Bacterial vaginosis-driven changes in vaginal T cell phenotypes and their implications for HIV susceptibility.

Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent in reproductive-age women worldwide. Adverse outcomes associated with BV include an increased risk of sexually acquired Human Immunodeficiency Virus (HIV), yet the immunological mechanisms underlying this association are not well understood. To investigate BV driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and peripheral blood mononuclear cells (PBMC). Immunofluorescence analysis of genital mucosal tissues revealed a reduced density of CD3+CD4+CCR5+ cells in the VT lamina propria of individuals with compared to those without BV (median 243.8 cells/mm2 BV- vs 106.9 cells/mm2 BV+, p=0.043). High-parameter flow cytometry of VT biopsies revealed an increased frequency in individuals with compared to those without BV of dysfunctional CD39+ conventional CD4+ T cells (Tconv) (median frequency 15% BV- vs 30% BV+, padj=0.0331) and tissue-resident CD69+CD103+ Tconv (median frequency 24% BV- vs 38% BV+, padj=0.0061), previously reported to be implicated in HIV acquisition and replication. Our data suggests that BV elicits diverse and complex VT T cell alterations and expands on potential immunological mechanisms that may promote adverse outcomes including HIV susceptibility.

Real-world performance of point-of-care vs. standard-of-care HIV viral load testing in western Kenya: Secondary analysis of Opt4Kids and Opt4Mamas studies.

Routine HIV viral load testing is important for evaluating HIV treatment outcomes, but conventional viral load testing has many barriers including expensive laboratory equipment and lengthy results return times to patients. A point-of-care viral load testing technology, such as GeneXpert HIV-1 quantification assay, could reduce these barriers by decreasing cost and turnaround time, however real-world performance is limited. We conducted a secondary analysis using 900 samples collected from participants in two studies to examine the performance of GeneXpert as point-of-care viral load compared to standard-of-care testing (which was conducted with two centralized laboratories using traditional HIV-1 RNA PCR quantification assays). The two studies, Opt4Kids (n = 704 participants) and Opt4Mamas (n = 820 participants), were conducted in western Kenya from 2019-2021 to evaluate the effectiveness of a combined intervention strategy, which included point-of-care viral load testing. Paired viral load results were compared using four different thresholds for virological non-suppression, namely ≥50, ≥200, ≥400, ≥1000 copies/ml. At a threshold of ≥1000 copies/mL, paired samples collected on the same day: demonstrated sensitivities of 90.0% (95% confidence interval [CI] 68.3, 98.8) and 66.7% (9.4, 99.2), specificities of 98.4% (95.5, 99.7) and 100% (96.5, 100), and percent agreements of 97.7% (94.6, 99.2) and 99.1% (95.0, 100) in Opt4Kids and Opt4Mamas studies, respectively. When lower viral load thresholds were used and the paired samples were collected an increasing number of days apart, sensitivity, specificity, and percent agreement generally decreased. While specificity and percent agreement were uniformly high, sensitivity was lower than expected. Non-specificity of the standard of care testing may have been responsible for the sensitivity values. Nonetheless, our results demonstrate that GeneXpert may be used reliably to monitor HIV treatment in low- and middle- income countries to attain UNAID's 95-95-95 HIV goals.

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.

A randomized, controlled clinical trial of acupoint catgut embedding as an effective control of functional anorectal pain.

BACKGROUND: Patients with functional anorectal pain (FAP) usually feel pain in the anal region, foreign body sensation, and defecation disorders. The pain may radiate to the perineum, thighs, and waist. Conventional biofeedback, local nerve block and surgical treatment have certain limitations. Thread-embedding acupuncture (TEA) is a complementary and alternative therapy, which is widely used in the clinical practice of traditional Chinese medicine to treat functional anorectal pain. This study evaluated the efficacy and safety of the catgut-embedding acupuncture in patients with FAP. METHODS: FAP patients were enrolled and randomly divided into a thread-embedding acupuncture group (n = 35) and a sham-embedding acupuncture control group (n = 36). Patients underwent treatment twice monthly for 2 months and were assessed before and after treatments for visual analogue scales (VAS) of anorectal pain, VAS of lumbar pain or soreness, VAS of abdominal distension or pain, anal incontinence index, and SF-36 quality of life. The SF-36 quality of life score included assessment of physical functioning, role-physical, bodily-pain, general health, role-emotional, social functioning, vitality, and mental health. RESULT: The total effective rate was 85.71% for the treatment group versus 8.33% of the controls after 2 months (P < .001). The patients' anal rectum VAS score was significantly higher after treatment versus pretreatment (P < .01), while the physical functioning, role-physical, bodily-pain, role-emotional, and mental health in the experimental group and the role-emotional, and mental health in the control group were all significantly improved versus pretreatment (P < .05). The anorectal VAS score, anal incontinence index, and the SF-36 scores of the physical functioning, role-physical, bodily-pain, role-emotional, and mental health were better in the treatment group compared to the control group (P < .05). Most importantly, there were no adverse reactions observed in either group during the treatment. CONCLUSION: The thread-embedding acupuncture treatment effectively and safely improved the emotional anxiety and quality of life in FAP patients.

