Advanced HIV: diagnosis, treatment, and prevention

doi:10.1016/S2352-3018(19)30189-4

The Lancet HIV

Volume 6, Issue 8, August 2019, Pages e540-e551

https://doi.org/10.1016/S2352-3018(19)30189-4 Get rights and content

Summary

Substantial progress has been made this century in bringing millions of people living with HIV into care, but progress for early HIV diagnosis has stalled. Individuals first diagnosed with advanced HIV have higher rates of mortality than those diagnosed at an earlier stage even after starting antiretroviral therapy (ART), resulting in substantial costs to health systems. Diagnosis of these individuals is hindered because many patients are asymptomatic, despite being severely immunosuppressed. Baseline CD4 counts and screening for opportunistic infections, such as tuberculosis and cryptococcus, is crucial because of the high mortality associated with these co-infections. Individuals with advanced HIV should have rapid ART initiation (except when found to have symptoms, signs, or a diagnosis of cryptococcal meningitis) and those in treatment failure should switch treatment. Overcoming barriers to testing and adherence through the development of differentiated care models and providing psychosocial support will be key in reaching populations at high risk of presenting with advanced HIV.

Introduction

Substantial progress has been made in the identification of individuals with HIV and starting them on antiretroviral therapy (ART): 21·7 million of the estimated 36·9 million people living with HIV worldwide are now on treatment.¹ The number of AIDS-related deaths in 2017 was the lowest ever in the 21st century and the incidence of HIV infections has been decreasing.¹ However, these seemingly promising statistics obscure the full story. The estimated 21·7 million individuals starting ART includes those who are lost to follow-up and who are double counted when they return to care. Furthermore, CD4 count at ART initiation has now plateaued, suggesting that progress towards earlier HIV diagnosis has effectively stalled.² Updates and future directions in preventing, diagnosing, and treating advanced HIV and associated co-infections are the focus of this Review.

In this Review, we define advanced HIV using the WHO definition,³ which for adults, adolescents, and children older than age 5 years, is a CD4 cell count less than 200 cells per μL or a WHO clinical stage III or IV event.⁴ Any child younger than age 5 years with HIV is considered to have advanced HIV disease. Individuals presenting to care with a CD4 count of less than 350 cells per μL or presenting with an AIDS-defining illness (regardless of CD4 count) are considered to have late presentation of HIV, according to the European Late Presenter Consensus definition.⁵

Section snippets

Scope of the problem

Two broad groups of individuals present with advanced HIV: individuals who are ART-naive and those who are ART-experienced.

ART-naive patients have never had ART and have advanced disease at the time of initial HIV diagnosis. Several studies have identified risk factors for these individuals, including male gender, older than age 50 years, heterosexual, and a migrant.6, 7, 8, 9, 10, 11, 12, 13, 14 These risk factors emphasise groups not traditionally considered to be at high risk of acquiring

Implications of advanced HIV

A high incidence of advanced HIV leads to adverse effects for patients and health systems. Compared with people with less advanced disease, individuals who start ART at low CD4 counts have a high risk of mortality, which is related to their poor immunological status when ART is initiated.¹⁷ Given that these patients tend to be sicker and often admitted to hospital, the fact that advanced HIV places burden on already strained health-care systems is not surprising; although high-resource settings

Diagnosis

An important first step in the management of advanced HIV disease is case-finding. Although many individuals are diagnosed on presentation with a concurrent symptomatic opportunistic infection, many others remain asymptomatic despite severe immunosuppression. Studies of patients in Africa and Asia indicate that between 6% and 8% of patients with CD4 counts of less than 100 cells per μL have asymptomatic cryptococcal antigenaemia.25, 26, 27, 28, 29 In the REALITY Trial³⁰ done in Kenya, Malawi,

Tuberculosis

Tuberculosis is the leading cause of death among people living with HIV, not only among patients admitted to hospital, but also for outpatients, as noted by autopsy results in those with advanced HIV. One study from South Africa found evidence of tuberculosis in 47% of patients who underwent a minimally invasive autopsy, 38% of whom had not started treatment.³²

Despite the morbidity and mortality associated with co-infection with tuberculosis and HIV, most individuals are not screened; even

ART regimens for advanced HIV

The CADIRIS study⁶⁰ assessed if the addition of a CCR5 antagonist (eg, maraviroc) to a tenofovir, emtricitabine, and efavirenz regimen could reduce the incidence of immune reconstitution inflammatory syndrome (IRIS) in patients with CD4 counts of 100 cells per μL or less who were starting ART. Unfortunately, this strategy showed no difference in frequency of or time to IRIS between the experimental and placebo groups.

