Introduction
The President’s Emergency Plan for AIDS Relief (PEPFAR), launched by the United States government in 2003, was initially conceived to increase access to lifesaving antiretroviral treatment (ART) among people living with HIV (PLHIV) in low-income countries and to prevent new HIV infections. PEPFAR’s reach continues to expand: as of September 2019, PEPFAR was sustaining nearly 15.7 million PLHIV on treatment [
1].
PEPFAR’s goal is to achieve HIV epidemic control, defined as the point at which the number of new HIV infections is less than the number of all-cause deaths among PLHIV, and when both infections and deaths are decreasing, in the countries it supports [
2,
3]. To date, PEPFAR has focused on decreasing new HIV infections through prevention, case-finding, and treatment efforts, and in most countries, new infections are indeed decreasing [
4,
5]. HIV-related mortality also has declined globally, by about one-third between 2010 and 2018; however, there were still 770,000 HIV-related deaths (uncertainty bounds: 570,000–1.1 million) in 2018 [
5]. Realizing a meaningful vision of epidemic control means that PEPFAR and HIV program implementers must work not only to drive down infections, but also mortality.
To that end, PEPFAR has become increasingly engaged in understanding and addressing mortality among PLHIV, specifically by addressing advanced HIV disease (AHD) with opportunistic infections (OIs). This commentary reviews the epidemiology of AHD and describes recent developments in identifying AHD and in preventing, diagnosing, and treating selected OIs. It describes the ways in which PEPFAR and other global HIV program stakeholders are applying these developments to decrease mortality among PLHIV. Finally, it discusses PEPFAR’s current efforts in supporting surveillance of mortality among PLHIV to guide programmatic priorities in decreasing mortality in this population.
Epidemiology of advanced HIV disease and mortality among PLHIV
HIV-related mortality is higher among PLHIV who present to or re-enter clinical care with AHD than among those PLHIV who do not present with AHD [
6,
7]. Among all PLHIV aged ≥ 5 years, AHD is defined as having either a CD4 cell count < 200 cells/µL or a World Health Organization (WHO) HIV clinical stage 3 or 4 condition at presentation for care; all children living with HIV aged < 5 years are categorized as having AHD [
4,
8]. AHD occurs among both ART-naïve and ART-experienced individuals. The most common causes of death among adults with AHD are tuberculosis (TB), cryptococcal meningitis, and severe bacterial infections (SBIs) [
4,
9,
10].
Although estimates of AHD prevalence among PLHIV vary, AHD is not uncommon. Data from South Africa show nearly one-third of HIV patients entering care have AHD [
11]. Preliminary results from community-based Population HIV Impact Assessment surveys conducted during 2016–2018 in nine PEPFAR-supported countries found 11─22% of newly-diagnosed adult PLHIV had a CD4 cell count < 200 cells/µL [
12].
Identifying AHD is crucial to ensure that these PLHIV receive focused interventions against associated OIs. Early intervention is key, because AHD-related death can occur soon after initial presentation or re-engagement in care: among the REALITY trial cohort of PLHIV with CD4 cell count < 100 cells/µL, 12.7% died within 48 weeks of enrollment, with the highest mortality occurring during the first 4 weeks on ART [
13]. To combat AHD-related mortality, WHO provides guidelines for timely application of a package of care [
4]. The package includes interventions for preventing, diagnosing, and treating common OIs, including TB, cryptococcal meningitis, and SBIs, and for ensuring rapid initiation on ART and intensified adherence support.
TB is the most common identified cause of death among PLHIV worldwide, accounting for one-third of all HIV-related deaths in 2018 [
14], but its role in mortality is likely underestimated. A 2015 meta-analysis of 36 autopsy studies among PLHIV in resource-limited settings found that TB was considered the cause of death in 91.4% (95% CI 85.8–97.0%) of those with TB. Additionally, TB remained undiagnosed at death in 45.8% (95% CI 32.6–59.1%) of TB cases [
15]. PLHIV may have limited symptoms of pulmonary TB or unrecognized extrapulmonary TB. Furthermore, because TB incidence among PLHIV on ART remains up to six times higher than among those not infected with HIV, adjunctive strategies to reduce TB-related mortality are critical. For instance, treating TB infection among PLHIV, after controlling for ART, was associated with a 39% reduction in mortality [
16].
