Sexual behaviour among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: Data from the ECHO randomized trial.

BACKGROUND: Contraceptive use has complex effects on sexual behaviour and mood, including those related to reduced concerns about unintended pregnancy, direct hormonal effects and effects on endogenous sex hormones. We set out to obtain robust evidence on the relative effects of three contraceptive methods on sex behaviours, which is important for guiding contraceptive choice and future contraceptive developments. METHODS: This is a secondary analysis of data from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial in which 7,829 HIV-uninfected women from 12 sites in Eswatini, Kenya, South Africa and Zambia seeking contraception were randomly assigned to intramuscular depot-medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (Cu-IUD) or the levonorgestrel (LNG) implant. Data collected for 12 to 18 months using 3-monthly behavioural questionnaires that relied on recall from the preceding 3 months, were used to estimate relative risk of post-baseline sex behaviours, as well as sexual desire and menstrual bleeding between randomized groups using modified Poisson regression. RESULTS: We observed small but generally consistent effects wherein DMPA-IM users reported lower prevalence of specified high risk sexual behaviours than implant users than Cu-IUD users (the '>' and '<' symbols indicate statistically significant differences): multiple sex partners 3.6% < 4.8% < 6.2% respectively; new sex partner 3.0% < 4.0% <5.3%; coital acts 16.45, 16.65, 17.12 (DMPA-IM < Cu-IUD); unprotected sex 65% < 68%, 70%; unprotected sex past 7 days 33% <36%, 37%; sex during vaginal bleeding 7.1%, 7.1% < 8.9%; no sex acts 4.1%, 3.8%, 3.4% (DMPA-IM > Cu-IUD); partner has sex with others 10% < 11%, 11%. The one exception was having any sex partner 96.5%, 96.9% < 97.4% (DMPA-IM < Cu-IUD). Decrease in sexual desire was reported by 1.6% > 1.1% >0.5%; amenorrhoea by 49% > 41% >12% and regular menstrual pattern by 26% <35% < 87% respectively. CONCLUSIONS: These findings suggest that women assigned to DMPA-IM may have a modest decrease in libido and sexual activity relative to the implant, and the implant relative to the Cu-IUD. We found more menstrual disturbance with DMPA-IM than with the implant (and as expected, both more than the Cu-IUD). These findings are important for informing the contraceptive choices of women and policymakers and highlight the need for robust comparison of the effects of other contraceptive methods as well.

Early HIV viral suppression associated with subsequent 12-month treatment success among people living with HIV in South Africa.

BACKGROUND: We analyzed the STREAM (Simplifying HIV TREAtment and Monitoring) study to determine risk factors associated with HIV viraemia and poor retention 18 months after initiation of antiretroviral therapy (ART). METHODS: The STREAM study was an open-label randomized controlled trial in Durban, South Africa, that enrolled 390 people living with HIV presenting for their first HIV viral load measurement ~6 months after ART initiation. We used modified Poisson regression with robust standard errors to describe associations between baseline characteristics and three HIV outcomes 18 months after ART initiation: HIV viraemia (>50 copies/mL), poor retention in HIV care, and a composite outcome of poor retention in care and/or HIV viraemia. RESULTS: Approximately 18 months after ART initiation, 45 (11.5%) participants were no longer retained in care and 43 (11.8%) had viraemia. People with CD4 counts <200 and those with viraemia 6 months after ART initiation were significantly more likely to have viraemia 18 months after ART initiation (adjusted relative risk [aRR] 4.0; 95% confidence interval [CI] 2.1-7.5 and aRR 5.5; 95% CI 3.3-9.0, respectively). People who did not disclose their HIV status and had viraemia after ART initiation were more likely to not be retained in care 12 months later (aRR 2.6; 95% CI 1.1-6.1 and aRR 2.2; 95% CI 1.0-4.8). People with a CD4 count <200 and those with viraemia were more likely to not achieve the composite outcome 18 months after ART initiation. CONCLUSIONS: Viraemia after ART initiation was the strongest predictor of subsequent viraemia and poor care retention. Understanding early indicators can help target our interventions to better engage people who may be more likely to experience persistent viraemia or disengage from HIV care.

Behavioral Modeling and its Association with PrEP and ART Use in Ugandan HIV-Serodifferent Couples.

