Retreatment of Chronic Hepatitis C Infection: Real-World Regimens and Outcomes From National Treatment Programs in Three Low- and Middle-Income Countries.

Access to recommended second-line treatments is limited for patients who fail initial hepatitis C virus (HCV) therapy in low- and middle-income countries. Alternative regimens and associated outcomes are not well understood. Through a pooled analysis of national program data in Egypt, Georgia, and Myanmar, we observed SVR rates >90% for alternative retreatment regimens.

Integrating antiretroviral therapy into antenatal care and maternal and child health settings: a systematic review and meta-analysis.

OBJECTIVE: To determine whether integrating antiretroviral therapy (ART) into antenatal care (ANC) and maternal and child health (MCH) clinics could improve programmatic and patient outcomes. METHODS: The authors systematically searched PubMed, Embase, African Index Medicus and LiLACS for randomized controlled trials, prospective cohort studies, or retrospective cohort studies comparing outcomes in ANC or MCH clinics that had and had not integrated ART. The outcomes of interest were ART coverage, ART enrolment, ART retention, mortality and transmission of human immunodeficiency virus (HIV). FINDINGS: Four studies met the inclusion criteria. All were conducted in ANC clinics. Increased enrolment of pregnant women in ART was observed in ANC clinics that had integrated ART (relative risk, RR: 2.09; 95% confidence interval, CI; 1.78-2.46; I(2): 15%). Increased ART coverage was also noted in such clinics (RR: 1.37; 95% CI: 1.05-1.79; I(2): 83%). Sensitivity analyses revealed a trend for the national prevalence of HIV infection to explain the heterogeneity in the size of the effect of ART integration on ART coverage (P = 0.13). Retention in ART was similar in ANC clinics with and without ART integration. CONCLUSION: Although few data were available, ART integration in ANC clinics appears to lead to higher rates of ART enrolment and ART coverage. Rates of retention in ART remain similar to those observed in referral-based models.

Résumé OBJECTIF: Déterminer si l'intégration de la thérapie antirétrovirale (TAR) dans les établissements de soins prénataux (ESP) et de santé maternelle et infantile (SMI) pourrait améliorer les résultats du programme et la santé du patient. MÉTHODES: Les auteurs ont systématiquement recherché via PubMed, Embase, African Index Medicus et LILACS des essais contrôlés randomisés, des études de cohorte prospectives et des études de cohorte rétrospectives comparant les résultats des cliniques ESP ou SMI ayant ou n'ayant pas intégré la TAR. Les résultats pris en compte comprenaient la couverture, la participation et la rétention de la TAR, ainsi que la mortalité et la transmission du virus d'immunodéficience humaine (VIH). RÉSULTATS: Quatre études répondaient aux critères d'inclusion. Toutes ont été menées dans des cliniques ESP. Une participation accrue des femmes enceintes à la TAR a été observée dans les cliniques ESP qui l'avaient intégrée (risque relatif, RR: 2,09; intervalle de confiance IC à 95%: 1,78 à 2,46; I: 15%). Une couverture plus importante de la TAR a également été notée dans ces cliniques (RR: 1,37; IC à 95%: 1,05 à 1,79; I: 83%). Les analyses de sensibilité ont révélé une tendance à la prévalence nationale de l'infection par le VIH pour expliquer l'hétérogénéité de la taille de l'effet de l'intégration de la TAR sur sa couverture (P = 0,13). La rétention de la TAR était similaire dans les cliniques ESP avec ou sans intégration de la TAR. CONCLUSION: Bien que peu de données aient été disponibles, l'intégration de la TAR dans les cliniques ESP semblait entraîner une augmentation des taux de participation et de couverture de la TAR. Les taux de rétention de la TAR restent semblables à ceux qui sont observés dans les modèles de référence.

