When to Initiate Antiretroviral Therapy in HIV and Aging (Updated 6/5/17)

For older HIV-infected patients, antiretroviral therapy is recommended for all, regardless of CD4 cell count.

  • Antiretroviral therapy is extremely important for older HIV-infected patients as these individuals have a greater risk of developing serious non-AIDS complications.
  • Antiretroviral therapy should be initiated as early as possible in older patients due to the frequent blunted immune response and relatively poor CD4 cell increases in response to antiretroviral therapy.
  • Clinicians should not withhold therapy in older patients due to concerns for poor virologic responses to therapy as available data suggest older patients have high virologic response rates.
  • Older patients on antiretroviral therapy should receive close monitoring for adverse drug effects related to antiretroviral therapy.

Multiple cohort studies involving untreated HIV-infected persons have established that older persons have a more rapid progression to AIDS and shortened survival when compared with younger persons [1-4]. For HIV-infected persons older than 50, limited data exist from randomized, controlled antiretroviral therapy clinical trials, as most randomized therapy trials have excluded persons older than 50 or 60. A retrospective analysis of 253 patients 50 years of age or older found antiretroviral therapy substantially improved survival rates [5]. Several large retrospective studies have clearly shown delayed and diminished CD4 cell recovery after starting antiretroviral therapy in older HIV-infected patients when compared with younger age groups[6-9]. Studies have shown conflicting results with respect to virologic responses in older versus younger [10-13], with the most comprehensive study showing high virologic response rates [14] and no significant difference in virologic responses based in older versus younger adults [8] .

The major antiretroviral therapy guidelines that most influences clinical practice in the United States—the Department of Health and Human Services (DHHS) Panel guidelines [15]—recommends initiating antiretroviral therapy in all persons infected with HIV.  The recommendation to use antiretroviral therapy in all HIV-infected persons is based on reducing the risk of disease progression and decreasing the risk of HIV transmission. Data from several large cohort studies have strongly suggested a survival advantage with initiation of antiretroviral therapy earlier in the course of HIV disease [16, 17]. In addition, growing evidence suggests that uncontrolled HIV infection produces a “chronic inflammatory state” associated with an increased risk of developing cardiovascular disease [18] and non-AIDS malignancies  [19], and CD4 counts below 500 are associated with higher cardiovascular risk [20], and risk for non-AIDS malignancies [21]. Further, in a large cohort study, investigators reported 10-year mortality in persons 45 to 65 years of age was lower when antiretroviral therapy was initiated at a CD4 threshold of 500 cells/mm3 than delaying to a threshold of 350 cells/mm3  [22].  The rationale for recommending antiretroviral therapy for the prevention of HIV transmission is based on several recent studies, most notably the landmark HPTN 052 trial that showed a greater than 95% reduction in HIV transmission in HIV serodiscordant couples when the HIV-infected partner received antiretroviral therapy [23].

The January 2016 DHHS Antiretroviral Therapy guidelines specifically addressed the use of antiretroviral therapy for persons 50 and older, recommending initiating antiretroviral therapy in all persons older than 50 years of age regardless of CD4 cell count, primarily because, when compared with younger patients, these older HIV-infected individuals have increased risk for non-AIDS related complications and they have diminished CD4 cell count recovery in response to antiretroviral therapy [15].  Further, the DHHS guidelines emphasized that older individuals potentially have increased risk for HIV transmission or acquisition, for several reasons, including (1) alterations reduced mucosal and immunologic defenses may occur with post-menopausal atrophic vaginitis, (2) older individuals have less incentive to use of condoms given the lack of need for pregnancy prevention, and (3) persons older than 50 have lower frequency of HIV screening given their perceived low risk for HIV infection  [24].

The use of antiretroviral therapy in older HIV-infected patients presents several challenges, predominantly due to the increased prevalence of non-HIV-related comorbid medical conditions, such as hyperlipidemia, hypertension, diabetes, and coronary artery disease [25]. In addition, older patients may have age- related changes in body composition that can alter medication volume of distribution and influence drug pharmacokinetics. Compared with younger patients, older patients are more likely to be taking multiple medications not related to HIV and thus increasing the likelihood for drug-drug interactions. Further, several studies have shown older HIV- infected patients have increased risk for developing drug-related toxicity, including hyperglycemia, elevated creatinine, and unfavorable alterations in lipid profile [7].

