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Background Prior to the widespread availability of antiretroviral therapy (ART), men living with human immunodeficiency virus (HIV) with urethritis had increased concentrations of HIV in semen. This study aims to better evaluate HIV shedding in men with urethritis receiving ART, and its implications for the cure of HIV. Methods Men living with HIV with urethritis taking ART ≥12 weeks were enrolled at a sexually transmitted infections clinic in Lilongwe, Malawi. Study follow-up included visits at 1, 2, 4, 8, 12, 24, 36, and 48 weeks after urethritis diagnosis and treatment. Matched blood and semen samples were collected at all visits, and all additional episodes of urethritis were followed with extra visits 1, 2, and 4 weeks after treatment. Results There were 111 men enrolled in the study between January 2017–March 2019, and 77 (69%) were suppressed in the blood (<400 copies/mL). Among the 77 men, 87 episodes of urethritis were evaluated during follow-up. Of the 87 episodes, 15 episodes (17%) had instances of seminal viral shedding ≥400 copies/mL despite viral suppression in the blood. During nonurethritis follow-up, ≤6% of men at each visit had a viral load ≥400 copies/mL in the semen while maintaining viral suppression in the blood. Conclusions An HIV cure requires the elimination of HIV from every body compartment, but available ART does not currently accomplish this. Our study highlights the male genital tract as a local source of HIV that can be reversibly activated. A better understanding of this phenomenon is important to advance the HIV cure field. [ABSTRACT FROM AUTHOR]

Background Understanding sexual networks involving acute human immunodeficiency virus (HIV)-1 infections (AHI) may lead to prevention opportunities to mitigate high rates of onward transmission. We evaluated HIV-1 phylogenetic and behavioral characteristics among persons with AHI and their referred partners. Methods Between 2012 and 2014, 46 persons with AHI in Malawi participated in a combined behavioral and biomedical intervention. Participants referred sexual partners by passive referral. Demographics and sexual behaviors were collected through interviews and HIV-1 genetic relationships were assessed with phylogenetics. Results Among 45 AHI participants with HIV-1 sequences, none was phylogenetically-linked with another AHI index. There were 19 (42%) AHI participants who referred a single partner that returned for testing. Most partners (n = 17) were HIV-infected, with 15 (88%) presenting with an established infection. There were 14 index-partner pairs that had sequences available; 13 (93%) pairs were phylogenetically-linked dyads. The AHI index was female in 7/13 (54%) dyads. Age-disparate relationships among dyads were common (≥5-year age difference in 67% of dyads), including 3/6 dyads involving a male index and a younger woman. Index participants with a referred partner were more likely to report no casual partners and to be living with their current partner than participants not in dyads. Conclusions Passive-partner referral successfully identified partners with genetically-similar HIV infections—the likely source of infection—but only 40% of index cases referred partners who presented for HIV-1 testing. Future work evaluating assisted partner notification may help reach susceptible partners or more people with untreated HIV-1 infections connected to acute transmission. Clinical Trials Registration NCT01450189 [ABSTRACT FROM AUTHOR]

Understanding sexual behavior following diagnosis of acute HIV infection (AHI) is key to developing prevention programs targeting individuals diagnosed with AHI. We conducted separate qualitative and quantitative interviews with individuals newly diagnosed ( n = 19) with AHI at 1-, 4- and 12-weeks post-diagnosis and one qualitative interview with individuals who had previously been diagnosed with AHI ( n = 18) in Lilongwe, Malawi and Johannesburg, South Africa between October 2007 and June 2008. The majority of participants reported engaging in sexual activity following diagnosis with AHI with a significant minority reporting unprotected sex during this time. Most participants perceived to have changed their behavior following diagnosis. However, participants reported barriers to condom use and abstinence, in particular, long term relationships and the need for disclosure of sero-status. Understanding of increased infectiousness during AHI was limited. Participants reported a desire for a behavioral intervention at the time of AHI diagnosis, however, there were differences by country in the types of interventions participants found acceptable. Studies are underway to determine the feasibility, acceptability and potential effectiveness of interventions designed for individuals with AHI. [ABSTRACT FROM AUTHOR]

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We measured enteric parasitic infection prevalence and the effect of treatment on human immunodeficiency virus (HIV) RNA levels to assess their importance to HIV primary care in resource-limited settings. Adults in Lilongwe, Malawi, were evaluated, treated, and followed-up for parasitic and HIV infections. Of 389 patients, 266 (68%) were HIV infected. Helminth infections were more common in HIV-uninfected than in HIV-infected patients (39% vs. 17%). Among HIV-infected patients, helminth infections were associated with higher CD4 cell counts but not with higher HIV RNA levels. Successful treatment of parasitic infections had no effect on HIV RNA levels. Although common, parasitic infections did not impact HIV RNA levels. [ABSTRACT FROM AUTHOR]

