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Introduction: In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource-constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes. Discussion: USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use. Conclusions: In this paper, we describe the importance and implementation of USFDA's tentative approval process to review ARVs for resource-constrained settings. We also highlight the impact of patents and exclusivities on review of HIV drugs under tFDA and illustrate the concepts using a new HIV drug as an example. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: A number of antiretroviral HIV prevention products are efficacious in preventing HIV infection. However, the sexual and reproductive health needs of many women extend beyond HIV prevention, and research is ongoing to develop multi‐purpose prevention technologies (MPTs) that offer dual HIV and pregnancy protection. We do not yet know if these products will be an efficient use of constrained health resources. In this paper, we estimate the cost‐effectiveness of combinations of candidate multi‐purpose prevention technologies (MPTs), in South Africa among general population women and female sex workers (FSWs). Methods: We combined a cost model with a static model of product impact based on incidence data in South Africa to estimate the cost‐effectiveness of five candidate co‐formulated or co‐provided MPTs: oral PrEP, intravaginal ring, injectable ARV, microbicide gel and SILCS diaphragm used in concert with gel. We accounted for the preferences of end‐users by predicting uptake using a discrete choice experiment (DCE). Product availability and protection were systematically varied in five potential rollout scenarios. The impact model estimated the number of infections averted through decreased incidence due to product use over one year. The comparator for each scenario was current levels of male condom use, while a health system perspective was used to estimate discounted lifetime treatment costs averted per HIV infection. Product benefit was estimated in disability‐adjusted life years (DALYs) averted. Benefits from contraception were incorporated through adjusting the uptake of these products based on the DCE and through estimating the costs averted from avoiding unwanted pregnancies. We explore the additional impact of STI protection through increased uptake in a sensitivity analysis. Results: At central incidence rates, all single‐ and multi‐purpose scenarios modelled were cost‐effective among FSWs and women aged 16–24, at a governmental willingness‐to‐pay threshold of $1175/DALY averted (range: $214–$810/DALY averted among non‐dominant scenarios), however, none were cost‐effective among women aged 25–49 (minimum $1706/DALY averted). The cost‐effectiveness of products improved with additional protection from pregnancy. Estimates were sensitive to variation in incidence assumptions, but robust to other parameters. Conclusions: To the best of our knowledge, this is the first study to estimate the cost‐effectiveness of a range of potential MPTs; suggesting that MPTs will be cost‐effective among higher incidence FSWs or young women, but not among lower incidence older women. More work is needed to make attractive MPTs available to potential users who could use them effectively. [ABSTRACT FROM AUTHOR]

Introduction: Expanding and sustaining antiretroviral therapy (ART) coverage may require simplified HIV service delivery strategies that concomitantly reduce the burden of care on the health system and patients while ensuring optimal outcomes. We conducted a systematic review to assess the impact of reduced frequency of clinic visits and drug dispensing on patient outcomes. Methods: As part of the development process of the World Health Organization antiretroviral (ARV) guidelines, we systematically searched medical literature databases for publications up to 30 August 2016. Information was extracted on trial characteristics, patient characteristics and the following outcomes: mortality, morbidity, treatment adherence, retention, patient and provider acceptability, cost and patients exiting the programme. When feasible, conventional pairwise metaanalyses were conducted. Results and discussion: Of 6443 identified citations, 21 papers, pertaining to 16 studies, were included in this review, with 11 studies contributing to analyses. Although analyses were feasible, they were limited by the sparse evidence base, despite the importance of the research area, and relatively low quality. Comparative analyses of eight studies reporting on frequency of clinic visits showed that less frequent clinic visits led to higher odds of being retained in care (odds ratio [OR]: 1.90; 95% CI: 1.21-2.99). No differences were found with respect to viral failure, morbidity or mortality; however, most estimates were favourable to reduced clinic visits. Reduced frequency of ARVs pick-ups showed a trend towards better retention (OR: 1.93; 95% CI: 0.62-6.04). Strategies using community support tended to have better outcomes; however, their implementation varied, particularly by location. External validity may be questionable. Conclusions: Our systematic review suggests that reduction of clinical visits (and likely ARVs pick-ups) may improve clinical outcomes, and that they are a viable option to relieve health systems and reduce burden of care for PLHIV. Strategies aimed at reducing clinic visits or drug refill services should focus on stable patients who are virally suppressed, tolerant to their drug regimen and fully adherent. These strategies may be critical to the current changes taking place in HIV treatment policy; thus, due to the data limitations, further high quality research is needed to inform policy and programmatic interventions. [ABSTRACT FROM AUTHOR]

