Upregulation of PTPRC and Interferon Response Pathways in HIV-1 Seroconverters Prior to Infection.

Human immunodeficiency virus 1 (HIV-1) exposed seronegative (HESN) individuals may have unique characteristics that alter susceptibility to HIV-1 infection. However, identifying truly exposed HESN is challenging. We utilized stored data and biospecimens from HIV-1 serodifferent couple cohorts, in which couples' HIV-1 exposures were quantified based on unprotected sex frequency and viral load of the partner with HIV-1. We compared peripheral blood gene expression between 15 HESN and 18 seroconverters prior to infection. We found PTPRC (encoding CD45 antigen) and interferon-response pathways had significantly higher expression among individuals who went on to become seropositive and thus may be a signature for increased acquisition risk.

Sexually Transmitted Infection Point-of-Care Testing in Resource-Limited Settings: A Narrative Review Guided by an Implementation Framework.

ABSTRACT: Most sexually transmitted infections (STIs) are acquired in resource-limited settings (RLSs) where laboratory diagnostic access is limited. Advancements in point-of-care testing (POC) technology have the potential to bring STI testing to many RLSs. We define POC as performed near the patient and with results readily available to inform clinical practice. The World Health Organization Special Programme for Research and Training in Tropical Diseases further outlines desirable POC characteristics with the REASSURED criteria.Despite advantages related to immediate test-and-treat care, integrating POC into RLS health care systems can present challenges that preclude reliance on these tests. In 2018, we incorporated molecular near-POC for chlamydia, gonorrhea, and trichomoniasis and SDBioline treponemal immunochromatographic testing confirmed by rapid plasma reagin for syphilis diagnosis at the Mbarara University of Science and Technology Research Laboratory in rural southwestern Uganda. We describe our experiences with STI POC as a case example to guide a narrative review of the field using the Consolidated Framework for Implementation Research as a conceptual framework.Although POC and near-POC are described as easy to use, the challenges of limited person-power, health care processes, limited infrastructure/resources, high costs, and quality control obstacles can impede the impact of these tests. Increased investment in operators, training, and infrastructure, restructuring health care systems to accommodate increased POC access, and optimizing costs are all crucial to the successful implementation of STI POC in RLS. Expanded STI POC in RLS will increase access to accurate diagnoses, appropriate treatment, and engagement in partner notification, treatment, and prevention efforts.

"I felt very small and embarrassed by the health care provider when I requested to be tested for syphilis": barriers and facilitators of regular syphilis and HIV testing among female sex workers in Uganda.

BACKGROUND: Periodic testing of female sex workers (FSW) for sexually transmitted infections (STIs) is a core component of global and national responses to achieve population-level STI elimination. We conducted a qualitative study to explore barriers and facilitators of regular syphilis and HIV testing among FSW in Uganda. METHODS: Within a quasi-experimental study among 436 FSW to assess the effect of peer education and text message reminders on uptake of regular STI and HIV testing among FSW, we conducted 48 qualitative interviews in four cities in Uganda from August-December 2018. We purposively selected FSW who tested for syphilis and HIV every 3-6 months; 12 FSW were interviewed in each city. Sex worker interviews explored: 1) reasons for periodic syphilis and HIV testing; 2) barriers and facilitators of testing; 3) experiences of testing; and 4) challenges faced while seeking testing services. Data were analyzed using thematic content analysis. RESULTS: Thematic analysis revealed individual- and health system-level barriers and facilitators of testing. For syphilis, barriers were a) interpersonal stigma, low perceived severity of syphilis and testing misconceptions (individual); and b) judgmental provider attitudes, paucity of facilities offering syphilis testing, stockouts of test kits and high cost (health system). Facilitators were c) desire to remain healthy, get married and have children, knowing the benefits of early treatment, influence of male partners/clients and normative testing behaviors (individual); and d) sex worker clinics offering dual syphilis/HIV testing (health system). For HIV, barriers included: a) internalized stigma (individual); and b) unfavorable clinic hours, stigma, discrimination, and unfriendly provider (health system). Facilitators were a) motivations to stay healthy and attract clients, habitual testing, self-efficacy, doubts about accuracy of negative test results, and use of post-exposure prophylaxis (individual); and d) availability of testing facilities (health system). Syphilis and HIV had similar testing barriers and facilitators. CONCLUSIONS: HIV programs are likely to be important entry points for syphilis testing among FSW. Multi-level interventions to address testing barriers should consider focusing on these service delivery points. Extending the dual syphilis and HIV testing approach to FSW may improve testing uptake for both infections at public health facilities and decrease population-level incidence.