Concerns have been raised regarding the risk of IRIS among patients on

Principles of ART initiation

Patients with advanced HIV have a high risk of mortality, particularly in the first 6 months of ART initiation.17, 74 WHO has recommended that patients with advanced HIV should be offered rapid initiation of ART.

As recently as 2010, patients' readiness was assessed before starting therapy.⁷⁵ This practice stemmed from historical beliefs that all patients with HIV must complete extensive adherence training before ART initiation, which often required months to complete. A secondary analysis of a

Prevention of advanced HIV

Moving forward, sustained progress is needed in preventing advanced HIV by extending the reach of testing, and reducing barriers to care.

Many cases of HIV remain undiagnosed, and several groups in particular tend to be late presenters, including men, older individuals, and migrants.6, 7, 8, 10, 11, 12 Therefore, understanding the reasons for this discrepancy must precede developing strategies for mitigation. To encourage individuals to seek testing at earlier asymptomatic stages of disease

Conclusion

Tremendous progress has been made in bringing millions of individuals living with HIV into care, but late diagnosis remains a pressing issue in key populations. Most new infections in several regions of the world are among key populations, and data-driven approaches to understand risk and improved epidemiological surveillance for these populations are crucial.¹ Such an approach was used in Kenya, with a survey that sought to measure outcomes following a national HIV prevention programme for key

Search strategy and selection criteria

We searched PubMed for original research, reviews, and viewpoint articles describing advanced HIV among adults, using the term “advanced HIV” in the title or abstract. 340 articles published in English from Nov 1, 2013, to Oct 31, 2018, were reviewed, in addition to references of relevant articles. Papers were retained for this scoping review if they discussed the diagnosis, treatment, or prevention of advanced HIV; also included were those that discussed antiretroviral therapy (ART) initiation

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Cited by (45)