Background. Little is known about the epidemiologic profile of trichomoniasis in men and its relationship to human immunodeficiency virus (HIV) infection. Among men presenting for care for symptomatic sexually transmitted infections (STIs) in Malawi, trichomoniasis is not considered for first-line treatment. Methods. We conducted a cross-sectional survey of 1187 men attending either a dermatology or STI outpatient clinic in the capital of Malawi. Men were interviewed, and the etiologies of the STIs were determined. Results. At the STI clinic (n = 756 men), we identified 150 men (20%) with Trichomonas vaginalis infection, 358 men (47%) with HIV infection, and 335 men (44%) with Neisseria gonorrhoeae infection. At the dermatology clinic (n = 431 men), we identified 54 (13%), 118 (27%), and 2 (0.5%) men, respectively. At both clinics, a lower education level and reporting never having used a condom were predictive of T. vaginalis infection. Only at the dermatology clinic was older age associated with infection, and only at the STI clinic were marital, genital ulcer disease, and HIV-infection status associated with T. vaginalis infection. At the STI clinic, urethral symptoms attributable to trichomoniasis were more severe among HIV-positive men than among HIV-negative men. Conclusions. Given its high prevalence and the increased risk for HIV transmission, T. vaginalis infection should be reconsidered for inclusion in the Malawi STI-treatment regimen for men. [ABSTRACT FROM AUTHOR]

Objective: By a randomised, double-blind, placebo-controlled trial of aciclovir 800 mg twice daily for 5 days added to the syndromic management of genital ulcer disease (GUD) to determine the impact on ulcer healing and HIV outcomes.Methods: Patients presenting with GUD in Malawi were evaluated for HIV and herpes simplex virus type-2 (HSV-2) serologies, ulcer aetiology, lesional, genital and plasma HIV-1 RNA and CD4+ count. Patients were followed up at days 2, 4, 7, 14 and 28. The primary study outcome was ulcer healing at day 14, with secondary outcomes being lesional and genital HIV-1 shedding at day 14 and HIV-1 plasma viral load at day 28 among HIV-1/HSV-2 co-infected individuals.Results: Four hundred and twenty-two patients (74% male) were randomised (208 to aciclovir, 214 to placebo), of whom 61% were HIV-1 seropositive and 72% HSV-2 seropositive; 67% (267/398) had HSV-2 ulcers. 85% of ulcers were healed at day 14 with no difference between treatment arms (risk ratio (RR)=1.02, 95% CI 0.93 to 1.11). Among 244 HIV-1/HSV-2 co-infected individuals, aciclovir reduced lesional HIV-1 RNA (adjusted RR=0.64, 95% CI 0.41 to 0.99) and seminal HIV-1 RNA (adjusted RR=0.59, 95% CI 0.40 to 0.88), but not cervical HIV-1 RNA or plasma HIV-1 RNA.Conclusions: Episodic HSV treatment with aciclovir added to syndromic management did not produce a significant clinical benefit in this African population. [ABSTRACT FROM AUTHOR]

Background: Gentamicin has been used for the treatment of gonorrhea in Malawi since 1993. However, declining clinical cure rates have been suspected. We evaluated current Neisseria gonorrhoeae susceptibility to gentamicin in vitro and clinically.Methods: Men with acute urethritis were recruited at the Bwaila District Hospital STI Clinic in Lilongwe, Malawi, between January 2017 and August 2019. All men provided urethral swabs for etiological testing at enrollment and test of cure (TOC), 1 week later, using Gram-stained microscopy and culture. We used Etest to determine minimum inhibitory concentrations (MICs) of gentamicin, azithromycin, cefixime, ceftriaxone, ciprofloxacin, and spectinomycin; disc diffusion for tetracycline susceptibility; and whole-genome sequencing (WGS) to verify/refute treatment failure.Results: Among 183 N. gonorrhoeae culture-positive men enrolled, 151 (82.5%) had a swab taken for TOC. Of these 151 men, 16 (10.6%) had a positive culture at TOC. One hundred forty-one baseline isolates were tested for gentamicin susceptibility using Etest: 2 (1.4%), MIC = 2 μg/mL; 111 (78.7%), MIC = 4 μg/mL; and 28 (19.9%), MIC = 8 μg/mL. All isolates were susceptible to azithromycin, cefixime, ceftriaxone, and spectinomycin, whereas 63.1% had intermediate susceptibility or resistance to ciprofloxacin. Almost all (96.1%) isolates were resistant to tetracycline. All examined isolates cultured at TOC (n = 13) had gentamicin MICs ≤8 μg/mL. Ten men had pretreatment and posttreatment isolates examined by whole-genome sequencing; 2 (20%) were verified new infections (4119 and 1272 single-nucleotide polymorphisms), whereas 8 (80%) were confirmed treatment failures (0-1 single-nucleotide polymorphism).Conclusions: Gentamicin MICs poorly predict gonorrhea treatment outcome with gentamicin, and treatment failures are verified with gonococcal strains with in vitro susceptibility to gentamicin. The first-line treatment of gonorrhea in Malawi should be reassessed. [ABSTRACT FROM AUTHOR]

Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with (n=19) and without (n=5) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication. IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI. [ABSTRACT FROM AUTHOR]

The article presents a study on the role of acute and early HIV infection in the spread of HIV in Lilongwe, Malawi. The study intends to determine the transmission prevention strategies for HIV infection considering the higher transmission of the virus during its acute and early stages. The finding suggest the relevance of implementing early prevention strategies to complement the interventions for spreading the virus during chronic infection.

The article discusses the study which examines the sexual partnership patterns and spread of HIV and sexually transmitted infection (STI) in Lilongwe, Malawi. The researchers have conducted HIV tests and calculated partnership lengths, temporal gaps between partners, and periods of overlap across partners at an STI clinic. The study implies that both long-term and narrow spaced partnerships could present substantial risk for transmission of STI and HIV infections.

Abstract: There are limited data on acute HIV infection (AHI) prevalence during pregnancy. Malawian pregnant women admitted in the third trimester and meeting eligibility criteria underwent dual HIV rapid antibody testing. AHI prevalence was retrospectively detected through HIV RNA pooling of seronegative plasma. Among 3,825 pregnant women screened, dual HIV rapid testing indicated that 30.2% were HIV positive, 69.7% were HIV negative, and 0.1% were indeterminate. Sensitivity and specificity of dual rapid testing was 99.0% and 98.7%, respectively. Of 2,666 seronegative specimens, 2,327 had samples available for HIV RNA pooling; 5 women (0.21%) (95% confidence interval, 0.03–0.40%) had AHI with a median peripartum viral load of 1,324,766 copies/mL. Pregnant women are at risk for AHI, warranting counseling of all women and their sexual partners about incident HIV during pregnancy. Dual HIV rapid tests have high sensitivity and specificity. HIV testing should be repeated in the third trimester and/or at delivery. [Copyright &y& Elsevier]

The article discusses the results of a study assessing the cost-effectiveness of treating trichomoniasis to avert HIV transmission in men seeking treatment for sexually transmitted diseases in Lilongwe, Malawi. The decision tree analysis was used to assess program costs and outcomes in a one-year population study. The results suggest that incorporating metronidazole to treat male trichomoniasis could represent a cost-effective means to reduce HIV transmission in this high-risk group.

Objectives/goal: Most resource-poor settings rely on syndromic criteria to diagnose genital ulcer disease (GUD). However, the etiologic pathogens of GUD vary temporally and geographically, and current criteria may not reflect changes in the prevalence of specific pathogens.Study: In 1999, we estimated the prevalence of Treponema pallidum (Tp), herpes simplex virus (HSV), and Haemophilus ducreyi (Hd) in Malawi. We then used regression coefficients of independent correlates of HSV and Hd to develop weighted diagnostic algorithms, in which weights were beta-coefficients corresponding to each factor.Results: Overall, a decrease in the proportion of sexually transmitted disease attributable to GUD was noted in 7 years. Thirty-five percent were attributable to HSV, 30% to H. ducreyi, and 4% to T. pallidum. Areas under the receiver operating characteristic curves for weighted and unweighted HSV diagnostic algorithms were 67.6% and 66.5%, respectively. There was no significant difference in the explanatory performance of the weighted and unweighted algorithms.Conclusions: Unweighted algorithms can therefore be used to improve diagnostic accuracy of GUD. [ABSTRACT FROM AUTHOR]

