Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV
Management of the Treatment-Experienced Patient
Poor CD4 Cell Recovery and Persistent Inflammation Despite Viral Suppression
Last Updated: April 8, 2015; Last Reviewed: April 8, 2015
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
Despite marked improvements in antiretroviral treatment (ART), morbidity and mortality in individuals with HIV continues to be greater than in the general population, particularly when ART is delayed until advanced disease stages. These morbidities include cardiovascular disease, many non-AIDS cancers, non-AIDS infections, chronic obstructive pulmonary disease, osteoporosis, type II diabetes, thromboembolic disease, liver disease, renal disease, neurocognitive dysfunction, and frailty.1 Although health-related behaviors and toxicities of antiretroviral (ARV) drugs may also contribute to the increased risk of illness and death, poor CD4 T lymphocyte (CD4) cell recovery, persistent immune activation, and inflammation likely also contribute to the risk.
Poor CD4 Cell Recovery
As long as ART-mediated viral suppression is maintained, peripheral blood CD4 cell counts in most individuals with HIV will continue to increase for at least a decade. The rate of CD4 cell recovery is typically most rapid in the first 3 months of suppressive ART, followed by more gradual increases over time.2-4 If ART-mediated viral suppression is maintained, most individuals will eventually recover CD4 counts in the normal range (>500 cells/mm3); however, approximately 15% to 20% of individuals who initiate ART at very low CD4 counts (<200 cells/mm3) may plateau at abnormally low CD4 cell counts.3-5 Early initiation of ART in individuals with recent HIV diagnoses likely provides the best opportunity for maximal CD4 cell recovery.6
Persistently low CD4 cell counts despite ART-mediated viral suppression are associated with increased risk of morbidity and mortality. For example, individuals with HIV who have 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 cell counts.7 Lower CD4 cell counts during ART-mediated viral suppression are associated with an increased risk of non-AIDS morbidity and mortality,8-11 including cardiovascular disease,12 osteoporosis and fractures,13 liver disease,14 and infection-related cancers.15 The prognostic importance of higher CD4 cell counts likely spans all ranges of CD4 cell counts, though incremental benefits are harder to discern once CD4 counts increase to >500 cells/mm3.16
Individuals with poor CD4 cell recovery should be evaluated for modifiable causes of CD4 cell lymphopenia. Concomitant medications should be reviewed, with a focus on those known to decrease white blood cells or, specifically, CD4 cells (e.g., cancer chemotherapy, interferon, zidovudine,17 or the combination of tenofovir disoproxil fumarate [TDF] and didanosine [ddI]).18,19 If possible, these drugs should be substituted for or discontinued. Untreated coinfections (e.g., HCV, HIV-2) and serious medical conditions (e.g., malignancy) should also be considered as possible causes of CD4 lymphopenia, particularly in individuals with consistently declining CD4 cell counts (and percentages) and/or in those with CD4 counts consistently below 100 cells/mm3. In many cases, no obvious cause for suboptimal immunologic response can be identified.
Despite strong evidence linking low CD4 cell counts and increased morbidity during ART-mediated viral suppression, no adjunctive therapies that increase CD4 cell count beyond levels achievable with ART alone have been proven to decrease morbidity or mortality. Adding ARV drugs to an already suppressive ART regimen does not improve CD4 cell recovery,20-25 and does not reduce morbidity or mortality. Therefore, ART intensification is not recommended as a strategy to improve CD4 cell recovery (AI). In individuals maintaining viral suppression, switching ARV drug classes in a suppressive regimen also does not consistently improve CD4 cell recovery and is not recommended (BIII).26 Two large clinical trials, powered to assess impact on clinical endpoints (AIDS and death), evaluated the role of interleukin-2, an immune-based therapy, in improving CD4 cell recovery. Interleukin-2 adjunctive therapy resulted in CD4 cell count increases but with no observable clinical benefit. Therefore, interleukin-2 is not recommended (AI).27 Other immune-based therapies that increase CD4 cell counts (e.g., growth hormone, interleukin-7) are under investigation. However, none of the therapies have been evaluated in clinical endpoint trials; therefore, whether any of these approaches will offer clinical benefit is unclear. Currently, such immune-based therapies should not be used except in the context of a clinical trial.
