Understanding effective post-test linkage strategies for HIV prevention and care: a scoping review.

INTRODUCTION: Following HIV testing services (HTS), the World Health Organization recommends prompt linkage to prevention and treatment. Scale-up of effective linkage strategies is essential to achieving the global 95-95-95 goals for maintaining low HIV incidence by 2030 and reducing HIV-related morbidity and mortality. Whereas linkage to care including same-day antiretroviral therapy (ART) initiation for all people with HIV is now routinely implemented in testing programmes, linkage to HIV prevention interventions including behavioural or biomedical strategies, for HIV-negative individuals remains sub-optimal. This review aims to evaluate effective post-HTS linkage strategies for HIV overall, and highlight gaps specifically in linkage to prevention. METHODS: Using the five-step Arksey and O'Malley framework, we conducted a scoping review searching existing published and grey literature. We searched PubMed, Cochrane Library, CINAHL, Web of Science and EMBASE databases for English-language studies published between 1 January 2010 and 30 November 2023. Linkage interventions included as streamlined interventions-involving same-day HIV testing, ART initiation and point-of-care CD4 cell count/viral load, case management-involving linkage coordinators developing personalized HIV care and risk reduction plans, incentives-financial and non-financial, partner services-including contact tracing, virtual-like social media, quality improvement-like use of score cards, and peer-based interventions. Outcomes of interest were linkage to any form of HIV prevention and/or care including ART initiation. RESULTS: Of 2358 articles screened, 66 research studies met the inclusion criteria. Only nine linkage to prevention studies were identified (n = 9/66, 14%)-involving pre-exposure prophylaxis, voluntary medical male circumcision, sexually transmitted infection and cervical cancer screening. Linkage to care studies (n = 57/66, 86%) focused on streamlined interventions in the general population and on case management among key populations. DISCUSSION: Despite a wide range of HIV prevention interventions available, there was a dearth of literature on HIV prevention programmes and on the use of messaging on treatment as prevention strategy. Linkage to care studies were comparatively numerous except those evaluating virtual interventions, incentives and quality improvement. CONCLUSIONS: The findings give insights into linkage strategies but more understanding of how to provide these effectively for maximum prevention impact is needed.

Reasons for disengagement from antiretroviral care in the era of "Treat All" in low- or middle-income countries: a systematic review.

INTRODUCTION: Disengagement from antiretroviral therapy (ART) care is an important reason why people living with HIV do not achieve viral load suppression become unwell. METHODS: We searched two databases and conference abstracts from January 2015 to December 2022 for studies which reported reasons for disengagement from ART care. We included quantitative (mainly surveys) and qualitative (in-depth interviews or focus groups) studies conducted after "treat all" or "Option B+" policy adoption. We used an inductive approach to categorize reasons: we report how often reasons were reported in studies and developed a conceptual framework for reasons. RESULTS: We identified 21 studies which reported reasons for disengaging from ART care in the "Treat All" era, mostly in African countries: six studies in the general population of persons living with HIV, nine in pregnant or postpartum women and six in selected populations (one each in people who use drugs, isolated indigenous communities, men, women, adolescents and men who have sex with men). Reasons reported were: side effects or other antiretroviral tablet issues (15 studies); lack of perceived benefit of ART (13 studies); psychological, mental health or drug use (13 studies); concerns about stigma or confidentiality (14 studies); lack of social or family support (12 studies); socio-economic reasons (16 studies); health facility-related reasons (11 studies); and acute proximal events such as unexpected mobility (12 studies). The most common reasons for disengagement were unexpected events, socio-economic reasons, ART side effects or lack of perceived benefit of ART. Conceptually, studies described underlying vulnerability factors (individual, interpersonal, structural and healthcare) but that often unexpected proximal events (e.g. unanticipated mobility) acted as the trigger for disengagement to occur. DISCUSSION: People disengage from ART care for individual, interpersonal, structural and healthcare reasons, and these reasons overlap and interact with each other. While HIV programmes cannot predict and address all events that may lead to disengagement, an approach that recognizes that such shocks will happen could help. CONCLUSIONS: Health services should focus on ways to encourage clients to engage with care by making ART services welcoming, person-centred and more flexible alongside offering adherence interventions, such as counselling and peer support.