Text message reminders and peer education increase HIV and Syphilis testing among female sex workers: a pilot quasi-experimental study in Uganda.

BACKGROUND: Globally, female sex workers (FSW) are disproportionately affected by HIV and other sexually transmitted infections (STIs). However, uptake of STI and HIV testing services among FSW in sub-Saharan Africa remains low. We aimed to assess the effect of FSW-led peer education and text message reminders on 3-monthly syphilis and HIV testing among FSW in Uganda. METHODS: Between September 2019 and February 2020, we implemented weekly peer education sessions and bi-monthly SMS reminders for FSW in Mbarara (intervention city). Peer education sessions were implemented by 20 FSW, who received five days of basic training as peer educators. We held monthly meetings with peer educators throughout the six-month implementation period. FSW in Mbale (control city) continued to receive standard of care consisting of HIV testing outreach campaigns, and facility-based testing. Using a quasi-experimental design in one intervention city, and one control city, we conducted pre- and post- questionnaire-based surveys on recent syphilis and HIV testing behavior among FSW in July-October 2018, and March 2020. We compared proportions and prevalence ratios at baseline and follow-up using chi-square tests and negative binomial regression. RESULTS: We conducted 436 interviews (200 before/236 after) with FSW. At baseline similar proportions reported taking an HIV test (57 % vs. 54 %; p = 0.72), and a syphilis serology test (35 % vs. 39 %; p = 0.67) in the intervention and control cities, respectively, in the prior three months. After the intervention, this proportion increased to 82 % (95 % confidence interval [CI] 74.0-88.2) for HIV, and 81 % (95 % CI: 73.0-87.0) for syphilis in the intervention city. Relative to baseline in the control city, the proportion testing for HIV was unchanged (52 %) but decreased for syphilis (26 %). CONCLUSIONS: Bi-monthly text message reminders with weekly peer education sessions increased uptake of 3-monthly syphilis and HIV testing in a Ugandan female sex work population and could help increase sex worker engagement in HIV/STI services in line with World Health Organization recommendations.

HIV and syphilis testing behaviors among heterosexual male and female sex workers in Uganda.

BACKGROUND: In Sub-Saharan Africa where HIV disproportionately affects women, heterosexual male sex workers (HMSW) and their female clients are at risk of acquiring or transmitting HIV and other STIs. However, few studies have described HIV and STI risk among HMSW. We aimed to assess and compare recent HIV and syphilis screening practices among HMSW and female sex workers (FSW) in Uganda. METHODS: Between August and December 2019, we conducted a cross-sectional study among 100 HMSW and 240 female sex workers (FSW). Participants were enrolled through snowball sampling, and an interviewer-administered questionnaire used to collect data on HIV and syphilis testing in the prior 12 and 6 months respectively. Integrated change model constructs were used to assess intentions, attitudes, social influences, norms and self-efficacy of 3-monthly Syphilis and 6-monthly HIV testing. Predictors of HIV and syphilis recent testing behaviors were estimated using negative binomial regression. RESULTS: We enrolled 340 sex workers of whom 100 (29%) were HMSW. The median age was 27 years [interquartile range (IQR) 25-30] for HMSW and 26 years [IQR], (23-29) for FSW. The median duration of sex work was 36 and 30 months for HMSW and FSW, respectively. HMSW were significantly less likely than FSW to have tested for HIV in the prior 12 months (50% vs. 86%; p = 0.001). For MSW, non-testing for HIV was associated with higher education [adjusted prevalence ratio (aPR) 1.66; 95% confidence interval (CI) 1.09-2.50], poor intention to seek HIV testing (aPR 1.64; 95% CI 1.35-2.04), perception that 6-monthly HIV testing was not normative (aPR 1.33; 95% CI 1.09-1.67) and low self-efficacy (aPR 1.41; 95% CI 1.12-1.79). Not testing for syphilis was associated with low intention to seek testing (aPR 3.13; 95% CI 2.13-4.55), low self-efficacy (aPR 2.56; 95% CI 1.35-4.76), negative testing attitudes (aPR 2.33; 95% CI 1.64-3.33), and perception that regular testing was not normative (aPR 1.59; 95% CI 1.14-2.22). CONCLUSIONS: Non-testing for HIV and syphilis was common among HMSW relative to FSW. Future studies should evaluate strategies to increase testing uptake for this neglected sub-population of sex workers.