Integrating Pre-Exposure Prophylaxis (PrEP) delivery into Antiretroviral Therapy (ART) programs bridges the Human Immunodeficiency Virus (HIV) prevention gap for HIV-serodifferent couples prior to the partner living with HIV achieving viral suppression. Behavioral modeling is one mechanism that could explain health-related behavior among couples, including those using antiretroviral medications, but few tools exist to measure the extent to which behavior is modeled. Using a longitudinal observational design nested within a cluster randomized trial, this study examined the factor structure and assessed the internal consistency of a novel 24-item, four-point Likert-type scale to measure behavioral modeling and the association of behavioral modeling with medication-taking behaviors among heterosexual, cis-gender HIV-serodifferent couples. In 149 couples enrolled for research, a five-factor model provided the best statistical and conceptual fit, including attention to partner behavior, collective action, role modeling, motivation, and relationship quality. Behavioral modeling was associated with medication-taking behaviors among members of serodifferent couples. Partner modeling of ART/PrEP taking could be an important target for assessment and intervention in HIV prevention programs for HIV serodifferent couples.

Structural influences on delivery and use of oral HIV PrEP among adolescent girls and young women seeking post abortion care in Kenya.

Background: Adolescent girls and young women (AGYW) in East and southern Africa experience a disproportionate burden of HIV incidence. Integrating HIV pre-exposure prophylaxis (PrEP) within existing programs is a key component of addressing this disparity. Methods: We evaluated an oral PrEP program integrated into post-abortion care (PAC) in Kenya from March 2021 to November 2022. Technical advisors trained staff at PAC clinics on PrEP delivery, abstracted program data from each clinic, and collected data on structural characteristics. Utilizing a modified Poisson regression, we estimated the effect of structural factors on the probability of PrEP offer and uptake. Findings: We abstracted data on 6877 AGYW, aged 15-30 years, across 14 PAC clinics. PrEP offers were made to 57.4% of PAC clients and 14.1% initiated PrEP. Offers were associated with an increased probability at clinics that had consistent supply of PrEP (relative risk (RR):1.81, 95% CI: 1.1-2.95), inconsistent HIV testing commodities (RR: 1.89, 95% CI: 1.29-2.78), had all providers trained (RR: 1.65, 95% CI: 1.01, 2.68), and were public (RR: 1.89, 95% CI: 1.29-2.78). These same factors were associated with PrEP uptake: consistent supply of PrEP (RR: 2.71, 95% CI: 1.44-5.09), inconsistent HIV testing commodities (RR: 2.55, 95% CI: 1.39-4.67), all providers trained (RR: 2.61, 95% CI: 1.38-4.92), and were public (RR: 2.55, 95% CI: 1.39-4.67). Interpretation: Greater success with integration of HIV prevention into reproductive health services will likely require investments in systems, such as human resources and PrEP and HIV testing commodities, to create stable availability and ensure consistent access. Funding: PrEDIRA 2 was supported by funding from Children's Investment Fund Foundation (R-2001-04433). Ms. Zia was funded by the NIH Ruth L. Kirchstein pre-doctoral award (5F31HD105494-02) and Dr. Heffron was funded by National Institute of Mental Health (K24MH123371).

Intimate Partner Violence and Adherence to PrEP and ART Among Ugandan HIV Serodifferent Couples.

BACKGROUND: Intimate partner violence (IPV) is associated with increased risk of HIV acquisition and reduced engagement in HIV care. There is limited understanding of the ways in which IPV exposure and other maladaptive relationship dynamics may influence adherence to antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP) for individuals in committed, HIV serodifferent partnerships. METHODS: We used binomial generalized linear mixed-effect regression models to evaluate the association between IPV exposure and ART/PrEP adherence among members of serodifferent couples in Uganda. Secondarily, we assessed the association between relationship powerlessness and ART/PrEP adherence. RESULTS: We enrolled and followed both partners in 149 heterosexual serodifferent couples. The partner living with HIV was female in 64% of couples. IPV exposure was associated with low ART adherence (15% vs. 5% in quarters with no IPV, odds ratio: 4.78, 95% confidence interval: 1.48 to 15.42), but not low PrEP adherence (33% vs. 36%, P = 0.69). Among HIV-negative individuals, those reporting moderate relationship powerlessness were less likely to have poor PrEP adherence compared with those with low relationship powerlessness (20% vs. 30%, odds ratio: 0.57, 95% confidence interval: 0.36 to 0.90). We observed no association between relationship powerlessness and ART adherence. CONCLUSIONS: We found that IPV exposure was associated with low adherence to ART and that relationship powerlessness was associated with good adherence to PrEP. These findings contribute to the evidence base outlining the influence of IPV and relationship power on ART/PrEP adherence for individuals in HIV serodifferent unions.

Impact of point-of-care HIV viral load and targeted drug resistance mutation testing on viral suppression among Kenyan pregnant and postpartum women: results from a prospective cohort study (Opt4Mamas).