Impact of climate change and natural disasters on fungal infections.

The effects of climate change and natural disasters on fungal pathogens and the risks for fungal diseases remain incompletely understood. In this literature review, we examined how fungi are adapting to an increase in the Earth's temperature and are becoming more thermotolerant, which is enhancing fungal fitness and virulence. Climate change is creating conditions conducive to the emergence of new fungal pathogens and is priming fungi to adapt to previously inhospitable environments, such as polluted habitats and urban areas, leading to the geographical spread of some fungi to traditionally non-endemic areas. Climate change is also contributing to increases in the frequency and severity of natural disasters, which can trigger outbreaks of fungal diseases and increase the spread of fungal pathogens. The populations mostly affected are the socially vulnerable. More awareness, research, funding, and policies on the part of key stakeholders are needed to mitigate the effects of climate change and disaster-related fungal diseases.

HIV and fungal priority pathogens.

The burden of invasive fungal infections associated with opportunistic fungal pathogens is a persistent challenge, particularly among people with advanced HIV disease. In October, 2022, WHO published the Fungal Priority Pathogens List (FPPL)-the first global effort to systematically prioritise fungal pathogens. Of the 19 pathogens in the WHO FPPL, four opportunistic pathogens in particular cause invasive diseases in people living with HIV: Cryptococcus neoformans, Histoplasma spp, Pneumocystis jirovecii, and Talaromyces marneffei. These four fungal pathogens are major causes of illness and death in people with advanced HIV and overwhelmingly affect those in low-income and middle-income countries. Access to diagnostics, improved surveillance, targeted support for innovation, and an enhanced public health focus on these diseases are needed in the effort to reduce HIV-associated deaths.

Person-centred, integrated non-communicable disease and HIV decentralized drug distribution in Eswatini and South Africa: outcomes and challenges.

INTRODUCTION: Non-communicable diseases (NCDs) are highly prevalent in people living with HIV above 50 years of age and account for increasing mortality. There is little published evidence supporting person-centred, integrated models of HIV care, hypertension and diabetes treatment in southern Africa, and no data demonstrating mortality reduction. Where clinical visits for NCDs and HIV cannot be combined, integrated medication delivery presents an opportunity to streamline care and reduce patient costs. We present experiences of integrated HIV and NCD medication delivery in Eswatini and South Africa, focusing on programme successes and implementation challenges. Programmatic data from Eswatini's Community Health Commodities Distribution (CHCD) from April 2020 to December 2021 and South Africa's Central Chronic Medicines Dispensing and Distribution (CCMDD) from January 2016 to December 2021 were provided by programme managers and are summarized here. DISCUSSION: Launched in 2020, Eswatini's CHCD provides over 28,000 people with and without HIV with integrated services, including HIV testing, CD4 cell count testing, antiretroviral therapy refills, viral load monitoring and pre-exposure prophylaxis alongside NCD services, including blood pressure and glucose monitoring and hypertension and diabetes medication refills.  Communities designate neighbourhood care points and central gathering places for person-centred medication dispensing.  This programme reported fewer missed medication refill appointments among clients in community settings compared to facility-based settings. South Africa's CCMDD utilizes decentralized drug distribution to provide medications for over 2.9 million people, including those living with HIV, hypertension and diabetes.  CCMDD incorporates community-based pickup points, facility "fast lanes" and adherence clubs with public sector health facilities and private sector medication collection units.  There are no out-of-pocket payments for medications or testing commodities.  Wait-times for medication refills are lower at CCMDD sites than facility-based sites.  Innovations to reduce stigma include uniformly labelled medication packages for NCD and HIV medications. CONCLUSIONS: Eswatini and South Africa demonstrate person-centred models for HIV and NCD integration through decentralized drug distribution. This approach adapts medication delivery to serve individual needs and decongest centralized health facilities while efficiently delivering NCD care.  To bolster programme uptake, additional reporting of integrated decentralized drug distribution models should include HIV and NCD outcomes and mortality trends.

Ending AIDS deaths requires improvements in clinical care for people with advanced HIV disease who are seriously ill.

