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Background and Objectives: Fever defervescence in scrub typhus, a zoonotic bacterial infection is used as a surrogate marker of disease resolution. Failure of fever defervescence prompts clinicians to suspect alternate diagnoses and treatment. In this observational study, various treatment regimens were correlated with clinical outcomes., Methods: All adult patients with a diagnosed scrub typhus were included; various antibiotic regimens used and clinical outcomes were studied. Data was analyzed using SPSS software for windows 16, with a 2-sided P-value of 0.05 or less was considered statistically significant., Results: In 177 hospitalized patients with scrub typhus, combination therapy (doxycycline and azithromycin) was used in 74 subjects with doxycycline and azithromycin used in 46 and 57 subjects, respectively. Incidence of delayed defervescence was seen in 31.6%, Combination therapy being preferred in sicker patients (SOFA score 8.82). Presence of respiratory dysfunction was associated with a delay in fever defervescence [risk ratio 2.50(1.18-5.3)]. Patients receiving doxycycline did better in terms of oxygen requirement and the presence of hypotension. The overall case fatality rate was 5.6%. The severity of illness rather than the choice of antibiotics predicted the outcome in scrub typhus., Interpretation & Conclusion: Combination therapy with doxycycline and azithromycin is the most common regimen used. Incidence of delayed defervescence (31.6%) is increasing despite therapy and the involvement of respiratory dysfunction is an independent predictor of delayed fever defervescence., Competing Interests: None