INTRODUCTION: Lack of viral suppression (VS) among pregnant and breastfeeding women living with HIV poses challenges for maternal and infant health, and viral load (VL) monitoring via centralized laboratory systems faces many barriers. We aimed to determine the impact of point-of-care (POC) VL and targeted drug resistance mutation (DRM) testing in improving VS among pregnant and postpartum women on antiretroviral therapy. METHODS: We conducted a pre/post-intervention prospective cohort study among 820 pregnant women accessing HIV care at five public-sector facilities in western Kenya from 2019 to 2022. The pre-intervention or "control" group consisted of standard-of-care (SOC) centralized VL testing every 6 months and the post-intervention or "intervention" group consisted of a combined strategy of POC VL every 3 months, targeted DRM testing, and clinical management support. The primary outcome was VS (VL ≤1000 copies/ml) at 6 months postpartum; secondary outcomes included uptake and turnaround times for VL testing and sustained VS. RESULTS: At 6 months postpartum, 321/328 (98%) of participants in the intervention group and 339/347 (98%) in the control group achieved VS (aRR 1.00, 95% confidence interval [CI] 0.98, 1.02). When assessing VS using a threshold of <40 copies/ml, VS proportions were lower overall (90-91%) but remained similar between groups. Among women with viraemia (VL>1000 copies/ml) who underwent successful DRM testing in the intervention group, all (46/46, 100%) had some DRMs and 20 (43%) had major DRMs (of which 80% were nucleos(t)ide reverse transcriptase inhibitor mutations). POC VL testing uptake was high (>89%) throughout pregnancy, delivery, and postpartum periods, with a median turnaround time of 1 day (IQR 1, 4) for POC VL in the intervention group and 7 days (IQR 5, 9) for SOC VL in the control group. Sustained VS throughout follow-up was similar between groups with either POC or SOC VL testing (90-91% for <1000 copies/ml, 62-70% for <40 copies/ml). CONCLUSIONS: Our combined strategy markedly decreased turnaround time but did not increase VS rates, which were already very high, or sustained VS among pregnant and postpartum women living with HIV. Further research on how best to utilize POC VL and DRM testing is needed to optimize sustained VS among this population.

HIV Drug Resistance Patterns and Characteristics Associated with Clinically Significant Drug Resistance among Children with Virologic Failure on Antiretroviral Treatment in Kenya: Findings from the Opt4Kids Randomized Controlled Trial.

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1-14 years enrolled from March 2019 to December 2020 from five facilities in Kisumu County, Kenya, were included. Children were randomized 1:1 to control (standard-of-care) or intervention (point-of-care viral load (POC VL) testing every three months with targeted genotypic drug resistance testing (DRT) for virologic failure (VF) (≥1000 copies/mL)). A multidisciplinary committee reviewed CHIV with DRT results and offered treatment recommendations. We describe DR mutations and present logistic regression models to identify factors associated with clinically significant DR. We enrolled 704 children in the study; the median age was 9 years (interquartile range (IQR) 7, 12), 344 (49%) were female, and the median time on ART was 5 years (IQR 3, 8). During the study period, 106 (15%) children had DRT results (84 intervention and 22 control). DRT detected mutations associated with DR in all participants tested, with 93 (88%) having major mutations, including 51 (54%) with dual-class resistance. A history of VF in the prior 2 years (adjusted odds ratio (aOR) 11.1; 95% confidence interval (CI) 6.3, 20.0) and less than 2 years on ART at enrollment (aOR 2.2; 95% CI 1.1, 4.4) were associated with increased odds of major DR. DR is highly prevalent among CHIV on ART with VF in Kenya. Factors associated with drug resistance may be used to determine which children should be prioritized for DRT.

Effect of 6-Month HIV Preexposure Prophylaxis Dispensing With Interim Self-testing on Preexposure Prophylaxis Continuation at 12 Months: A Randomized Noninferiority Trial.