Over 4 million adults are living with advanced HIV disease with approximately 650 000 fatalities from HIV reported in 2021. People with advanced HIV disease have low immunity and can present to health services in two ways: those who are well but at high risk of developing severe disease, and those who are severely ill. These two groups require specific management approaches that place different demands on the health system. The first group can generally be supported in primary care settings but require differentiated care to meet their needs. The second group are at high risk of death and need focused diagnostics and clinical care, and possibly hospitalisation. Investments in high-quality clinical management of patients with advanced HIV disease who are seriously ill at primary care or hospital level (often only for a brief period of time during their acute illness) improves the likelihood that their condition will stabilise and that they will recover. Providing high-quality and safe clinical care that is accessible to these groups of people living with HIV who are at risk of severe illness and death is a key priority for reaching the global target of zero AIDS deaths.

Treatment Outcomes After Offering Same-Day Initiation of Human Immunodeficiency Virus Treatment-How to Interpret Discrepancies Between Different Studies.

The World Health Organization recommends same-day initiation of antiretroviral therapy (ART) for all persons diagnosed with HIV and ready to start treatment. Evidence, mainly from randomized trials, indicates offering same-day ART increases engagement in care and viral suppression during the first year. In contrast, most observational studies using routine data find same-day ART to be associated with lower engagement in care. We argue that this discrepancy is mainly driven by different time points of enrollment, leading to different denominators. While randomized trials enroll individuals when tested positive, most observational studies start at the time point when ART is initiated. Thus, most observational studies omit those who are lost between diagnosis and treatment, thereby introducing a selection bias in the group with delayed ART. This viewpoint article summarizes the available evidence and argues that the benefits of same-day ART outweigh a potential higher risk of attrition from care after ART initiation.

Strengthening implementation guidelines for HIV service delivery: Considerations for future evidence generation and synthesis.

Ingrid Eshun-Wilson and colleagues summarize gaps in primary HIV implementation research methods and reporting, and propose areas for future methodological development.

Interventions to reduce deaths in people living with HIV admitted to hospital in low- and middle-income countries: A systematic review.

People living with HIV (PLHIV) admitted to hospital have a high risk of death. We systematically appraised evidence for interventions to reduce mortality among hospitalised PLHIV in low- and middle-income countries (LMICs). Using a broad search strategy with terms for HIV, hospitals, and clinical trials, we searched for reports published between 1 Jan 2003 and 23 August 2021. Studies of interventions among adult HIV positive inpatients in LMICs were included if there was a comparator group and death was an outcome. We excluded studies restricted only to inpatients with a specific diagnosis (e.g. cryptococcal meningitis). Of 19,970 unique studies identified in search, ten were eligible for inclusion with 7,531 participants in total: nine randomised trials, and one before-after study. Three trials investigated systematic screening for tuberculosis; two showed survival benefit for urine TB screening vs. no urine screening, and one which compared Xpert MTB/RIF versus smear microscopy showed no difference in survival. One before-after study implemented 2007 WHO guidelines to improve management of smear negative tuberculosis in severely ill PLHIV, and showed survival benefit but with high risk of bias. Two trials evaluated complex interventions aimed at overcoming barriers to ART initiation in newly diagnosed PLHIV, one of which showed survival benefit and the other no difference. Two small trials evaluated early inpatient ART start, with no difference in survival. Two trials investigated protocol-driven fluid resuscitation for emergency-room attendees meeting case-definitions for sepsis, and showed increased mortality with use of a protocol for fluid administration. In conclusion, ten studies published since 2003 investigated interventions that aimed to reduce mortality in hospitalised adults with HIV, and weren't restricted to people with a defined disease diagnosis. Inpatient trials of diagnostics, therapeutics or a package of interventions to reduce mortality should be a research priority. Trial registration: PROSPERO Number: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019150341.

Ongoing High Prevalence of Severe Immune Suppression Among Children in South Africa.