Resumen OBJETIVO: Determinar si la integración del tratamiento antirretroviral (TAR) en la atención prenatal (APN) y la salud materno-infantil (SMI) podría mejorar los resultados programáticos y del paciente. MÉTODOS: Partiendo de las bases de datos PubMed, Embase, Index Medicus de la Región de África y LiLACS, los autores realizaron búsquedas sistemáticas de ensayos controlados aleatorizados, estudios de cohortes prospectivos o estudios de cohortes retrospectivos en los que se compararon los resultados en clínicas de APN o SMI que habían y que no habían integrado el TAR. Los resultados de interés fueron la cobertura del TAR, la inclusión en el TAR, la retención en el TAR, la mortalidad y la transmisión del virus de la inmunodeficiencia humana (VIH). RESULTADOS: Cuatro estudios cumplieron los criterios de inclusión. Todos ellos se realizaron en clínicas de APN. Se observó un aumento de la inclusión de mujeres embarazadas en el TAR en aquellas clínicas de APN que se habían integrado el TAR (riesgo relativo, RR: 2,09, intervalo de confianza del 95%, IC; 1,78-2,46; I: 15%). En estas clínicas también se observó un aumento de la cobertura del TAR (RR: 1,37; IC del 95%: 1,05­1,79; I: 83%). Los análisis de sensibilidad revelaron una tendencia en la prevalencia nacional de la infección por el VIH para explicar la heterogeneidad en la magnitud del efecto de la integración del TAR sobre la cobertura del TAR (P=0,13). La retención en el TAR fue similar en las clínicas de APN con y sin integración del TAR. CONCLUSIÓN: A pesar de la escasez de los datos disponibles, la integración del TAR en las clínicas de APN parece traducirse en mayores tasas de inclusión en el TAR y de cobertura del TAR. Las tasas de retención en el TAR siguen siendo similares a las observadas en los modelos basados en derivaciones médicas.

Reducing HIV and AIDS in adolescents: opportunities and challenges.

Adolescents are critical to efforts to end the AIDS epidemic. Few national AIDS strategies explicitly program for children in their second decade of life. Adolescents (aged 10-19 years) are therefore largely invisible in global, regional, and country HIV and AIDS reports making it difficult to assess progress in this population. We have unprecedented knowledge to guide investment towards greater impact on HIV prevention, treatment, and care in adolescents, but it has not been applied to reach those most vulnerable and optimize efficiency and scale. The cost of this is increasing AIDS-related deaths and largely unchanged levels of new HIV infections in adolescents. An AIDS-free generation will remain out of reach if the global community does not prioritize adolescents. National AIDS responses must be accountable to adolescents, invest in strengthening and monitoring protective and supportive laws and policies and access for adolescents to high impact HIV interventions.

Towards an improved investment approach for an effective response to HIV/AIDS.

Substantial changes are needed to achieve a more targeted and strategic approach to investment in the response to the HIV/AIDS epidemic that will yield long-term dividends. Until now, advocacy for resources has been done on the basis of a commodity approach that encouraged scaling up of numerous strategies in parallel, irrespective of their relative effects. We propose a strategic investment framework that is intended to support better management of national and international HIV/AIDS responses than exists with the present system. Our framework incorporates major efficiency gains through community mobilisation, synergies between programme elements, and benefits of the extension of antiretroviral therapy for prevention of HIV transmission. It proposes three categories of investment, consisting of six basic programmatic activities, interventions that create an enabling environment to achieve maximum effectiveness, and programmatic efforts in other health and development sectors related to HIV/AIDS. The yearly cost of achievement of universal access to HIV prevention, treatment, care, and support by 2015 is estimated at no less than US$22 billion. Implementation of the new investment framework would avert 12·2 million new HIV infections and 7·4 million deaths from AIDS between 2011 and 2020 compared with continuation of present approaches, and result in 29·4 million life-years gained. The framework is cost effective at $1060 per life-year gained, and the additional investment proposed would be largely offset from savings in treatment costs alone.

Patient outcomes in public sector hepatitis C treatment programmes: a retrospective cohort analysis across five low- and middle-income countries.