Low male partner attendance after syphilis screening in pregnant women leads to worse birth outcomes: the Syphilis Treatment of Partners (STOP) randomised control trial.

Background Maternal syphilis causes poor birth outcomes, including congenital syphilis. Testing and treatment of partners prevents reinfection, but strategies to improve partner attendance are failing. The aim of this study was to determine the effectiveness of three partner notification strategies. METHODS: Pregnant women with a positive point-of-care treponemal test at three antenatal clinics (ANCs) in Kampala, Uganda, were randomised 1:1:1 to receive either notification slips (NS; standard of care), NS and a text messages (SMS) or NS and telephone calls. The primary outcome was the proportion of partners who attended the ANC and were treated for syphilis. RESULTS: Between 2015 and 2016, 17130 pregnant women were screened; 601 (3.5%) had a positive treponemal result, and 442 were enrolled in the study. Only 81 of 442 partners (18.3%; 23/152 (15.1%), 31/144 (21.5%) and 27/146 (18.5%) in the NS only, NS + SMS and NS + telephone call groups respectively) attended an ANC for follow-up; there were no significant differences between the groups. Twelve per cent of women attended the ANC with their male partner, and this proportion increased over time. Partner non-treatment was independently associated with adverse birth outcomes (odds ratio 2.75; 95% confidence interval 2.36-3.21; P < 0.001). CONCLUSIONS: Only 18.3% of partners of pregnant women who tested positive for syphilis received treatment. Female partners of non-attendant men had worse birth outcomes. Encouraging men to accompany women to the ANC and testing both may address the urgent need to treat partners of pregnant women in sub-Saharan Africa to reduce poor fetal outcomes.

Perspectives on male partner notification and treatment for syphilis among antenatal women and their partners in Kampala and Wakiso districts, Uganda.

BACKGROUND: Syphilis screening can be successfully integrated into antenatal clinics, and potentially avert significant morbidity and mortality to unborn infants. A minority of male partners report for testing and treatment, increasing the likelihood of reinfection. We conducted a qualitative study to understand factors influencing male partners to seek treatment after syphilis notification by their pregnant partners. METHODS: A purposeful sample of 54 adults who participated in the STOP (Syphilis Treatment of Partners) study was stratified by gender (24 women, 30 male partners) and enrolled for in-depth interviews which were audio recorded, transcribed, and analyzed using the thematic approach. RESULTS: The participants' median age (IQR) was 32 years (25-44), 87% were married, and 57.4% (31/74) had attained secondary education. Fourteen of 22 (63%) female participants reported that they sometimes experienced domestic violence. Male participant's knowledge of syphilis and their perception of their valued role as responsible fathers of an unborn baby facilitated return. Female's fear of partner's violence and poor communication between partners, were barriers against delivery of the notification forms to partners and subsequent treatment of partners. For men, fear of injection pain, perceptions of syphilis as a genetic disease and as a woman's problem, busy work schedules, poor access to good STD services, shared facilities with women in clinics, as well as HIV-related stigma were important barrier factors. CONCLUSIONS: The return to the clinic for treatment of male partners after partner notification by infected pregnant women, was low due to limited knowledge about syphilis, fear of painful injection, fears of domestic violence, lack of communication skills (individual characteristics) and syphilis disease characteristics such as signs and symptoms. This, combined with health services characteristics such as structural barriers that hinder male partner treatment, low access, low capacity, work/time challenges, inadequate laboratory services and low clinic personnel capacity; threatens efforts to eliminate mother-to-child infection of syphilis. Improved public messaging about syphilis, better services, legal and policy frameworks supporting STD notification and treatment in resource-constrained settings are needed for effective STD control. TRIAL REGISTRATION: Clinicaltrials.gov NCT02262390 ., Date Registered October 8 2014.