BACKGROUND: Among children in Southern Africa severe immune suppression (SIS) has declined, but most continue to initiate antiretroviral therapy (ART) with SIS. SETTING: Using data from South Africa, we describe SIS at ART start and on ART between 2007 and 2020, among children <5 years with a CD4%/cell count at ART start and ≥1 subsequent measure. METHODS: Gap in care was defined as >9 months without a recorded visit. We defined SIS according to age and CD4%/cell count. A multistate model was used to estimate transition probabilities between 5 states: SIS on ART; Stable, not SIS; Early Gap, commencing <9 months from ART start; Late Gap, commencing ≥9 months on ART; and Death. RESULTS: Among 2536 children, 70% had SIS at ART start, and 36% experienced SIS on ART. An increasing proportion were age <1 year at ART initiation (2007-2009: 43% to 2013-2020: 55%). Increasingly, SIS on ART occurred after a gap, in those with SIS on ART for >1 year, and after a period of unknown immune status. Later year of ART initiation was associated with reduced transition from SIS on ART to Stable. Infants and those initiating ART with SIS were more likely to transition from Stable to SIS. Viremia strongly predicted death from both the on ART states. CONCLUSIONS: Increasingly SIS occurred among ART-experienced children. Those starting ART with SIS and during infancy remained especially vulnerable to SIS once on treatment. Managing ART in these children may be more complex and further reducing AIDS-related mortality is likely to remain challenging.

Advanced HIV disease and engagement in care among patients on antiretroviral therapy in South Africa: results from a multi-state model.

OBJECTIVE: Despite improved access to antiretroviral therapy (ART) for people with HIV (PWH), HIV continues to contribute considerably to morbidity and mortality. Increasingly, advanced HIV disease (AHD) is found among PWH who are ART-experienced. DESIGN: Using a multi-state model we examined associations between engagement with care and AHD on ART in South Africa. METHODS: Using data from IeDEA Southern Africa, we included PWH from South Africa, initiating ART from 2004 to 2017 aged more than 5 years with a CD4+ cell count at ART start and at least one subsequent measure. We defined a gap as no visit for at least 18 months. Five states were defined: 'AHD on ART' (CD4+ cell count <200 cells/µl), 'Clinically Stable on ART' (CD4+ cell count ≥200 or if no CD4+ cell count, viral load <1000 copies/ml), 'Early Gap' (commencing ≤18 months from ART start), 'Late Gap' (commencing >18 months from ART start) and 'Death'. RESULTS: Among 32 452 PWH, men and those aged 15-25 years were more likely to progress to unfavourable states. Later years of ART start were associated with a lower probability of transitioning from AHD to clinically stable, increasing the risk of death following AHD. In stratified analyses, those starting ART with AHD in later years were more likely to re-engage in care with AHD following a gap and to die following AHD on ART. CONCLUSION: In more recent years, those with AHD on ART were more likely to die, and AHD at re-engagement in care increased. To further reduce HIV-related mortality, efforts to address the challenges facing these more vulnerable patients are needed.

Advanced HIV disease and health-related suffering-exploring the unmet need of palliative care.

With more than 38 million people living with HIV worldwide, the scale-up of antiretroviral therapy ensures nearly 28 million of them receive regular treatment. However, a substantial number of deaths still occur every year from AIDS-related complications, with approximately 680 000 deaths in 2021. Of the estimated 56·8 million people globally in need of palliative care in 2020, only 7 million can access services. Providing palliative care services can help alleviate health-related suffering, such as pain and disease-related symptoms, and improve wellbeing. This Viewpoint discusses the unrealised potential of palliative care in individuals with advanced HIV disease. Key areas of training for health-care workers include appropriate sensitisation, training in palliative care, and effective communication. Advance care planning supports both the individual and their family and is therefore of crucial importance. Integration of palliative care in HIV programmes is needed to address health-related suffering, particularly for advanced HIV disease.

Access to Medicines for Treating People With Cryptococcal Meningitis.

Cryptococcal meningitis accounts for 1 in 5 AIDS-related deaths globally. World Health Organization guidelines strongly recommend a single high dose of liposomal amphotericin B as part of preferred treatment, but this drug remains unaffordable in most low- and middle-income countries. A proactive approach is needed from manufacturers and other stakeholders to improve access.

Good or best practice statements: proposal for the operationalisation and implementation of GRADE guidance.

