Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

Management of People With HIV and Antiretroviral Therapy Experience

Suboptimal CD4 Cell Recovery Despite Viral Suppression

Introduction

Most people with HIV who achieve and maintain antiretroviral therapy (ART)–mediated viral suppression experience increases in peripheral blood CD4 T lymphocyte (CD4) cell counts over time^1-4 and recovery of CD4 counts to within the normal range (>500 cells/mm³) of people without HIV.^5-7 However, some people who started ART at low CD4 counts do not experience recovery to the desired immunologic goal of >500 cells/mm³ despite sustained virologic suppression on ART.^2,3,8 Promptly initiating ART in people diagnosed early with HIV provides the best opportunity for maximal CD4 cell recovery.^9,10 

There is no clear consensus on terminology to use or thresholds that define “suboptimal CD4 cell recovery.”^11,12 A common threshold used for “suboptimal CD4 cell recovery” is CD4 ≤500 cells/mm³ after several years of suppressive ART. The term “immunologic nonresponse” also has been used to describe a lack of CD4 cell recovery, with common thresholds of <200 cells/mm³ or <350 cells/mm³ after several years of suppressive ART.¹² Some experts consider an increase of <200 cells/mm³ above baseline after 24 months as an inadequate immunologic response for people with CD4 counts ≤500 cells/mm³. The relationship between improved clinical outcomes and higher CD4 counts likely spans all ranges of CD4 counts, although incremental benefits are harder to discern once CD4 counts reach moderate-to-high levels,¹³ especially beyond 500 cells/mm³. Rarely, people with HIV may experience substantial declines in CD4 counts while maintaining virologic suppression on ART.¹⁴

Clinical Consequences

Persistently low CD4 counts despite ART-mediated viral suppression are associated with increased risk of morbidity, hospitalizations, and mortality. Data from two large international cohorts of people with HIV initiating ART as early as 1996 showed that individuals with HIV and CD4 counts ≤200 cells/mm³ despite at least 3 years of suppressive ART had a 2.6-fold greater risk of mortality than those with higher CD4 counts.¹⁵ A multicenter cohort study from Spain of individuals who started ART with low CD4 counts between 2005 and 2019 found that those whose CD4 counts remained <200 cells/mm³ after 2 years of ART had a 4.6-fold greater risk of mortality than those with CD4 >500 cells/mm³.¹⁶

People with CD4 counts <200 cells/mm³ despite at least 1 year of suppressive ART are at increased risk of AIDS-related and non–AIDS-related events.^17-23 This population is at risk of severe infections (e.g., pneumonia) and is less likely to mount a robust immune response following vaccination.²⁴ In addition, these individuals have an increased risk of infection-related cancers (e.g., Epstein-Barr virus-associated lymphoma, human papillomavirus–associated malignancies, hepatocellular carcinoma associated with hepatitis B virus [HBV] or hepatitis C virus [HCV]). A cohort study of people with HIV from 1996 to 2020 demonstrated that people with CD4 <200 cells/mm³ had a 3.5-fold higher risk of infection-related cancers compared to people with CD4 ≥500 cells/mm³.²⁵ Another study found that CD4 count <350 cells/mm³ was associated with non–AIDS-defining, smoking-related, and other malignancies.²⁶ People with HIV who receive chemotherapy or radiation therapy can also experience CD4 count decline. One study reported a 27% increase in mortality for every 100 cells/mm³ decrease in CD4 count.²⁷ Lastly, cardiovascular disease and other comorbidities have also been observed at increased rates in people with low CD4 recovery.^15,28-35

Pathogenesis

Suboptimal CD4 recovery after ART-mediated virologic suppression is typically associated with higher levels of inflammation and immune activation³⁶ and is most frequently observed in people with older age, prior AIDS-defining illness, lower nadir CD4 count,^16,37 and some coinfections (e.g., HCV).^38-40 The association of higher inflammation levels with persistently low CD4 counts is likely multifactorial and, to some extent, may be driven by inadequate immunologic control of other chronic viral infections, based on observed decreases in inflammation after treatment of cytomegalovirus and chronic HCV infection.^41,42 Numerous factors have deleterious effects on T-cell survival and proliferation, such as chronic coinfections, a persistently activated innate immune system (due to stimuli such as microbial translocation and dysbiosis), more severe fibrosis of lymph node tissue with disruption of naive T-cell homeostasis, potential senescence of hematopoietic progenitors, and possibly autoantibodies.^43-46

CD4 count may occasionally decline despite suppressive ART, which may be due to a new medication, a new underlying malignancy, infection, or autoimmune disorder, including the presence of anti-CD4 autoantibodies,^44,45 and/or dysregulation of interleukin-7 (IL-7)–mediated naive T-cell homeostasis or more accentuated immune senescence.^14,47,48

Alternative Causes of Suboptimal CD4 Cell Recovery

Evaluation of people with suboptimal CD4 cell recovery should begin with identifying modifiable causes, such as concomitant medications that reduce total white blood cells, particularly lymphocytes and CD4 cells. When possible, these drugs should be discontinued and replaced with alternatives if necessary. Untreated coinfections (e.g., HCV, Mycobacterium avium complex, histoplasmosis) and serious medical conditions (e.g., malignancy, autoimmune disease) may also contribute to CD4 lymphopenia, particularly in people with declining CD4 counts (and percentages) while on suppressive ART and in those with CD4 consistently <100 cells/mm³. Treating coinfections and optimizing management of contributing conditions should be pursued when feasible.

