The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, has had a negative impact on establishing interventions to reduce mortality. We suggest that setting 95-95-95 targets for CD4 testing, cryptococcal antigen and TB testing, and treatment that are aligned to the WHO AHD package of care would be a step in the right direction to achieving the greater goal of the WHO End TB strategy and the proposed new strategy to end cryptococcal meningitis deaths. However, these targets will only be achieved if there is healthcare worker training, expanded access to bedside point-of-care diagnostics for hospitalised patients and those in outpatient care who meet the criteria for AHD, and health systems strengthening to minimise delays in initiating the WHO-recommended therapies for TB and cryptococcal disease.

Purpose: Plasma albumin, a biomarker for hepatic function, is reported to correspondingly decrease in concentration as disease severity increases in chronic infections including HIV and TB. Our objective was to develop a semi-mechanistic disease progression model to quantify plasma albumin concentration changes during TB and HIV therapy and identify the associated covariate factors. Methods: Plasma albumin concentration data was collected at specified times for 3 months from 262 HIV participants receiving efavirenz based anti retroviral therapy. Of these, 158 were TB co-infected and on Rifampicin based anti –tuberculosis co-treatment. An indirect response model with zero order albumin production and first order elimination was developed in NONMEM version 7.2 to describe our data. Genotype (CYP2B6*6 and 11, CYP3A5, ABCB1c.3435C>T and ABCB1rs), TB disease status, baseline age, body weight, plasma creatinine, alanine transaminase enzyme and CD4⁺ count were the potential model covariates tested. Results: The proposed model successfully described plasma albumin concentration changes in the study population. There was a 10.9% and 48.6% increase in albumin production rates in HIV only and TB co-infected participants respectively. Participants co-infected with TB showed a 44.2% lower baseline albumin secretion rate than those without TB while ABCB1c.3435C>T mutation was associated with a 16% higher steady state albumin secretion rate following treatment. Conclusion: A semi-mechanistic model describes plasma albumin concentration changes in HIV patients on ART. Further work is required to establish the utility of the model in monitoring disease progression and predicting prognosis in HIV and TB co-infected patients in absence of or during treatment.

Among HIV-infected adults attending non-governmental organization voluntary counseling and testing (VCT) sites in Uganda that provide a nine-month course of isoniazid preventive treatment (IPT), we report on loss to follow-up (LTFU) and its associated risk factors. The design was a retrospective cohort study of program data spanning a three year period (2006-2008). A total of 586 IPT patients were enrolled of whom 335 (57.1%) were females with a mean age of 34 years. Of those starting IPT, 341 (58.1%) were lost to follow-up, 197 (33.6%) completed IPT, 29 (4.9%) were discontinued and 19 (3.2%) died. The return rates at one, three, five and seven months were 78.0% (457), 62.1% (364), 52.9% (310) and 33.6% (197) respectively. Being less than 30 years of age, widowed, separated, or divorced were found to be associated with a higher risk of loss to follow-up. Sudden improvement in retention on IPT was observed between the years 2006 and 2007, although causes of the improvement are poorly understood hence the need for more research. At non-governmental VCT sites in Uganda, six out of ten individuals enrolled on IPT are lost to follow-up and efforts to reduce this attrition including systems strengthening might play a critical role in the success of IPT programs.

Tuberculosis preventive treatment (TPT) is a mainstay for reducing the tuberculosis (TB) burden among people living with human immunodeficiency virus (PLHIV). Context-specific challenges hinder TPT uptake and completion among PLHIV. During 2022–2024, a mixed-methods design was used to evaluate the TPT cascade and explore its facilitators and barriers among PLHIV availing care from 12 PEPFAR-supported health facilities in Uganda. The quantitative component included analysis of routine programmatic data, and the qualitative component included focus group discussions and in-depth interviews with healthcare workers and PLHIV. A total of 1349 PLHIV were enrolled in the evaluation. Among PLHIV newly initiated on ART (≤3 months), 74% started TPT, and 98% of them completed it. In PLHIV already on ART, 87% had initiated TPT (76% before and 11% during this evaluation), with a treatment completion rate of 98%. The facilitators for TPT implementation included access to shorter TPT regimens, integration of services, and adherence counseling. Barriers included knowledge gaps, pill burden, TPT drug stock-outs, and documentation inconsistencies. The TPT completion rate was higher than the national target (90%), but the TPT initiation remains low. Improved access to shorter regimens, adherence counseling, better documentation, and service integration can sustain the completion rate and improve the initiation rate in Uganda and possibly elsewhere.

