Advanced HIV disease during the first six months on antiretroviral therapy in Zambia: research protocol for a prospective, observational, multi-cohort study

Late presentation to care and antiretroviral therapy (ART) initiation with advanced human immunodeficiency virus (HIV) disease are common in Latin America. We estimated the impact of these conditions on mortality in the region. We included adults enrolled during 2001-2014 at HIV care clinics. We estimated the adjusted attributable risk (AR) and population attributable fraction (PAF) for all-cause mortality of presentation to care with advanced HIV disease (advanced LP), ART initiation with advanced HIV disease, and not initiating ART. Advanced HIV disease was defined as CD4of <200 cells/μL or acquired immune deficiency syndrome. AR and PAF were derived using marginal structural models. Of 9,229 patients, 56% presented with advanced HIV disease. ARs of death for advanced LP were 86%, 71%, and 58%, and PAFs were 78%, 58%, and 43% at 1, 5, and 10 years after enrollment. Among people without advanced LP, ARs of death for delaying ART were 39%, 32%, and 37% at 1, 5, and 10 years post-enrollment and PAFs were 20%, 14%, and 15%. Among people with advanced LP, ART decreased the hazard of death by 63% in the first year after enrollment, but 93% of these started ART; thus universal ART among them would reduce mortality by only 10%. Earlier presentation to care and earlier ART initiation would prevent most HIV deaths in Latin America.

Background: Overall, Benue state has attained the Joint United Nations Programme on human immunodeficiency virus (HIV)/AIDS (UNAIDS) 95-95-95 target, placing it on the verge of HIV epidemic control. However, gaps remain in achieving 95% viral suppression by the Advanced HIV Disease (AHD) subpopulation. Aim: This study compares the proportion of treatment-naive and treatment-experienced clients with AHD in Benue State. It also determines the viral load suppression rate and its predictors among treatment-naive and treatment-experienced clients with AHD in the State. Materials and Methods: This was a hospital-based, retrospective and comparative cross-sectional study of all HIV-infected people with AHD who were receiving antiretroviral therapy (ART) services in Benue State between 1 October 2020 and 30 September 2023. Results: Of the 160 randomly selected participants for analysis, the median age was higher among ART-experienced clients, 38 years versus 35.5 years (interquartile range: 25–43) and 106 (66.3%) were females. Most clients who are ART naïve or ART-experienced and achieved viral suppression (86.3% vs. 90.0%) were similar in age, sex and marital status. In multivariable analysis, only adolescents showed a statistically significant association with viral load suppression in ART naïve clients compared to ART-experienced clients (adjusted OR 17.24; 95% confidence interval, 1.36–219.16; P = 0.03). Conclusion: This study highlights the necessity for targeted interventions to improve retention and viral load suppression, especially for those newly diagnosed with AHD. Sustaining the progress in the HIV program will require robust, age-specific and person-centred strategies that focus on enhancing the treatment outcomes.

Despite advances in antiretroviral therapy (ART), a notable proportion of individuals still present with advanced HIV disease (AHD) at treatment initiation, defined by CD4 < 200 cells/µL or WHO stage 3/4. This group experiences higher mortality and more opportunistic infections. While guidelines exist, they often do not address AHDclientsspecific needs early in treatment. Addressing these gaps could improve outcomes. Between September 2022 and June 2023, we surveyed a sequential sample of clients initiating ART or ≤6 months post-initiation at 18 primary healthcare facilities across three provinces. This observational cohort collected socio-demographic data, HIV care history, and service delivery preferences, and linked surveys to routine medical records and described client characteristics using descriptive statistics. Relative risks and risk differences compared outcomes between AHD and non-AHD clients. Primary outcomes were 6-month retention and viral load suppression. Of 1,098 clients (72% female, median age 33), 938 had CD4 or WHO staging at ART start. Of these, 29% (n = 275) had AHD, with a median CD4 of 108 cells/µL. AHD clients were more often male (44% vs. 21%), older (median age: 38 vs. 31 years), and sought care due to illness (63% vs. 33%). TB diagnosis (42% vs. 12%) and testing (76% vs. 67%) were higher. Service preferences and health resource use were similar. Retention at 6 months was similar (80% vs. 75%), but mortality was higher in AHD clients (1.0% vs. 0.2%). AHD clients had more low-level viremia (24% vs. 11%; RR = 2.27, 95% CI = 1.67-3.09) and slightly lower suppression (43% vs. 47%). AHD remains a key barrier to optimal ART outcomes. Clients with AHD experienced poorer viral suppression, despite similar retention rates highlighting the need for early detection, tailored clinical support, and strengthened monitoring. Updating ART guidelines to addressAHD-specificneeds is critical to improving outcomes in this high-risk population.