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.

Do community measures impact the effectiveness of a community led HIV testing intervention. Secondary analysis of an HIV self-testing intervention in rural communities in Zimbabwe.

BACKGROUND: There is a growing body of evidence for the role that communities can have in producing beneficial health outcomes. There is also an increasing recognition of the effectiveness and success of community-led interventions to promote public health efforts. This study investigated whether and how community-level measures facilitate a community-led intervention to achieve improved HIV outcomes. METHODS: This is a secondary analysis of survey data from a cluster randomised trial in 40 rural communities in Zimbabwe. The survey was conducted four months after the intervention was initiated. Communities were randomised 1:1 to either paid distribution arm, where HIV self-test (HIVST) kits were distributed by a paid distributor, or community-led whereby members of the community were responsible for organising and conducting the distribution of HIVST kits. We used mixed effects logistic regression to assess the effect of social cohesion, problem solving, and HIV awareness on HIV testing and prevention. RESULTS: We found no association between community measures and the three HIV outcomes (self-testing, new HIV diagnosis and linkage to VMMC or confirmatory testing). However, the interaction analyses highlighted that in high social cohesion communities, the odds of new HIV diagnosis was greater in the community-led arm than paid distribution arm (OR 2.06 95% CI 1.03-4.19). CONCLUSION: We found some evidence that community-led interventions reached more undiagnosed people living with HIV in places with high social cohesion. Additional research should seek to understand whether the effect of social cohesion is persistent across other community interventions and outcomes. TRIAL REGISTRATION: PACTR201607001701788.

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.

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].

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.

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.

Teleneurocritical care is associated with equivalent billable charges to in-person neurocritical care for patients with acute stroke.

INTRODUCTION: Teleneurocritical care (TNCC) provides virtual care for hospitals who do not have continuous neurointensivist coverage. It is not known if TNCC is cost effective nor which variables impact the total billed charges per patient encounter. We characterize cost, defined by charge characteristics of TNCC compared to in-person neurocritical care (NCC), for patients with acute ischemic or hemorrhagic stroke requiring ICU care. METHODS: We performed a retrospective review from 2018 to 2021 of prospectively collected multinstitutional databases from a large, integrated, not-for-profit health system with an in-person NCC and spoke TNCC sites. The primary outcome was the total billable charge per TNCC patient with acute ischemic or hemorrhagic stroke compared to in-person NCC. Secondary outcomes were functional outcome, transfer rate, and length of stay (LOS). RESULTS: A total of 1779 patients met inclusion criteria, 1062 at the hub in-person NCC hospital and 717 at spoke TNCC hospitals. Total billed patient charges of TNCC were similar to in-person NCC (median 104% of the cost per in-person NCC patient, 95% CI: 99%-108%). From 2018 to 2021, the charge difference between TNCC and NCC was not different (r2 = 0.71, p = 0.16). Both age and length stay were independently predictive of charges: for every year older the charge increased by US $6.3, and every day greater LOS the charge increased by $2084.3 (p < 0.001, both). TNCC transfer rates were low, and TNCC had shorter LOS and greater favorable functional outcome. DISCUSSION: TNCC was associated with similar patient financial charges as compared to in-person NCC. Standardization of care and the integrated hub-spoke value-focused operational procedures of TNCC may be applicable to other healthcare systems, however, further prospective study is needed.

Bibliometric analysis of authorship patterns in publications from a research group at the London School of Hygiene & Tropical Medicine, 2016-2020.