Persistent poor clinical outcomes of people living with HIV presenting with AIDS and late HIV diagnosis – results from the ICONA cohort in Italy, 2009-2022
2024, International Journal of Infectious Diseases
Limited data are available on the long-term outcomes in recent years for late HIV diagnosis (LD).
All subjects with HIV enrolled in the ICONA cohort in 2009-2022 who started antiretroviral treatment (ART) within 4 months from diagnosis were included and divided into: (i) pre-ART CD4 count ≥350/mm³ without AIDS (non-LD), (ii) pre-ART CD4 count <350/mm³ without AIDS (LD asymptomatic), and (iii) with AIDS events pre-ART (LD-AIDS). The estimated probability and independent risk for mortality (all-cause and cause-specific) and treatment failure were evaluated.
Of 6813 participants (2448 non-LD, 3198 LD asymptomatic, and 1167 LD-AIDS), 161 (2.4%) died after ART initiation. At survival analysis, a higher probability of all-cause mortality has been identified for LD than non-LD (P <0.001) and within the former, for LD-AIDS over LD asymptomatic (P <0.001). After adjusting for confounders, LD showed a higher risk of all-cause mortality (vs non-LD adjusted hazard ratio (aHR) 5.51, P <0.001) and, in particular, being an AIDS presenter predicted a greater risk of all-cause (aHR = 4.42, P <0.001), AIDS-related (adjusted subhazard ratio [aSHR] = 16.86, P <0.001), and non-AIDS–related mortality (aSHR = 1.74, P = 0.022) than the rest of the late presenters. Among the short-term survivors in the LD-AIDS group, the long-term mortality was mediated by the lack of immune recovery at 2 years. Finally, LD compared with non-LD and, particularly, among the former, LD-AIDS over LD asymptomatic showed a greater risk of treatment failure.
In recent years, LD subjects, particularly, AIDS presenters, remained at a higher risk of poorer outcomes. Public health strategies for early HIV diagnosis are urgently needed to constrain the mortality gap.
Retiring the term AIDS for more descriptive language
2024, The Lancet HIV
The term acquired immunodeficiency syndrome (AIDS) was coined to describe a condition marked by weakened cell-mediated immunity in the absence of a clear cause. Due to unfortunate messaging during the early days of the HIV epidemic, this term became loaded with stigma. After the discovery of HIV, the term AIDS became redundant, but its use has persisted and has come to embody negative connotations in the current landscape of the HIV epidemic. People commonly associate AIDS with a terminal illness. This misconception promotes stigma by others, including health-care workers, but also self-stigma, which can prevent individuals from accessing health care. Also, the link between AIDS and gay men generated during the early epidemic with use of the term gay-related immune disorder is misleading regarding which populations are at risk, which can delay diagnosis. The use of the term AIDS is now discouraged by several professional associations, some of which ironically have the word as part of their name. Ending use of the term AIDS would not eradicate stigma. However, this term has outlasted its usefulness, and we should transition towards more descriptive language that aligns with contemporary challenges in HIV.
Evaluation of factors associated with high advanced HIV disease and mortality in Southwestern China: a retrospective cohort study, 2005–2020
2024, Public Health
To assess the prevalence, all-cause mortality and determinants of advanced HIV disease (AHD) or severe immunosuppression (SIS) in the rural–urban communities of Southwestern China.
Retrospective cohort study.
Data on HIV/AIDS cases reported in 2005–20 were collected from Case Report System. A binary logistic regression model assessed the risk factors of AHD/SIS prevalence. Survival curves across rural–urban regions were compared using Kaplan–Meier estimates and log-rank tests. Determinants of all-cause mortality were identified using the Cox proportional hazard model.
Among 14,533 newly diagnosed HIV/AIDS patients, 7497 (51.6%) presented with AHD and 2564 (17.6%) with SIS. Compared with urban patients, rural patients had a higher prevalence of AHD (56.7% vs 40.7%) and SIS (20.1% vs 12.4%), all-cause mortality (AHD 12.3 vs 5.6, SIS 16.3 vs 5.5, per 100 person-years). Their 5-year survival probability (AHD 59.5% vs 77.1%; SIS 54.4% vs 76.3%) and mean survival time (AHD 106.5 vs 140.6 months, SIS 95.3 vs 144.2 months, p < 0.0001) were lower. Rural patients had an increased risk of SIS prevalence (adjusted odds ratios 1.45, 95% confidence interval [CI] 1.28–1.64; p < 0.0001) and mortality of the total cohort (adjusted hazard ratios 1.41, 95% CI 1.29–1.55; p < 0.0001), AHD cohort (1.38, 1.24–1.54; p < 0.0001), and SIS cohort (1.49, 1.23–1.81; p < 0.0001).
A high prevalence of AHD/SIS was a severe phenomenon that caused high mortality in rural areas. A regional point-of-care strategy targeting AHD/SIS detection and management is essential for reducing the mortality risk.
Management of advanced HIV disease in Africa
2023, The Lancet HIV
Vertical HIV transmission within 18 months post partum among women on lifelong antiretroviral therapy for HIV in Dar es Salaam, Tanzania: a prospective cohort study
2023, The Lancet HIV
Citation Excerpt :
Enrolling on a care programme late in pregnancy might also be a proxy of other risk factors for vertical transmission, such as poor awareness and low social support, and incident HIV infection among women who tested negative for HIV in early pregnancy.24 The twice as high rate observed among women with advanced HIV disease might be attributed to a compromised immune response, the presence of drug-resistant mutations, and poor adherence to ART, predisposing individuals to an increased viral load and subsequent vertical transmission.25,26 Similarly, the higher rate of transmission among women on second-line ART regimens (ie, protease inhibitors) than among those on first-line ART (ie, NNRTI) could indicate persistence of poor adherence to ART, multiple drug-resistant mutations, and high viraemia in these women, who have a history of treatment failure on first-line ART.27,28
