Human Immunodeficiency Virus Response Research Articles

Viral-Host Interactions and Immune Responses in HIV-Infected Infants: A Review

Human Immunodeficiency Virus (HIV) infection in infants presents distinctive challenges due to their developing immune systems and unique viral-host interactions compared to adults. This review examines current knowledge on viral-host interactions and immune responses in HIV-infected infants, focusing on immune development, viral dynamics, and therapeutic implications. The immune system of infants undergoes rapid maturation during early life, influencing their susceptibility to HIV infection and responses to antiretroviral therapy (ART). Key aspects include thymic function, cytokine profiles, and the establishment of immune memory, which collectively shape immune responses against HIV. Viral dynamics in HIV-infected infants differ markedly from those in adults, characterized by high viral loads, diverse viral subtypes, and the early establishment of viral reservoirs within immune cells. These reservoirs, particularly in sanctuary sites like the central nervous system, pose challenges for achieving viral eradication and long-term remission. Effective management requires strategies to characterize and target these reservoirs, alongside early intervention to mitigate viral replication and preserve immune function. Advances in viral monitoring technologies and treatment regimens are essential for improving clinical outcomes and reducing the global burden of pediatric HIV infection. Keywords: HIV, infants, viral-host interactions, immune responses, immune development, viral dynamics, therapeutic interventions

Abstract 120: A closer Look at colorectal cancer risk: Insights from the complex relationship of HIV, helminths, and immune responses

Abstract The advent of antiretroviral therapy has markedly increased the survival rates of individuals with human immunodeficiency virus (HIV). However, this demographic, particularly in low-middle-income countries (LMICs) where HIV-helminth co-infections are prevalent, remains susceptible to infections. The intricate interplay between helminth infections and HIV susceptibility, often inducing immunological phenotypes that heighten vulnerability, remains poorly understood. Studies have shown the association between HIV-helminth co-infections and elevated susceptibility to colorectal cancer (CRC), introducing an additional layer of health concerns for this already vulnerable population. This retrospective observational study delves into the profound effects of HIV-helminth co-infections on immune responses, with a specific focus on type 2 T helper (Th2) cell immunomodulation and susceptibility to CRC. Utilizing samples from a master project (n=414), 80 systematically randomized individuals were categorized into uninfected control, HIV-infected only, helminth-infected only, and HIV-helminth co-infected groups. Parasite detection employed the Kato-Katz technique, and serum testing was conducted for helminth-specific antibodies. Serological HIV testing, viral load categorization, white blood cell counts, and differential analyses were performed. Human ProcartaPlex Panel 1 was used for cytokine profiling of immune stimulatory and inhibitory soluble proteins. A significant reduction in B and T lymphocyte attenuator (BTLA) (p=0.049) in helminth infections compared to the control. The association of BTLA with its ligand, herpesvirus entry mediator (HVEM), establishes a direct link between the CD28 and tumor necrosis factor receptor (TNFR) families, triggering wide-ranging and robust immune responses. Subsequently, a notable reduction in CD28 was observed in HIV-infected subjects (p=0.003), followed by helminth-infected and HIV-helminth co-infected individuals (p=0.03) compared to the control. Furthermore, programmed death ligand-2 (PD-L2) expression, a major contributor to alternatively activated macrophage polarization during helminth infections, was significantly increased in the HIV-helminth co-infected group (p = 0.05), favoring a shift towards Th2 immune responses. These observed alterations underscore the complexity of the immunological interplay in co-infected individuals, emphasizing an additional risk factor for colorectal cancer development. This necessitates a comprehensive understanding, providing valuable insights for the development of therapeutic strategies in LMICs and similar settings, addressing the heightened risk of CRC within this population. Citation Format: Botle P. Damane, Thanyani V. Mulaudzi, Sayed S. Kader, Ropo E. Ogunsakin, Pragalathan Naidoo, Zodwa Dlamini, Zilungile L. Mkhize-Kwitshana. A closer Look at colorectal cancer risk: Insights from the complex relationship of HIV, helminths, and immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 120.

