Modelling the impact of CD4 testing on mortality from TB and cryptococcal meningitis among patients with advanced HIV disease in nine countries

Abstract

Introduction: Despite antiretroviral therapy (ART) scale-up among people living with HIV (PLHIV), those with advanced HIV disease (AHD) (defined in adults as CD4 count <200 cells/mm³ or clinical stage 3 or 4), remain at high risk of death from opportunistic infections. The shift from routine baseline CD4 testing towards viral load testing in conjunction with "Test and Treat" has limited AHD identification.

Methods: We used official estimates and existing epidemiological data to project deaths from tuberculosis (TB) and cryptococcal meningitis (CM) among PLHIV-initiating ART with CD4 <200 cells/mm³ , in the absence of select World Health Organization recommended diagnostic or therapeutic protocols for patients with AHD. We modelled the reduction in deaths, based on the performance of screening/diagnostic testing and the coverage and efficacy of treatment/preventive therapies for TB and CM. We compared projected TB and CM deaths in the first year of ART from 2019 to 2024, with and without CD4 testing. The analysis was performed for nine countries: South Africa, Kenya, Lesotho, Mozambique, Nigeria, Uganda, Zambia, Zimbabwe and the Democratic Republic of Congo.

Results: The effect of CD4 testing comes through increased identification of AHD and consequent eligibility for protocols for AHD prevention, diagnosis and management; algorithms for CD4 testing avert between 31% and 38% of deaths from TB and CM in the first year of ART. The number of CD4 tests required per death averted varies widely by country from approximately 101 for South Africa to 917 for Kenya.

Conclusions: This analysis supports retaining baseline CD4 testing to avert deaths from TB and CM, the two most deadly opportunistic infections among patients with AHD. However, national programmes will need to weigh the cost of increasing CD4 access against other HIV-related priorities and allocate resources accordingly.

Keywords: CD4 testing; TB mortality; advanced HIV disease; cryptococcal meningitis; deaths averted; mortality.

Figure 1

Tuberculosis (TB) model structure. Abbreviations: α, aggregate diagnostic sensitivity; β, aggregate diagnostic specificity; CFR_m, case fatality ratio missed TB cases; CFR_n, case fatality ratio notified TB cases; p, assumed TB prevalence among the screening population.

Figure 2

Cryptococcal meningitis (CM) model structure. The population is divided into three distinct groups: Group 1 with symptomatic CM at presentation, Group 2 with sub‐clinical CSF+ CM and Group 3 with CSF– CM. The model assumes two treatment regimens and a pre‐emptive therapy regimen, each characterized by a coverage $e_i$ and an efficacy ${\tau }_i$. Group 1 are assumed to be easily diagnosed and put on the available treatment regimen. Groups 2 and 3 must be first correctly identified as advanced HIV cases (α) in order to be screened for CM. If identified, Group 2 receive either a test for CSF‐positivity (c ₁) followed by the available treatment regimen, or else a test for cryptococcal antigenemia, if available (c ₂), followed by preventive therapy. If identified as advanced HIV, Group 3 receive a test for cryptococcal antigenemia, if available, followed by preventive therapy. See Table 3 for parameter values. Abbreviations: CrAg, cryptococcal antigen; CSF, cerebrospinal fluid.

Figure 3

Selected results for South Africa, 2019–2024. Figures 3a and b show total deaths for the TB and CM models, respectively, for three scenarios: with CD4 testing, without CD4 testing and under no intervention (before application of the mortality reduction factor F). Figures 3c and d show the crude mortality rate from TB and CM for each scenario. Figure 3e shows the number of false‐positive TB diagnoses with and without CD4 testing. Figure 3f shows the number of CD4 tests that must be performed per death averted (deaths averted is deaths without CD4 testing minus deaths with CD4 testing) from CM only, TB only, and for CM and TB deaths combined. The overall decline in deaths and false‐positive diagnoses over 2019–2024 (a, b, e) is driven by a decline in the projected number of new ART initiations, as overall ART coverage expands, and patients initiate at higher CD4.

Figure 4

CD4 test per death averted from the TB and CM models combined, for nine countries. The number of CD4 tests per death averted from TB and CM combined, among ART <1 year with CD4 <200 cells/mm³, for the period 2019–2024. Countries vary by nearly an order of magnitude in the number of CD4 tests to avert deaths from TB and CM. Abbreviations: ART, antiretroviral therapy; CM, cryptococcal meningitis; TB, tuberculosis.