Advanced HIV Disease: A Review of Diagnostic and Prophylactic Strategies

Alice Lehman; Jayne Ellis; Elizabeth Nalintya; Nathan C. Bahr; Angela Loyse; Radha Rajasingham

HIV Medicine. 2023;24(8):859-876.

Abstract and Introduction

Abstract

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.

Introduction

In 2016, the United Nations General Assembly set a goal to end AIDS by 2030 with an interim goal to reduce AIDS-related deaths to fewer than 500 000 by 2020; unfortunately that goal has not been met.^[1] An estimated 650 000 AIDS-related deaths occurred in 2021,^[2] with the majority occurring among people living with advanced HIV disease (AHD). 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 AHD remains unchanged at approximately 30%.^[3–6] Fifty percent of persons with AHD report prior engagement to care. ART failure and insufficient retention in HIV care are major causes of AHD.^[7]

People living with AHD are at high risk for opportunistic infections (OIs) which drive mortality. Common OIs include tuberculosis (TB), cryptococcal disease, severe bacterial infection (SBI), toxoplasmosis, pneumocystis pneumonia (PJP), and, in specific regions, histoplasmosis and talaromycosis. In the REALITY trial, among ambulatory PWH with CD4 <100 cells/mm³, 13% died within 48 weeks, with the highest mortality occurring during the first 4 weeks on ART.^[8] Similarly, in the REMSTART trial, 16% of participants with AHD died by 28 weeks.^[9] This likely represents a gross underestimate of routine care mortality among persons with AHD outside of clinical trials.^[10–12] Studies of patients hospitalized with AHD report >20% mortality, primarily due to TB.^[13–15]

In 2017, the WHO published guidelines for the management of AHD that included a comprehensive package of care for screening and prophylaxis of major OIs (Table 1) based on the above-mentioned trials among AHD outpatients.^[3,8,9] In the interim, ART regimens have evolved: integrase inhibitors are first-line therapy globally, and the diagnostic landscape has changed. In this review, we discuss novel diagnostic and OI prophylaxis strategies for people with AHD and highlight key research and implementation gaps together with potential solutions. Given the breadth of AHD-related OI management, we focus our discussion on emerging diagnostics, prophylactic strategies, and new areas of investigation.

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Next Section

Abstract and Introduction
Identification of People With AHD: CD4 Testing as the Gateway to the AHD Package of Care
AHD-associated Opportunistic Infections
Areas for Future Research
Conclusions
References

Table 1. World Health Organization recommendations for opportunistic infection screening and prophylaxis, stratified by CD4 cell count.
	Always recommended	CD4 <350 cells/μl	CD4 <200 cells/μl	CD4 <100 cells/μl
Rapid ART initiation^a
TPT (without active TB)
Xpert MTB/RIF (if TB symptoms present)
Cotrimoxazole prophylaxis
Medication adherence support
CrAg screening
Fluconazole preemptive therapy if CrAg-positive
TB LAM

^aDeferred if clinical symptoms of TB or cryptococcal meningitis present.
Abbreviations: ART, antiretroviral; CrAg, cryptococcal antigen; LAM, lipoarabinomannan; MTB, Mycobacterium tuberculosis; RIF, rifampin; TB, tuberculosis; TPT, tuberculosis preventive therapy.

Table 2. Summary of tuberculosis point-of-care diagnostics performance, costs and recommendations.
Test name	Specimen	Sensitivity/specificity	WHO recommendations [8]	Time to result	Cost (US$)	Comments
Alere LAM Abbott	Urine	CD4 <200 cells/μl: • Sensitivity 45% (95% CI 31% to 61%) • Specificity 89% (95% CI 77% to 94%) [93] CD4 <100 cells/μl: • Sensitivity 54% (95% CI 38% to 69%) • Specificity 88% (95% CI 77% to 94%) [93]	Inpatient: WHO strongly recommends LF-LAM to assist in diagnosis of active TB in PWH with signs/symptoms of TB with AHD OR Seriously ill PWH with CD4 count ≤200 cells/mm³ irrespective of signs/symptoms of TB (Strong recommendation) Outpatient: WHO suggests using LF-LAM to assist in diagnosis of active TB in PWH with signs/symptoms of TB OR PWH who are seriously ill with CD4 count ≤100 cells/mm³ irrespective of signs/symptoms of TB (Conditional recommendation)	<1 h	$3.70	• Commercially available • No electricity needed • Higher sensitivity in disseminated TB disease
Fujifilm SILVAMP FujiLAM	Urine	Sensitivity 53% (95% CI 44% to 62%), specificity 99% (95% CI 97% to >99%) [94] Inpatient: 70% sensitivity, 90% specificity for hospitalized PWH Outpatient: 75% sensitivity, 89% specificity in PWH [95]	NA	<1 h	$6.00 [96]	• Not commercially available • No electricity needed • Higher sensitivity in persons with HIV
Xpert MTB/RIF Ultra Cepheid	Sputum Synovial fluid Pleural fluid Lymph node Blood [34] CSF [33] Oral swab	Pulmonary TB [38]: Sputum: sensitivity 68%, specificity 98% Tongue: sensitivity 91.8% [35] Buccal: sensitivity 50% [37, 38] Extrapulmonary TB [38]: Pleural: sensitivity 38%–61%, specificity 96%–99% Lymph node biopsy: sensitivity 67%, specificity 96% Synovial: sensitivity 96%, specificity 97% CSF: sensitivity 87%, specificity 88% Blood: sensitivity 37% [34] Stool (children): sensitivity 63%, specificity 100% [97]	• First use in adults and children for pulmonary TB evaluation (Strong recommendation) • First use in adults and children for TB meningitis CSF evaluation (Strong recommendation) • May be used in PWH with suspected disseminated TB on blood (Conditional recommendation)	<2 h	$12.63 [98]	• Commercially available • Requires GeneXpert machine • Requires electrical supply • Can test for rifampin resistance • Increased sensitivity in blood with lower CD4 or haemoglobin • Increased sensitivity in TB endemic countries
Xpert MTB Host Response (MTB-HR)	Sputum	Pulmonary TB: sensitivity 87%, specificity 94% [34]	NA	<2 h		• Not commercially available • Uses 3-gene signature to create a TB Score • 10% in study population HIV infection, limited numbers with advanced disease
TrueNAT/TrueNAT Plus	Sputum	• AFB smear + patients: Sensitivity 73% (95% CI 68–78) Specificity 80% (95% CI 75–84) [37] • AFB smear negative patients: Sensitivity 37% (95% CI 27–48) Specificity 46% (95% CI 36–57) [37]	May be used in exchange for Xpert MTB/RIF Ultra for suspected pulmonary TB (Conditional recommendation)	1 h	$13.20 [98]	• Commercially available • No electricity needed • Can be performed in peripheral laboratories and primary health centres • Can test for rifampin resistance • No data in children • Temperature stable
Cell-free MTB DNA detection	Plasma Urine	• Plasma: sensitivity 97% (80%–100%), specificity 94% (71%–100%) [32] Urine: sensitivity 83.7% (71%–91%), specificity 100% (86%–100%) [43]	NA	1 day		• Not commercially available • Limited data in PWH Sensitive for pulmonary and extra-pulmonary TB in children with HIV