Psychosocial correlates of regular syphilis and HIV screening practices among female sex workers in Uganda: a cross-sectional survey.

BACKGROUND: Limited data are available regarding correlates of regular sexually transmitted infections (STIs) and HIV screening among female sex workers (FSW) in Sub-Saharan Africa. In this study, we aimed to assess the frequency of regular syphilis and HIV screening and the psychosocial correlates associated with screening among FSW in Uganda. METHODS: This cross-sectional correlational study was conducted among 441 FSW, aged 17-49 years. We enrolled FSW through peer referrals and ascertained self-reported data on number of serological tests for HIV, syphilis and other STIs in the prior 12 months using an interviewer-administered questionnaire. In addition, we assessed attitudes, norms, social influences and self-efficacy towards 3-monthly Syphilis and 6-monthly HIV testing. We estimated the correlates of regular STI and HIV testing using negative binomial regression. RESULTS: Of the respondents 420 (95.2%) reported to have ever taken an HIV test with 297 (67.4%) testing two or more times in the prior 12 months. Over half of the respondents (59%) reported ever taking a syphilis test with only 62 (14.1%) reporting testing three or more times in the prior 12 months. After adjusting for socio-demographics, attitude and norms, high perceived self-efficacy was associated with a 33% increase in the likelihood of repeated HIV testing [prevalence ratio (PR), 1.33, 95% confidence interval (CI) 1.15-1.53] while low perceived confidence was associated with a 25% decrease in the likelihood of repeated HIV testing (PR, 0.75, 95% CI 0.63-0.89). Similarly low attitudes and norms were associated with a decrease of 52.6% (PR, 0.47, 95% CI 0.37-0.61) and 47% (PR, 0.53, 95% CI 0.41-0.69) in the likelihood of repeated syphilis testing respectively. CONCLUSION: Compared to HIV, uptake of repeated syphilis testing was very low. Correlates of HIV testing include; perceived self-efficacy amidst barriers and perceived confidence for HIV and low attitudes and accepting norms for syphilis. Health campaigns should emphasize overcoming barriers to HIV testing while promoting attitudes and norms including integration of serological syphilis testing and other STIs into HIV services.

Challenges of Rapid Plasma Reagin Interpretation in Syphilis Screening in Uganda: Variability in Nontreponemal Results Between Different Laboratories.

BACKGROUND: Syphilis is a cause of morbidity and mortality and is of particular concern in pregnancy in low-income countries because of the risks associated with maternal-fetal transmission. Ugandan national guidelines recommend a nontreponemal rapid plasma reagin (RPR) followed by treponemal testing for diagnosis of syphilis. The RPR test confirms a reactive specific treponemal test, or confirms serological "cure" with a 4-fold dilutional decrease; RPR is beset with technical and biological limitations, making accurate diagnosis and appropriate treatment problematic. The aim of this analysis was to compare performance of RPR testing in different laboratories. METHODS: Stored, freeze-thawed sera from 215 participants were additionally tested for RPR and dilutional titer in 2 different reference laboratories. Discrepant results were tested at a third reference laboratory which served as a tie-breaker. Equivalence in RPR titer was defined as within 2-fold or less. All patients with reactive rapid tests were treated as per Ugandan National Guidelines. RESULTS: Of 215 sera, 97 (45.1%) were RPR reactive in clinic laboratory A, 81 (37.7%) and 65 (30.2%) were RPR reactive in laboratories B and C, respectively. All reported positive in laboratory C were positive in laboratory B. Discrepant results were tested in laboratory D. χ Test was highly significant (P = <0.001) for difference between each dyad of laboratories (A and B, A and C, and B and C) RPR results. There were significant differences between RPR titers by paired t test and Wilcox rank test (P = <0.001); with up to a 3-fold difference between laboratories. Two one-sided test approach demonstrated nonequivalence. Agreement between laboratories B-D, and C-D: 48 (98.0%) of 49 and 34 (69.4%) of 49, respectively (P = <0.001). Laboratories B and D showed no significant difference and had equivalent RPR titers. Laboratories C and D had different titers (P = <0.001) and were not equivalent. CONCLUSIONS: We found significant interlaboratory discrepant RPR results. A 3-fold difference in results is likely to be clinically significant and could result in undertreatment or overtreatment. These data demonstrate a key limitation of the RPR test and underline the urgent need for a more reproducible quantitative test than the current RPR for diagnosing and determining cure of syphilis.