Cryptococcal meningitis accounts for 15% of acquired immunodeficiency syndrome (AIDS)-related deaths and 15–20% of deaths among hospitalized PLHIV [
9,
17]. Cryptococcal antigen (CrAg) can be detected in the blood before the development of meningitis, and cryptococcal antigenemia is seen more frequently among PLHIV with CD4 cell count < 100 cells/µL than among PLHIV with higher CD4 cell counts [
17]. Recent data show that cryptococcal antigenemia is also common in PLHIV with CD4 cell count < 200 cells/µL [
18]. Treatment for cryptococcal meningitis is labor-intensive and difficult in low-income countries.
SBIs comprise major organ system infections including bacterial pneumonia, isolated bacteremia, and severe diarrhea. They are estimated to contribute to over one-third of hospitalizations among PLHIV globally and are a leading cause of death [
9]. In the REALITY trial, among PLHIV with CD4 cell count < 100 cells/µL, the most common cause of death was “unknown” (5% cumulative incidence), while confirmed SBI accounted for 1.9%. However, it is hypothesized that some of the burden of unknown cause of death might be attributed to undiagnosed SBIs [
13,
19]. Although these infections are not universally considered OIs, incidence is lower in people who start ART immediately and maintain immune function [
20,
21]. If diagnosed or suspected, these can generally be treated with conventional antibiotics.
Despite the WHO guidelines to prevent AHD-related mortality among PLHIV, there are significant logistical and financial barriers to identifying PLHIV with AHD and implementing these interventions. PEPFAR and HIV program implementers play a significant role in facilitating guidelines implementation by helping clinicians identify those with AHD and by expanding access to evidence-based innovations in preventing, diagnosing, and treating OIs. A summary of how PEPFAR supports these interventions can be found in Table
1.
Table 1
Summary of PEPFAR supports for interventions to identify advanced HIV disease; prevent, diagnose, and treat opportunistic infections; and conduct surveillance of mortality among PLHIV
Identifying advanced HIV disease (AHD) | Use of a point-of-care test that differentiates CD4 cell count as binary greater than or less than 200 cells/µL | Once test is WHO pre-qualified, PEPFAR plans to support use of this test to target PLHIV at increased risk of AHD |
Preventing AHD-related mortality and associated opportunistic infections (OIs) | Rapid ART initiation using optimized ART | Rapid ART initiation as cornerstone of HIV programming, scaling up integrase-based ART regimens |
TB preventive treatment | Commitment to ensure all eligible PLHIV on ART receive TPT by 2022 |
Cryptococcal antigen (CrAg) testing and cryptococcal meningitis preventive interventions | Recognition of importance of CrAg testing and cryptococcal meningitis preventive interventions in PEPFAR guidance |
Prevention of severe bacterial infections (SBI) using co-trimoxazole | Co-trimoxazole is mainstay of PEPFAR guidance and programming |
Diagnosing OIs | Use of Xpert MTB/RIF testing among PLHIV with presumptive TB | Improving implementation of Xpert MTB/RIF, through optimizing distribution of machines, improving specimen transfer networks, and scaling up Xpert MTB/RIF Ultra |
Use of urine lateral flow lipoarabinomannan (LF-LAM) to diagnose and screen for active TB among PLHIV with AHD1 | PEPFAR guidelines recommend use of LF-LAM among PLHIV with a CD4 cell count < 200 cells/µL |
Treating OIs | Integration of HIV and TB services | PEPFAR programming emphasizes co-location of HIV and TB services and timely return of TB testing results to inform ART initiation |
Option of all-oral induction therapy for cryptococcal meningitis | Working with other global HIV programmers in scaling up clinical implementation of this all-oral option |
Surveillance of mortality among PLHIV | Conduct systematic surveillance of mortality | Use of an indicator TX_ML in its data reporting systems to track loss to follow up, including loss from mortality, allowing routine reporting on mortality |
Surveillance of mortality among PLHIV on ART in PEPFAR programs
To understand mortality among PLHIV on ART it serves, PEPFAR supports several approaches to mortality surveillance, including civil registration and vital statistics (CRVS) systems, verbal autopsy, and mortuary surveillance. However, these approaches are not standardized across all PEPFAR country programs and lack reporting requirements, limiting the utility of these data. To address these limitations, in October 2018 PEPFAR introduced a new indicator, TX_ML, defined as the number of PLHIV on ART with no clinical contact after 28 days since their last expected contact, in its data reporting systems focused on loss to follow-up (LTFU), including LTFU from mortality, among all PLHIV on ART supported by PEPFAR [
41,
42].