Abbreviations: AFB, acid-fast bacilli; AHD, advanced HIV disease; CI, confidence interval; CSF, cerebrospinal fluid; LAM, lipoarabinomannan; LF, lateral flow; MTB, Mycobacterium tuberculosis; NA, not available; PWH, people with HIV; RIF, rifampin; TB, tuberculosis; WHO, World Health Organization.

Table 3. Summary of tuberculosis preventive therapy options.
Regimen	Drug	Adult dose	Duration	Side effects Hepatotoxicity Hypersensitivity reaction Cutaneous reaction Peripheral neuropathy Gastrointestinal intolerance	Costs (US$) [9] total direct cost includes medication costs, supply costs, clinic costs and health system costs	Literature highlights	Adult pill burden Isoniazid 300 mg Rifampin 300 mg Rifapentine 150 mg	Advantages	Disadvantages
6H, 9H Isoniazid preventive therapy (IPT)	Isoniazid	300 mg daily	6 months OR 9 months	Increased risk of hepatotoxicity with 9H	6H: $0.19/dose $25 total $374 total direct costs 9H: $0.19/dose $52 total $499 total direct costs	Systematic review shows IPT reduces the overall risk for TB by 33% (RR 0.67; 95% CI 0.51; 0.87), with a 64% risk reduction for people with a positive TST (RR 0.36; 95% CI 0.22; 0.61) [99] No controlled clinical trials comparing 9H vs. 6H Systematic review and meta-analysis of PWH in settings with high TB prevalence and transmission showed that continuous IPT can reduce the risk for active TB by 38% more than 6 months' isoniazid [100]	Daily	Affordable, well studied Low pill burden	Long duration Lower completion rates
3HP	Rifapentine + Isoniazid	900 mg weekly + 900 mg weekly	3 months	Greatest hepatotoxicity risk	$11.12/dose $133 total $412 total direct costs In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion [101]	No significant difference in the incidence of active TB between participants given a 3HP and 6H or 9H (RR 0.73, 95% CI 0.23; 2.30) The risk for hepatotoxicity was significantly lower with 3HP in adult PWH (RR 0.26, 95% CI 0.12; 0.55) [102]	Weekly	Shorter duration Weekly administration Higher completion rates Less hepatotoxicity	Drug interactions: Double dolutegravir dose during TPT Avoid rifamycin containing regimens in patients on protease inhibitors and nevirapine Variable access to rifapentine Higher costs
3HR	Rifampin + isoniazid	300 mg daily + 600 mg daily	3 months		$0.85/dose $76 total $355 total direct costs	A systematic review showed that the efficacy and the safety profile of 3–4 months' daily rifampicin plus isoniazid were similar to those on 6 months of isoniazid [103]	Daily	Shorter duration	Drug interactions: • Double dolutegravir dose during TPT • Avoid rifamycin-containing regimens in patients on protease inhibitors and nevirapine Variable access to rifapentine Higher costs
4R	Rifampin	600 mg daily	4 months		$0.65/dose $78 total $365 total direct costs	A systematic review found similar efficacy for 3–4 months' daily rifampicin and 6H (OR 0.78; 95% CI 0.41;1.46) Individuals given rifampicin daily for 3–4 months had a lower risk for hepatotoxicity than those treated with isoniazid monotherapy (OR 0.03; 95% CI 0.00;0.48) [104]	Daily	Shorter duration Single drug Low pill burden
1HP	Daily rifapentine + isoniazid	600 mg daily + 300 mg daily *Not studied in pregnant participants	1 month		$7.23/dose $202.44 total $421 total direct costs (estimated from 3HP data)	An RCT showed non-inferiority comparing 1HP to 9H for active TB or death. Serious adverse events were equivocal between groups. Treatment completion was higher in 1HP group [47]	Daily	Shortest duration

Abbreviations: CI, confidence interval; IPT, isoniazid preventive therapy; OR, odds ratio; RCT, randomized controlled trial; RR, relative risk; TB, tuberculosis; TST, tuberculin skin test.