Background: The integrase inhibitor dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens., Methods: We updated an existing individual-based model of HIV transmission and progression in adults to consider information on the risk of neural tube defects in women taking dolutegravir at time of conception, as well as the effects of dolutegravir on weight gain. The model accounted for drug resistance in determining viral suppression, with consequences for clinical outcomes and mother-to-child transmission. We sampled distributions of parameters to create various epidemic setting scenarios, which reflected the diversity of epidemic and programmatic situations in sub-Saharan Africa. For each setting scenario, we considered the situation in 2018 and compared ART initiation policies of an efavirenz-based regimen in women intending pregnancy, and a dolutegravir-based regimen in others, and a dolutegravir-based regimen, including in women intending pregnancy. We considered predicted outcomes over a 20-year period from 2019 to 2039, used a 3% discount rate, and a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted., Findings: Considering updated information on risks and benefits, a policy of ART initiation with a dolutegravir-based regimen rather than an efavirenz-based regimen, including in women intending pregnancy, is predicted to bring population health benefits (10 990 DALYs averted per year) and to be cost-saving (by $2·9 million per year), leading to a reduction in the overall population burden of disease of 16 735 net DALYs per year for a country with an adult population size of 10 million. The policy involving ART initiation with a dolutegravir-based regimen in women intending pregnancy was cost-effective in 87% of our setting scenarios and this finding was robust in various sensitivity analyses, including around the potential negative effects of weight gain., Interpretation: In the context of a range of modelled setting scenarios in sub-Saharan Africa, we found that a policy of ART initiation with a dolutegravir-based regimen, including in women intending pregnancy, was predicted to bring population health benefits and be cost-effective, supporting WHO's strong recommendation for dolutegravir as a preferred drug for ART initiators., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Intense research activity in HPV modelling over this decade has prompted the development of additional guidelines to those for general modelling. A specific framework is required to address different policy questions and unique complexities of HPV modelling. HPV-FRAME is an initiative to develop a consensus statement and quality-based framework for epidemiologic and economic HPV models. Its development involved an established process. Reporting standards have been structured according to seven domains reflecting distinct policy questions in HPV and cancer prevention and categorised by relevance to a population or evaluation. Population-relevant domains are: 1) HPV vaccination in pre-adolescent and young adolescent individuals; 2) HPV vaccination in older individuals; 3) targeted vaccination in men who have sex with men; 4) considerations for individuals living with HIV and 5) considerations for low- and middle-income countries. Additional considerations applicable to specific evaluations are: 6) cervical screening or integrated cervical screening and HPV vaccination approaches and 7) alternative vaccine types and alternative dosing schedules. HPV-FRAME aims to promote the development of models in accordance with an explicit framework, to better enable target audiences to understand a model's strength and weaknesses in relation to a specific policy question and ultimately improve the model's contribution to informed decision-making., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The clinical syndrome in symptomatic HIV associated CNS viral escape is poorly defined. We attempted to describe the clinical syndrome, laboratory profile, radiological features and outcomes of HIV infected patients with symptomatic central nervous system (CNS) viral escape in our study., Methods: This is a retrospective study were adult patients with HIV infection on cART admitted with a diagnosis of CD8 encephalitis or CNS viral escape in a large teaching hospital in South India was identified., Results: The mean age of the eleven patients included in the study was 37.5 years. Most patients had received almost a decade of antiretroviral treatment at diagnosis (mean: 11.18 years). All patients presented with global cerebral syndrome. Cognitive decline, tremors, and headaches were common manifestations. All patients had lymphocytic pleocytosis (mean cell count: 44.63 cells/ml; lymphocyte percentage: 94.81%) with elevated protein (mean: 125.36 mg/dl). All patients were on boosted protease inhibitors (81.8% on Atazanavir and 18.18% Lopinavir). All except one patient was on Tenofovir and lamivudine combination therapy. White matter changes and deep brain nuclei involvement were common. Most patients required a change of cART to regimens with better CNS penetration and suppression of the resistant virus in the plasma and improved., Conclusion: CNS viral escape should be considered as a differential among patients on Atazanavir presenting with non-focal cerebral syndrome and CSF lymphocytic pleocytosis., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: As prevalence of undiagnosed HIV declines, it is unclear whether testing programmes will be cost-effective. To guide their HIV testing programmes, countries require appropriate metrics that can be measured. The cost-per-diagnosis is potentially a useful metric., Methods: We simulated a series of setting-scenarios for adult HIV epidemics and ART programmes typical of settings in southern Africa using an individual-based model and projected forward from 2018 under two policies: (i) a minimum package of "core" testing (i.e. testing in pregnant women, for diagnosis of symptoms, in sex workers, and in men coming forward for circumcision) is conducted, and (ii) core-testing as above plus additional testing beyond this ("additional-testing"), for which we specify different rates of testing and various degrees to which those with HIV are more likely to test than those without HIV. We also considered a plausible range of unit test costs. The aim was to assess the relationship between cost-per-diagnosis and the incremental cost-effectiveness ratio (ICER) of the additional-testing policy. The discount rate used in the base case was 3% per annum (costs in 2018 U.S. dollars)., Results: There was a strong graded relationship between the cost-per-diagnosis and the ICER. Overall, the ICER was below $500 per-DALY-averted (the cost-effectiveness threshold used in primary analysis) so long as the cost-per-diagnosis was below $315. This threshold cost-per-diagnosis was similar according to epidemic and programmatic features including the prevalence of undiagnosed HIV, the HIV incidence and a measure of HIV programme quality (the proportion of HIV diagnosed people having a viral load <1000 copies/mL). However, restricting to women, additional-testing did not appear cost-effective even at a cost-per-diagnosis of below $50, while restricting to men additional-testing was cost-effective up to a cost-per-diagnosis of $585. The threshold cost per diagnosis for testing in men to be cost-effective fell to $256 when the cost-effectiveness threshold was $300 instead of $500, and to $81 when considering a discount rate of 10% per annum., Conclusions: For testing programmes in low-income settings in southern African there is an extremely strong relationship between the cost-per-diagnosis and the cost-per-DALY averted, indicating that the cost-per-diagnosis can be used to monitor the cost-effectiveness of testing programmes., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: African-born individuals in the U.S. are disproportionately affected by HIV yet have low HIV testing rates. We conducted a mixed methods study to assess the uptake and feasibility of a novel strategy for integrating HIV testing into residential health fairs among African-born individuals in Seattle, WA., Methods: From April to May 2018, we held six health fairs at three apartment complexes with high numbers of African-born residents. Fairs included free point-of-care screening for glucose, cholesterol, body mass index, blood pressure, and HIV, as well as social services and health education. The health fairs were hosted in apartment complex common areas with HIV testing conducted in private rooms. Health fair participants completed a series of questionnaires to evaluate demographics, access to health services, and HIV testing history. We conducted 18 key informant interviews (KIIs) with health fair participants and community leaders to identify barriers to HIV testing among African-born individuals., Results: Of the 111 adults who accessed at least one service at a health fair, 92 completed questionnaires. Fifty-five (61%) were female, 48 (52%) were born in Africa, and 55 (63%) had health insurance. Half of African-born participants accepted HIV testing; all tested negative. The most common reasons for declining testing were lack of perceived risk for HIV and knowledge of HIV status. We identified a high prevalence of non-communicable diseases (NCDs) among health fair participants; among those tested, 77% (55/71) were overweight/obese, 39% (31/79) had blood pressure > 140/90 mmHg, and 30% (22/73) had total cholesterol > 200 mg/dL. KIIs identified community stigma and misinformation as major barriers to HIV testing among African-born individuals., Conclusions: Residential health fairs are a feasible method to increase HIV testing among African-born individuals in Seattle. The high prevalence of NCDs highlights the importance of integrating general preventive services within HIV testing programs in this population., Competing Interests: The authors have declared that no competing interests exist.