A cross-sectional analysis of Trichomonas vaginalis infection among heterosexual HIV-1 serodiscordant African couples.

OBJECTIVES: Trichomonas vaginalis is the most prevalent curable STI worldwide and has been associated with adverse health outcomes and increased HIV-1 transmission risk. We conducted a cross-sectional analysis among couples to assess how characteristics of both individuals in sexual partnerships are associated with the prevalence of male and female T. vaginalis infection. METHODS: African HIV-1 serodiscordant heterosexual couples were concurrently tested for trichomoniasis at enrolment into two clinical trials. T. vaginalis testing was by nucleic acid amplification or culture methods. Using Poisson regression with robust standard errors, we identified characteristics associated with trichomoniasis. RESULTS: Among 7531 couples tested for trichomoniasis, 981 (13%) couples contained at least one infected partner. The prevalence was 11% (n=857) among women and 4% (n=319) among men, and most infected individuals did not experience signs or symptoms of T. vaginalis. Exploring concordance of T. vaginalis status within sexual partnerships, we observed that 61% (195/319) of T. vaginalis-positive men and 23% (195/857) of T. vaginalis-positive women had a concurrently infected partner. In multivariable analysis, having a T. vaginalis-positive partner was the strongest predictor of infection for women (relative risk (RR) 4.70, 95% CI 4.10 to 5.38) and men (RR 10.09, 95% CI 7.92 to 12.85). For women, having outside sex partners, gonorrhoea, and intermediate or high Nugent scores for bacterial vaginosis were associated with increased risk of trichomoniasis, whereas age 45 years and above, being married, having children and injectable contraceptive use were associated with reduced trichomoniasis risk. Additionally, women whose male partners were circumcised, had more education or earned income had lower risk of trichomoniasis. CONCLUSIONS: We found that within African HIV-1 serodiscordant heterosexual couples, the prevalence of trichomoniasis was high among partners of T. vaginalis-infected individuals, suggesting that partner services could play an important role identifying additional cases and preventing reinfection. Our results also suggest that male circumcision may reduce the risk of male-to-female T. vaginalis transmission.

Effect of suppressive acyclovir administered to HSV-2 positive mothers from week 28 to 36 weeks of pregnancy on adverse obstetric outcomes: a double-blind randomised placebo-controlled trial.

BACKGROUND: Acyclovir (ACV) given to HSV-2 positive women after 36 weeks reduces adverse outcomes but its benefit at lower gestation was undocumented. We determined the effect of oral acyclovir administered from 28 to 36 weeks on premature rupture of membranes (PROM) primarily and preterm delivery risk. METHODS: This was a randomized, double-blind placebo-controlled trial among 200 HSV-2 positive pregnant women at 28 weeks of gestation at Mulago Hospital, Uganda. Participants were assigned randomly (1:1) to take either acyclovir 400 mg orally twice daily (intervention) or placebo (control) from 28 to 36 weeks. Both arms received acyclovir after 36 weeks until delivery. Development of Pre-PROM by 36 weeks and preterm delivery were outcomes. RESULTS: One hundred women were randomised to acyclovir and 100 to placebo arms between January 2014 and February 2015. There was tendency towards reduction of incidence of PROM at 36 weeks but this was not statistically significant (4.0% versus 10.0%; RR 0.35; 95% 0.11-1.10) in the acyclovir and placebo arms respectively. However, there was a significant reduction in the incidence of preterm delivery (11.1% versus 23.5%; RR 0.41; 95% 0.20-0.85) in the acyclovir and placebo arms respectively. CONCLUSIONS: Oral acyclovir given to HSV-2 positive pregnant women from 28 to 36 weeks reduced incidence of preterm delivery but did not significantly reduce incidence of pre-PROM. TRIAL REGISTRATION: www.pactr.org, PACTR201311000558197 .