OBJECTIVES: Given limited data on factors associated with hepatitis C virus (HCV) treatment discontinuation and failure in low- and middle-income countries, we aimed to describe patient populations treated for HCV in five countries and identify patient groups that may need additional support. DESIGN: Retrospective cohort analysis using routinely collected data. SETTING: Public sector HCV treatment programmes in India (Punjab), Indonesia, Myanmar, Nigeria (Nasarawa) and Vietnam. PARTICIPANTS: 104 957 patients who initiated treatment in 2016-2022 (89% from Punjab). PRIMARY OUTCOMES: Treatment completion and cure. RESULTS: Patient characteristics and factors associated with outcomes varied across countries and facilities. Across all patients, median age was 40 years (IQR: 29-52), 30.6% were female, 7.0% reported a history of injecting drugs, 18.2% were cirrhotic and 4.9% were coinfected with HIV. 79.8% were prescribed sofosbuvir+daclastasvir. Of patients with adequate follow-up, 90.6% (89,551) completed treatment. 77.5% (69,426) of those who completed treatment also completed sustained virological testing at 12 weeks (SVR12), and of those, 92.6% (64 305) were cured. In multivariable-adjusted models, in most countries, significantly lower treatment completion was observed among patients on 24-week regimens (vs 12-week regimens) and those initiated in later years of the programme. In several countries, males, younger patients <20 years and certain groups of cirrhotic patients were less likely to complete treatment or be cured. In Punjab, treatment completion was also lower in those with a family history of HCV and people who inject drugs (PWID); in other countries, outcomes were comparable for PWID. CONCLUSION: High proportions of patients completed treatment and were cured across patient groups and countries. SVR12 follow-up could be strengthened. Males, younger people and those with decompensated cirrhosis on longer regimens may require additional support to complete treatment and achieve cure. Adequate programme financing, minimal user fees and implementation of evidence-based policies will be critical to close gaps.

Initial success from a public health approach to hepatitis C testing, treatment and cure in seven countries: the road to elimination.

With political will, modest financial investment and effective technical assistance, public sector hepatitis C virus (HCV) programmes can be established in low- and middle-income countries as a first step towards elimination. Seven countries, with support from the Clinton Health Access Initiative (CHAI) and partners, have expanded access to HCV treatment by combining programme simplification with market shaping to reduce commodity prices. CHAI has supported a multipronged approach to HCV programme launch in Cambodia, India, Indonesia, Myanmar, Nigeria, Rwanda and Vietnam including pricing negotiations with suppliers, policy development, fast-track registrations of quality-assured generics, financing advocacy and strengthened service delivery. Governments are leading programme implementation, leveraging HIV programme infrastructure/financing and focusing on higher-HCV prevalence populations like people living with HIV, people who inject drugs and prisoners. This manuscript aims to describe programme structure and strategies, highlight current commodity costs and outline testing and treatment volumes across these countries. Across countries, commodity costs have fallen from >US$100 per diagnostic test and US$750-US$900 per 12-week pan-genotypic direct-acting antiviral regimen to as low as US$80 per-cure commodity package, including WHO-prequalified generic drugs (sofosbuvir + daclatasvir). As of December 2019, 5900+ healthcare workers were trained, 2 209 209 patients were screened, and 120 522 patients initiated treatment. The cure (SVR12) rate was >90%, including at lower-tier facilities. Programmes are successfully implementing simplified, decentralised public health approaches. Combined with political will and affordable pricing, these efforts can translate into commitments to achieve global targets. However, to achieve elimination, additional investment in scale-up is required.

Beyond the first 25 years: The International AIDS Society and its role in the global response to AIDS.

Dr. Pedro Cahn, International AIDS Society (IAS) President and Mr. Craig McClure, IAS Executive Director, provide their thoughts and analysis on the current and future role of the IAS as part of the global response to HIV/AIDS.

Integration of HIV infant testing into immunization programmes: a systematic review.