Despite advances in antiretroviral therapy (ART), a notable proportion of individuals still present with advanced HIV disease (AHD) at treatment initiation, defined by CD4 < 200 cells/µL or WHO stage 3/4. This group experiences higher mortality and more opportunistic infections. While guidelines exist, they often do not address AHD clients specific needs early in treatment. Addressing these gaps could improve outcomes. Between September 2022 and June 2023, we surveyed a sequential sample of clients initiating ART or ≤6 months post-initiation at 18 primary healthcare facilities across three provinces. This observational cohort collected socio-demographic data, HIV care history, and service delivery preferences, and linked surveys to routine medical records and described client characteristics using descriptive statistics. Relative risks and risk differences compared outcomes between AHD and non-AHD clients. Primary outcomes were 6-month retention and viral load suppression. Of 1,098 clients (72% female, median age 33), 938 had CD4 or WHO staging at ART start. Of these, 29% (n = 275) had AHD, with a median CD4 of 108 cells/µL. AHD clients were more often male (44% vs. 21%), older (median age: 38 vs. 31 years), and sought care due to illness (63% vs. 33%). TB diagnosis (42% vs. 12%) and testing (76% vs. 67%) were higher. Service preferences and health resource use were similar. Retention at 6 months was similar (80% vs. 75%), but mortality was higher in AHD clients (1.0% vs. 0.2%). AHD clients had more low-level viremia (24% vs. 11%; RR = 2.27, 95% CI = 1.67–3.09) and slightly lower suppression (43% vs. 47%). AHD remains a key barrier to optimal ART outcomes. Clients with AHD experienced poorer viral suppression, despite similar retention rates highlighting the need for early detection, tailored clinical support, and strengthened monitoring. Updating ART guidelines to address AHD-specific needs is critical to improving outcomes in this high-risk population.

An urgent need exists for point-of-care diagnostics to detect tuberculosis (TB) among people with advanced human immunodeficiency virus (HIV) disease. The Fujifilm SILVAMP TB LAM (FujiLAM II) is a novel point-of-care assay that detects mycobacterial lipoarabinomannan (LAM) antigen in the urine to identify TB. We present a validation of the FujiLAM II assay on prospectively collected urine samples from outpatient adults with advanced HIV disease in Uganda. We performed a prospective diagnostic accuracy study of the FujiLAM II assay among outpatients with advanced HIV disease at 16 clinics Uganda. FujiLAM II was run on cryopreserved urine. We determined diagnostic performance for the FujiLAM II test against the cases of confirmed TB (Xpert or mycobacterial culture positive) versus cases without TB. We additionally assessed sensitivity and specificity of the FujiLAM II assay as compared with confirmed TB among pre-specified subgroups: CD4 <100 cells/µL versus 100-200 cells/µL, antiretroviral therapy (ART) naive versus experienced, and CRP <5 mg/L versus ≥5 mg/L. Among 583 participants who had FujiLAM II testing performed, the FujiLAM II assay demonstrated 54% (25/46) (95% confidence interval [CI]: 40%-69%) sensitivity to identify confirmed TB and 95% (326/342) (95% CI: 93% to 98%) specificity to identify the absence of TB. Among participants with CD4 cell counts <100 cells/µL, FujiLAM II sensitivity was 69% (95% CI: 53%-85%) and specificity was 94% (95% CI: 90%-97%). Among participants with serum C-reactive protein (CRP) ≥5 mg/L, the FujiLAM II assay exhibited a sensitivity of 62% (95% CI: 46%-77%) and specificity of 93% (95% CI: 89%-98%). FujiLAM II is a point-of-care, non-sputum based TB diagnostic with moderate sensitivity and high specificity in outpatients with advanced HIV disease.