Persistent Immune Activation and Inflammation
Although poor CD4 cell recovery likely contributes to morbidity and mortality during ART-mediated viral suppression, there is increasing focus on persistent immune activation and inflammation as potentially independent mediators of risk. HIV infection results in heightened systemic immune activation and inflammation, effects that are evident during acute infection, persist throughout chronic untreated infection, and predict more rapid CD4 cell decline and progression to AIDS and death, independent of plasma HIV RNA levels.28 Although immune activation declines with suppressive ART, it often persists at abnormal levels in many individuals with HIV maintaining long-term ART-mediated viral suppression—even in those with CD4 cell recovery to normal levels.29,30 Immune activation and inflammatory markers (e.g., IL-6, D-dimer, hs-CRP) also predict mortality and non-AIDS morbidity during ART-mediated viral suppression, including cardiovascular and thromboembolic events, cancer, neurocognitive dysfunction, and frailty.28 Although individuals with poor CD4 cell recovery (i.e., counts persistently <350 cells/mm3) tend to have greater immune activation and inflammation than those with greater recovery,29 the relationship between innate immune activation and inflammation and morbidity/mortality is largely independent of CD4 cell count.31,32 Even in individuals with CD4 counts >500 cells/mm3, there is evidence that immune activation and inflammation contribute to morbidity and mortality.33 Thus, innate immune activation and inflammation are potentially important targets for future interventions.
Although the drivers of persistent immune activation during ART are not completely understood, HIV persistence, coinfections, and microbial translocation likely play important roles.28 Interventions to reduce each of these presumed drivers are currently being investigated. Importantly, adding ARV drugs to an already suppressive ART regimen (ART intensification) does not consistently improve immune activation.20-23,25 Although some studies have suggested that switching an ART regimen to one with a more favorable lipid profile may improve some markers of immune activation and inflammation,34,35 these studies have limitations and results are not consistent across markers and among studies. Thus, at this time, ART modification cannot be recommended as a strategy to reduce immune activation (BIII). Other commonly used medications with anti-inflammatory properties (e.g., statins, aspirin) are being studied, and preliminary evidence suggests that some may reduce immune activation in treated HIV infection.36,37 However, because no intervention specifically targeting immune activation or inflammation has been studied in a clinical outcomes trial in treated HIV infection, no interventions to reduce immune activation are recommended at this time.
In the absence of proven interventions, there is currently no clear rationale to monitor levels of immune activation and inflammation in treated HIV infection. Furthermore, many of the inflammatory markers that predict morbidity and mortality fluctuate significantly in individuals with HIV. Thus, clinical monitoring with immune activation or inflammatory markers is not currently recommended (AII). The focus of care to reduce chronic non-AIDS morbidity and mortality should be on maintaining ART-mediated viral suppression and addressing strategies to reduce risk factors (e.g., smoking cessation, healthy diet, and exercise) and managing chronic comorbidities such as hypertension, hyperlipidemia, and diabetes (AII).
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- Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS. Jul 27 2001;15(11):1369-1377. Available at https://www.ncbi.nlm.nih.gov/pubmed/11504958.
- Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. Mar 15 2009;48(6):787-794. Available at http://www.ncbi.nlm.nih.gov/pubmed/19193107.
- Lok JJ, Bosch RJ, Benson CA, et al. Long-term increase in CD4+ T-cell counts during combination antiretroviral therapy for HIV-1 infection. AIDS. Jul 31 2010;24(12):1867-1876. Available at http://www.ncbi.nlm.nih.gov/pubmed/20467286.
- Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. Feb 1 2007;44(3):441-446. Available at https://www.ncbi.nlm.nih.gov/pubmed/17205456.
- Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. Jan 17 2013;368(3):218-230. Available at http://www.ncbi.nlm.nih.gov/pubmed/23323898.
- Engsig FN, Zangerle R, Katsarou O, et al. Long-term mortality in HIV-positive individuals virally suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis. May 2014;58(9):1312-1321. Available at http://www.ncbi.nlm.nih.gov/pubmed/24457342.
- Lewden C, Bouteloup V, De Wit S, et al. All-cause mortality in treated HIV-infected adults with CD4 >=500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol. Apr 2012;41(2):433-445. Available at http://www.ncbi.nlm.nih.gov/pubmed/22493325.
- Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. Apr 23 2008;22(7):841-848. Available at https://www.ncbi.nlm.nih.gov/pubmed/18427202.
- Achhra AC, Amin J, Law MG, et al. Immunodeficiency and the risk of serious clinical endpoints in a well studied cohort of treated HIV-infected patients. AIDS. Jul 31 2010;24(12):1877-1886. Available at http://www.ncbi.nlm.nih.gov/pubmed/20588170.
- Smurzynski M, Wu K, Benson CA, Bosch RJ, Collier AC, Koletar SL. Relationship between CD4+ T-cell counts/HIV-1 RNA plasma viral load and AIDS-defining events among persons followed in the ACTG longitudinal linked randomized trials study. J Acquir Immune Defic Syndr. Sep 1 2010;55(1):117-127. Available at https://www.ncbi.nlm.nih.gov/pubmed/20622677.
- Lichtenstein KA, Armon C, Buchacz K, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. Clin Infect Dis. Aug 15 2010;51(4):435-447. Available at https://www.ncbi.nlm.nih.gov/pubmed/20597691.
- Yong MK, Elliott JH, Woolley IJ, Hoy JF. Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients. J Acquir Immune Defic Syndr. Jul 1 2011;57(3):205-210. Available at http://www.ncbi.nlm.nih.gov/pubmed/21522014.
- Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. Aug 14-28 2006;166(15):1632-1641. Available at https://www.ncbi.nlm.nih.gov/pubmed/16908797.
- Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. Oct 18 2008;22(16):2143-2153. Available at https://www.ncbi.nlm.nih.gov/pubmed/18832878.
- Young J, Psichogiou M, Meyer L, et al. CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. PLoS Med. 2012;9(3):e1001194. Available at http://www.ncbi.nlm.nih.gov/pubmed/22448150.
- Huttner AC, Kaufmann GR, Battegay M, Weber R, Opravil M. Treatment initiation with zidovudine-containing potent antiretroviral therapy impairs CD4 cell count recovery but not clinical efficacy. AIDS. May 11 2007;21(8):939-946. Available at https://www.ncbi.nlm.nih.gov/pubmed/17457087.
- Barrios A, Rendon A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS. Mar 24 2005;19(6):569-575. Available at https://www.ncbi.nlm.nih.gov/pubmed/15802975.
- Negredo E, Bonjoch A, Paredes R, Puig J, Clotet B. Compromised immunologic recovery in treatment-experienced patients with HIV infection receiving both tenofovir disoproxil fumarate and didanosine in the TORO studies. Clin Infect Dis. Sep 15 2005;41(6):901-905. Available at https://www.ncbi.nlm.nih.gov/pubmed/16107993.
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- Hatano H, Strain MC, Scherzer R, et al. Increase in 2-Long Terminal Repeat Circles and Decrease in D-dimer After Raltegravir Intensification in Patients With Treated HIV Infection: A Randomized, Placebo-Controlled Trial. J Infect Dis. Nov 2013;208(9):1436-1442. Available at http://www.ncbi.nlm.nih.gov/pubmed/23975885.
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- Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. Apr 2010;16(4):460-465. Available at https://www.ncbi.nlm.nih.gov/pubmed/20228817.
- Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. Jul 17 2010;24(11):1697-1707. Available at http://www.ncbi.nlm.nih.gov/pubmed/20467288.
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- Tenorio AR, Zheng Y, Bosch RJ, et al. Soluble Markers of Inflammation and Coagulation but Not T-Cell Activation Predict Non-AIDS-Defining Morbid Events During Suppressive Antiretroviral Treatment. J Infect Dis. May 1 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/24795473.
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- Lake JE, McComsey GA, Hulgan T, et al. Switch to raltegravir decreases soluble CD14 in virologically suppressed overweight women: the Women, Integrase and Fat Accumulation Trial. HIV Med. Aug 2014;15(7):431-441. Available at http://www.ncbi.nlm.nih.gov/pubmed/24506429.
- Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. Clin Infect Dis. Feb 2014;58(4):588-595. Available at http://www.ncbi.nlm.nih.gov/pubmed/24253250.
- O'Brien M, Montenont E, Hu L, et al. Aspirin attenuates platelet activation and immune activation in HIV-infected subjects on antiretroviral therapy: A Pilot Study. J Acquir Immune Defic Syndr. Feb 12 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23406976.