achieved high rates of linkage of HIV-positive people to HIV clinics, roughly a third of whom initiated ART, and of those more than 80% were virally suppressed at 9 months. Uptake of male circumcision was almost two-times higher in men who received text message reminders or lay counsellor visits than in those who received standard-of-care clinic referral. Clinic barriers to ART initiation should be addressed in future strategies to increase the proportion of HIV-positive people accessing treatment and achieving viral suppression. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health.