Importance: Daily oral HIV preexposure prophylaxis (PrEP) delivery requires quarterly clinic visits for HIV testing and drug refilling that are costly to health systems and clients. Objective: To evaluate whether 6-month PrEP dispensing supported with interim HIV self-testing (HIVST) results in noninferior PrEP continuation outcomes at 12 months compared with standard quarterly clinic visits. Design, Setting, and Participants: This randomized noninferiority trial was conducted from May 2018 to May 2021 with 12 months of follow-up among PrEP clients aged 18 years or older who were returning for their first refill at a research clinic in Kiambu County, Kenya. Intervention: Participants were randomized 2:1 to (1) 6-month PrEP dispensing with semiannual clinic visits and interim HIVST at 3 months or (2) standard-of-care (SOC) PrEP delivery with 3-month dispensing, quarterly clinic visits, and clinic-based HIV testing. Main Outcomes and Measures: Prespecified 12-month outcomes included recent HIV testing (any in past 6 months), PrEP refilling, and PrEP adherence (detectable tenofovir-diphosphate concentrations in dried blood spots). Binomial regression models were used to estimate risk differences (RDs), and a 1-sided 95% CI lower bound (LB) of -10% or greater was interpreted as noninferior. Results: A total of 495 participants were enrolled, with 329 enrolled in the intervention group and 166 enrolled in the SOC group; 330 (66.7%) were women, 295 (59.6%) were in serodifferent relationships, and the median (IQR) age was 33 (27-40) years. At 12 months, 241 individuals in the intervention group (73.3%) and 120 in the SOC group (72.3%) returned to clinic. In the intervention group, recent HIV testing was noninferior (230 individuals [69.9%]) compared with the SOC group (116 [69.9%]; RD, -0.33%, 95% CI LB, -7.44%). PrEP refilling in the intervention group (196 [59.6%]) was inconclusive compared with the SOC group (104 [62.7%]; RD, -3.25%; 95% CI LB, -10.84%), and PrEP adherence was noninferior in the intervention group (151 [45.9%]) compared with the SOC group (70 [42.2%]; RD, 4.96%; 95% CI LB, -2.46%). No HIV seroconversions were observed over the follow-up period. Conclusions and Relevance: In this analysis of secondary trial end points at 1 year, semiannual PrEP dispensing with interim HIVST resulted in noninferior recent HIV testing and PrEP adherence compared with SOC quarterly PrEP dispensing. This novel model has the potential to optimize PrEP delivery. Trial Registration: ClinicalTrials.gov Identifier: NCT03593629.

Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya.

Introduction: Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies. Methods: Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition. Results: Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36-90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively). Conclusion: TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR. Clinical Trial Registration: NCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382].

Implementation and scale-up of a single-visit, screen-and-treat approach with thermal ablation for sustainable cervical cancer prevention services: a protocol for a stepped-wedge cluster randomized trial in Kenya.

BACKGROUND: An important cervical cancer prevention strategy in low- and middle-income countries (LMICs) has been single-visit screen-and-treat (SV-SAT) approach, using visual inspection with acetic acid (VIA) and ablative treatment with cryotherapy to manage precancerous lesions. While SV-SAT with VIA and cryotherapy have established efficacy, its population level coverage and impact on reducing cervical cancer burden remains low. In Kenya, the estimated cervical cancer screening uptake among women aged 30-49 is 16% and up to 70% of screen-positive women do not receive treatment. Thermal ablation for treatment of precancerous lesions of the cervix is recommended by the World Health Organization and has the potential to overcome logistical challenges associated with cryotherapy and facilitate implementation of SV-SAT approach and increase treatment rates of screen-positive women. In this 5-year prospective, stepped-wedge randomized trial, we plan to implement and evaluate the SV-SAT approach using VIA and thermal ablation in ten reproductive health clinics in central Kenya. METHODS: The study aims to develop and evaluate implementation strategies to inform the national scale-up of SV-SAT approach with VIA and thermal ablation through three aims: (1) develop locally tailored implementation strategies using multi-level participatory method with key stakeholders (patient, provider, system-level), (2) implement SV-SAT approach with VIA and thermal ablation and evaluate clinical and implementation outcomes, and (3) assess the budget impact of SV-SAT approach with VIA and thermal ablation compared to single-visit, screen-and-treat method using cryotherapy. DISCUSSION: Our findings will inform national scale-up of the SV-SAT approach with VIA and thermal ablation. We anticipate that this intervention, along with tailored implementation strategies will enhance the adoption and sustainability of cervical cancer screening and treatment compared to the standard of care using cryotherapy. TRIAL REGISTRATION: NCT05472311.

Clinical outcomes of intrauterine device insertions by newly trained providers: The ECHO trial experience.

Objectives: To assess the rates of failed insertion, expulsion, and perforation when intrauterine device (IUD) insertions were done by newly trained clinicians, and to examine factors that may affect these outcomes. Study design: We evaluated skill-based outcomes following IUD insertion at 12 African sites in a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial. Before trial initiation, we provided competency-based IUD training to clinicians and offered ongoing clinical support. We used Cox proportional hazards regression to examine factors associated with expulsion. Results: Among 2582 IUD acceptors who underwent first attempted IUD insertion, 141 experienced insertion failure (5.46%) and seven had uterine perforation (0.27%). Perforation was more common among breastfeeding women within three months postpartum (0.65%) compared with non-breastfeeding women (0.22%). We recorded 493 expulsions (15.5 per 100 person-years, 95% confidence interval [CI] 14.1─16.9): 383 partial and 110 complete. The risk of IUD expulsion was lower among women older than 24 years (aHR 0.63, 95% CI 0.50─0.78) and may be higher among nulliparous women. (aHR 1.65, 95% CI 0.97─2.82). Breastfeeding (aHR 0.94, 95% CI 0.72─1.22) had no significant effect on expulsion. IUD expulsion rate was highest during the first three months of the trial. Conclusions: IUD insertion failure and uterine perforation rates in our study were comparable to those reported in the literature. These results suggest that training, ongoing support, and opportunities to apply new skills were effective in ensuring good clinical outcomes for women receiving IUD insertion by newly trained providers. Implications: Data from this study support recommendations to program managers, policymakers, and clinicians that IUDs can be inserted safely in resource-constrained settings when providers receive appropriate training and support.