Background: The introduction of option B+-rapid initiation of lifelong antiretroviral therapy regardless of disease status for HIV-infected pregnant and breastfeeding women-can dramatically reduce HIV transmission during pregnancy, birth, and breastfeeding. Despite significant investments to scale-up Option B+, results have been mixed, with high rates of loss to follow-up, sub-optimal viral suppression, continued pediatric HIV transmission, and HIV-associated maternal morbidity. The Systems Analysis and Improvement Approach (SAIA) cluster randomized trial demonstrated that a package of systems engineering tools improved flow through the prevention of mother-to-child HIV transmission (PMTCT) cascade. This five-step, facility-level intervention is designed to improve understanding of gaps (cascade analysis), guide identification and prioritization of low-cost workflow modifications (process mapping), and iteratively test and redesign these modifications (continuous quality improvement). This protocol describes a novel model for SAIA delivery (SAIA-SCALE) led by district nurse supervisors (rather than research nurses), and evaluation procedures, to serve as a foundation for national scale-up., Methods: The SAIA-SCALE stepped wedge trial includes three implementation waves, each 12 months in duration. Districts are the unit of assignment, with four districts randomly assigned per wave, covering all 12 districts in Manica province, Mozambique. In each district, the three highest volume health facilities will receive the SAIA-SCALE intervention (totaling 36 intervention facilities). The RE-AIM framework will guide SAIA-SCALE's evaluation. Reach describes the proportion of clinics and population in Manica province reached, and sub-groups not reached. Effectiveness assesses impact on PMTCT process measures and patient-level outcomes. Adoption describes the proportion of districts/clinics adopting SAIA-SCALE, and determinants of adoption using the Organizational Readiness for Implementing Change (ORIC) tool. Implementation will identify SAIA-SCALE core elements and determinants of successful implementation using the Consolidated Framework for Implementation Research (CFIR). Maintenance describes the proportion of districts sustaining the intervention. We will also estimate the budget and program impact from the payer perspective for national scale-up., Discussion: SAIA packages user-friendly systems engineering tools to guide decision-making by frontline health workers, and to identify low-cost, contextually appropriate PMTCT improvement strategies. By integrating SAIA delivery into routine management structures, this pragmatic trial is designed to test a model for national intervention scale-up., Trial Registration: ClinicalTrials.gov NCT03425136 (registered 02/06/2018).