ABSTRACTIntroductionDespite advances in antiretroviral therapy (ART), notable proportion of individuals still present with advanced HIV disease (AHD) at treatment initiation, defined by CD4 counts &lt;200cells/µL or WHO stage 3/4 conditions. This group faces higher mortality and more opportunistic infections. While clinical guidelines are available, they do not adequately address the unique needs of AHD patients, particularly early in treatment. Addressing these gaps could improve care and outcomes.MethodsFrom 9/2022-6/2023 we surveyed a sequential sample of clients presenting for ART initiation or ≤6 months post-initiation at 18 primary healthcare facilities across three provinces. We elicited socio-demographic data, HIV care history, and service delivery preferences and expectations and linked survey responses to routine medical record data. We used descriptive statistics to summarise client characteristics and calculated relative risks and risk differences to compare outcomes between AHD and non-AHD clients. The primary outcomes were 6-month retention and viral load suppression, categorized as suppressed (&lt;50 copies/mL), low-level viremia (50–1,000 copies/mL), or unsuppressed (≥1,000 copies/mL) at the 6-month viral load test.ResultsOf 1,098 clients (72% female, median age=33), 938 had CD4 count or WHO staging recorded at ART initiation. Of these 29% (n=275) had advanced HIV disease (AHD), with a median CD4 count of 108 cells/µL. AHD clients were more likely to be male (44% vs.21%), older (38 vs.31 years), and seek care due to illness (63% vs. 33%). They also had higher rates of TB (42% vs.12%) and TB testing (76% vs. 67%). Service preferences and healthcare resource utilization were similar across groups. Retention at six months was similar (80% vs. 75%), but AHD clients had higher mortality (1.0% vs. 0.2%). AHD clients were more likely to experience low-level viremia (24% vs. 11%; RR=2.27, 95%CI=1.67-3.09) and less likely to achieve viral suppression (43% vs. 47%).ConclusionsAHD remains a barrier to optimal ART outcomes in South Africa. Low-level viremia in the first six months highlights the need for targeted care models with early detection, rapid ART initiation, and tailored support to address specific needs of AHD clients. Updating ART guidelines to specifically provide for AHD will be important in improving outcomes for this group.Study registrationClinicaltrials.govNCT05454839,Clinicaltrials.govNCT05454852

BackgroundDespite tremendous progress in antiretroviral therapy (ART) and access to ART, many patients have advanced human immunodeficiency virus (HIV) disease (AHD). Patients on AHD, whether initiating ART or providing care after disengagement, have an increased risk of morbidity and mortality. The Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) launched an enhanced care package using a hub-and-spoke model to optimize AHD care in Malawi. This model improves supply availability and appropriate linkage to care. We utilized a hub-and-spoke model to share health facility challenges and recommendations on the AHD package for screening and diagnosis, prophylaxis, treatment, and adherence support.MethodsThis qualitative study assessed the facility-level experiences of healthcare workers (HCWs) and lay cadres (LCs) providing AHD services to patients through an intervention package. The study population included HCWs and LCs supporting HIV care at four intervention sites. Eligible study participants were recruited by trained Research Assistants with support from the health facility nurse to identify those most involved in supporting patients with AHD. A total of 32 in-depth interviews were conducted. Thematic content analysis identified recurrent themes and patterns across participants’ responses.ResultsWhile HCWs and LCs stated that most medications are often available at both hub and spoke sites, they reported that there are sometimes limited supplies and equipment to run samples and tests necessary to provide AHD care. More than half of the HCWs stated that AHD training sufficiently prepared them to handle AHD patients at both the hub and spoke levels. HCWs and LCs reported weaknesses in the patient referral system within the hub-and-spoke model in providing a linkage of care to facilities, specifically improper referral documentation, incorrect labeling of samples, and inconsistent availability of transportation. While HCWs felt that AHD registers were time-consuming, they remained motivated as they thought they provided better patient services.ConclusionsThese findings highlight the importance of offering comprehensive AHD services. The enhanced AHD program addressed weaknesses in service delivery through decentralization and provided services through a hub-and-spoke model, improved supply availability, and strengthened linkage to care. Additionally, addressing the recommendations of service providers and patients is essential to improve the health and survival of patients with AHD.