The UNAIDS estimate of vertical HIV transmission in Tanzania is high (11%), despite 84% uptake of antiretroviral therapy (ART) among pregnant women with HIV. We aimed to evaluate vertical transmission and its determinants by 18 months post partum among women on lifelong ART in routine health-care settings in Tanzania.
We conducted a prospective cohort study in 226 health facitilies across Dar-es-Salaam, Tanzania. Eligible participants were pregnant women of any age with HIV, and later their infants, who enrolled in routine health-care services for the prevention of vertical transmission. We prospectively followed up mother–infant pairs at routine monthly visits until 18 months post partum and extracted data from the care and treatment clinic (CTC2) database, a national electronic database that stores patient-level HIV care and treatment clinic data. The primary outcome was time from birth to HIV diagnosis, defined as a positive infant HIV DNA PCR or antibody test from age 18 months. We used the Kaplan-Meier method to estimate cumulative risk of vertical transmission by 18 months post partum and Cox proportional hazards regression with shared frailties to account for potential clustering in health facilities to evaluate predictors of transmission.
Between Jan 1, 2015, and Dec 31, 2017, 22 930 pregnant women with HIV (median age 30 years, IQR 25–34) enrolled on a care programme. After excluding 9140 (39·9%) women and 539 (2·4%) infants with missing outcome data, 13 251 (59·0%) mother–infant pairs were analysed, of whom 6072 (45·8%) women were already on ART before pregnancy. By 18 months post partum, 159 (1·2%) of 13 251 infants were diagnosed with HIV, equivalent to a risk of vertical transmission of 1·4% (95% CI 1·2–1·6). In the complete case analysis, the rates of vertical transmission were higher among women who enrolled in the third trimester of pregnancy than among those who enrolled in the first trimester (adjusted hazard ratio 3·01, 95% CI 1·59–5·70; p=0·0003), among women with advanced HIV disease than among those with early-stage disease (1·89, 1·22–2·93; p=0·0046), and among women who were on a second-line ART regimen than among those on a first-line regimen (3·58, 1·08–11·82; p=0·037). By contrast, the rate of vertical transmission was lower among women who were already on ART at enrolment than among those starting ART at enrolment (0·39, 0·25–0·60; p<0·0001) as well as among women in high-volume clinics than among those in low-volume clinics (0·46 (0·24–0·90; p<0·0097).
Provision of ART for life (WHO's option B+ recommendation) has reduced the risk of vertical transmission to less than 2% among pregnant women with HIV in routine care settings in urban Tanzania. There is still a need to improve timely HIV diagnosis and ART uptake, and to optimise follow-up for the prevention of vertical transmission and the uptake of infant HIV testing.
Swedish International Development Cooperation Agency.
Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4<sup>+</sup> T lymphocytes in HIV-infected immune non-responders
2022, eBioMedicine
Citation Excerpt :
However, none of these independent factors can fully be explained.3–7 Conversion or intense ART regimens in INRs have no effect on CD4 cell counts, and the latter are more vulnerable to AIDS-related and non-AIDS-related illness and death.8,9 Thymic output is a pivotal process in immune reconstitution and can be inferred by assessing T cell receptor excision circles (TREC) and naive CD4 cells expressing CD31+, which are termed recent thymic emigrants (RTE).10
HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4⁺ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). The mechanism of unrecoverable CD4 cells in INRs and whether ferroptosis plays a role are not fully understood.
Ninety-two people living with HIV (PLHIVs) who experienced four-year ART with sustained viral suppression, including 27 INRs, 34 partial responders (PRs), and 31 complete responders (CRs); and 26 uninfected control participants (UCs) were analysed for 16 immune parameters with flow cytometry. Then plasma lipid, iron and oxidation, and antioxidant indicators were detected by ELISA, and CD4 cells were sorted out and visualised under transmission electron microscopy. Finally, ferroptosis inhibitors were added, and alterations in CD4 cell phenotype and function were observed.
We found decreased recent thymic emigrants (RTE), over-activation and over-proliferation phenotypes, diminished killing function, decreased IL-7R and more severe inflammation; increased lipid peroxidation in the mitochondria and disruptions of the mitochondrial structure, showing typical features of ferroptosis in CD4 cells in INRs. Additionally, ferroptosis inhibitors could reduce inflammation and repair mitochondrial damage. Meanwhile, ELISA results showed increased plasma free fatty acids (FFA) and an imbalance of oxidative and antioxidant systems in INRs. Flow cytometry results displayed alterations of both transferrin receptor (CD71) and lipid transporter (CD36) expressions on the surface of CD4 cells. Mechanistically, there was a stronger correlation between CD36 expression and mitochondrial lipid peroxidation production, ferroptosis makers, and inflammation indicators; while amino acid transporter (CD98) was more related to killing functions; and CD71 was more closely related to activation status in CD4 cells.
Cellular metabolism was closely correlated with its diverse functions in INRs. Ferroptosis was observed in CD4 cells of INRs, and inhibiting ferroptosis through modulating mitochondrial disorders and inflammation may offer an alternative immunological strategy for reinvigorating CD4 cells in INRs.
This research was supported by the 13th Five-year Plan, Ministry of Science and Technology of China (2018ZX10302-102), Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20191802), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202126).