Introduction: Women in regions with high HIV prevalence are at high risk of HIV acquisition during pregnancy and postpartum, and acute maternal HIV contributes a substantial proportion of infant HIV infections. Pre-exposure prophylaxis (PrEP) could prevent HIV during pregnancy/postpartum; however, identifying women who would most benefit from PrEP in this period is challenging. Women may not perceive risk, may not know partner HIV status and partners may have external partners during this period. PrEP offer in pregnancy could be universal or risk guided., Methods and Analysis: The PrEP Implementation for Mothers in Antenatal Care (PrIMA) study is a cluster randomised trial that aims to determine the best model for PrEP implementation in pregnancy, among women attending public sector maternal child health clinics in Western Kenya (HIV prevalence >25%). Twenty clinics are randomised to either universal PrEP offer following standardised counselling ('Universal arm' 10 clinics) or risk screening with partner self-test option ('Targeted arm' 10 clinics). Four thousand women will be enrolled and followed through 9-month postpartum. The primary analysis will be intention to treat. Outcomes reflect the balance between HIV preventive effectiveness and avoiding unnecessary PrEP exposure to women at low risk and include: maternal HIV incidence, PrEP uptake, PrEP adherence, PrEP duration, 'appropriate' PrEP use (among women with objective evidence of potential risk), infant birth outcomes, infant growth and partner self-testing uptake. To better understand the feasibility and acceptability of the provision of PrEP in these settings, qualitative interviews and cost-effectiveness analyses will be conducted., Ethics and Dissemination: The protocol was approved by the institutional review boards at Kenyatta National Hospital and the University of Washington. An external advisory panel monitors adverse and social harm events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy makers, community and participants., Trial Registration Number: NCT03070600., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In low-income and middle-income countries, courses of antibiotics are routinely given to term newborns whose mothers had prolonged rupture of membranes (PROM). Rational antibiotic use is vital given rising rates of antimicrobial resistance and potential adverse effects of antibiotic exposure in newborns. However missing cases of sepsis can be life-threatening.This is a quality improvement evaluation of a protocol for minimal or no antibiotics in term babies born after PROM in Papua New Guinea. Asymptomatic, term babies born to women with PROM >12 hours prior to birth were given a stat dose of antibiotics, or no antibiotics if the mother had received intrapartum antibiotics, reviewed and discharged at 48-72 hours with follow-up. Clinical signs of sepsis within the first week and the neonatal period were assessed. Of 170 newborns whose mothers had PROM, 133 were assessed at 7 days: signs of sepsis occurred in 10 babies (7.5%; 95% CI 4.4% to 13.2%) in the first week. Five had isolated fever, four had skin pustules and one had fever with periumbilical erythema. An additional four (3%) had any sign of sepsis between 8 and 28 days. There was one case of bacteraemia and no deaths. 37 were lost to follow-up, but hospital records did not identify any subsequent admissions for infection. A rate of sepsis was documented that was comparable with other studies in low-income countries. This protocol may reduce antimicrobial resistance and consequences of antibiotic exposure in newborns, provided safeguards are in place to monitor for signs of sepsis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The integrase inhibitor dolutegravir could have a major role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barrier to resistance, good tolerability, and low cost, but there is uncertainty over appropriate policies for use relating to the potential for drug resistance spread and a possible increased risk of neural tube defects in infants if used in women at the time of conception. We used an existing individual-based model of HIV transmission, progression, and the effect of ART with the aim of informing policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains., Methods: We used an existing individual-based model of HIV transmission and progression in adults, which takes into account the effects of drug resistance and differential drug potency in determining viral suppression and clinical outcomes to compare predicted outcomes of alternative ART regimen policies. We calculated disability adjusted life-years (DALYs) for each policy, assuming that a woman having a child with a neural tube defect incurs an extra DALY per year for the remainder of the time horizon and accounting for mother-to-child transmission. We used a 20 year time horizon, a 3% discount rate, and a cost-effectiveness threshold of US$500 per DALY averted., Findings: The greatest number of DALYs is predicted to be averted with use of a policy in which tenofovir, lamivudine, and dolutegravir is used in all people on ART, including switching to tenofovir, lamivudine, and dolutegravir in those currently on ART, regardless of current viral load suppression and intention to have (more) children. This result was consistent in several sensitivity analyses. We predict that this policy would be cost-saving., Interpretation: Using a standard DALY framework to compare health outcomes from a public health perspective, the benefits of transition to tenofovir, lamivudine, and dolutegravir for all substantially outweighed the risks., Funding: Bill & Melinda Gates Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Antiretroviral therapy (ART) for HIV-infected persons and pre-exposure prophylaxis (PrEP) for uninfected persons are extraordinarily effective strategies for HIV prevention. In Africa, the region which shoulders the highest HIV burden, HIV care is principally delivered through public health HIV care clinics, offering an existing platform to incorporate PrEP delivery and maximize ART and PrEP synergies. However, successfully bringing this integrated approach to scale requires an implementation science evaluation in public health settings., Methods: The Partners Scale Up Project is a prospective, pragmatic implementation evaluation, designed as a stepped-wedge, cluster-randomized trial, operating at 24 clinics in Kenya. In collaboration with the Kenya Ministry of Health, we are catalyzing scaled implementation of PrEP delivery integrated in HIV care clinics. The intervention package includes staff training, clinic streamlined access to PrEP commodity from the Kenya Medical Supply Authority, and ongoing intensive technical assistance to rigorously assess how PrEP delivery is implemented. PrEP service delivery including retention efforts are conducted by the clinic staff with no additional resources from the project. Guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework and Consolidated Framework for Implementation Science Research, project progress and learning are documented through ongoing monitoring and process evaluations, including chart abstraction and individual and key informant interviews, to evaluate pragmatic rollout and understand barriers and facilitators for successful PrEP delivery in this setting. In this staged rollout design, each step provides data for both pre-implementation (baseline) and implementation periods, and we will compare time points across steps in the baseline versus implementation periods., Discussion: Cost-effective delivery models are urgently needed to maximize the public health impact of PrEP and ART. The Partners Scale Up Project will set the stage for full-scale PrEP implementation fully run and owned by the Kenya Ministry of Health. The work combines nationally sponsored PrEP delivery with technical support and implementation science from academic partners, defining a new but sustainable paradigm for public health collaboration., Trial Registration: Registered with ClinicalTrials.gov on February 14, 2017: NCT03052010 .

Competing Interests: Competing interests: None declared.