In 2017, the World Health Organization (WHO) published guidelines for the management of advanced human immunodeficiency virus (HIV) disease within a public health approach. Recent data suggest that more than a third of people starting antiretroviral therapy (ART) do so with advanced HIV disease, and an increasing number of patients re-present to care at an advanced stage of HIV disease following a period of disengagement from care. These guidelines recommend a standardized package of care for adults, adolescents, and children, based on the leading causes of morbidity and mortality: tuberculosis, severe bacterial infections, cryptococcal meningitis, toxoplasmosis, and Pneumocystis jirovecii pneumonia. A package of targeted interventions to reduce mortality and morbidity was recommended, based on results of 2 recent randomized trials that both showed a mortality reduction associated with delivery of a simplified intervention package. Taking these results and existing recommendations into consideration, WHO recommends that a package of care be offered to those presenting with advanced HIV disease; depending on age and CD4 cell count, the package may include opportunistic infection screening and prophylaxis, including fluconazole preemptive therapy for those who are cryptococcal antigen positive and without evidence of meningitis. Rapid ART initiation and intensified adherence interventions should also be proposed to everyone presenting with advanced HIV disease.

BackgroundThe South African national HIV program has increased antiretroviral therapy (ART) coverage over the last decade, supported by policy changes allowing for earlier ART initiation. However, many patients still enter care with advanced (<200 cells/μL) and very advanced (<100 cells/μL) HIV disease. We assessed disease progression at entry to care using nationwide laboratory data.MethodsWe constructed a national HIV cohort using laboratory records containing HIV RNA loads and CD4 counts from 2004 to 2016 to determine entry into care. We estimated numbers and proportions of adults with the first CD4 count <100 cells/ μL or 100–199 cells/μL. We calculated relative risks of presenting with advanced disease associated with male sex.Results8.04 million first CD4 results were identified. From 2005 to 2011, the proportion of patients entering into care with CD4 count <200 cells/μL declined from 46.8% to 35.6%. From 2011 onward, the proportion of patients entering ART with advanced HIV disease has remained relatively unchanged. In 2016, we estimated that of 654 868 patients entering care, 32.9% had advanced HIV disease, and 16.8% had very advanced HIV disease. Men were almost twice as likely as women (23.1% vs 12.6% ) to enter care with very advanced HIV disease.ConclusionsThe proportion of patients presenting with advanced HIV disease in South Africa remains consistently high despite ART scale-up, representing a large and avoidable burden of morbidity. Early HIV diagnosis, rapid linkage to ART and approaches to attract men into early ART initiation should be prioritized.

The number of patients who present with advanced human immunodeficiency virus (HIV) disease [defined as a helper lymphocyte (CD4) count <50 cells/mm3 or the presence of an acquired immunodeficiency syndrome (AIDS)-defining illness] is increasing. In the USA during 1994-1999, a relatively stable proportion of 43% of people diagnosed with HIV infection were tested late in the infection (had AIDS diagnosed within 1 year of diagnosis). A recent review of newly diagnosed infections in 2003 found that 301/977 (31%) of patients in the UK and Ireland presented late (<200 CD4 cells/mm3). Before a diagnosis is made, patients with advanced disease do not benefit from antiretroviral therapy and may continue to transmit the infection to others. Furthermore, when antiretroviral therapy is initiated in patients with CD4 counts of 201-350 cells/mm(3), the risk of death is lower than when treatment is started at lower CD4 cell counts. With the increasing prevalence of HIV in women and African immigrants, some doctors are concerned that different management approaches need to be used in these groups. This article reviews the evidence and some clinical scenarios for patients with advanced disease without complications and women and Africans who may present with advanced HIV disease. The aim is to offer practical advice on therapeutic options for treatment-naïve patients who present with advanced HIV disease on the basis of available clinical evidence.

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. Using a multi-state model we examined associations between engagement with care and AHD on ART in South Africa. 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'. 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. 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.