HIHISIV: a database of gene expression in HIV and SIV host immune response

In the battle of the host against lentiviral pathogenesis, the immune response is crucial. However, several questions remain unanswered about the interaction with different viruses and their influence on disease progression. The simian immunodeficiency virus (SIV) infecting nonhuman primates (NHP) is widely used as a model for the study of the human immunodeficiency virus (HIV) both because they are evolutionarily linked and because they share physiological and anatomical similarities that are largely explored to understand the disease progression. The HIHISIV database was developed to support researchers to integrate and evaluate the large number of transcriptional data associated with the presence/absence of the pathogen (SIV or HIV) and the host response (NHP and human). The datasets are composed of microarray and RNA-Seq gene expression data that were selected, curated, analyzed, enriched, and stored in a relational database. Six query templates comprise the main data analysis functions and the resulting information can be downloaded. The HIHISIV database, available at https://hihisiv.github.io, provides accurate resources for browsing and visualizing results and for more robust analyses of pre-existing data in transcriptome repositories.

Facteurs structurels et communautaires augmentant la vulnérabilité des hommes ayant des relations sexuelles avec des hommes dans la riposte au virus de l’immunodéficience humaine au Burkina Faso

Worldwide and particularly in Africa, Men who have sex with men (MSM) can play a significant role in response to the Human Immunodeficiency Virus (HIV). In Burkina Faso the fight against HIV within this population seems to be limited by violence towards MSM. The goal of this study was to identify the social obstacles to HIV response among MSM in Burkina Faso. It has been a descriptive study with an exploratory aim in a mainly qualitative approach. It was conducted in the two biggest cities as well as two border ones of the country. Nonstructural interviews have been conducted with the help of prevention MSM actors. The data have been thematically analyzed. In the structural level, homosexuality is publically condemned by politicians some of whom seeking its criminalization. According to them it has "come from elsewhere" and is "contrary to morals". Even though there is no legally punishing regulation against it, political and administrative authorities and security forces do not protect MSM against homophobic violence. There is not enough care structures for MSM in the country. At the community level, many religious leaders condemn homosexuality, considered as a sin; they view homosexuality as an "abomination". MSM feel that they are victims of homophobic violence. The MSM are victims of violence from populations and state institutions too. To reach MSM by activities in response to HIV these obstacles must necessarily be removed.

The initial interplay between HIV and mucosal innate immunity.

Human Immunodeficiency Virus (HIV) is still one of the major global health issues, and despite significant efforts that have been put into studying the pathogenesis of HIV infection, several aspects need to be clarified, including how innate immunity acts in different anatomical compartments. Given the nature of HIV as a sexually transmitted disease, one of the aspects that demands particular attention is the mucosal innate immune response. Given this scenario, we focused our attention on the interplay between HIV and mucosal innate response: the different mucosae act as a physical barrier, whose integrity can be compromised by the infection, and the virus-cell interaction induces the innate immune response. In addition, we explored the role of the mucosal microbiota in facilitating or preventing HIV infection and highlighted how its changes could influence the development of several opportunistic infections. Although recent progress, a proper characterization of mucosal innate immune response and microbiota is still missing, and further studies are needed to understand how they can be helpful for the formulation of an effective vaccine.

Contribution of Sex Differences to HIV Immunology, Pathogenesis, and Cure Approaches.

Approximately 38 million people were living with human immunodeficiency virus (HIV) in 2020 and 53% of those infected were female. A variety of virological and immunological sex-associated differences (sexual dimorphism) in HIV infection have been recognized in males versus females. Social, behavioral, and societal influences play an important role in how the HIV pandemic has affected men and women differently. However, biological factors including anatomical, physiologic, hormonal, and genetic differences in sex chromosomes can each contribute to the distinct characteristics of HIV infection observed in males versus females. One striking example of this is the tendency for women to have lower HIV plasma viral loads than their male counterparts early in infection, though both progress to AIDS at similar rates. Sex differences in acquisition of HIV, innate and adaptive anti-HIV immune responses, efficacy/suitability of specific antiretroviral drugs, and viral pathogenesis have all been identified. Sex differences also have the potential to affect viral persistence, latency, and cure approaches. In this brief review, we summarize the major biological male/female sex differences in HIV infection and their importance to viral acquisition, pathogenesis, treatment, and cure efforts.