Delivery of Community-based Antiretroviral Therapy to Maintain Viral Suppression and Retention in Care in South Africa.

BACKGROUND: To determine whether the Centralized Chronic Medication Dispensing and Distribution (CCMDD) program in South Africa's differentiated ART delivery model affects clinical outcomes, we assessed viral load (VL) suppression and retention in care between patients participating in the program and those receiving the clinic-based standard of care. METHODS: Clinically stable people living with HIV (PLHIV) eligible for differentiated care were referred to the national CCMDD program and followed up for up to 6 months. In this secondary analysis of trial cohort data, we estimated the association between routine patient participation in the CCMDD program and their clinical outcomes of viral suppression (<200 copies/mL) and retention in care. RESULTS: Among 390 PLHIV, 236 (61%) were assessed for CCMDD eligibility; 144 (37%) were eligible, and 116 (30%) participated in the CCMDD program. Participants obtained their ART in a timely manner at 93% (265/286) of CCMDD visits. VL suppression and retention in care was very similar among CCMDD-eligible patients who participated in the program compared with patients who did not participate in the program (aRR: 1.03; 95% CI: 0.94-1.12). VL suppression alone (aRR: 1.02; 95% CI: 0.97-1.08) and retention in care alone (aRR: 1.03; 95% CI: 0.95-1.12) were also similar between CCMDD-eligible PLHIV who participated in the program and those who did not. CONCLUSION: The CCMDD program successfully facilitated differentiated care among clinically stable participants. PLHIV participating in the CCMDD program maintained a high proportion of viral suppression and retention in care, indicating that community-based ART delivery model did not negatively affect their HIV care outcomes.

PrEP uptake and HIV viral suppression when PrEP is integrated into Ugandan ART clinics for HIV-negative members of HIV-serodifferent couples: A stepped wedge cluster randomized trial.

Background: Global scale-up of HIV pre-exposure prophylaxis (PrEP) includes services to HIV-negative people in partnerships with people living with HIV (serodifferent couples). Data are needed on HIV outcomes, including uptake and adherence to PrEP and antiretroviral treatment (ART), to describe the impact of integrating PrEP into an existing HIV program. Methods: Using a stepped-wedge cluster randomized trial design, we launched PrEP delivery for HIV-negative members of serodifferent couples in Uganda by integrating PrEP into existing ART programs for people living with HIV. The program provided PrEP training for ART providers, ongoing technical assistance, and a provisional supply chain mechanism for PrEP medication. Primary data on PrEP initiation, PrEP refills, ART initiation, and HIV viremia at 6 months (measured at 42-270 days) were collected through data abstraction of medical records from HIV-serodifferent couples sequentially enrolling at the ART clinics. Modified Poisson regression models, controlling for time and cluster, compared viral suppression (<1000 copies/ml) before and after launch of the PrEP program. This trial was registered at ClinicalTrials.gov, NCT03586128. Findings: From June 1, 2018-December 15, 2020, 1,381 HIV-serodifferent couples were enrolled across 12 ART clinics in Kampala and Wakiso, Uganda, including 730 enrolled before and 651 after the launch of PrEP delivery. During the baseline period, 99.4% of partners living with HIV initiated ART and 85.0% were virally suppressed at 6 months. Among HIV-negative partners enrolled after PrEP launched, 81.0% (527/651) initiated PrEP within 90 days of enrolling; among these 527, 11.2% sought a refill 6 months later. In our powered intent-to-treat analysis, 82.1% and 76.7% of partners living with HIV were virally suppressed, respectively, which was not a statistically significant difference (RR=0.94, 95% CI: 0.82-1.07) and was stable across sensitivity analyses. Interpretation: Integration of PrEP into ART clinics reached a high proportion of people in HIV-serodifferent relationships and did not improve the already high frequency of HIV viral suppression among partners living with HIV. Funding: National Institute of Mental Health (R01MH110296).

Accuracy of 2 Rapid Antigen Tests During 3 Phases of SARS-CoV-2 Variants.