Updated by David Spach, MD

1-20-17

References

  1. Balslev U, Monforte AD, Stergiou G, Antunes F, Mulcahy F, Pehrson PO, et al. Influence of age on rates of new AIDS-defining diseases and survival in 6546 AIDS patients. Scandinavian journal of infectious diseases 1997; 29(4):337-343.
  2. Phillips AN, Carr A, Neuhaus J, Visnegarwala F, Prineas R, Burman WJ, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther 2008; 13(2):177-187.
  3. Rezza G. Determinants of progression to AIDS in HIV-infected individuals: an update from the Italian Seroconversion Study. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17 Suppl 1:S13-16.
  4. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360(9327):119-129.
  5. Perez JL, Moore RD. Greater effect of highly active antiretroviral therapy on survival in people aged > or =50 years compared with younger people in an urban observational cohort. Clin Infect Dis 2003; 36(2):212-218.
  6. Khanna N, Opravil M, Furrer H, Cavassini M, Vernazza P, Bernasconi E, et al. CD4+ T cell count recovery in HIV type 1-infected patients is independent of class of antiretroviral therapy. Clin Infect Dis 2008; 47(8):1093-1101.
  7. Silverberg MJ, Leyden W, Horberg MA, DeLorenze GN, Klein D, Quesenberry CP. Older age and the response to and tolerability of antiretroviral therapy. Archives of internal medicine 2007; 167(7):684-691.
  8. Althoff KN, Gebo KA, Gange SJ, Klein MB, Brooks JT, Hogg RS, et al. CD4 count at presentation for HIV care in the United States and Canada: are those over 50 years more likely to have a delayed presentation? AIDS Res Ther 2010; 7:45.
  9. Sabin CA, Smith CJ, Monforte AD, Battegay M, Gabiano C, Galli L, et al. Response to combination antiretroviral therapy: variation by age – The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group.
  10. Silverberg MJ, Lau B, Justice AC, Engels E, Gill MJ, Goedert JJ, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis 2012; 54(7):1026-1034.
  11. Paredes R, Mocroft A, Kirk O, Lazzarin A, Barton SE, van Lunzen J, et al. Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: results from the EuroSIDA study. Archives of internal medicine 2000; 160(8):1123-1132.
  12. Manfredi R, Calza L, Cocchi D, Chiodo F. Antiretroviral treatment and advanced age: epidemiologic, laboratory, and clinical features in the elderly. Journal of acquired immune deficiency syndromes (1999) 2003; 33(1):112-114.
  13. Lampe FC, Gatell JM, Staszewski S, Johnson MA, Pradier C, Gill MJ, et al. Changes over time in risk of initial virological failure of combination antiretroviral therapy: a multicohort analysis, 1996 to 2002. Arch Intern Med 2006; 166(5):521-528.
  14. Horberg MA, Hurley LB, Klein DB, Towner WJ, Kadlecik P, Antoniskis D, et al. The HIV Care Cascade Measured Over Time and by Age, Sex, and Race in a Large National Integrated Care System. AIDS Patient Care STDS 2015; 29(11):582-590.
  15. Services DHS. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Considerations for Antiretroviral Use in Special Patient Populations—HIV and the Older Patient. Department of Health and Human Services. January 26, 2016. AIDSInfo. AIDSInfo 2016.
  16. Kitahata, M. Effect of early versus deferred antiretroviral therapy for HIV on survival. The New England journal of medicine 2009; 360(18):1815–1826.
  17. Sterne JAC, May M, Costagliola D, de Wolf F, Phillips AN, Harris R, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009; 373(9672):1352-1363.
  18. Phillips AN, Lee CA, Elford J, Webster A, Janossy G, Timms A, et al. More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts. J Acquir Immune Defic Syndr 1991; 4(10):970-975.
  19. Bruyand M, Thiebaut R, Lawson-Ayayi S, Joly P, Sasco AJ, Mercie P, et al. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis 2009; 49(7):1109-1116.
  20. Lichtenstein KA, Armon C, Buchacz K, Chmiel JS, Buckner K, Tedaldi EM, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. Clin Infect Dis 2010; 51(4):435-447.
  21. Guiguet M, Boué F, Cadranel J, Lang J-M, Rosenthal E, Costagliola D. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. The lancet oncology 2009; 10(12):1152-1159.
  22. Edwards JK, Cole SR, Westreich D, Mugavero MJ, Eron JJ, Moore RD, et al. Age at Entry Into Care, Timing of Antiretroviral Therapy Initiation, and 10-Year Mortality Among HIV-Seropositive Adults in the United States. Clin Infect Dis 2015; 61(7):1189-1195.
  23. Cohen M, et al. Prevention of HIV-1 Infection with Early Antiretroviral Therapy. NEW ENGL J MED 2011; (365):493-505.
  24. Adekeye OA, Heiman HJ, Onyeabor OS, Hyacinth HI. The new invincibles: HIV screening among older adults in the U.S. PLoS One 2012; 7(8):e43618.
  25. Skiest D. et al. The importance of comorbidity in HIV-infected patients over 55: a retrospective case-control study. The American journal of medicine 1996; 101(6):605–611.
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