Assessing Antiretroviral Inventory Management Data Quality, Through Adopting Potential Digital Solutions: Case Study of ART Clinics in Western Equatoria State, South Sudan

Background: The human immunodeficiency virus response in South Sudan has worsened the country’s situation unlike recovering from the devastating civil conflicts. The people living with the human immunodeficiency virus who are on antiretroviral drugs will need access to quality drugs to improve their health and prolong their lives, having sustainable access to drugs depends on effective inventory management and reliable data quality. The study aims: The study aims to examine the quality of inventory management data in antiretroviral clinics in the context of South Sudan with a particular focus on Western Equatoria health facilities. Method: The study adopted a descriptive cross-sectional research design using a mixed-method research approach (qualitative and quantitative). A total of 20 antiretroviral therapy clinics in Western Equatoria State (WES) were considered the target population of the study comprising ARV dispensers, Data clerks, ART clinicians, and ART facility Directors. Findings: 75% of study respondents were male, and it was observed that most of the interviewees had good experiences of more than 10 years in providing services to people living with HIV. Data quality was measured using a five-point Likert scale analysis, the respondents reported that the data quality was compliant in terms of accuracy, consistency, relevancy, validity, and genuineness of consumption data at ART clinics in WES. Regarding factors affecting inventory management, the infrastructures took the leading among others like the capacity of Human resources at public facilities and tools for managing data among others. Conclusion: Based on the findings, respondents who participated in this study reported satisfaction with data quality in Western Equatoria ART clinics. Based on the views of the majority, the antiretroviral therapy clinics used to compile accurate, consistent, relevant, and valid, data of their inventory.

Treatment-adjusted prevalence to assess HIV testing programmes.

Scale-up of human immunodeficiency virus (HIV) testing and antiretroviral therapy (ART) for people living with HIV has been increasing in sub-Saharan Africa. As a result, areas with high HIV prevalence are finding a declining proportion of people testing positive in their national testing programmes. In eastern and southern Africa, where there are settings with adult HIV prevalence of 12% and above, the positivity from national HIV testing services has dropped to below 5%. Identifying those in need of ART is therefore becoming more costly for national HIV programmes. Annual target-setting assumes that national testing positivity rates approximate that of population prevalence. This assumption has generated an increased focus on testing approaches which achieve higher rates of HIV positivity. This trend is a departure from the provider-initiated testing and counselling strategy used early in the global HIV response. We discuss a new indicator, treatment-adjusted prevalence, that countries can use as a practical benchmark for estimating the expected adult positivity in a testing programme when accounting for both national HIV prevalence and ART coverage. The indicator is calculated by removing those people receiving ART from the numerator and denominator of HIV prevalence. Treatment-adjusted prevalence can be readily estimated from existing programme data and population estimates, and in 2019, was added to the World Health Organization guidelines for HIV testing and strategic information. Using country examples from Kenya, Malawi, South Sudan and Zimbabwe we illustrate how to apply this indicator and we discuss the potential public health implications of its use from the national to facility level.

HIV Response Interventions that Integrate HIV Molecular Cluster and Social Network Analysis: A Systematic Review.

Due to improved efficiency and reduced cost of viral sequencing, molecular cluster analysis can be feasibly utilized alongside existing human immunodeficiency virus (HIV) prevention strategies. The goal of this paper is to elucidate how HIV molecular cluster and social network analyses are being integrated to implement HIV response interventions. We searched PubMed, Scopus, PsycINFO, and Cochrane Library databases for studies incorporating both HIV molecular cluster and social network data. We identified 32 articles that combined analyses of HIV molecular sequences and social or sexual networks. All studies were descriptive. Six studies described network interventions informed by molecular and social data but did not fully evaluate their efficacy. There is no current standard for incorporating molecular and social network analyses to inform interventions or data demonstrating its utility. More research must be conducted to delineate benefits and best practices for leveraging molecular data for network-based interventions.

The Importance of Cellular Immune Response to HIV: Implications for Antibody Production and Vaccine Design.

Despite many years from the discovery of human immunodeficiency virus (HIV), a prophylactic vaccine against HIV is still needed. The failure of most of the vaccine clinical trials in the field has different causes, mainly due by the difficulties to identify the correct antigen able to prime the optimal B cell lineage and then make the series of somatic mutations necessary to generate broadly neutralizing antibodies (bNAbs). B cells are responsible for the bNAbs production; however, their function is strongly influenced by the presence of a population of CD4+ T lymphocytes, mainly present in the lymphoid organs, the T follicular helper cells (Tfh). In this review, the importance of the contribution of Tfh cells in HIV response is highlighted and future therapy perspectives based on these observations are described. The advanced technology available nowadays and the wide knowledge built over the past years for HIV may eventually create the best scenario for the generation of an effective vaccine.

Human immunodeficiency virus funding and access to treatment in sub-Saharan Africa.