Background: Persons with acute HIV infection (AHI) are highly infectious and responsible for a disproportionate share of incident infections. Immediate antiretroviral therapy (ART) rapidly reduces blood viral loads (VLs), but genital VLs after ART initiation during AHI are less well described., Setting: Lilongwe, Malawi, 2012-2014., Methods: HIV-seronegative and HIV-serodiscordant persons aged ≥18 years were screened for AHI (RNA positive) and randomized to standard of care, behavioral intervention, or behavioral intervention plus short-term ART (raltegravir/emtricitabine/tenofovir) (1:2:2). Persons who were ART eligible under Malawi guidelines could receive first-line therapy. Blood and genital VLs were assessed at weeks 1, 4, 8, and 12. Fisher's Exact test was used to compare viral suppression by ART status., Results: Overall, 46 persons with AHI were enrolled; of whom, 17 started ART within 12 weeks. Median blood VL at AHI diagnosis was 836,115 copies/mL. At week 12, 7% (1/14) of those who initiated ART had a blood VL of ≥400 copies/mL, compared with 100% (23/23; P < 0.0001) of those who did not initiate ART (median VL: 61,605 copies/mL). Median genital VL at week 1 was 772 copies/mL, with 13 of 22 (59%) having VL of ≥400 copies/mL. At week 12, 0 of 10 (0%) of those who initiated ART had genital VL of ≥400 copies/mL, compared with 7 of 15 (47%) of those who did not initiate ART (P = 0.02)., Conclusion: Although highly correlated, VLs in blood and genital fluids occupy discrete biological compartments with distinct virologic dynamics. Our results corroborate the dramatic reduction in both compartments after ART initiation. Increasing AHI screening and rapidly initiating treatment is key to interrupting transmission., Competing Interests: Supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01 AI083059 to W.C.M.; T32AI007001 to S.E.R.]; and the University of North Carolina Center for AIDS Research (CFAR) [P30 AI050410]. Merck & Co provided raltegravir. Gilead provided emtricitabine/tenofovir. M.S.C. is on the Advisory Board for Merck and Gilead. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Monitoring the burden of and trends in sexually transmitted infection syndromes is useful in informing syndromic management guidelines. Among sexually transmitted infection clinic patients in Lilongwe, Malawi, between 2006 and 2015, genital discharge, lower abdominal pain, and genital ulcer syndromes were common. Prevalence of most syndromes remained stable during the 10-year period., Competing Interests: Conflict of Interest and Sources of Funding: The authors do not have any conflicts of interest to declare. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under award numbers R01 AI083059, R01 AI114320, and 5R01 DK108424-03. M.M. was supported by NIH, The Fogarty Global Health Fellowship Program Grant No. D43 TW009340. J.S.C. was supported by NIH, National Institute of Allergy and Infectious Diseases (T32 AI070114). This work received support from Lilongwe DHO, Ministry of Health, Lilongwe, Malawi; UNC Project, Malawi, Lilongwe Malawi; and UNC Institute of Global Health and Infectious Diseases., (Copyright © 2020 American Sexually Transmitted Diseases Association. All rights reserved.)

Background: HIV Vaccine Trials Network 703/HIV Prevention Trials Network 081 is a phase 2b randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of passively infused monoclonal antibody VRC01 in preventing HIV acquisition in heterosexual women between the ages of 18 and 50 years at risk of HIV. Participants were enrolled at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe. It is one of the 2 Antibody Mediated Prevention efficacy trials, with HIV Vaccine Trials Network 704/HIV Prevention Trials Network 085, evaluating VRC01 for HIV prevention., Methods: Intense community engagement was used to optimize participant recruitment and retention. Participants were randomly assigned to receive intravenous VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo in a 1:1:1 ratio. Infusions were given every 8 weeks with a total of 10 infusions and 104 weeks of follow-up after the first infusion., Results: Between May 2016 and September 2018, 1924 women from sub-Saharan Africa were enrolled. The median age was 26 years (interquartile range: 22-30), and 98.9% were Black. Sexually transmitted infection prevalence at enrollment included chlamydia (16.9%), trichomonas (7.2%), gonorrhea (5.7%), and syphilis (2.2%). External condoms (83.2%) and injectable contraceptives (61.1%) were the methods of contraception most frequently used by participants. In total, through April 3, 2020, 38,490 clinic visits were completed with a retention rate of 96% and 16,807 infusions administered with an adherence rate of 98%., Conclusions: This proof-of-concept, large-scale monoclonal antibody study demonstrates the feasibility of conducting complex trials involving intravenous infusions in high incidence populations in sub-Saharan Africa., Competing Interests: J.R.M. reports an NIH patent for VRC01. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: HIV diagnosis is the necessary first step towards HIV care initiation, yet many persons living with HIV (PLWH) remain undiagnosed. Employing multiple HIV testing strategies in tandem could increase HIV detection and promote linkage to care. We aimed to assess an intervention to improve HIV detection within socio-sexual networks of PLWH in two sexually transmitted infections (STI) clinics in Lilongwe, Malawi., Methods: We conducted a randomized controlled trial to evaluate an intervention combining acute HIV infection (AHI) screening, contract partner notification and social contact referral versus the Malawian standard of care: serial rapid serological HIV tests and passive partner referral. Enrolment occurred between 2015 and 2019. HIV-seropositive persons (two positive rapid tests) were randomized to the trial arms and HIV-seronegative (one negative rapid test) and -serodiscordant (one positive test followed by a negative confirmatory test) persons were screened for AHI with HIV RNA testing. Those found to have AHI were offered enrolment into the intervention arm. Our primary outcome of interest was the number of new HIV diagnoses made per index participant within participants' sexual and social networks. We also calculated total persons, sexual partners and PLWH (including those previously diagnosed) referred per index participant., Results: A total of 1230 HIV-seropositive persons were randomized to the control arm, and 561 to the intervention arm. Another 12,713 HIV-seronegative or -serodiscordant persons underwent AHI screening, resulting in 136 AHI cases, of whom 94 enrolled into the intervention arm. The intervention increased the number of new HIV diagnoses made per index participant versus the control (ratio: 1.9; 95% confidence interval (CI): 1.2 to 3.1). The intervention also increased the numbers of persons (ratio: 2.5; 95% CI: 2.0 to 3.2), sexual partners (ratio: 1.7; 95% CI: 1.4 to 2.0) and PLWH (ratio: 2.3; 95% CI: 1.7 to 3.2) referred per index participant., Conclusions: Combining three distinct HIV testing and referral strategies increased the detection of previously undiagnosed HIV infections within the socio-sexual networks of PLWH seeking STI care. Combination HIV detection strategies that leverage AHI screening and socio-sexual contact networks offer a novel and efficacious approach to increasing HIV status awareness., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial., Methods: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t 1/2app ) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800., Findings: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t 1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015)., Interpretation: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials., Funding: National Institute of Allergy and Infectious Diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States., Methods and Findings: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population., Conclusions: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress., Trial Registration: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800., Competing Interests: RJL has received study medication, consulting fees and travel support from Gilead Sciences. He has received consulting fees and travel support from Merck, Inc. HD has received honoraria from Pfizer-South Africa, Novartis-South Africa, MSD-South Africa and Adcock Ingram for speaking engagements and has received travel support from Mylan-South Africa, Novartis-South Africa and Aspen-South Africa. AYL received research grants from NIH and has led studies in which study drug was donated by Gilead Sciences. DM and ARR are paid employees of ViiV Healthcare. WRS is a paid employee of ViiV Healthcare with stock in ViiV Healthcare and GlaxoSmithKline. CWH has research contracts with ViiV/GlaxoSmithKline and the NIH through Johns Hopkins and the University of Washington. MAM received grant support through the NIH, and received grant support through ViiV/GSK on work external to this study. JS is a member of Merck KGaA's Bioethics Advisory Panel and Stem Cell Research Oversight Committee; and he is a member of IQVIA's (formerly Quintiles) Ethics Advisory Panel. JJE is a consultant to Merck, Gilead Sciences, Janssen, and ViiV Healthcare; and he is an investigator on research contracts from ViiV Healthcare, Janssen, and Gilead Sciences.