TX_ML reporting is intended to ensure programmatic action is being taken to locate PLHIV who have missed clinical visits, and that outcomes are accurately documented. [
12]. It is the first PEPFAR indicator to systematically categorize outcomes among those reported as LTFU, and requires reporting on the number of PLHIV who died, who were not traced or were unsuccessfully traced (the truly LTFU), who transferred out, or who stopped ART [
42].
Implementation of this indicator marks the first time that PEPFAR has required routine reporting on mortality among PLHIV on ART. This indicator also includes optional reporting on cause of death (COD). In the absence of robust CRVS systems, PEPFAR has also provided guidance on the method of standardized mortality recording and reporting, by recording in-facility deaths in a dedicated tracking register and utilizing standard Medical Certificate of Death and COD forms. For deaths in the community, verbal autopsy is recommended.
These data are collected not only for surveillance purposes but also to inform programmatic activity. Mortality data can be compared between sites and districts, as well as by age and sex, to determine the geographic areas and demographic groups with higher proportions of deaths or types of deaths, thus guiding specific interventions. Tracking mortality data over time can reveal important epidemiologic trends, including the number of all-cause deaths among PLHIV. PEPFAR guidance encourages developing or strengthening national CRVS systems, which can then be used to track other disease-specific mortality or to assess the impact of public health interventions. Additionally, this focus on mortality as an outcome is a key component of strengthening HIV case-based surveillance, a cornerstone of sustainable HIV programs. Ultimately, documenting COD among PLHIV in PEPFAR programs can focus resources on interventions aimed at decreasing preventable deaths.
Conclusions
The mandates of HIV programming are to prevent the spread of infection and reduce morbidity and mortality associated with HIV. PEPFAR and other global HIV stakeholders, through a focus on HIV prevention, case-finding, and provision of ART, have made a substantial impact in decreasing new HIV infections in low-income countries. Comprehensively addressing HIV-related mortality incorporates identifying and treating PLHIV with AHD; preventing, diagnosing, and treating OIs; tracing PLHIV lost from care; and improving mortality surveillance. These efforts include expanding access to integrase inhibitor-based ART regimens, diagnostics distinguishing between PLHIV with low CD4 and higher CD4 cell counts, and differentiated, intensified care for PLHIV with AHD. These efforts are necessarily collaborative, with PEPFAR working with Ministries of Health and international organizations to advance this approach.
The current COVID-19 pandemic has introduced a new threat to the care and well-being of PLHIV. Though research to date is not definitive, PLHIV may suffer a higher rate of severe disease from COVID itself [
43,
44] and, perhaps more importantly, from discontinuity of HIV and co-morbidity care while health services are limited or shifted to COVID response. PEPFAR is working to adapt its service delivery models to both mitigate risk of COVID transmission among PLHIV and to maintain continuity of HIV care; these adaptations include an acceleration in multi-month dispensing to minimize need for clinic visits, development of true community care models, and changes in clinic flow and use of space to minimize risk to PLHIV in facilities. In this way, PEPFAR and other global HIV programmers can continue to reduce mortality among PLHIV.
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