Human immunodeficiency virus (HIV) treatment prevents illness, death, and transmission. The 90-90-90 disease control target is only 73% of people living with HIV virally suppressed. For 2010 to 2019, we abstracted HIV funding data for 40 countries in sub-Saharan Africa (70% of global HIV burden and >99% of HIV burden in the region in 2018). During 2010-2019, there was ∼$52 billion funding for 40 countries (99% Africa HIV burden). Domestic funding ranged from $0 to $3.2 billion. PEPFAR funding was $32 billion (average $1.4 billion; range $0.089-4.3 billion) among 22 countries. Global Fund averaged $306 million ($1.9 million to $1.1 billion) for 40 countries. Among PLHIV, known HIV status averaged 80% (11% to 94%). ART coverage averaged 64% (9% to 90%). Viral suppression among PLHIV ranged from 8% to 87%. Of the 40 countries, 21 reported under 60% of PLHIV to be on treatment and 13 did not report viral suppression for 2018. Achieving 90-90-90 is feasible in challenging settings if resources are used efficiently. Despite the significant investment in the HIV response, many countries have not reached the 90-90-90 target. Greater attention to efficiency and prioritizing important targets will be required to end AIDS in Africa.

COVID-19 Pandemic as "Curate's Egg" on Human Immunodeficiency Virus Infection: A Commentary.

It is a high time not to sideline human immunodeficiency virus (HIV) response during the 2019 coronavirus disease (COVID-19) crisis. COVID-19 will affect the decade’s hard-earned gains from HIV care delivery and response. At the same time, it could be an important time for the COVID-19 containment response to help minimize the occurrence of a new infection. Sexual contact is the main transmission ways in HIV dynamics. However, COVID-19 prevention and control strategies such as movement restrictions, physical and social distancing will reduce exposure to such kinds of risk behaviors. Those containment strategies, including stringent infection prevention and control at health facilities, may minimize transmission of HIV infection and will reduce the incidence of new HIV infection. While recognizing the immense challenges of the COVID-19 pandemic, efforts should be made by governments and international organizations to maintain the response to HIV and to ensure that the progress made against HIV is not lost. In addition, it is very crucial to undertake further researches on the status of new HIV infection during the COVID-19.

Three lessons for the COVID-19 response from pandemic HIV

The HIV pandemic provides lessons for the response to the novel coronavirus disease 2019 (COVID-19) pandemic: no vaccine is available for either and there are no licensed pharmaceuticals for COVID-19, just as there was not for HIV infection in the early years. Population behaviour will determine the pandemic trajectory of COVID-19,1 just as it did for HIV.

Immune activation markers in individuals with HIV-1 disease and their correlation with HIV-1 RNA levels in individuals on antiretroviral therapy

BackgroundCurrently CD4+ T lymphocyte counts and HIV-1 RNA levels are being utilized to predict outcome of human immunodeficiency virus (HIV) disease. Recently, the role of immune activation in HIV disease progression and response to treatment is being investigated. This study focused on the expression of CD38 and HLA-DR on lymphocyte subsets in various groups of HIV-infected individuals and to determine their association with HIV-1 disease progression. MethodsNinety-eight cases of patients with HIV/AIDS in different disease stages and twenty-four healthy HIV-negative individuals were included in the cross-sectional study. Their immune function and abnormal immune activation markers (CD38 & HLA-DR) were detected using a flowcytometer, and HIV-1 RNA levels in individuals receiving antiretroviral drugs were estimated. ResultsThe immune activation marker levels were significantly different between patients with different disease stages (P < 0.001). A significant negative correlation was observed between peripheral blood CD4+ T cell counts and immune activation markers. Also, a significant positive correlation was observed between HIV-1 RNA levels and CD38+CD8+ T lymphocyte. ConclusionImmune activation markers (CD38 & HLA-DR) increase with disease progression. CD38+ on CD8+ T lymphocyte correlates well with HIV1 RNA levels in individuals failing on antiretroviral therapy.