Introduction: Achieving the Joint United Nations Programme on HIV and AIDS 90-90-90 targets requires models of HIV care that expand antiretroviral therapy (ART) coverage without overburdening health systems. Point-of-care (POC) viral load (VL) testing has the potential to efficiently monitor ART treatment, while enrolled nurses may be able to provide safe and cost-effective chronic care for stable patients with HIV. This study aims to demonstrate whether POC VL testing combined with task shifting to enrolled nurses is non-inferior and cost-effective compared with laboratory-based VL monitoring and standard HIV care., Methods and Analysis: The STREAM (Simplifying HIV TREAtment and Monitoring) study is an open-label, non-inferiority, randomised controlled implementation trial. HIV-positive adults, clinically stable at 6 months after ART initiation, will be recruited in a large urban clinic in South Africa. Approximately 396 participants will be randomised 1:1 to receive POC HIV VL monitoring and potential task shifting to enrolled nurses, versus laboratory VL monitoring and standard South African HIV care. Initial clinic follow-up will be 2-monthly in both arms, with VL testing at enrolment, 6 months and 12 months. At 6 months (1 year after ART initiation), stable participants in both arms will qualify for a differentiated care model involving decentralised ART pickup at community-based pharmacies. The primary outcome is retention in care and virological suppression at 12 months from enrolment. Secondary outcomes include time to appropriate entry into the decentralised ART delivery programme, costs per virologically suppressed patient and cost-effectiveness of the intervention compared with standard care. Findings will inform the scale up of VL testing and differentiated care in HIV-endemic resource-limited settings., Ethics and Dissemination: Ethical approval has been granted by the University of KwaZulu-Natal Biomedical Research Ethics Committee (BFC296/16) and University of Washington Institutional Review Board (STUDY00001466). Results will be presented at international conferences and published in academic peer-reviewed journals., Trial Registration: NCT03066128; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: The aim of this paper was to review and compare HIV vaccine cost-effectiveness analyses and describe the effects of uncertainty in model, methodology, and parameterization., Methods: We systematically searched MEDLINE (1985 through May 2016), EMBASE, the Tufts CEA Registry, and reference lists of articles following Cochrane guidelines and PRISMA reporting. Eligibility criteria included peer-reviewed manuscripts with economic models estimating cost-effectiveness of preventative HIV vaccines. Two reviewers independently assessed study quality and extracted data on model assumptions, characteristics, input parameters, and outcomes., Results: The search yielded 71 studies, of which 11 met criteria for inclusion. Populations included low-income (n=7), middle-income (n=4), and high-income countries (n=2). Model structure varied including decision tree (n=1), Markov (n=5), compartmental (n=4), and microsimulation (n=1). Most measured outcomes in quality adjusted life-years (QALYs) gained (n=6) while others used unadjusted (n=3) or disability adjusted life-years (n=2). HIV vaccine cost ranged from $1.54 -$75 USD in low-income countries, $55-$100 in middle-income countries, and $500-$1,000 in the United States. Base case ICERs ranged from dominant (cost-offsetting) to $91,000 per QALY gained., Conclusion: Most models predicted HIV vaccines would be cost-effective. Model assumptions about vaccine price, HIV treatment costs, epidemic context, and willingness to pay influenced results more consistently than assumptions on HIV transmission dynamics., Competing Interests: Conflicts of Interest and Sources of Funding: BA received support for this review in part from grant number T32HS013853 from the Agency for Healthcare Research and Quality and in part by a 2015 Trainee Support Grant from the University of Washington Center for AIDS Research (CFAR), an NIH funded program under award number P30AI027757. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the National Institutes of Health. The authors declare no competing interests.

Introduction: Male partner HIV testing has been recognized as an important component of prevention of mother-to-child HIV transmission. Scheduled home-based couple HIV testing may be an effective strategy to reach men., Methods: Women attending their first antenatal visit at Kisumu County Hospital in Kenya were randomized to home-based education and HIV testing within 2 weeks of enrollment (HOPE) or to written invitations for male partners to attend clinic (INVITE). Male partner HIV testing and maternal child health outcomes were compared at 6 months postpartum., Results: Of 1101 women screened, 620 were eligible and 601 were randomized to HOPE (n = 306) or INVITE (n = 295). At 6 months postpartum, male partners were more than twice as likely [relative risk (RR) = 2.10; 95% CI (CI): 1.81 to 2.42] to have been HIV tested in the HOPE arm [233 (87%)] compared with the INVITE arm [108 (39%)]. Couples in the HOPE arm [192 (77%)] were 3 times as likely (RR = 3.17; 95% CI: 2.53 to 3.98) to have been tested as a couple as the INVITE arm [62 (24%)] and women in the HOPE arm [217 (88%)] were also twice as likely (RR = 2.27; 95% CI: 1.93 to 2.67) to know their partner's HIV status as the INVITE arm [98 (39%)]. More serodiscordant couples were identified in the HOPE arm [33 (13%)] than in the INVITE arm [10 (4%)] (RR = 3.38; 95% CI: 1.70 to 6.71). Maternal child health outcomes of facility delivery, postpartum family planning, and exclusive breastfeeding did not vary by arm., Conclusions: Home-based HIV testing for pregnant couples resulted in higher uptake of male partner and couple testing, as well as higher rates of HIV status disclosure and identification of serodiscordant couples. However, the intervention did not result in higher uptake of maternal child health outcomes, because facility delivery and postpartum family planning were high in both arms, whereas exclusive breastfeeding was low. The HOPE intervention was successful at its primary aim to increase HIV testing and disclosure among pregnant couples and was able to find more serodiscordant couples compared with the invitation-only strategy., Trial Registration: Clinicaltrials.gov registry: NCT01784783., Competing Interests: The authors have no funding or conflicts of interest to disclose.