An evidence-based approach is considered the gold standard for health decision-making. Sometimes, a guideline panel might judge the certainty that the desirable effects of an intervention clearly outweigh its undesirable effects as high, but the body of supportive evidence is indirect. In such cases, the application of the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach for grading the strength of recommendations is inappropriate. Instead, the GRADE Working Group has recommended developing ungraded best or good practice statement (GPS) and developed guidance under which circumsances they would be appropriate.Through an evaluation of COVID-1- related recommendations on the eCOVID Recommendation Map (COVID-19.recmap.org), we found that recommendations qualifying a GPS were widespread. However, guideline developers failed to label them as GPS or transparently report justifications for their development. We identified ways to improve and facilitate the operationalisation and implementation of the GRADE guidance for GPS.Herein, we propose a structured process for the development of GPSs that includes applying a sequential order for the GRADE guidance for developing GPS. This operationalisation considers relevant evidence-to-decision criteria when assessing the net consequences of implementing the statement, and reporting information supporting judgments for each criterion. We also propose a standardised table to facilitate the identification of GPS and reporting of their development. This operationalised guidance, if endorsed by guideline developers, may palliate some of the shortcomings identified. Our proposal may also inform future updates of the GRADE guidance for GPS.

An updated systematic review of HIV-associated cryptococcal meningitis treatment strategies.

BACKGROUND: The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines. METHODS: We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021. RESULTS: One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7-29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4-33.4%) in the control group. The absolute difference in 10-week mortality was -3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p < 0.001). CONCLUSIONS: In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events.

A Systematic Review of COVID-19 Vaccine Antibody Responses in People With HIV.

HIV infection is a significant independent risk factor for severe coronavirus disease 2019 (COVID-19) disease and death. We summarize COVID-19 vaccine responses in people with HIV (PWH). A systematic literature review of studies from January 1, 2020, to March 31, 2022, of COVID-19 vaccine immunogenicity in PWH from multiple databases was performed. Twenty-eight studies from 12 countries were reviewed. While 22 (73%) studies reported high COVID-19 vaccine seroconversion rates in PWH, PWH with lower baseline CD4 counts, CD4/CD8 ratios, or higher baseline viral loads had lower seroconversion rates and immunologic titers. Data on vaccine-induced seroconversion in PWH are reassuring, but more research is needed to evaluate the durability of COVID-19 vaccine responses in PWH.

A Living Database of HIV Implementation Research (LIVE Project): Protocol for Rapid Living Reviews.

BACKGROUND: HIV implementation research evolves rapidly and is often complex and poorly characterized, which makes the synthesis of data on HIV implementation strategies inherently difficult. This is further compromised by prolonged data abstraction processes due to variable interventions, outcomes, and context, and delays in the publication of review findings; this can all result in outdated and irrelevant systematic reviews. OBJECTIVE: The LIVE project (A Living Database of HIV Implementation Research) aims to overcome these challenges by applying an implementation science lens to the conduct of rapid living systematic reviews and meta-analyses to inform HIV service delivery priorities and guideline development. METHODS: The LIVE project will generate a series of living systematic reviews exploring implementation strategies for improving HIV cascade outcomes (HIV infection, HIV diagnosis, linkage and retention in HIV care, viral suppression, and mortality). We will search Embase and MEDLINE as well databases specific to review questions for studies conducted after 2004 using predefined search terms to identify studies conducted in any age group or setting, and using implementation strategies that target policy makers, society, health organizations, health workers, and beneficiaries of care and their families. Both randomized controlled trials and observational studies will be included to ensure reviews include pragmatic data. In addition to assessments of methodological quality, features of the implementation strategies, relevance for implementation, and evidence quality will be determined using recognized frameworks. After initial publication, knowledge gaps will be identified, and review questions and search strategies revised to address ongoing critical areas of inquiry. Updated searches will be conducted every 6 months, with subsequent ongoing screening, data abstraction, and revision of meta-analyses. RESULTS: As of July 2022, five reviews are at various stages of development within the LIVE project. Three systematic reviews are underway and living review processes are in development for two reviews with estimated completion over the next 12 months. CONCLUSIONS: This project and resulting systematic reviews will provide critical insights for HIV service delivery to inform international guideline development. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37070.