Introduction: To systematically review the literature on mother-to-child transmission in breastfed infants whose mothers received antiretroviral therapy and support the process of updating the World Health Organization infant feeding guidelines in the context of HIV and ART. Methods: We reviewed experimental and observational studies; exposure was maternal HIV antiretroviral therapy (and duration) and infant feeding modality; outcomes were overall and postnatal HIV transmission rates in the infant at 6, 9, 12 and 18 months. English literature from 2005 to 2015 was systematically searched in multiple electronic databases. Papers were analysed by narrative synthesis; data were pooled in random effects meta-analyses. Postnatal transmission was assessed from four to six weeks of life. Study quality was assessed using a modified Newcastle-Ottawa Scale (NOS) and GRADE. Results and discussion: Eleven studies were identified, from 1439 citations and review of 72 abstracts. Heterogeneity in study methodology and pooled estimates was considerable. Overall pooled transmission rates at 6 months for breastfed infants with mothers on antiretroviral treatment (ART) was 3.54% (95% CI: 1.15-5.93%) and at 12 months 4.23% (95% CI: 2.97-5.49%). Postnatal transmission rates were 1.08 (95% CI: 0.32-1.85) at six and 2.93 (95% CI: 0.68-5.18) at 12 months. ART was mostly provided for PMTCT only and did not continue beyond six months postpartum. No study provided data on mixed feeding and transmission risk. Conclusions: There is evidence of substantially reduced postnatal HIV transmission risk under the cover of maternal ART. However, transmission risk increased once PMTCT ART stopped at six months, which supports the current World Health Organization recommendations of life-long ART for all. [ABSTRACT FROM AUTHOR]

Introduction: Towards the end of the twentieth century, significant success was achieved in reducing incidence in several global HIV epidemics through ongoing prevention strategies. However, further progress in risk reduction was uncertain. For one thing, it was clear that social vulnerability had to be addressed, through research on interventions addressing health systems and other structural barriers. As soon as antiretroviral treatment became available, researchers started to conceive that antiretrovirals might play a role in decreasing either susceptibility in uninfected people or infectiousness among people living with HIV. In this paper we focus on the origin, present status, and potential contribution of pre-exposure prophylaxis (PrEP) within the combination HIV prevention framework. Discussion: After a phase of controversy, PrEP efficacy trials took off. By 2015, daily oral PrEP, using tenofovir alone or in combination with emtricitabine, has been proven efficacious, though efficacy seems heavily contingent upon adherence to pill uptake. Initial demonstration projects after release of efficacy results have shown that PrEP can be implemented in real settings and adherence can be high, leading to high effectiveness. Despite its substantial potential, beliefs persist about unfeasibility in reallife settings due to stigma, cost, adherence, and potential risk compensation barriers. Conclusions: The strategic synergy of behavioural change communication, biomedical strategies (including PrEP), and structural programmes is providing the basis for the combination HIV prevention framework. If PrEP is to ever become a key component of that framework, several negative beliefs must be confronted based on emerging evidence; moreover, research gaps regarding PrEP implementation must be filled, and appropriate prioritization strategies must be set up. Those challenges are significant, proportional to the impact that PrEP implementation may have in the global response to HIV. [ABSTRACT FROM AUTHOR]

Introduction: Global scale up of antiretroviral therapy is changing the context of HIV‐related stigma. However, stigma remains an ongoing concern in many countries. Groups of people living with HIV can contribute to the reduction of stigma. However, the pathways through which they do so are not well understood. Methods: This paper utilizes data from a qualitative study exploring the impact of networked groups of people living with HIV in Jinja and Mbale districts of Uganda. Participants were people living with HIV (n=40), members of their households (n=10) and their health service providers (n=15). Data were collected via interviews and focus group discussions in 2010, and analyzed inductively to extract key themes related to the approaches and outcomes of the groups’ anti‐stigma activities. Results: Study participants reported that HIV stigma in their communities had declined as a result of the collective activities of groups of people living with HIV. However, they believed that stigma remained an ongoing challenge. Gender, family relationships, social and economic factors emerged as important drivers of stigma. Challenging stigma collectively transcended individual experiences and united people living with HIV in a process of social renegotiation to achieve change. Groups of people living with HIV provided peer support and improved the confidence of their members, which ultimately reduced self‐stigma and improved their ability to deal with external stigma when it was encountered. Conclusions: Antiretroviral therapy and group‐based approaches in the delivery of HIV services are opening up new avenues for the collective participation of people living with HIV to challenge HIV stigma and act as agents of social change. Interventions for reducing HIV stigma should be expanded beyond those that aim to increase the resilience and coping mechanisms of individuals, to those that build the capacity of groups to collectively cope with and challenge HIV stigma. Such interventions should be gender sensitive and should respond to contextual social, economic and structural factors that drive stigma. [ABSTRACT FROM AUTHOR]