Background: The World Health Organization recommends the use of syndromic management for patients presenting with genital ulcer disease (GUD) in developing countries. However, effective treatment guidelines depend on a current country-specific GUD etiological profile, which may change over time., Methods: From 2004 to 2006, we conducted a cross-sectional analysis of baseline data from patients presenting with GUD at a reference STI clinic in Lilongwe, Malawi. Participants were enrolled in a randomized clinical trial of acyclovir added to syndromic management and followed up for up to 28 days. Serologies for HIV (using parallel rapid tests), herpes simplex virus type 2 (HSV-2; using Focus HerpeSelect IgG2 ELISA [Focus Technologies, Cypress Hill, CA]), and syphilis (rapid plasma reagin confirmed by Treponema pallidum hemagglutination) were determined, with plasma HIV-1 RNA and CD4 count in HIV-positive patients. Genital ulcer disease etiology was determined by real-time multiplex polymerase chain reaction from lesional swabs., Results: A total of 422 patients with GUD (313 men; 74%) were enrolled. Overall seroprevalence of HIV-1, HSV-2, and syphilis were 61%, 72%, and 5%, respectively. Ulcer etiology was available for 398 patients and showed the following: HSV-2, 67%; Haemophilus ducreyi, 15%; T. pallidum, 6%; lymphogranuloma venereum, 6%; mixed infections, 14%, and no etiology, 20%. Most HSV-2 ulcers were recurrent (75%). Among all patients with HSV-2, HIV prevalence was high (67%) and HIV seroprevalence was higher among patients with recurrent HSV-2 compared with patients with first-episode HSV-2 (78% vs. 39%, P < 0.001)., Conclusions: Herpes simplex virus type 2 ulcers are highly prevalent in this symptomatic population and strongly associated with HIV. Unlike most locations in sub-Saharan Africa, H. ducreyi remains prevalent in this population and requires periodic monitoring and an appropriate treatment regimen.

Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine. We compared phenotypic and genetic variation in HIV-1 env genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission. We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell. We confirmed an earlier observation that the transmitted viruses were, on average, modestly underglycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event. We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies. We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of env, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.