Background:Despite expanded access to antiretroviral therapy (ART) and the rollout of the World Health Organization’s (WHO) ‘test-and-treat’ strategy, the proportion of people with HIV (PWH) presenting with advanced HIV disease (AHD) remains unchanged at approximately 30%. Fifty percent of persons with AHD report prior engagement to care. ART failure and insufficient retention in HIV care are major causes of AHD. People living with AHD are at high risk for opportunistic infections and death. In 2017, the WHO published guidelines for the management of AHD that included a comprehensive package of care for screening and prophylaxis of major opportunistic infections (OIs). In the interim, ART regimens have evolved: integrase inhibitors are first-line therapy globally, and the diagnostic landscape is evolving. The objective of this review is to highlight novel point-of-care (POC) diagnostics and treatment strategies that can facilitate OI screening and prophylaxis for persons with AHD.Methods:We reviewed the WHO guidelines for recommendations for persons with AHD. We summarized the scientific literature on current and emerging diagnostics, along with emerging treatment strategies for persons with AHD. We also highlight the key research and implementation gaps together with potential solutions.Results:While POC CD4 testing is being rolled out in order to identify persons with AHD, this alone is insufficient; implementation of the Visitect CD4 platform has been challenging given operational and test interpretation issues. Numerous non-sputum POC TB diagnostics are being evaluated, many with limited sensitivity. Though imperfect, these tests are designed to provide rapid results (within hours) and are relatively affordable for resource-poor settings. While novel POC diagnostics are being developed for cryptococcal infection, histoplasmosis and talaromycosis, implementation science studies are urgently needed to understand the clinical benefit of these tests in the routine care.Conclusions:Despite progress with HIV treatment and prevention, a persistent 20%–30% of PWH present to care with AHD. Unfortunately, these persons with AHD continue to carry the burden of HIV-related morbidity and mortality. Investment in the development of additional POC or near-bedside CD4 platforms is urgently needed. Implementation of POC diagnostics theoretically could improve HIV retention in care and thereby reduce mortality by overcoming delays in laboratory testing and providing patients and healthcare workers with timely same-day results. However, in real-world scenarios, people with AHD have multiple comorbidities and imperfect follow-up. Pragmatic clinical trials are needed to understand whether these POC diagnostics can facilitate timely diagnosis and treatment, thereby improving clinical outcomes such as HIV retention in care.

Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies.*,†,§ To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694,138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended "treat-all" guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence.

Early mortality and morbidity remain high in children initiating antiretroviral therapy (ART), especially in sub-Saharan Africa. Many children still present with advanced human immunodeficiency virus (HIV) disease. Tuberculosis, pneumonia, and severe bacterial infections are the main causes of hospital admission in HIV-infected children. In contrast to adults with advanced HIV disease, cryptococcal disease is not common in childhood, although there is a peak in infancy and adolescence. Interventions such as TB screening in symptomatic children, and isoniazid and cotrimoxazole prophylaxis should be implemented. There is evidence suggesting that rapid initiation (within 1 week) of ART in children with severe malnutrition or those with advanced HIV disease admitted to hospital is not beneficial and should be delayed until their condition has been stabilized. Research informing the prevention of severe bacterial infections, the management of pediatric immune reconstitution inflammatory syndrome, and other potential strategies to decrease morbidity and mortality in HIV-infected children are urgently needed.

BackgroundInformation about burden, characteristics, predictors, and outcomes of advanced human immunodeficiency virus disease (AHD) is scarce in rural settings of sub-Saharan Africa. Human immunodeficiency virus (HIV) infections and associated deaths remain high despite specific guidelines issued by the World Health Organization (WHO).MethodsBurden of AHD and 6-month death/loss to follow-up (LTFU) were described among 2498 antiretroviral therapy (ART)–naive nonpregnant people with HIV (PWH) aged >15 years enrolled in the Kilombero Ulanga Antiretroviral Cohort in rural Tanzania between 2013 and 2019. Baseline characteristics associated with AHD and predictors of death/LTFU among those with AHD were analyzed using multivariate logistic and Cox regression, respectively.ResultsOf the PWH, 62.2% had AHD at diagnosis (66.8% before vs 55.7% after national uptake of WHO “test and treat” guidelines in 2016). At baseline, older age, male sex, lower body mass index, elevated aminotransferase aspartate levels, severe anemia, tachycardia, decreased glomerular filtration rate, clinical complaints, impaired functional status, and enrollment into care before 2018 were independently associated with AHD. Among people with AHD, incidence of mortality, and LTFU were 16 and 34 per 100 person-years, respectively. WHO clinical stage 3 or 4, CD4 counts <100 cells/µL, severe anemia, tachypnea, and liver disease were associated with death/LTFU.ConclusionsMore than 50% of PWH enrolled in our cohort after test and treat implementation still had AHD at diagnosis. Increasing HIV testing and uptake and implementation of the WHO-specific guidelines on AHD for prevention, diagnosis, treatment of opportunistic infections, and reducing the risks of LTFU are urgently needed to reduce morbidity and mortality.