Genital Herpes Simplex Virus Type 2 Shedding Among Adults With and Without HIV Infection in Uganda.

BACKGROUND: Despite the high prevalence of herpes simplex virus type 2 (HSV-2) in sub-Saharan Africa, the natural history of infection among Africans is not well characterized. We evaluated the frequency of genital HSV shedding in HIV-seropositive and HIV-seronegative men and women in Uganda. METHODS: Ninety-three HSV-2-seropositive Ugandan adults collected anogenital swab specimens for HSV DNA quantification by polymerase chain reaction 3 times daily for 6 weeks. RESULTS: HSV-2 was detected from 2484 of 11 283 swab specimens collected (22%), with a median quantity of 4.3 log10 HSV copies/mL (range, 2.2-8.9 log10 HSV copies/mL). Genital lesions were reported on 749 of 3875 days (19%), and subclinical HSV shedding was detected from 1480 of 9113 swab specimens (16%) collected on days without lesions. Men had higher rates of total HSV shedding (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.3-2.9]; P < .001); subclinical shedding (RR, 1.7 [95% CI, 1.1-2.7]; P = .01), and genital lesions (RR, 2.1 [95% CI, 1.2-3.4]; P = .005), compared with women. No differences in shedding rates or lesion frequency were observed based on HIV serostatus. CONCLUSIONS: HSV-2 shedding frequency and quantity are high among HSV-2-seropositive adults in sub-Saharan Africa, including persons with and those without HIV infection. Shedding rates were particularly high among men, which may contribute to the high prevalence of HSV-2 and early acquisition among African women.

Clinical Evaluation of 2 Point-of-Care Lateral Flow Tests for the Diagnosis of Syphilis.

A diagnostic performance study comparing the only Food and Drug Administration-approved, point-of-care (POC) treponemal test (Syphilis Health Check) and the World Health Organization pre-qualified SD Bioline POC treponemal test against a treponemal hemagglutination test (TPHA) and a sequential algorithm of nontreponemal rapid plasma reagin and TPHA found both POC tests had >85% sensitivity compared with the TPHA and >85% sensitivity and >95% specificity compared with the rapid plasma reagin and TPHA standards.

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.).

Daily oral tenofovir and emtricitabine-tenofovir preexposure prophylaxis reduces herpes simplex virus type 2 acquisition among heterosexual HIV-1-uninfected men and women: a subgroup analysis of a randomized trial.

BACKGROUND: Daily oral preexposure prophylaxis (PrEP) using the antiretroviral tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC-TDF) reduces the risk for HIV-1 acquisition. Tenofovir has in vitro activity against herpes simplex virus type 2 (HSV-2). OBJECTIVE: To assess the efficacy of daily oral PrEP with tenofovir and FTC-TDF in the prevention of HSV-2 acquisition. DESIGN: Subgroup analysis of data from a randomized, placebo-controlled trial with concealed allocation. (ClinicalTrials.gov: NCT00557245). SETTING: Multiple sites in Kenya and Uganda. PARTICIPANTS: Heterosexual men and women who were seronegative for HIV-1 and HSV-2 and at high risk for HIV-1 acquisition due to having an HIV-1-infected partner. INTERVENTION: Once-daily oral tenofovir disoproxil fumarate (TDF), alone or combined with emtricitabine (FTC-TDF), compared with placebo. MEASUREMENTS: HSV-2 seroconversion. RESULTS: A total of 131 participants seroconverted to HSV-2 (79 of 1041 assigned to tenofovir or FTC-TDF PrEP [HSV-2 incidence, 5.6 per 100 person-years] and 52 of 481 assigned to placebo [HSV-2 incidence, 7.7 per 100 person-years]). The hazard ratio (HR) for HSV-2 acquisition with daily oral PrEP was 0.70 (95% CI, 0.49 to 0.99; P = 0.047) compared with placebo, and the absolute risk reduction was 2.1 per 100 person-years. Among the 1044 participants with HSV-2-infected partners, the HR for PrEP was 0.67 (CI, 0.46 to 0.98; P = 0.038) compared with placebo, and the absolute risk reduction was 3.1 per 100 person-years. LIMITATION: Randomization was not stratified by HSV-2 status, and diagnostic tests to exclude participants with acute HSV-2 at baseline are not available. CONCLUSION: Daily oral tenofovir-based PrEP significantly reduced the risk for HSV-2 acquisition among heterosexual men and women. Modest protection against HSV-2 is an added benefit of HIV-1 prevention with oral tenofovir-based PrEP. PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.