BACKGROUND: Integration of HIV infant testing into immunization sessions is one of the strategies designed to increase coverage of early infant diagnosis. OBJECTIVE: To determine the evidence on the outcomes of such integration. METHODS: A systematic review of peer-reviewed and grey literature was undertaken from electronic sources such as MEDLINE, Google Scholar, websites of international agencies, past conferences and ministries of health reports published between year 2002 and 2013. Randomized controlled trials, observational and qualitative studies were searched and those meeting selection criteria were selected and relevant information extracted using structured tool. Statistical pooling was not possible owing to the heterogeneity of the study designs and outcome measures. RESULTS: Of the nine articles which met the selection criteria, none used a randomized controlled design. Of these, five articles measured mother's acceptability of their infants being tested for HIV during its first pentavalent or DPT vaccination visit, and 89·5-100% accepted. Four articles reported the proportion of mothers who returned for HIV test results, ranging from 56·8% to 86·0%. Increased uptake of HIV testing following integration was confirmed by two articles. Only one study in Tanzania determined the uptake of vaccinations following integration, with urban facilities showing stable or slight increase of monthly vaccine uptake while decreases were observed across the rural sites. In two articles, stigma was perceived by service-providers and mothers as the potential risk following integration, particularly in rural settings. DISCUSSION: Despite the limited number of articles, the findings in this systematic review suggest that HIV testing during immunization clinic visits is acceptable and feasible as a possible model for service delivery. However, the impact on vaccination uptake needs further study.

EXAFS studies of the zinc sites of UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC).

Extended X-ray absorption fine structure (EXAFS) spectroscopy has been used to determine the structure of the Zn(II) sites in UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC) from Aquifex aeolicus and Pseudomonas aeruginosa. The active site Zn(II) is four coordinate, with exclusively low-Z (nitrogen and oxygen) ligation in both enzymes. The amplitude of the outer-shell scattering from the histidine ligands is best fit using two histidine ligands, suggesting a ZnO(2)(His)(2) site, where O most likely represents a conserved aspartate and a solvent molecule. The same structure was found for Co(II)-substituted A. aeolicus LpxC, although in this case it is possible that the coordination sphere may expand to include a fifth low-Z ligand. EXAFS data were also measured for the Escherichia coli LpxC enzyme. When a single Co(II) is substituted for Zn(II) in the active site of E. coli LpxC, EXAFS data show the same ligand environment as is found for the P. aeruginosa and A. aeolicus enzymes. However, the EXAFS data for E. coli LpxC with two zinc ions bound per protein, with the second Zn(II) acting as an inhibitory metal, demonstrates that the inhibitory metal is bound to at least two high-Z (sulfur, presumably thiolate, or chlorine) ligands. Results of the outer-shell scattering analysis, combined with previous studies of the LpxC enzyme, indicate a novel zinc binding motif not found in any previously studied zinc metalloproteins.

Executive summary: opportunities for action and impact to address HIV and AIDS in adolescents.

INTRODUCTION: The global HIV epidemic in adolescents is not controlled, and this group has not received sufficient attention in programming and research efforts addressing HIV prevention, treatment, and care. METHODS: A global technical consultation on adolescents and HIV addressing services and research gaps was convened by United Nations Children's Fund and the London School of Hygiene and Tropical Medicine in July 2013. Proceedings from this meeting are presented in this issue of the Supplement. RESULTS: Several reviews highlight poor levels of coverage of critical HIV prevention, treatment, and care interventions for adolescents, disparities in HIV prevalence among adolescent girls, and low-risk perceptions associated with risk behaviors among key risk groups. Others underscore the significance of clear national targets and strengthening data, government involvement, enhanced systems capacity and policy, engagement of community and adolescent social networks, and of mobile and internet technologies to the success of interventions for adolescents. Finally, reviews identified several efficacious interventions for adults that could benefit from operational research to inform optimizing implementation in adolescents and how to do so with maximal cost efficiency and impact on the epidemic. CONCLUSIONS: Addressing the adolescent gap in the response to the HIV epidemic is essential to a more sustainable and effective response and is critical to overall adolescent health and well-being. The global community has the means and the responsibility to put measures in place to make AIDS-free survival the reality for children in this second decade of life.