BACKGROUND: Authors from low and middle-income country (LMIC) institutions are under-represented in publications of research based in LMICs. This case study of publications from authors within the Medical Research Council International Statistics and Epidemiology Group (MRC-ISEG), a global health research group affiliated to the London School of Hygiene & Tropical Medicine in the UK, aims to describe patterns in authorship and factors associated with under-representation. METHODS: Papers were included if they were published between January 2016 and December 2020 inclusive, included an author from the MRC-ISEG and described work conducted in a LMIC. Authors' affiliations were classified using World Bank country income classifications into LMIC affiliations only, high-income country (HIC) affiliations only and mixed LMIC/HIC affiliations. Multinomial logistic regression analysis was used to assess associations of author affiliation category with authorship position, and whether patterns varied by journal impact factor quartile and multiple versus single-country studies. RESULTS: A total of 882 papers, including 10 570 authors describing research conducted in 61 LMICs, were included. Compared with authors of HIC-only affiliation, those with LMIC-only affiliation were less likely to be in first authorship position (relative risk ratio (RRR)=0.51, 95% CI 0.44 to 0.60) and mixed HIC/LMIC affiliation authors were more likely (RRR=2.80, 95% CI 2.35 to 3.34). Compared with authors of HIC-only affiliation, those with LMIC-only affiliation were less likely to be in last authorship position (RRR=0.20, 95% CI 0.16 to 0.24) and those with mixed HIC/LMIC affiliations were more likely (RRR=1.95, 95% CI 1.65 to 2.30). The proportion of senior authors with LMIC-only affiliation was lowest for the highest impact journals, and in multicountry versus single-country studies. CONCLUSION: Alongside increasing research capacity within LMICs, HIC institutions should ensure that LMIC-affiliated researchers are properly represented in global research. Academics working in global health should be judged on their involvement in representative collaborative research rather than individual achievements in authorship position.

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.

Teleneurocritical Care for Patients with Large Vessel Occlusive Ischemic Stroke Treated by Thrombectomy.

BACKGROUND: Teleneurocritical care (TNCC) provides 24/7 virtual treatment of patients with neurological disease in the emergency department or intensive care unit. However, it is not known if TNCC is safe, effective, or associated with similar outcomes compared with in-person neurocritical care. We aim to determine the effect of daily inpatient consults from TNCC on the outcomes of patients with large vessel occlusive acute ischemic stroke treated by thrombectomy. METHODS: A multicenter, retrospective cohort of consecutive patients ≥ 18 years old with acute ischemic stroke from a large vessel occlusion treated by thrombectomy were identified from 2018 to 2021 within a telehealth network of an integrated not-for-profit health care system in the United States. The primary end point was good functional outcome, i.e., modified Rankin Scale 0-3, at the time of hospital discharge in patients receiving in-person neurocritical care versus TNCC. RESULTS: A total of 437 patients met inclusion criteria, 226 at the in-person hospital (median age 67, 53% women) and 211 at the two TNCC hospitals (median age 74, 49% women). The rate of successful endovascular therapy (modified Thrombolysis in Cerebral Infarction score 2b-3) was not different among hospitals. Good functional outcome at discharge was similar between in-person neurocritical care and TNCC (in-person 31.4% vs. TNCC 33.5%, odds ratio 0.88, 95% confidence interval 0.6-1.3; p = 0.64). Only National Institutes of Health stroke scale and age were multivariable predictors of outcome. There were no differences in mortality (9.3% vs. 13.2%, p = 0.19), intensive care unit length of stay (2.1 vs. 1.9 days, p = 0.39), or rate of symptomatic intracerebral hemorrhage (6.8% vs. 6.6%, p = 0.47) between in-person neurocritical care and TNCC. CONCLUSIONS: Teleneurocritical care allows for equivalent favorable functional outcomes compared with in-person neurocritical care for patients with acute large vessel ischemic stroke receiving thrombectomy. The standardized protocols used by TNCC in this study, specifically the comprehensive 24/7 treatment of patients in the intensive care unit for the length of their stay, may be relevant for other health systems with limited in-person resources; however, additional study is required.

Temporal dynamics of emotional processing: Parsing trial-wise variance of the late positive potential using Generalizability Theory.

The reliability of individual trial event-related potential (ERP) components extracted from electroencephalogram has been consistently questioned since ERP research began. This ambivalence is based on misunderstood assumptions stemming from Cronbach and Classical Test Theory. Contemporary methods allow for the reliability of individual ERP trials to be estimated and for analyses of these trial-level ERP components to be meaningfully parsed. We illustrate the use of Generalizability Theory procedures in estimating the reliability of trial-level ERPs using the late positive potential (LPP), a neural measure of motivated attention toward emotionally evocative stimuli. Individuals (N = 88) completed a passive viewing task while continuous EEG was recorded. Variability in trial-level LPP responses was decomposed into facets corresponding to individual differences, chronological trial within block, stimulus type, their two-way interactions, and specific stimuli. We estimated various reliability coefficients and found that both overall and category-specific person-level LPP estimates have good-to-excellent reliability, while the reliability of within-person differences (i.e., change) between arousal categories was fair for the early LPP. These results were generally consistent across time windows, but were highest early in the LPP time course. We argue that investigating reliability using trial-level data allows researchers to pursue hypotheses focused on neurophysiological dynamics that unfold over the course of an experiment and not risk false inferences (i.e., ecological fallacy) when using person-level aggregates to deduce such processes. Moreover, such analyses provide information that allows researchers to optimize their protocols by potentially reducing the number of individual trials, burden on participants, and cost, while retaining sufficient reliability.