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

HIV testing and counselling is the first crucial step for linkage to HIV treatment and prevention. However, despite high HIV burden in sub-Saharan Africa, testing coverage is low, particularly among young adults and men. Community-based HIV testing and counselling (testing outside of health facilities) has the potential to reduce coverage gaps, but the relative impact of different modalities is not well assessed. We conducted a systematic review of HIV testing modalities, characterizing community (home, mobile, index, key populations, campaign, workplace and self-testing) and facility approaches by population reached, HIV positivity, CD4 count at diagnosis and linkage. Of 2,520 abstracts screened, 126 met eligibility criteria. Community HIV testing and counselling had high coverage and uptake and identified HIV-positive people at higher CD4 counts than facility testing. Mobile HIV testing reached the highest proportion of men of all modalities examined (50%, 95% confidence interval (CI) = 47-54%) and home with self-testing reached the highest proportion of young adults (66%, 95% CI = 65-67%). Few studies evaluated HIV testing for key populations (commercial sex workers and men who have sex with men), but these interventions yielded high HIV positivity (38%, 95% CI = 19-62%) combined with the highest proportion of first-time testers (78%, 95% CI = 63-88%), indicating service gaps. Community testing with facilitated linkage (for example, counsellor follow-up to support linkage) achieved high linkage to care (95%, 95% CI = 87-98%) and antiretroviral initiation (75%, 95% CI = 68-82%). Expanding home and mobile testing, self-testing and outreach to key populations with facilitated linkage can increase the proportion of men, young adults and high-risk individuals linked to HIV treatment and prevention, and decrease HIV burden.

Background: HIV case-finding and linkage to care are critical for control of HIV transmission. In Kenya, >50% of seropositive individuals are unaware of their status. Assisted partner notification is a public health strategy that provides HIV testing to individuals with sexual exposure to HIV and are at risk of infection and disease. This parallel, cluster-randomized controlled trial will evaluate the effectiveness, cost-effectiveness, and feasibility of implementing HIV assisted partner notification services at HIV testing sites (clusters) in Kenya., Methods/design: Eighteen sites were selected among health facilities in Kenya with well-established, high-volume HIV testing programs, to reflect diverse communities and health-care settings. Restricted randomization was used to balance site characteristics between study arms (n = 9 per arm). Sixty individuals testing HIV positive ('index partners') will be enrolled per site (inclusion criteria: ≥18 years, positive HIV test at a study site, willing to disclose sexual partners, and never enrolled for HIV care; exclusion criteria: pregnancy or high risk of intimate partner violence). Index partners provide names and contact information for all sexual partners in the past 3 years. At intervention sites, study staff immediately contact sexual partners to notify them of exposure, offer HIV testing, and link to care if HIV seropositive. At control sites, passive partner referral is performed according to national guidelines, and assisted partner notification is delayed by 6 weeks. Primary outcomes, assessed 6 weeks after index partner enrollment and analyzed at the cluster level, are the number of partners accepting HIV testing and number of HIV infections diagnosed and linked to care per index partner. Secondary outcomes are the incremental cost-effectiveness of partner notification and the costs of identifying >1 partner per index case. Participants are closely monitored for adverse outcomes, particularly intimate partner violence. The study is unblinded due to practical limitations., Discussion: This rigorously designed trial will inform policy decisions regarding implementation of HIV partner notification services in Kenya, with possible application to other parts of sub-Saharan Africa. Examination of effectiveness and cost-effectiveness in diverse settings will enable targeted application and define best practices., Trial Registration: ClinicalTrials.gov NCT01616420 .

While the uptake of voluntary medical male circumcision (VMMC) is increasing, South Africa has only attained 20% of its target to circumcise 80% of adult men by 2015. Understanding the factors influencing uptake is essential to meeting these targets. This qualitative study reports on findings from focus-group discussions with men in rural KwaZulu-Natal, South Africa, about what factors influence their perceptions of VMMC. The study found that VMMC is linked to perceptions of masculinity and male gender identity including sexual health, sexual performance and pleasure, possible risk compensation and self-identity. Findings highlight the need to understand how these perceptions of sexual health and performance affect men's decisions to undergo circumcision and the implications for uptake of VMMC. The study also highlights the need for individualised and contextualised information and counselling that can identify, understand and address the perceptions men have of VMMC, and the impacts they believe it will have on them.