Importance: Variants of SARS-CoV-2 have sequence variations in the viral genome that may alter the accuracy of rapid diagnostic tests. Objective: To assess the analytical and clinical accuracy of 2 rapid diagnostic tests for detecting SARS-CoV-2 during 3 phases of variants. Design, Setting, and Participants: This diagnostic study included participants aged 18 years or older who reported onset of COVID-19-like symptoms within the prior 5 days and were tested at multiple COVID-19 testing locations in King County, Washington, from February 17, 2021, to January 11, 2022, during 3 distinct phases of SARS-CoV-2 infection (pre-Delta, Delta, and Omicron). Interventions: Two anterior nasal swab specimens were collected from each participant-1 for onsite testing by the SCoV-2 Ag Detect Rapid Self-Test and 1 for reverse transcriptase-polymerase chain reaction (RT-PCR) testing. Main Outcomes and Measures: The analytical limit of detection of the 2 rapid diagnostic tests (SCoV-2 Ag Detect Rapid Self-Test and BinaxNOW COVID-19 Ag Card) was assessed using Omicron (B.1.1.529/BA.1), Delta (B.1.617.2), and a wild-type (USA-WA1/2020) variant. Diagnostic sensitivity and specificity of clinical testing for the rapid antigen tests were compared with that of RT-PCR testing. Results: A total of 802 participants were enrolled (mean [SD] age, 37.3 [13.3] years; 467 [58.2%] female), 424 (52.9%) of whom had not received COVID-19 vaccination and presented a median of 2 days (IQR, 1-3 days) from symptom onset. Overall, no significant differences were found in the analytical limit of detection or clinical diagnostic accuracy of rapid antigen testing across SARS-CoV-2 variants. The estimated limit of detection for both rapid nucleocapsid antigen tests was at or below a 50% tissue culture infectious dose of 62.5, and the positive percent agreement of the SCoV-2 Ag Detect Rapid Self-Test ranged from 81.2% (95% CI, 69.5%-89.9%) to 90.7% (95% CI, 77.9%-97.4%) across the 3 phases of variants. The diagnostic sensitivity increased for nasal swabs with a lower cycle threshold by RT-PCR, which correlates with a higher viral load. Conclusions and Relevance: In this diagnostic study, analytical and clinical performance data demonstrated accuracy of 2 rapid antigen tests among adults with COVID-19 symptoms across 3 phases of SARS-CoV-2 variants. The findings suggest that home-based rapid antigen testing programs may be an important intervention to reduce global SARS-CoV-2 transmission.

Point-of-care HIV viral load and targeted drug resistance mutation testing versus standard care for Kenyan children on antiretroviral therapy (Opt4Kids): an open-label, randomised controlled trial.

BACKGROUND: Feasible, scalable, and cost-effective approaches to ensure virological suppression among children living with HIV are urgently needed. The aim of the Opt4Kids study was to determine the effect of point of care viral load and targeted drug resistance mutation testing in improving virological suppression among children on antiretroviral therapy (ART) in Kenya. METHODS: In this open-label, individually randomised controlled trial, we enrolled children living with HIV aged 1-14 years and who were either newly initiating or already receiving ART at five study facilities in Kenya. Participants were randomly allocated 1:1 to receive the intervention of point-of-care viral load testing every 3 months, targeted drug resistance mutation testing, and clinical decision support (point-of-care testing) or to receive the standard care (control group), stratified by facility site and age groups (1-9 years vs 10-14 years). Investigators were masked to the randomised group. The primary efficacy outcome was virological suppression (defined as a viral load of <1000 copies per mL) by point-of-care viral load testing at 12 months after enrolment in all participants with an assessment. This study is registered with ClinicalTrials.gov, NCT03820323. FINDINGS: Between March 7, 2019, and December 31, 2020, we enrolled 704 participants. Median age at enrolment was 9 years (IQR 7-12), 344 (49%) participants were female and 360 (51%) were male, and median time on ART was 5·8 years (IQR 3·1-8·6). 536 (76%) of 704 had documented virological suppression at enrolment. At 12 months after enrolment, the proportion of participants achieving virological suppression in the intervention group (283 [90%] of 313 participants with a 12 month point-of-care viral load test) did not differ from that in the control group (289 [92%] of 315; risk ratio [RR] 0·99, 95% CI 0·94-1·03; p=0·55). We identified 138 episodes of viraemia in intervention participants, of which 107 (89%) samples successfully underwent drug resistance mutation testing and 91 (85%) had major drug resistance mutations. The median turnaround time for viral load results was 1 day (IQR 0-1) in the intervention group and 15 days (10-21) in the control group. INTERPRETATION: Point-of-care viral load testing decreased turnaround time and targeted drug resistance mutation testing identified a high prevalence of HIV drug resistance mutations in children living with HIV, but the combined approach did not increase rates of virological suppression. Further research in combination interventions, including point-of-care viral load and drug resistance mutation testing coupled with psychosocial support, is needed to optimise virological suppression for children living with HIV. FUNDING: National Institutes of Mental Health of the US National Institutes of Health, Thrasher Research Fund.