Provider-assisted methods of partner notification increase testing and counseling among sexual partners of patients diagnosed with HIV, however they are resource-intensive. The sexual partners of individuals enrolled in a clinical trial comparing different methods of HIV partner notification were analyzed to identify who was unlikely to seek testing on their own. Unconditional logistic regression was used to identify partnership characteristics, which were assigned a score based on their coefficient in the final model, and a risk score was calculated for each participant. The risk score included male partner sex, relationship duration 6-24 months, and index education > primary. A risk score of ≥ 2 had a sensitivity of 68% and specificity of 78% in identifying partners unlikely to seek testing on their own. A risk score to target partner notification can reduce the resources required to locate all partners in the community while increasing the testing yield compared to patient-referral.

Background: Most human immunodeficiency virus (HIV) point-of-care tests detect antibodies (Ab) but not p24 antigen (Ag) or RNA. In the absence of antibodies, p24 antigen and RNA typically indicate acute HIV infection. We conducted a field evaluation of the Determine® HIV-1/2 Ag/Ab Combo rapid test (Combo RT)., Methods: The antigen portion of the Combo RT (for acute HIV infection) was compared with a Roche Monitor HIV RNA polymerase chain reaction assay. The antibody portion of Combo RT (for established HIV infection) was compared with rapid test algorithms. Participants were enrolled at a sexually transmitted infection clinic and HIV testing and counseling center in Lilongwe, Malawi. Rapid testing was conducted with parallel testing in the clinic and serial testing in the center. The Combo RT was performed in clinic participants with negative or discordant antibody results and in all center participants., Results: Of the participants 838 were HIV negative, 163 had established HIV infection, and 8 had acute HIV infection. For detecting acute HIV infection, the antigen portion had a sensitivity of 0.000 and a specificity of 0.983. For detecting established HIV infection, the antibody portion had a sensitivity of 0.994 and a specificity of 0.992., Conclusions: Combo RT displayed excellent performance for detecting established HIV infection and poor performance for detecting acute HIV infection. In this setting, Combo RT is no more useful than current algorithms.

Background: Sexual partners of persons with newly diagnosed HIV infection require HIV counseling, testing and, if necessary, evaluation for therapy. However, many African countries do not have a standardized protocol for partner notification, and the effectiveness of partner notification has not been evaluated in developing countries ., Methods: Individuals with newly diagnosed HIV infection presenting to sexually transmitted infection clinics in Lilongwe, Malawi, were randomized to 1 of 3 methods of partner notification: passive referral, contract referral, or provider referral. The passive referral group was responsible for notifying their partners themselves. The contract referral group was given seven days to notify their partners, after which a health care provider contacted partners who had not reported for counseling and testing. In the provider referral group, a health care provider notified partners directly., Results: Two hundred forty-five index patients named 302 sexual partners and provided locator information for 252. Among locatable partners, 107 returned for HIV counseling and testing; 20 of 82 [24%; 95% confidence interval (CI): 15% to 34%] partners returned in the passive referral arm, 45 of 88 (51%; 95% CI: 41% to 62%) in the contract referral arm, and 42 of 82 (51%; 95% CI: 40% to 62%) in the provider referral arm (P < 0.001). Among returning partners (n = 107), 67 (64%) of were HIV infected with 54 (81%) newly diagnosed., Discussion: This study provides the first evidence of the effectiveness of partner notification in sub-Saharan Africa. Active partner notification was feasible, acceptable, and effective among sexually transmitted infections clinic patients. Partner notification will increase early referral to care and facilitate risk reduction among high-risk uninfected partners.

Objective: To date, CCR5 variants remain the only human genetic factors to be confirmed to impact HIV-1 acquisition. However, protective CCR5 variants are largely absent in African populations, in which sporadic resistance to HIV-1 infection is still unexplained. We investigated whether common genetic variants associate with HIV-1 susceptibility in Africans., Methods: We performed a genome-wide association study (GWAS) in a population of 1532 individuals from Malawi, a country with high prevalence of HIV-1 infection. Using single-nucleotide polymorphisms (SNPs) present on the genome-wide chip, we also investigated previously reported associations with HIV-1 susceptibility or acquisition. Recruitment was coordinated by the Center for HIV/AIDS Vaccine Immunology at two sexually transmitted infection clinics. HIV status was determined by HIV rapid tests and nucleic acid testing., Results: After quality control, the population consisted of 848 high-risk seronegative and 531 HIV-1 seropositive individuals. Logistic regression testing in an additive genetic model was performed for SNPs that passed quality control. No single SNP yielded a significant P value after correction for multiple testing. The study was sufficiently powered to detect markers with genotype relative risk 2.0 or more and minor allele frequencies 12% or more., Conclusion: This is the first GWAS of host determinants of HIV-1 susceptibility, performed in an African population. The absence of any significant association can have many possible explanations: rarer genetic variants or common variants with weaker effect could be responsible for the resistance phenotype; alternatively, resistance to HIV-1 infection might be due to nongenetic parameters or to complex interactions between genes, immunity and environment.