Interventions Tested to Improve CD4 Cell Recovery

For people with suboptimal CD4 cell recovery despite suppressive ART, effective interventions to increase CD4 counts and improve clinical outcomes have not been identified.⁴⁹ Strategies to raise CD4 counts by modifying or intensifying ART regimens have been evaluated in clinical trials. Intensification strategy by adding ARV drugs to a suppressive ART regimen does not improve CD4 cell recovery^50-56 and does not reduce morbidity or mortality. Therefore, ART intensification is not recommended as a strategy to improve CD4 cell recovery (AI). Similarly, switching ARV drugs or classes has not been shown to improve CD4 cell recovery substantially for individuals with viral suppression and is not recommended (AII).^57,58

Therapies targeting immunomodulatory pathways (e.g., interleukin-2 [IL-2], IL-7, growth hormone, thymosin alpha-1) have also been investigated as a strategy to increase CD4 counts.⁵⁹ Two large randomized trials, powered to assess impact on clinical endpoints (AIDS and death), evaluated the role of IL-2 for improving CD4 cell recovery. Although there is strong evidence linking low CD4 cell counts with increased morbidity, IL-2 adjunctive therapy did not decrease the risk of clinical events despite substantial increases in CD4 count.⁶⁰ Therefore, IL-2 is not recommended as a strategy to improve CD4 recovery (AI). Dysregulation in IL-7–mediated naive T-cell homeostasis has been reported among people with suboptimal CD4 recovery.^14,47,48 While several early-phase trials of human recombinant IL-7 treatment have shown an increase in CD4 counts among people with HIV on ART, no clinical trials designed to evaluate whether IL-7 treatment confers benefit on clinical outcomes have been performed.⁶¹

Additional interventions have been studied in early-phase trials, and some have demonstrated improvements in CD4 counts among people with HIV on ART with suboptimal CD4 cell recovery. These studies were not designed to evaluate clinical endpoints. Examples include the use of novel antivirals,⁶² repurposed medications,^63,64 probiotics,^65,66 plants and herbal treatments with medicinal properties,^67-69 and other nutritional supplements,⁷⁰ as well as human umbilical cord mesenchymal stem cell infusions^71,72 or allogenic natural killer cell immunotherapy.⁷³ As demonstrated by the IL-2 clinical trial results, randomized trials with clinical endpoints will be needed to establish clinical benefit. Because of the lack of clinical efficacy data from these alternative interventions, the use of adjunct therapies to improve immune recovery is not recommended, except in the context of a clinical trial (AII).

Prevention of Clinical Consequences

With continuous ART and viral suppression, life expectancy for people with HIV is approaching that of people without HIV. However, persistently low CD4 counts despite ART-mediated viral suppression are associated with higher rates of both AIDS and non–AIDS-related morbidity and mortality over the long term. Reducing AIDS- and non–AIDS-related morbidity and mortality remains a cornerstone of HIV treatment and is especially important for people with suboptimal CD4 recovery, given the increased risk of such outcomes. Risk for opportunistic infections (OIs) is generally low for people on ART with viral suppression, but some primary or secondary prophylaxis may need to be extended for certain OIs among people who do not experience CD4 recovery above certain thresholds (see the Adult OI Guidelines for specific guidance).

Given the increased risk for severe manifestations and/or poor outcomes from infections such as tuberculosis, HBV, and HCV, guidelines for screening for such infections should be followed closely, and treatments should be initiated promptly when indicated. Clinicians should also be vigilant about ensuring that people with HIV are up to date on vaccinations for preventable infections. It should be noted that live virus vaccines are contraindicated for people with CD4 counts <200 cells/mm³ (see Immunizations for Preventable Diseases in Adults and Adolescents With HIV in the Adult OI Guidelines for detailed recommendations).

For non-AIDS-related morbidities, providers should offer preventive counseling, evaluate and manage cardiovascular risk factors (see Cardiovascular Complications), ensure that screening for malignancies (e.g., colorectal cancer, anal or cervical cancer, hepatocellular carcinoma, lung cancer, breast cancer) is up to date (see Primary Care Guidance), initiate statin therapy when indicated (see Statin Therapy in People With HIV), and provide prompt care and referrals when appropriate.⁷⁴ As for all people with HIV, regardless of CD4 count, preventive counseling should address lifestyle modifiable risk factors, including but not limited to smoking cessation, abstinence from alcohol and substance use, dietary modification, regular exercise, and treatment optimization for comorbidities such as hypertension and diabetes. 

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