The impact and cost of the HIV/AIDS investment framework for adolescents.

BACKGROUND: In 2005, the resources needed to support orphans and vulnerable children in sub-Saharan Africa were estimated at US$ 1.1-4.1 billion. Approaches to support vulnerable children have changed considerably since then. This study updates previous estimates by including new types of support and information on support costs. METHODS: We considered 16 types of support categorized as economic strengthening, education support, social care and community outreach, and program support. The estimates combine the number of children in need of each intervention with unit costs derived from the literature and coverage goals based on current coverage and feasible future improvements. RESULTS: The number of children affected by AIDS in low- and middle-income countries varies from 58 million to 315 million depending on the definition of need. The resources required to provide support to children living in poor households will grow from US$ 4.2 billion in 2012 to US$ 5-8 billion by 2020. Almost two-thirds of these resources will be needed for Sub-Saharan Africa. The largest needs are for cash transfers, community care workers, early childhood development, block grants for education, M&E monitoring and evaluation, and direct material support. DISCUSSION: The results show that we can significantly improve the coverage of services for vulnerable children with only modest increases in resources. This results from stable or declining numbers of orphans and children living with HIV plus economic growth that is moving more households out of poverty. The results also reflect an important shift toward providing support to strengthen families and communities that care for children rather than direct material support. CONCLUSION: More resources are required to support children affected by AIDS, but new approaches to provide that support will be cost effective and have broad social and economic benefits.

Integration of HIV infant testing into immunization programmes: a systematic review.

Background: Integration of HIV infant testing into immunization sessions is one of the strategies designed to increase coverage of early infant diagnosis. Objective: To determine the evidence on the outcomes of such integration. Methods: A systematic review of peer-reviewed and grey literature was undertaken from electronic sources such as MEDLINE, Google Scholar, websites of international agencies, past conferences and ministries of health reports published between year 2002 and 2013. Randomized controlled trials, observational and qualitative studies were searched and those meeting selection criteria were selected and relevant information extracted using structured tool. Statistical pooling was not possible owing to the heterogeneity of the study designs and outcome measures. Results: Of the nine articles which met the selection criteria, none used a randomized controlled design. Of these, five articles measured mother's acceptability of their infants being tested for HIV during its first pentavalent or DPT vaccination visit, and 89·5-100% accepted. Four articles reported the proportion of mothers who returned for HIV test results, ranging from 56·8% to 86·0%. Increased uptake of HIV testing following integration was confirmed by two articles. Only one study in Tanzania determined the uptake of vaccinations following integration, with urban facilities showing stable or slight increase of monthly vaccine uptake while decreases were observed across the rural sites. In two articles, stigma was perceived by service-providers and mothers as the potential risk following integration, particularly in rural settings. Discussion: Despite the limited number of articles, the findings in this systematic review suggest that HIV testing during immunization clinic visits is acceptable and feasible as a possible model for service delivery. However, the impact on vaccination uptake needs further study.

Determinants of HIV drug resistance and public health implications in low- and middle-income countries.

Global scale-up of antiretroviral therapy (ART) in low- and middle-income countries (LMICs) is an unprecedented public health achievement. With planned efforts of expanded ART access including earlier treatment initiation and the use of antiretroviral (ARV) drugs for prophylaxis, increasing levels of HIV drug resistance (HIVDR) are expected.Several factors may lead to selection and transmission of significant HIVDR in LMICs, which will lead to decreased population-level efficacy of standard first- and second-line ART regimens. These factors include low genetic barrier of some ARVs to resistance development, drug-drug interactions, inappropriate prescribing practices, interruption of drug supply, poor retention in care and lack of routine viral load monitoring.To maximize long-term effectiveness of available ARVs, policy makers and programme managers in LMICs should routinely monitor programme factors associated with emergence and transmission of HIVDR and implement routine HIVDR surveillance following standardized methods. When surveillance results suggest the need for action, specific public health interventions must be taken to adjust ART programme functioning to minimize further emergence and transmission of HIVDR.In this paper, we review ARV drug, HIV, patient and programme-related determinants of HIVDR. Additionally, we summarize the World Health Orgnization's global HIVDR surveillance and prevention strategy and describe resulting public health and policy implications.