Background: Malawi adopted syndromic management of sexually transmitted infections in 1993. Based on clinical efficacy and cost, gentamicin 240 mg intramuscularly, and doxycycline 100 mg twice daily x 7 days was selected as the first line regimen to treat urethritis. We sought to establish current laboratory-based Neisseria gonorrhoeae antibiotic susceptibility patterns for Malawi and describe the pattern of susceptibility since syndromic management began., Methods: Between May 15 and August 10, 2007, 126 men with urethritis attending the STD clinic at Kamuzu Central Hospital in Lilongwe had history, genital exam, and urethral swabs taken. All were treated with gentamicin and doxycycline in accordance with Malawi guidelines. Gonorrhea was diagnosed by Gram stain and culture. Antimicrobial susceptibility patterns in gonococcal isolates were determined by disk diffusion and E-test minimum inhibitory concentration (MIC) determination and agar dilution MIC determination., Results: One hundred six isolates were cultured, and MICs were determined for 100. High levels of resistance to tetracycline and penicillin were observed, but isolates were uniformly susceptible to both gentamicin and ciprofloxacin. Susceptibility patterns identified by the agar dilution MIC and E-test MIC agreed., Conclusions: The most recent study continues the trend of high susceptibility of gonococcal isolates to gentamicin in Malawi after 14 years of use and suggests agar dilution MICs may be substituted with the simpler E-test methods in future susceptibility testing. However because of the lack of susceptibility criteria for aminoglycosides for N. gonorrhoeae and the difficulty obtaining clinical/in vitro correlates in this setting, caution should be exercised in using these data for modifying treatment regimens.

Objective: Individuals with acute (preseroconversion) HIV infection (AHI) are important in the spread of HIV. The identification of AHI requires the detection of viral proteins or nucleic acids with techniques that are often unaffordable for routine use. To facilitate the efficient use of these tests, we sought to develop a risk score algorithm for identifying likely AHI cases and targeting the tests towards those individuals., Design: A cross-sectional study of 1448 adults attending a sexually transmitted infections (STI) clinic in Malawi., Methods: Using logistic regression, we identified risk behaviors, symptoms, HIV rapid test results, and STI syndromes that were predictive of AHI. We assigned a model-based score to each predictor and calculated a risk score for each participant., Results: Twenty-one participants (1.45%) had AHI, 588 had established HIV infection, and 839 were HIV-negative. AHI was strongly associated with discordant rapid HIV tests and genital ulcer disease (GUD). The algorithm also included diarrhea, more than one sexual partner in 2 months, body ache, and fever. Corresponding predictor scores were 1 for fever, body ache, and more than one partner; 2 for diarrhea and GUD; and 4 for discordant rapid tests. A risk score of 2 or greater was 95.2% sensitive and 60.5% specific in detecting AHI., Conclusion: Using this algorithm, we could identify 95% of AHI cases by performing nucleic acid or protein tests in only 40% of patients. Risk score algorithms could enable rapid, reliable AHI detection in resource-limited settings.

Background: We conducted a prospective study to evaluate methods of detecting clients with sexually transmitted diseases (STDs) who were acutely coinfected with human immunodeficiency virus (HIV) in Lilongwe, Malawi., Methods: After informed consent was obtained, all clients with acute STDs were offered voluntary HIV counseling and testing by 2 rapid antibody tests. Samples from rapid test-negative or -discordant subjects were pooled (50 : 5 : 1) and tested for HIV RNA. Western blots were performed on all rapid test-discordant specimens with detectable HIV RNA. A subset of specimens received p24 antigen testing with standard and/or ultrasensitive methods. Patients with possible acute HIV infection were followed to confirm seroconversion., Results: A total of 1450 clients (34% female and 66% male) agreed to testing, of whom 588 (40.55%) had established HIV infection and 21 (1.45%) had acute infection. Discordant rapid antibody tests identified 7 of 21 (33.3% sensitivity), standard p24 antigen identified 12 of 16 (75% sensitivity), and ultrasensitive p24 antigen identified 15 of 17 (88% sensitivity) acute cases. By definition, the sensitivity of the RNA assay was 100%., Conclusions: Real-time pooled RNA testing for the detection of acute HIV infection is feasible in resource-limited settings. However, parallel rapid testing and p24 antigen testing are technologically simpler and together may detect approximately 90% of acute cases.