Background In Malawi, as in other sub-Saharan African countries, nurses manage patients of all ages on antiretroviral treatment (ART). Nurse management of children is rarely studied. We compare ART prescribing between nurses and clinical officers during routine clinic visits at an urban, public clinic to inform policy in paediatric ART management. Methods Caregivers of children on first-line ART provided information about visit dates, pill counts, ART dosage and formulation to a nurse and, subsequently, to a clinical officer. Nurses and clinical officers independently calculated adherence, dosage based on body weight, and set next appointment date. Clinical officers, but not nurses, accessed an electronic data system that made the calculations for them based on information from prior visits, actual and expected pill consumption, and standard drug supplies. Nurses calculated with pen and paper. For numerical variables, Bland-Altman graphs plot differences of each nurse-clinical officer pair against the mean, show the 95% limits of agreement (LoA), and also show the mean difference across all reviews. Kappa statistics assess agreement for categorical variables. Results A total of 704 matched nurse-clinical officer reviews of 367 children attending the ART clinics between March and July 2010 were analyzed. Eight nurses and 18 clinical officers were involved; two nurses and five clinical officers managed 100 visits or more. Overall, there was a good agreement between the two cadres. Differences between nurses and clinical officers were within narrow LoA and mean differences showed little deviation from zero, indicating little skewing towards one cadre. LoA of adherence and morning and evening ART dosages varied from −24% to 24%, −0.4 to 0.4 and −0.41 to 0.40 tablets, respectively, with mean differences (95% CI) of 0.003 (−0.9, 0.91), −0.005 (−0.02, 0.01) and −0.009 (−0.02, 0.01). Next appointment calculations differed more between cadres with LoA from −40 to 42 days [mean difference: 0.96 days (95% CI:−0.6 to 2.5)], but agreement in the ART formulation prescribed was very good (kappa 0.93). Conclusions Nurses' ART prescribing practices and calculations of adherence and next appointments are similar to clinical officers, although clinical officers used an electronic system. Our findings support the decision of Malawi's health officials to utilize nurses to manage paediatric ART patients. [ABSTRACT FROM AUTHOR]

Background In order to maximize the benefits of HIV care and treatment investments in sub-Saharan Africa, programs can broaden to target other diseases amenable to screening and efficient management. We nested cervical cancer screening into family planning clinics at select sites also receiving PEPFAR support for antiretroviral therapy (ART) rollout. This was done using visual inspection with acetic acid (VIA) by maternal child health nurses. We report on achievements and obstacles in the first year of the program in rural Mozambique. Methods VIA was taught to clinic nurses and hospital physicians, with a regular clinical feedback loop for quality evaluation and retraining. Cryotherapy using carbon dioxide as the refrigerant was provided at clinics; loop electrosurgical excision procedure (LEEP) and surgery were provided at the provincial hospital for serious cases. No pathology services were available. Results Nurses screened 4651 women using VIA in Zambézia Province in year one of the program, more than double the Ministry of Health service target. VIA was judged positive for squamous intraepithelial lesions in 8% ( n=380) of the women (9% if age ≥30 years ( n=3154) and 7% if age <30 years ( n=1497); p=0.02). Of the 380 VIA-positive women, 4% ( n=16) had lesions (0.3% of 4651 total screened) requiring referral to Quelimane Provincial Hospital. Fourteen (88%) of these 16 women were seen at the hospital, but records were inadequate to judge outcomes. Of women screened, 2714 (58%) either had knowledge of their HIV status prior to VIA or were subsequently sent for HIV testing, of which 583 (21%) were HIV positive. Conclusions Screening and clinical services were successfully provided on a large scale for the first time ever in these rural clinics. However, health manpower shortages, equipment problems, poor paper record systems and a limited ability to follow-up patients inhibited the quality of the cervical cancer screening services. Using prior HIV investments, chronic disease screening and management for cervical cancer is feasible even in severely resource-constrained rural Africa. [ABSTRACT FROM AUTHOR]