Combination HIV prevention is of high priority for increasing the impact of partially efficacious HIV prevention interventions for specific populations and settings. Developing the package requires critical review of local epidemiology of HIV infection regarding most-impacted populations and those at high risk of HIV transmission and acquisition, drivers of HIV infection, and available interventions to address these risk factors. Interventions should be considered in terms of the evidence basis for efficacy, potential synergies, and feasibility of delivery at scale, which is important to achieve high coverage and impact, coupled with high acceptability to populations, which will impact uptake, adherence, and retention. Evaluation requires process measures of uptake, adherence, retention, and outcome measures of reduction in HIV infectiousness and acquisition. Three examples of combination prevention concepts are summarized for men who have sex with men in the Americas, young women in sub-Saharan Africa, and HIV serodiscordant couples.

Maternal or neonatal tetanus causes deaths primarily in Asia and Africa and is usually the result of poor hygiene during delivery. In 2011, three neonatal tetanus cases were investigated in Papua New Guinea, and all three cases were delivered at home by untrained assistants. The babies were normal at birth but subsequently developed spasms. A neonatal tetanus case must be viewed as a sentinel event indicating a failure of public health services including immunization, antenatal care and delivery care. The confirmation of these cases led to the drafting of the Papua New Guinea National Action Plan for Maternal and Neonatal Tetanus Elimination. This included three rounds of a tetanus toxoid supplementary immunization campaign targeting women of childbearing age (WBCA) and strengthening of other clean delivery practices. The first immunization round was conducted in April and May 2012, targeting 1.6 million WBCA and achieved coverage of 77%. The government of Papua New Guinea should ensure detailed investigation of all neonatal tetanus cases reported in the health information system and perform subprovincial analysis of tetanus toxoid coverage following completion of all three immunization rounds. Efforts also should be made to strengthen clean delivery practices to help eliminate maternal and neonatal tetanus in Papua New Guinea.

Background: Antiretrovirals have substantial promise for HIV-1 prevention, either as antiretroviral treatment (ART) for HIV-1-infected persons to reduce infectiousness, or as pre-exposure prophylaxis (PrEP) for HIV-1-uninfected persons to reduce the possibility of infection with HIV-1. HIV-1 serodiscordant couples in long-term partnerships (one member is infected and the other is uninfected) are a priority for prevention interventions. Earlier ART and PrEP might both reduce HIV-1 transmission in this group, but the merits and synergies of these different approaches have not been analyzed., Methods and Findings: We constructed a mathematical model to examine the impact and cost-effectiveness of different strategies, including earlier initiation of ART and/or PrEP, for HIV-1 prevention for serodiscordant couples. Although the cost of PrEP is high, the cost per infection averted is significantly offset by future savings in lifelong treatment, especially among couples with multiple partners, low condom use, and a high risk of transmission. In some situations, highly effective PrEP could be cost-saving overall. To keep couples alive and without a new infection, providing PrEP to the uninfected partner could be at least as cost-effective as initiating ART earlier in the infected partner, if the annual cost of PrEP is <40% of the annual cost of ART and PrEP is >70% effective., Conclusions: Strategic use of PrEP and ART could substantially and cost-effectively reduce HIV-1 transmission in HIV-1 serodiscordant couples. New and forthcoming data on the efficacy of PrEP, the cost of delivery of ART and PrEP, and couples behaviours and preferences will be critical for optimizing the use of antiretrovirals for HIV-1 prevention. Please see later in the article for the Editors' Summary.

Background: Successful conduct of HIV vaccine efficacy trials entails identification and enrollment of at-risk populations, assessment of appropriate end points as measures of vaccine efficacy for prevention of HIV acquisition, and amelioration of disease course among infected vaccinees, as well as identification of potential confounders or effect modifiers. Although not invariably useful and bringing their own cost in terms of measurement and validation, a variety of biomarkers may aid at each stage of trial conduct., Methods: A review of selected articles, chosen based on quality, relevance of the biomarker to HIV vaccine trials, and availability of the publication, was conducted. The authors also drew experience from current trials and other planned or ongoing trials., Conclusions: Biomarkers are available to assess HIV incidence in potential study populations, but care is needed in interpreting results of these assays. During trial conduct, sexually transmitted infections such as herpes simplex virus type 2 may act as effect modifiers on primary and secondary end points, including HIV incidence and set point viral load. The utility of sexually transmitted infection biomarkers will likely depend heavily on local epidemiology at clinical trial sites. Analyses from recent large HIV vaccine efficacy trials point to the complexities in interpreting trial results and underscore the potential utility of biomarkers in evaluating confounding and effect modification.