Lesotho's minimum PMTCT package: lessons learned for combating vertical HIV transmission using co-packaged medicines.

INTRODUCTION: Mother-to-child transmission of HIV can be reduced to<5% with appropriate antiretroviral medications. Such reductions depend on multiple health system encounters during antenatal care (ANC), delivery and breastfeeding; in countries with limited access to care, transmission remains high. In Lesotho, where 28% of women attending ANC are HIV positive but where geographic and other factors limit access to ANC and facility deliveries, a Minimum PMTCT Package was launched in 2007 as an alternative to the existing facility-based approach. Distributed at the first ANC visit, it packaged together all necessary pregnancy, delivery and early postnatal antiretroviral medications for mother and infant. METHODS: To examine the availability, feasibility, acceptability and possible negative consequences of the Minimum PMTCT Package, data from a 2009 qualitative and quantitative study and a 2010 facility assessment were used. To examine the effects on ANC and facility-based delivery rates, a difference-in-differences analytic approach was applied to 2009 Demographic and Health Survey data for HIV-tested women who gave birth before and after Minimum PMTCT Package implementation. RESULTS: The Minimum PMTCT Package was feasible and acceptable to providers and clients. Problems with test kit and medicine stock-outs occurred, and 46% of women did not receive the Minimum PMTCT Package until at least their second ANC visit. Providing adequate instruction on the use of multiple medications represented a challenge. The proportion of HIV-positive women delivering in facilities declined after Minimum PMTCT Package implementation, although it increased among HIV-negative women (difference-in-differences=14.5%, p=0.05). The mean number of ANC visits declined more among HIV-positive women than among HIV-negative women after implementation, though the difference was not statistically significant (p=0.09). Changes in the percentage of women receiving≥4 ANC visits did not differ between the two groups. CONCLUSIONS: If supply issues can be resolved and adequate client educational materials provided, take-away co-packages have the potential to increase access to PMTCT commodities in countries where women have limited access to health services. However, efforts must be made to carefully monitor potential changes in ANC visits and facility deliveries, and further evaluation of adherence, safety and effectiveness are needed.

Progress, challenges, and new opportunities for the prevention of mother-to-child transmission of HIV under the US President's Emergency Plan for AIDS Relief.

In June 2011, the Joint United Nations Programme on HIV/AIDS, the US President's Emergency Plan for AIDS Relief (PEPFAR), and other collaborators outlined a transformative plan to virtually eliminate pediatric AIDS worldwide. The ambitious targets of this initiative included a 90% reduction in new pediatric HIV infections and a 50% reduction in HIV-related maternal mortality--all by 2015. PEPFAR has made an unprecedented commitment to the expansion and improvement of prevention of mother-to-child HIV transmission (PMTCT) services globally and is expected to play a critical role in reaching the virtual elimination target. To date, PEPFAR has been instrumental in the success of many national programs, including expanded coverage of PMTCT services, an enhanced continuum of care between PMTCT and HIV care and treatment, provision of more efficacious regimens for antiretroviral prophylaxis, design of innovative but simplified PMTCT approaches, and development of new strategies to evaluate program effectiveness. These accomplishments have been made through collaborative efforts with host governments, United Nations agencies, other donors (eg, the Global Fund for AIDS, Tuberculosis, and Malaria), nongovernmental organizations, and private sector partners. To successfully meet the ambitious global targets to prevent new infant HIV infections, PEPFAR must continue to leverage the existing PMTCT platform, while developing innovative approaches to rapidly expand quality HIV services. PEPFAR must also carefully integrate PMTCT into the broader combination prevention agenda for HIV, so that real progress can be made toward an "AIDS-free generation" worldwide.