Tailored HIV programmes and universal health coverage

Improvements in geospatial health data and tailored human immunodeficiency virus (HIV) testing, prevention and treatment have led to greater microtargeting of the HIV response, based on location, risk, clinical status and disease burden. These approaches show promise for achieving control of the HIV epidemic. At the same time, United Nations Member States have committed to achieving broader health and development goals by 2030, including universal health coverage (UHC). HIV epidemic control will facilitate UHC by averting the need to commit ever-increasing resources to HIV services. Yet an overly targeted HIV response could also distort health systems, impede integration and potentially threaten broader health goals. We discuss current approaches to achieving both UHC and HIV epidemic control, noting potential areas of friction between disease-specific microtargeting and integrated health systems, and highlighting opportunities for convergence that could enhance both initiatives. Examples of these programmatic elements that could be better aligned include: improved information systems with unique identifiers to track and monitor individuals across health services and the life course; strengthened subnational data use; more accountable supply chains that supply a broad range of services; and strengthened community-based services and workforces. We argue that the response both to HIV and to broader health threats should use these areas of convergence to increase health systems efficiency and mitigate the harm of any potential decrease in health funding. Further investments in implementation and monitoring of these programme elements will be needed to make progress towards both UHC and HIV epidemic control.

HIV and HCV augments inflammatory responses through increased TREM-1 expression and signaling in Kupffer and Myeloid cells.

Chronic infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects an estimated 35 million and 75 million individuals worldwide, respectively. These viruses induce persistent inflammation which often drives the development or progression of organ-specific diseases and even cancer including Hepatocellular Carcinoma (HCC). In this study, we sought to examine inflammatory responses following HIV or HCV stimulation of macrophages or Kupffer cells (KCs), that may contribute to virus mediated inflammation and subsequent liver disease. KCs are liver-resident macrophages and reports have provided evidence that HIV can stimulate and infect them. In order to characterize HIV-intrinsic innate immune responses that may occur in the liver, we performed microarray analyses on KCs following HIV stimulation. Our data demonstrate that KCs upregulate several innate immune signaling pathways involved in inflammation, myeloid cell maturation, stellate cell activation, and Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling. TREM1 is a member of the immunoglobulin superfamily of receptors and it is reported to be involved in systemic inflammatory responses due to its ability to amplify activation of host defense signaling pathways. Our data demonstrate that stimulation of KCs with HIV or HCV induces the upregulation of TREM1. Additionally, HIV viral proteins can upregulate expression of TREM1 mRNA through NF-кB signaling. Furthermore, activation of the TREM1 signaling pathway, with a targeted agonist, increased HIV or HCV-mediated inflammatory responses in macrophages due to enhanced activation of the ERK1/2 signaling cascade. Silencing TREM1 dampened inflammatory immune responses elicited by HIV or HCV stimulation. Finally, HIV and HCV infected patients exhibit higher expression and frequency of TREM1 and CD68 positive cells. Taken together, TREM1 induction by HIV contributes to chronic inflammation in the liver and targeting TREM1 signaling may be a therapeutic option to minimize HIV induced chronic inflammation.

Measles Seroprevalence and Vaccine Responses in Human Immunodeficiency Virus-infected Adolescents and Adults: A Systematic Review.

The World Health Organization (WHO) recommends an additional dose of measles-containing vaccine (MCV) for human immunodeficiency virus (HIV)-infected children receiving highly active antiretroviral therapy following immune reconstitution. We conducted a systematic review to synthesize available evidence regarding measles seroprevalence and measles vaccine immunogenicity, efficacy, and safety in HIV-infected adolescents and adults to provide the evidence base for recommendations on the need for measles vaccination. We conducted searches of 8 databases through 26 September 2017. Identified studies were screened independently by 2 reviewers. The search identified 30 studies meeting inclusion criteria. Across studies, measles seroprevalence among HIV-infected adolescents and adults was high (median, 92%; 27 studies), with no significant difference compared to HIV-uninfected participants (10 studies). In 6 studies that evaluated the immunogenicity of MCVs among seronegative HIV-infected adults, measles seropositivity at end of follow-up ranged from 0% to 56% (median, 39%). No severe adverse events were reported following measles vaccination in HIV-infected patients. Based on similar measles seroprevalence between HIV-infected and HIV-uninfected adolescents and adults, and the low response to vaccination, these studies do not support the need for an additional dose of MCV in HIV-infected adolescents and adults. These findings support WHO guidelines that measles vaccine be administered to potentially susceptible, asymptomatic HIV-infected adults, and may be considered for those with symptomatic HIV infection if not severely immunosuppressed. Measles-susceptible adolescents and adults, regardless of HIV status, may require targeted vaccination efforts to reach critical vaccination thresholds and achieve regional elimination goals.