Background: Data on the true burden of histoplasmosis in Uganda are limited, largely due to the scarcity of epidemiological studies. We aimed to describe the nationwide burden of histoplasmosis among persons with advanced HIV disease (AHD), highlighting the major challenges in diagnosis and treatment under routine HIV care. Methods: This was a prospective longitudinal study conducted at nine health facilities in Uganda. Persons with AHD (CD4 < 200 cells/mm3) were included and followed up for 2 years. Urine samples were sent to the Central Public Health Laboratories and tested using the Histoplasma galactomannan enzyme immunoassay in batches. Histoplasmosis was defined using standard criteria. Results: We enrolled 332 participants with AHD, and 66.6% were newly diagnosed with HIV. Over half were female (51.5%), with a median age of 35 years (interquartile range [IQR] = 29–42) for all participants. The median CD4 T-cell count was 73 cells/µL (IQR = 30.5–126.5). Eight (2.4%) participants were diagnosed with probable histoplasmosis. None of the cases received the recommended antifungals because they were not available in the country. After 2 years, 5 cases were still alive, 2 were lost to follow-up, and 1 died. Major challenges included missed diagnosis, low index of clinical suspicion, overlap of symptoms with those of pulmonary TB, high cost, limited access to antifungals such as voriconazole and itraconazole, radiology and laboratory investigations, and lack of knowledge about treatment guidelines. Conclusions: Histoplasmosis occurs at a low frequency among persons with AHD in Uganda. Numerous challenges hinder a definite diagnosis and treatment. However, despite these challenges, survival among persons with AHD in Uganda who have untreated histoplasmosis is relatively good.

Background: Invasive aspergillosis is a severe fungal disease with a high mortality rate, mostly seen in severely immunocompromised hosts, including persons with HIV/AIDS. The detection of galactomannan (GM) antigen is more sensitive than fungal cultures in diagnosis of invasive aspergillosis. We conducted a pilot study using the sōna Aspergillus GM Lateral Flow Assay on serum among people with advanced HIV disease (AHD) in Uganda to estimate the prevalence and factors associated with Aspergillus GM antigenemia in this population. Methods: This was a cross-sectional study conducted at 9 health facilities in Uganda in 2023. Persons presenting with AHD (CD4<200 cells/mm3) were consecutively enrolled. Data were collected using an interviewer-administered questionnaire, serum and sputum samples were tested both onsite and at the Central Public Health Laboratories using the sōna Aspergillus GM Lateral Flow Assay and culture, respectively. Logistic regression was performed at a 95% confidence intervals (CI) to assess the factors associated with Aspergillus GM antigenemia. Data were analyzed using SAS 9.4. Results: Aspergillus GM antigenemia was present in 119 of 332 (35.8%) of participants. Among 26 samples with Aspergillus growth, 30.8% were Aspergillus terreus, 26.9% were Aspergillus flavus, 26.9% were Aspergillus niger, 11.5% were Aspergillus fumigatus, and 3.8% were Aspergillus lentulus. Being an inpatient (adjusted odds ratio, 2.2; 95% CI, 1.3–4.5) and having HIV World Health Organization stage 3 or 4 disease (adjusted odds ratio, 3.9; 95% CI, 1.2–13.0) were independently associated with Aspergillus GM antigenemia. Conclusions: The high Aspergillus GM antigenemia of about 4 in 10 persons with AHD in Uganda may suggest a high burden of aspergillosis in this population. There is urgent need for further definitive studies incorporating host factors, clinical factors and radiological imaging to determine the burden of aspergillosis among people with AHD in Uganda.