Correlation between pill counts and biologic effects in an HIV-1 prevention clinical trial: implications for measuring adherence.

Clinic-based pill counts of unused study medication are frequently used to measure adherence in HIV-1 prevention trials. Monthly pill count adherence data from the Partners in Prevention HSV/HIV Transmission Study, a double-blind, placebo controlled trial of twice-daily acyclovir suppression of herpes simplex virus type 2 (HSV-2) in HIV-1 infected persons was used to compare changes between 3,381 placebo and active arm participants in two objective biologic measures of acyclovir's drug activity: reduction in plasma HIV-1 RNA and HSV-2 genital ulcer disease (GUD). Higher acyclovir pill count adherence was associated with greater reductions in plasma HIV-1 RNA and GUD, indicating pill count data is strongly correlated with biological effects of adherence. However, when calculated adherence exceeded 102 % (i.e., fewer pills returned than expected) and when pill counts were missing because bottles were not returned, plasma HIV-1 RNA and GUD effects were diminished, likely indicating periods of non-adherence.

Quantifying ongoing HIV-1 exposure in HIV-1-serodiscordant couples to identify individuals with potential host resistance to HIV-1.

BACKGROUND: Immunogenetic correlates of resistance to HIV-1 in HIV-1-exposed seronegative (HESN) individuals with consistently high exposure may inform HIV-1 prevention strategies. We developed a novel approach for quantifying HIV-1 exposure to identify individuals remaining HIV-1 uninfected despite persistent high exposure. METHODS: We used longitudinal predictors of HIV-1 transmission in HIV-1 serodiscordant couples to score HIV-1 exposure and define HESN clusters with persistently high, low, and decreasing risk trajectories. The model was validated in an independent cohort of serodiscordant couples. We describe a statistical tool that can be applied to other HESN cohorts to identify individuals with high exposure to HIV-1. RESULTS: HIV-1 exposure was best quantified by frequency of unprotected sex with, plasma HIV-1 RNA levels among, and presence of genital ulcer disease among HIV-1-infected partners and by age, pregnancy status, herpes simplex virus 2 serostatus, and male circumcision status among HESN participants. Overall, 14% of HESN individuals persistently had high HIV-1 exposure and exhibited a declining incidence of HIV-1 infection over time. CONCLUSIONS: A minority of HESN individuals from HIV-1-discordant couples had persistent high HIV-1 exposure over time. Decreasing incidence of infection in this group suggests these individuals were selected for resistance to HIV-1 and may be most appropriate for identifying biological correlates of natural host resistance to HIV-1 infection.

Retrospective Analysis of Ugandan Men with Urethritis Reveals Mycoplasma genitalium and Associated Macrolide Resistance.

The rising rates of antimicrobial resistance (AMR) in Mycoplasma genitalium globally and the association of this sexually transmitted infection (STI) with cervicitis, urethritis, and HIV are potentially of great public health concern. Data on the epidemiology of M. genitalium in men in sub-Saharan Africa are limited. We sought to determine the prevalence of M. genitalium and macrolide resistance in men with urethritis in Kampala, Uganda. Self-collected penile-meatal swabs and/or urine samples from men with symptomatic urethritis (n = 250) were retrospectively analyzed for the presence of M. genitalium and macrolide resistance markers with the Aptima M. genitalium and ResistancePlus M. genitalium assays. Additionally, demographic and STI coinfection data were used to investigate associations with M. genitalium infection. M. genitalium was detected in 12.8% (32/250) of individuals; 40.6% (n = 13) had M. genitalium monoinfection. Mutations associated with macrolide resistance were detected in 10.7% (3/28) of participants. Coinfection with Neisseria gonorrhoeae was common (41.0%), but M. genitalium was more prevalent in participants without N. gonorrhoeae coinfection (P = 0.001). M. genitalium is common in Ugandan men with urethritis both as a monoinfection and as a coinfection with other curable STIs. Macrolide resistance was present and warrants further research on treatment outcomes and the association between untreated M. genitalium and subsequent morbidity. IMPORTANCE Mycoplasma genitalium is a common sexually transmitted infection associated with urethritis in men. Little is known about M. genitalium infection in men with urethritis in Uganda. We report that 12% of participants in this study were positive for M. genitalium and that resistance to azithromycin, a macrolide antibiotic, is present. Furthermore, we show that either self-collected penile-meatal swabs or urine can be used for detection of M. genitalium.