Many successes have been achieved in HIV care in low- and middle-income countries (LMIC): increased number of HIV-infected individuals receiving antiretroviral treatment (ART), wide decentralization, reduction in morbidity and mortality and accessibility to cheapest drugs. However, these successes should not hide existing failures and difficulties. In this paper, we underline several key challenges. First, ensure long-term financing, increase available resources, in order to meet the increasing needs, and redistribute the overall budget in a concerted way amongst donors. Second, increase ART coverage and treat the many eligible patients who have not yet started ART. Competition amongst countries is expected to become a strong driving force in encouraging the least efficient to join better performing countries. Third, decrease early mortality on ART, by improving access to prevention, case-finding and treatment of tuberculosis and invasive bacterial diseases and by getting people to start ART much earlier. Fourth, move on from WHO 2006 to WHO 2010 guidelines. Raising the cut-off point for starting ART to 350 CD4/mm3 needs changing paradigm, adopting opt-out approach, facilitating pro-active testing, facilitating task shifting and increasing staff recruitments. Phasing out stavudine needs acting for a drastic reduction in the costs of other drugs. Scaling up routine viral load needs a mobilization for lower prices of reagents and equipments, as well as efforts in relation to point-of-care automation and to maintenance. The latter is a key step to boost the utilization of second-line regimens, which are currently dramatically under prescribed. Finally, other challenges are to reduce lost-to-follow-up rates; manage lifelong treatment and care for long-term morbidity, including drug toxicity, residual AIDS and HIV-non-AIDS morbidity and aging-related morbidity; and be able to face unforeseen events such as socio-political and military crisis. An old African proverb states that the growth of a deep-rooted tree cannot be stopped. Our tree is well rooted in existing field experience and is, therefore, expected to grow. In order for us to let it grow, long-term cost-effectiveness approach and life-saving evidence-based programming should replace short-term budgeting approach. [ABSTRACT FROM AUTHOR]

Introduction: Despite the relatively effective roll-out of free life-prolonging antiretroviral therapy (ART) in public sector clinics in Zambia since 2005, and the proven efficacy of ART, some people living with HIV (PLHIV) are abandoning the treatment. Drawing on a wider ethnographic study in a predominantly low-income, high-density residential area of Lusaka, this paper reports the reasons why PLHIV opted to discontinue their HIV treatment. Methods: Opened-ended, in-depth interviews were held with PLHIV who had stopped ART (n=25), ART clinic staff (n=5), religious leaders (n=5), herbal medicine providers (n=5) and lay home-based caregivers (n=5). In addition, participant observations were conducted in the study setting for 18 months. Interview data were analysed using open coding first, and then interpreted using latent content analysis. The presentation of the results is guided by a social-ecological framework. Findings: Patient attrition from ART care is influenced by an interplay of personal, social, health system and structural-level factors. While improved corporeal health, side effects and need for normalcy diminished motivation to continue with treatment, individuals also weighed the social and economic costs of continued uptake of treatment. Long waiting times for medical care and placing ''defaulters'' on intensive adherence counselling in the context of insecure labour conditions and livelihood constraints not only imposed opportunity costs which patients were not willing to forego, but also forced individuals to balance physical health with social integrity, which sometimes forced them to opt for faith healing and traditional medicine. Conclusions: Complex and dynamic interplay of personal, social, health system and structural-level factors coalesces to influence patient attrition from ART care. Consequently, while patient-centred interventions are required, efforts should be made to improve ART care by extending and establishing flexible ART clinic hours, improving patient-provider dialogue about treatment experiences and being mindful of the way intensive adherence counselling is being enforced. In the context of insecure labour conditions and fragile livelihoods, this would enable individuals to more easily balance time for treatment and their livelihoods. As a corollary, the perceived efficacy of alternative treatment and faith healing needs to be challenged through sensitizations targeting patients, religious leaders/faith healers and herbal medicine providers. [ABSTRACT FROM AUTHOR]

The great success in the prevention and treatment of pediatric HIV in high resource countries, and now in low resource countries, has changed the face of the HIV epidemic in children from one of near certain mortality to that of a chronic disease. However, these successes pose new challenges as perinatally HIV-infected youth survive into adulthood. Increased survival of HIV-infected children is associated with challenges in maintaining adherence to what is likely life-long therapy, and in selecting successive antiretroviral drug regimens, given the limited availability of pediatric formulations, limitations in pharmacokinetic and safety data of drugs in children, and the development of extensive drug resistance in multi-drug-experienced children. Pediatric HIV care must now focus on morbidity related to long-term HIV infection and its treatment. Survival into adulthood of perinatally HIV-infected youth in high resource countries provides important lessons about how the epidemic will change with increasing access to antiretroviral therapy for children in low resource countries. This series of papers will focus on issues related to management of perinatally infected youth and young adults [ABSTRACT FROM AUTHOR]