Efficiency of 6-month PrEP dispensing with HIV self-testing in Kenya: an open-label, randomised, non-inferiority, implementation trial.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) for HIV prevention is highly effective and is being implemented at scale at health clinics throughout sub-Saharan Africa. However, barriers to clinic-based PrEP delivery remain. We aimed to establish the efficiency of semiannual PrEP clinic visits supplemented with interim home-based HIV self-testing (HIVST) versus standard of care for HIV testing, drug refilling, and adherence among PrEP users. METHODS: This was a randomised, open-label, non-inferiority trial done at the Partners in Health and Research Development clinic in Thika, Kenya. Eligible participants were HIV-negative adults (≥18 years) at risk of acquiring HIV who had started PrEP at least 1 month before enrolment. Participants were randomly assigned (1:1:1) to 6-month PrEP dispensing plus interim blood-based HIVST (with biannual clinic visits), 6-month PrEP dispensing plus interim oral fluid-based HIVST (with biannual clinic visits), or standard of care PrEP delivery (3-month PrEP dispensing with quarterly clinic visits). The three coprimary outcomes, measured at 6 months, were HIV testing (any testing between enrolment and the 6-month visit), PrEP refilling, and PrEP adherence (detectable tenofovir diphosphate concentration in dried blood spots). All analyses were done according to the intention-to-treat principle. We used binomial regression models to estimate risk differences and one-sided 95% CIs. 6-month PrEP dispensing was considered non-inferior to standard of care if the lower limit bound of the one-sided 95% CI was greater than or equal to -10%. This study is registered with ClinicalTrials.gov, NCT03593629. FINDINGS: Between May 28, 2018, and Feb 24, 2020, 495 participants were enrolled: 165 men and 130 women in HIV serodifferent couples and 200 singly enrolled women. 166 participants were randomly assigned to the standard of care group, 163 to the 6-month PrEP dispensing plus oral-fluid HIVST group, and 166 to the 6-month PrEP dispensing plus blood-based HIVST group. At 6 months, 274 (83%) of 329 participants in the combined 6-month PrEP dispensing group had tested for HIV compared with 140 (84%) of 166 participants in the standard of care group (risk difference -1·15%, 95% CI lower bound -6·89). Among participants in the combined 6-month PrEP dispensing group, 257 (78%) participants refilled PrEP compared with 134 (81%) participants in the standard of care group (-2·60%, -8·88), and 200 (61%) participants were adherent to PrEP compared with 95 (57%) participants in the standard of care group (2·37%, -5·05). No participants acquired HIV during the study. INTERPRETATION: 6-month PrEP dispensing with HIVST for interim testing reduced the number of PrEP clinic visits in half without compromising HIV testing, retention, or adherence. FUNDING: US National Institute of Mental Health.

High HIV incidence among young women in South Africa: Data from a large prospective study.

INTRODUCTION: South Africa has the highest national burden of HIV globally. Understanding drivers of HIV acquisition in recently completed, prospective studies in which HIV was an endpoint may help inform the strategy and investments in national HIV prevention efforts and guide the design of future HIV prevention trials. We assessed HIV incidence and correlates of incidence among women enrolled in ECHO (Evidence for Contraceptive Options and HIV Outcomes), a large, open-label randomized clinical trial that compared three highly effective. reversible methods of contraception and rates of HIV acquisition. METHODS: During December 2015 to October 2018, ECHO followed sexually active, HIV-seronegative women, aged 16-35 years, seeking contraceptive services and willing to be randomized to one of three contraceptive methods (intramuscular depot medroxyprogesterone acetate, copper intrauterine device, or levonorgestrel implant) for 12-18 months at nine sites in South Africa. HIV incidence based on prospectively observed HIV seroconversion events. Cox proportional hazards regression models were used to define baseline cofactors related to incident HIV infection. RESULTS: 5768 women were enrolled and contributed 7647 woman-years of follow-up. The median age was 23 years and 62.5% were ≤24 years. A total of 345 incident HIV infections occurred, an incidence of 4.51 per 100 woman-years (95%CI 4.05-5.01). Incidence was >3 per 100 woman-years at all sites. Age ≤24 years, baseline infection with sexually transmitted infections, BMI≤30, and having new or multiple partners in the three months prior to enrollment were associated with incident HIV. CONCLUSIONS: HIV incidence was high among South African women seeking contraceptive services. Integration of diagnostic management of sexually transmitted infections alongside delivery of HIV prevention options in health facilities providing contraception services are needed to mitigate ongoing risks of HIV acquisition for this vulnerable population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02550067 was the main Clinical Trial from which this secondary, non-randomized / observational analysis was derived with data limited to just South African sites.

Elucidating Pathways Mediating the Relationship Between Male Sex and COVID-19 Severity.