Prevalence and antimicrobial resistance profiles of Neisseria gonorrhea and Chlamydia trachomatis isolated from individuals attending STD clinics in Kampala, Uganda.

Background: Sexually transmitted diseases (STDs) management in sub-Saharan Africa is syndromic but molecular diagnostics provide quicker, sensitive diagnosis and treatment. Effective STD control hinges on identification and treatment of infected persons and sexual partner contact tracing. Objectives: This study assessed feasibility of using the Xpert CT/NG test to identify prevalent Chlamydia trachomatis (CT) and Neisseria gonorrhea (NG) infections among STD clinic attendees and their sexual partners and tested for antimicrobial resistance for N. gonorrhea. Methods: A cross-sectional study was conducted at 4 outpatient STD clinics in Kampala, Uganda from February 2019 to October 2019. Participants received a syndromic diagnosis, were tested for NG and CT, as well as their sexual partners. Urine (men) and high vaginal swabs (women) were collected, examined using Xpert CT/NG assay. A total of 79 participants were enrolled at baseline of whom 25 had CT/NG. 21 partners of infected baseline participants and 7 partners of the 21 primary partners were enrolled. Results: The mean age of the reported sexual partners was 26 (18-43) years. The prevalence of NG was 25% at baseline and 18 % for CT. Nine (11.4%) people were dually infected. Men were more likely to have NG (p<0.001) at multivariable level. Two participants tested HIV-1 positive. On microbiological culture, 8 samples (2.5%) grew NG and all were resistant to penicillin, ciprofloxacin. For CT, we found a preponderance of the F-serovar in this population. Conclusion: The most prevalent organism was Neisseria gonorrhea. Generally, the prevalence of CT and NG was high. Infection proportions increased among primary partners, particularly women. Etiologic testing without partner tracing and treatment may underestimate burden of CT/NG in this population and contribute to re-infection.

A portable magnetofluidic platform for detecting sexually transmitted infections and antimicrobial susceptibility.

Effective treatment of sexually transmitted infections (STIs) is limited by diagnostics that cannot deliver results rapidly while the patient is still in the clinic. The gold standard methods for identification of STIs are nucleic acid amplification tests (NAATs), which are too expensive for widespread use and have lengthy turnaround times. To address the need for fast and affordable diagnostics, we have developed a portable, rapid, on-cartridge magnetofluidic purification and testing (PROMPT) polymerase chain reaction (PCR) test. We show that it can detect Neisseria gonorrhoeae, the pathogen causing gonorrhea, with simultaneous genotyping of the pathogen for resistance to the antimicrobial drug ciprofloxacin in <15 min. The duplex test was integrated into a low-cost thermoplastic cartridge with automated processing of penile swab samples from patients using magnetic beads. A compact instrument conducted DNA extraction, PCR, and analysis of results while relaying data to the user via a smartphone app. This platform was tested on penile swab samples from sexual health clinics in Baltimore, MD, USA (n = 66) and Kampala, Uganda (n = 151) with an overall sensitivity and specificity of 97.7% (95% CI, 94.7 to 100%) and 97.6% (95% CI, 94.1 to 100%), respectively, for N. gonorrhoeae detection and 100% concordance with culture results for ciprofloxacin resistance. This study paves the way for delivering accessible PCR diagnostics for rapidly detecting STIs at the point of care, helping to guide treatment decisions and combat the rise of antimicrobial resistant pathogens.