We have performed a serological survey of HPV type 16-antibody prevalence by age and sex in Sweden and used it as a basis for modelling the optimal vaccination strategies in this population. Samples of 3,317 subjects were tested for HPV16-specific antibodies. The observed age-specific seroprevalences along with sexual behaviour data were used to infer parameter values for a mathematical model representing Sweden and the preventive effect of possible strategies estimated. By the year 2055, vaccination of females starting at age 12 in 2008 was most efficient, estimated to prevent 5.8 million cumulative HPV16 infections. Catch-up programs had a strong additional preventive effect. Vaccination also targeting males increased protective effect by about 4%, but had lower preventive effect per vaccination given. Addition of an HPV serosurvey to existing models and data has enabled us to estimate effect of different vaccination strategies, optimized to the HPV epidemiology in our population.

Vaccines to prevent infection with the human papillomavirus (HPV) have recently been approved for use in preventing cervical precancer and cancer. This paper reviews the HPV vaccine effectiveness and cost-effectiveness studies published to date. In order to fully appreciate the strengths and limitations of the different studies, a short background is provided on the natural history of HPV and cervical cancer, current prevention strategies and HPV vaccine trial results to date. Each study is then summarized in terms of model structure, parameter estimates for the natural history of HPV and cervical cancer, assumptions regarding screening and vaccination, and key findings. The review concludes with recommendations for additional research and a five-year perspective.

We review studies of the implementation of human papillomavirus (HPV) vaccination programmes in developed and developing countries. The review spans the period from establishment of long-term vaccine efficacy follow-up studies, operational research on issues of vaccine preparedness, and relevant predictive modelling studies during the pre-licensure phase to plans of phase IV effectiveness trials, forms of epidemiological surveillance, and further operational research in the post-licensure phase. Much of the research is already ongoing. Depending on the results of the planned immuno bridging studies among HIV-negative and HIV-positive women, further phase III and/or phase IV trials may be warranted.

Objective: As a result of the HIV epidemic in Africa, much debate exists on whether institutionalized compared with community-based care provides optimum management of infected children. Previous reports calculated 89% mortality by age 3 years among outpatients in Malawi. No similar data are available for infected children in institutionalized care. We characterized patterns of morbidity and mortality among HIV-1-infected children residing at an orphanage in Nairobi., Methods: Medical records for 174 children followed over 5 years were reviewed. Mortality was analyzed by Kaplan-Meier methods with adjustment to account for survival in the community before admission. Anthropometric indices were calculated to include mean z scores for weight for length and length for age. Low indices reflected wasting and stunting. Opportunistic infections were documented., Results: Of 174 children, 64 had died. Survival was 70% at age 3 years. Morbidity included recurrent respiratory tract infections, gastroenteritis, parotitis, and lymphoid interstitial pneumonitis. No new cases of tuberculosis disease were noted after admission. Mean z scores for length for age suggested overall stunting (z = -1.65). Wasting was not observed (z = -0.39)., Conclusion: The optimal form of care for HIV-infected children in resource-poor settings may be the development of similar homes. Absence of tuberculosis disease in long-standing residents may have contributed to improved survival. Stunting in the absence of wasting implied that growth was compromised by opportunistic infections and other cofactors.

Effects of aging on the circadian rhythm of locomotor activity in males of Drosophila nasuta were investigated. The adult life of males was divided in 1-3 stages according to spontaneous changes in free-running period tau in constant darkness (DD): stage 1, days 1-19; stage 2, days 20-36; stage 3, days 37-43. Stage 1 was characterized by a bimodal activity pattern with a short light-induced morning peak and a prolonged evening peak when the flies were entrained to light-dark cycles of 12 hours of light, 12 hours of darkness (LD 12:12). The morning peak had a phase angle difference psi m (psi, the time from lights on in LD 12:12 cycles to the onset of morning peak) of about 0.1 h, while psi e (psi of evening peak) was about 9 h at stage 1. The transient morning peak was curtailed at the end of stage 1. At stage 2, the psi e was about 10 h, and the activity end was delayed by an addition of about 3 h of activity in the scotophase. The changes in tau during DD free runs were determined in two groups of flies: flies reared in LD 12:12 and flies reared in DD. In both groups, tau increased from about 23 h at stage 1 to about 25 h at stage 2. Stage 3 was characterized by arrhythmicity associated with highest mean activity level (total number of passes/fly/day) in the entrained and both free-running groups. The mean activity level increased significantly from stage 1 to stage 3 in all three groups of flies.