Know Your Response: Pilot Mapping of HIV Prevention Responses by Non-governmental Organizations in Southern Province, Zambia

ZAMBIA’S nation-wide adult Human Immunodeficiency virus (HIV) prevalence stood at 13.3 percent in 2014. In Southern Province, 12.8 percent of adult men and women aged 15-49 years were HIV positive. The prevalence was higher in women than in men (15.1% compared to 11.3%). The most recent data also suggested that key populations were disproportionately infected with HIV compared to the general population. The Measure Know Your Response (KYR) study took place from September 2013 to July 2014 in the Southern Province of Zambia. The aim was to map and characterize the HIV response among both government (health and none health) and non-government organizations (NGOs). The purpose was to identify gaps in the response, in particular in terms of the geographical areas and the key populations attended to and those disproportionately missed. This paper focuses on the results from the mapping of NGOs involved in HIV and AIDS response. For this aspect of the mapping data were collected using the NGO Sector Questionnaire. Focus was interventions of NGOs and their services to target populations across all the 12 districts of the Southern Province. All program implementers working in a given district were asked questions to assess the extent to which their HIV-prevention activities in the district included strategies to address all key populations, including gender issues. Data from the quantitative questionnaires was analyzed using STATA version 12.0 and Microsoft Excel. The results of the pilot test revealed gaps in both geographic spread and content of programs in the NGOs run HIV-prevention response. For instance, hardly any NGOs worked in the new and smaller districts of Pemba, Siavonga, and Zimba. Similarly, certain services, such as mass media campaigns, interpersonal education and persuasion programs were being implemented across all the districts. Further, fewer than three of the 93 organizations surveyed targeted key populations, notably sex workers, incarcerated populations, men who have sex with men (MSM), transgender people and injective drug users. With respect to gender, about 25% of the organizations did not integrate gender issues into their HIV-prevention activities. From a methodological standpoint, the pilot test revealed the need to examine dimensions of program content, quality and intensity. In spite of these limitations, the study permits us to know which interventions are being implemented by the NGO sector, contributing to new knowledge in Zambia about geographic gaps in the availability of HIV-prevention interventions.

Reaching Men: Addressing the Blind Spot in the HIV Response

Globally, men are less likely than women to access human immunodeficiency virus (HIV) testing, treatment, and care, and consequently experience disproportionate HIV-related mortality. To address men’s underutilization of HIV services, efforts are needed on two fronts: challenging the regressive gender norms that discourage men from seeking health services, and developing improved health system policies, programs, and service delivery strategies to ensure better provision of HIV services to men. It has long been understood that harmful gender norms make women vulnerable to HIV, and this understanding should expand to include the way these norms also put men at risk. This paper presents the data concerning men and HIV, explores the impact of gender norms, examines national and international policy developments, and chronicles the evolution of men’s place in the HIV response. It does so in part by tracing the efforts of Sonke Gender Justice, a South African nongovernmental organization working across Africa, that it promotes the engagement of men in the fight against the dual epidemics of gender inequality and HIV.

The Continuing Burden of Advanced HIV Disease Over 10 Years of Increasing Antiretroviral Therapy Coverage in South Africa.

BackgroundAntiretroviral treatment (ART) has been massively scaled up to decrease human immunodeficiency virus (HIV)–related morbidity, mortality, and HIV transmission. However, despite documented increases in ART coverage, morbidity and mortality have remained substantial. This study describes trends in the numbers and characteristics of patients with very advanced HIV disease in the Western Cape, South Africa.MethodsAnnual cross-sectional snapshots of CD4 distributions were described over 10 years, derived from a province-wide cohort of all HIV patients receiving CD4 cell count testing in the public sector. Patients with a first CD4 count <50 cells/µL in each year were characterized with respect to prior CD4 and viral load testing, ART access, and retention in ART care.ResultsPatients attending HIV care for the first time initially constituted the largest group of those with CD4 count <50 cells/µL, dropping proportionally over the decade from 60.9% to 26.7%. By contrast, the proportion who were ART experienced increased from 14.3% to 56.7%. In patients with CD4 counts <50 cells/µL in 2016, 51.8% were ART experienced, of whom 76% could be confirmed to be off ART or had recent viremia. More than half who were ART experienced with a CD4 count <50 cells/µL in 2016 were men, compared to approximately one-third of all patients on ART in the same year.ConclusionsOngoing HIV-associated morbidity now results largely from treatment-experienced patients not being in continuous care or not being fully virologically suppressed. Innovative interventions to retain ART patients in effective care are an essential priority for the ongoing HIV response.