PURPOSE: To examine associations between male sex and SARS-CoV-2 test positivity, severe COVID-19 disease, and death in a single-site cohort, and assess whether male sex impacts risk for severe COVID-19 disease through socioeconomic status (SES), comorbidities, or inflammation. MATERIALS AND METHODS: We conducted a retrospective cohort study with data collected from University of Washington Medicine EMR from March 1 to September 29, 2020. All persons, regardless of age, were included if they had a conclusive diagnostic COVID-19 PCR test result. Our exposure was sex assigned at birth. We used Poisson regression to assess associations between sex and COVID-19 test positivity, disease severity and COVID-19 related death, and linear regression to compare viral cycle threshold at the first positive test. We conducted mediation analyses to assess interventional indirect effects of male sex on severe COVID-19 risk through socioeconomic status (SES, based on area deprivation and insurance type), comorbidities, and inflammation status. Models controlled for age and race/ethnicity. RESULTS: Of 32,919 males and 34,733 females included, 1469 (4.5%) and 1372 (4.0%) tested positive for SARS-CoV-2, respectively. Males were 14% more likely to test positive (RR = 1.14; 95% CI: 1.06-1.23), had 80% higher risk for severe COVID-19 disease (RR = 1.80; 95% CI: 1.39-2.33) and had 58% higher risk for death (RR = 1.58; 95% CI: 1.10-2.26) compared to females after adjusting for age and race/ethnicity. Mediation analyses indicated non-significant interventional indirect effects of male sex on severe COVID-19 disease through elevated inflammatory markers, SES and comorbidities, but the greatest effect was through the inflammation pathway. CONCLUSION: Males appear to be at higher risk at all steps of the continuum of COVID-19 illness. The strongest mediating signal, albeit non-significant, is with inflammatory pathways. Further elucidation of causal pathways linking sex and COVID-19 severity is needed in larger cohorts.

Understanding Pre-Exposure Prophylaxis Adherence in Young Women in Kenya.

OBJECTIVE: To present detailed analyses of long-term pre-exposure prophylaxis (PrEP) use and associated behaviors and perceptions among young Kenyan women. DESIGN: Prospective, observational cohort. METHODS: The Monitoring PrEP among Young Adult women Study involved 18 to 24-year-old women at high HIV risk initiating PrEP in Kisumu and Thika, Kenya. Visits for PrEP counseling and dispensing, HIV testing, and socio-behavioral data collection occurred at Month 1 and quarterly for 2 years. PrEP adherence was measured with pharmacy refill and real-time electronic monitoring, plus tenofovir diphosphate levels in 15% of participants. HIV risk behavior and perception were assessed by self-report in weekly short message service surveys from Months 6-24. Predictors of adherence were assessed with multivariable logistic regression analysis. RESULTS: Three hundred forty-eight women (median age 21, VOICE risk score 7) were followed for 617 person-years. Pharmacy refills steadily declined from 100% (Month 0-1) to 54% (Months 22-24). Average electronically monitored adherence similarly declined from 65% (Month 0-1) to 15% (Months 22-24). Electronically monitored adherence had moderately high concordance with tenofovir diphosphate levels (67%). High average adherence (5+ doses/week) was seen at 385/1898 (20%) participant-visits and associated with low baseline VOICE risk score, >1 current sexual partner, ≤1-hour travel time to clinic, and the Kisumu site. short message service-reported behavior and risk perception were not associated with adherence. Four women acquired HIV (incidence 0.7/100 person-years). CONCLUSIONS: PrEP adherence was modest and declined over time. HIV risk was inconsistently associated with adherence; clinic access and site-level factors were also relevant. Relatively low HIV incidence suggests participants may have achieved protection through multiple strategies.

ART initiation among women newly diagnosed with HIV in a contraceptive trial in sub-Saharan Africa.

Current guidelines recommend starting antiretroviral therapy (ART) as soon as possible after HIV diagnosis to reduce morbidity, mortality and onward HIV transmission. We examined factors influencing ART initiation by women who seroconverted during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. ECHO, conducted between 2015 and 2018, enrolled HIV-negative, sexually active women, aged 16-35 years, from four African countries. Follow-up was 12-18 months, with quarterly HIV testing. Women with incident HIV infection received extensive counselling by trial staff and referral to local facilities for HIV care. Of 304 women with ≥90 days follow-up time since HIV diagnosis, 186(61.2%) initiated ART within 90 days, 69(22.7%) initiated after 90 days, and 49(16.1%) had not initiated by the end of the study. There were no statistically significant differences in characteristics among women who initiated ART ≤90 days versus those who did not. Frequent reasons for delayed or non-initiation of ART included not feeling ready to start ART and being newly diagnosed. In a large clinical trial, ART initiation was modest within 90 days of HIV diagnosis and grew to 84% with longer observation. Despite extensive counselling on the importance of early ART initiation, personal barriers delayed some women from starting ART.