Sexual transmission of HIV most closely reflects the concentration of HIV in the genital tract; HIV in the genital tract of subjects with acute HIV and some "classical" STDS is 8-10 times greater than in control subjects. It seems likely that these latter subjects lead to spread of HIV. Accordingly, the state of North Carolina committed to HIV testing that detects subjects with acute, recent, and established infection. We tested 109,500 samples over 9 months. We found 563 people with undiagnosed HIV infection. The majority of subjects were in STD clinics. This included 23 subjects with (pre-seroconversion) acute HIV infection (HIV RNA positive, antibody negative). The median blood HIV was 209,000 copies/ml, more than 10 times higher than in subjects with established HIV infection. Recognizing the increased number of subjects with unrecognized acute HIV infection in STD clinics, we conducted similar studies in STD Clinics in Malawi and South Africa. Between 1 and 2% of subjects had undetected acute HIV infection. The median viral burden in blood of subjects in Malawi was greater than 1,000,000 copies/ml. STDS and HIV are often co-transmitted, and STDS set the stage for subsequent HIV transmission. Prevention of sexual transmission of HIV likely requires maximal suppression of genital tract HIV viral burden, either through treatment of STDS or use of antiretroviral agents.

Variations in estimates of prevalence of trichomoniasis in men may reflect true differences in the burden of disease but are also affected by the performance of diagnostic methods and the type of specimen tested. In this study, men were evaluated at baseline and at follow-up, to evaluate syndromic management of urethritis and the effects of human immunodeficiency virus and trichomoniasis, in Lilongwe, Malawi. First-void urine specimens and urethral swabs were obtained at enrollment, for Trichomonas vaginalis culture; semen specimens were also obtained at follow-up. The sensitivities of testing methods using urine specimens and urethral swabs were equal; 67% of cases were identified by use of either specimen, and, in 47% of cases, both specimens tested positive. When semen specimens were included, all 3 specimens tested positive in only 19% of cases. Semen was the most sensitive single specimen, and, in 25.6% of cases, only semen specimens tested positive. Thus, prevalence of T. vaginalis infection in men is underestimated if only 1 specimen is tested.

Background: Acute (antibody-negative) HIV infection is associated with high transmission potential but is rarely recognized., Design: Cross-sectional study., Methods: We examined the prevalence and predictors of acute HIV infection among 1361 consecutive male outpatients attending sexually transmitted disease (STD; n = 929) and dermatology (n = 432) clinics in Lilongwe, Malawi. Serum specimens negative for HIV antibodies were screened by HIV RNA PCR using a highly specific pooling/resolution testing algorithm., Results: Five-hundred and fifty-three men (40.6%) were HIV antibody positive and 24 (1.8%) had acute HIV infection; 23 of 24 acutely infected men were from the STD clinic, where they represented 4.5% of all HIV antibody-negative men and 5.0% of all HIV infections. HIV RNA levels for acutely infected men were significantly higher [median (interquartile range), 6.10 (5.19-6.54) log10 HIV RNA copies/ml] than for 58 HIV antibody-positive men [4.42 (3.91-4.95) log10 copies/ml; P < 0.0001]. The factor most strongly associated with acute HIV infection was STD clinic attendance: (odds ratio, 15.2; 95% confidence interval, 2.04-113.0). In multivariate analysis considering only STD patients, factors associated with acute HIV infection included inguinal adenopathy, genital ulceration and age 24-26 years, the age stratum associated with peak incidence of HIV infection among Malawian men., Conclusions: Traditional HIV antibody tests alone are not sufficient to exclude HIV infection among men with acute STD in Malawi due to a surprising proportion of acute HIV infections in this population. Alternative screening methods are required for diagnosis of acute HIV infection; such screening could be important for research and for prevention of the sexual transmission of HIV in select populations.

Background: Male urethritis is generally treated syndromically, but failure of empirical treatment is common., Goal: The study goal was to evaluate the addition of metronidazole to the syndromic management of urethritis in Malawi in a randomized clinical trial., Study Design: Men with urethritis were randomized to receive either 2 g of metronidazole by mouth or placebo, in addition to standard care for urethritis (i.e., a single intramuscular dose of 240 mg gentamicin and 100 mg doxycycline twice daily for 7 days). The primary endpoints of the study included measurement of the effects of treatment on Trichomonas vaginalis, signs and symptoms of urethritis, and the concentration of HIV RNA in semen in dually infected subjects., Results: The overall prevalence of T vaginalis was 17.3% (71/411), and treatment with metronidazole cleared 95% of culture-positive infections, compared with 54% clearance among men receiving placebo (P = 0.006). Prevalence of persistent urethritis was observed in approximately 16% of both groups at the end of 1 week (29/179 of those receiving metronidazole versus 29/187 in the placebo group; P = 0.86). For a subset of HIV-infected men with trichomoniasis, the seminal plasma HIV RNA concentration was higher than in a group of HIV-positive control subjects (median copies/mL:35,000 vs. 1800 P = 0.06) [correction]., Conclusion: In areas with a high prevalence of trichomoniasis, the addition of metronidazole to the syndromic management of male urethritis can eliminate infection with T vaginalis and may help to reduce the transmission of HIV. Such treatment should be strongly considered as part of empirical therapy for urethritis in men in Malawi and places where T vaginalis infection in men is common.