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ReviewAdvanced HIV: diagnosis, treatment, and prevention

Summary

Introduction

Section snippets

Scope of the problem

Implications of advanced HIV

Diagnosis

Tuberculosis

ART regimens for advanced HIV

Principles of ART initiation

Prevention of advanced HIV

Conclusion

Search strategy and selection criteria

Pulmonology

Lancet

Lancet

Lancet

Lancet

Lancet HIV

Lancet Infect Dis

Lancet HIV

Lancet HIV

Lancet HIV

Lancet HIV

Lancet HIV

Lancet HIV

Miles to go—closing gaps, breaking barriers, righting injustices. Geneva: Joint United Nations Programme on HIV/AIDS

Global trends in CD4 cell count at the start of antiretroviral therapy: collaborative study of treatment programs

Clin Infect Dis

Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy

Interim WHO clinical staging of HIV/ AIDS and HIV/AIDS case definitions for surveillance

Late presentation of HIV infection: a consensus definition

HIV Med

Persistent high burden of advanced HIV disease among patients seeking care in South Africa's national HIV program: data from a nationwide laboratory cohort

Clin Infect Dis

Factors associated with presenting late or with advanced HIV disease in the Netherlands, 1996–2014: results from a national observational cohort

BMJ Open

Advanced HIV disease at enrolment in HIV care: trends and associated factors over a ten year period in Cambodia

PLoS One

The risk of late or advanced presentation of HIV infected patients is still high, associated factors evolve but impact on overall mortality is vanishing over calendar years: results from the Italian MASTER cohort

BMC Public Health

The high incidence of late presenters for HIV/AIDS infection in the Lodz province, Poland in the years 2009–2016: we are still far from the UNAIDS 90% target

AIDS Care

Late presentation for human immunodeficiency virus HIV diagnosis: results of a Belgian single centre

Acta Clin Belg

Factors associated with initiation of antiretroviral therapy in the advanced stages of HIV infection in six Ethiopian HIV clinics, 2012 to 2013

J Int AIDS Soc

Advanced HIV disease at entry into HIV care and initiation of antiretroviral therapy during 2006–2011: findings from four sub-saharan African countries

Clin Infect Dis

High prevalence and excess mortality of late presenters among HIV-1, HIV-2 and HIV-1/2 dually infected patients in Guinea-Bissau—a cohort study from West Africa

Pan Afr Med J

Missed opportunities for earlier diagnosis of HIV in patients who presented with advanced HIV disease: a retrospective cohort study

BMJ Open

High proportions of patients with advanced HIV are antiretroviral therapy experienced: hospitalization outcomes from 2 sub-Saharan African sites

Clin Infect Dis

Risk factors for early mortality on antiretroviral therapy in advanced

AIDS

Patient retention, clinical outcomes and attrition-associated factors of HIV-infected patients enrolled in Zimbabwe's national antiretroviral therapy programme, 2007–2010

PLoS One

Retention in HIV care and predictors of attrition from care among HIV-infected adults receiving combination anti-retroviral therapy in Addis Ababa

PLoS One

Patient retention in antiretroviral therapy programs up to three years on treatment in sub-Saharan Africa, 2007–2009: systematic review

Trop Med Int Health

Retention in care and patient-reported reasons for undocumented transfer or stopping care among HIV-infected patients on antiretroviral therapy in eastern Africa: application of a sampling-based approach

Clin Infect Dis

Antiretroviral therapy for the prevention of HIV-1 transmission

N Engl J Med

Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy

JAMA

Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa

Clin Infect Dis

Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count ≤100 cells/μL who start HIV therapy in resource-limited settings

Clin Infect Dis

Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda

Trop Med Int Health

Prevalence of cryptococcal antigenemia and cost-effectiveness of a cryptococcal antigen screening program—Vietnam

PLoS One

Asymptomatic cryptococcal antigenemia is associated with mortality among

J Int AIDS Soc

Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa

Review
Advanced HIV: diagnosis, treatment, and prevention