Current Treatment Options for HIV Elite Controllers: a Review

HIV Medicine (C Yoon, Section Editor)
  • 4 Downloads
Part of the following topical collections:
  1. Topical Collection on HIV Medicine

Abstract

Opinion statement

Initiating antiretroviral therapy (ART) in human immunodeficiency virus (HIV) elite controllers remains controversial, because current evidence does not definitively demonstrate that the benefits of ART outweigh risk in this patient population. However, it is the opinion of the authors that in developed countries, where first-line ART regimens have minimal toxicities, treatment of elite controllers should be strongly considered. Treatment of elite controllers has the potential to minimize the size of the HIV reservoir, which benefits elite controllers who choose to pursue future cure, dampen immune activation, diminish risk of transmission, and encourage linkage and engagement in care allowing HIV providers the opportunity to address HIV-associated non-AIDS conditions and other co-morbidities.

Purpose of review

This review aims to summarize literature relevant to the management of elite controllers for clinicians caring for patients living with HIV. Key topics include timing of antiretroviral therapy (ART) and ART in the unique populations of elite controllers with concomitant cardiovascular disease and hepatitis C co-infection, and undergoing immunosuppressive therapy for other co-morbidities.

Recent findings

The persistent HIV reservoir in elite controllers has two main implications. First, increased immune activation appears to adversely impact clinical outcomes in elite controllers, but the role of ART in addressing this effect remains unclear. Second, elite control duration can be limited, but certain factors may help to predict disease progression with implications on timing of ART.

Summary

Initiation of ART during elite control remains controversial, although there are multiple theoretical benefits. Elite controllers comprise a heterogeneous population of patients living with HIV, and optimal management involves weighing the risk and benefit of ART as well as monitoring of clinical consequences of increased immune activation.

Keywords

Elite controllers HIV Antiretroviral therapy Treatment options Cardiovascular disease Hepatitis C Immunosuppression 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Katherine Promer declares that she has no conflicts of interest.

Dr. Maile Y Karris has served as an advisory board memory for Gilead Sciences and receives research funding to the institution from Gilead Sciences.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373(9):795–807. This randomized clinical trial compared rates of serious adverse events in immediate ART initiation versus waiting for a decline in CD4+ T cell count to below 350.CrossRefGoogle Scholar
  2. 2.
    • TEMPRANO ANRS Study Group, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373(9):808–22. This randomized clinical trial compared rates of serious illness in immediate ART initiation versus waiting for a decline in CD4+ T cell count to below 500.CrossRefGoogle Scholar
  3. 3.
    Grinsztejn B, Hosseinipour MC, Ribaudo HJ, Swindells S, Eron J, Chen YQ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomized controlled trial. Lancet Infect Dis. 2014;14(4):281–90.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Grabar S, Selinger-Leneman H, Abgrall S. Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV. AIDS. 2009;23(9):1163–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Sajadi MM, Constantine N, Abgrall S, et al. Epidemiologic characteristics and natural history of HIV-1 natural viral suppressors. J Acquir Immune Defic Syndr. 2009;50(4):403–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    •• Crowell TA, Gebo KA, Blankson JN, HIV Research Network, et al. Hospitalization rates among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis. 2015;211(11):1692. This observational study found elite controllers experienced higher rates of hospitalization than medical controllers.–702.CrossRefPubMedGoogle Scholar
  7. 7.
    •• Leon A, Perez I, Ruiz-Mateos E, EC and Immune Pathogenesis Working group of the Spanish AIDS Research Network, et al. Rate and predictors of progression in elite and viremic HIV-1 controllers. AIDS. 2016;30(8):1209–20. This cohort study identifies risk factors to predict rates of disease progression in elite controllers.CrossRefPubMedGoogle Scholar
  8. 8.
    Olson AD, Meyer L, Prins M, Thiebaut R, Gurdasani D, Guiguet M, et al. An evaluation of HIV controller definitions within a large seroconverters cohort collaboration. PLoS One. 2014;9(1):e86719.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Okulicz JF, Marconi VC, Ladrum ML, et al. Clinical outcomes of elite controllers, viremic controllers and long term non-progressors in the US Department of Defense natural history study. J Infect Dis. 2009;200(11):1714–23.CrossRefPubMedGoogle Scholar
  10. 10.
    Lucero C, Torres B, Leon A, et al. Rate and predictors of non-AIDS events in a cohort of HIV-infected patients with a CD4 T cell count above 500 cells/mm(3). AIDS Res Hum Retrovir. 2013;29(8):1161–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    •• Crowell TA, Ganesan A, Berry SA, Infectious Disease Clinical Research Program (IDCRP) HIV Working Group, et al. Hospitalizations among HIV controllers and persons with medically controlled HIV in the U.S. Military HIV Natural History Study. J Int AIDS Soc. 2016;19(1):20524. This observational study found no significant difference in hospitalization rates between elite controllers and patients’ medical controllers.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gonzalo-Gil E, Ikediobi U, Sutton RE. Mechanisms of virologic control and clinical characteristics of HIV+ elite/viremic controllers. Yale J Biol Med. 2017;90:245–59.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Palacios JA, Perez-Pinar T, Toro C, Sanz-Minguela B, Moreno V, Valencia E, et al. Long-term nonprogressor and elite controller patients who control viremia have a higher percentage of methylation in their HIV-1 proviral promoters than aviremic patients receiving highly active antiretroviral therapy. J Virol. 2012;86(23):13081–4.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Malnati MS, Ugolotti E, Monti MC, Battista DD, Vanni I, Bordo D, et al. Activating killer immunoglobulin receptors and HLA-C: a successful combination providing HIV-1 control. Sci Rep. 2017;7:42470.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Freund NT, Wang H, Scharf L, et al. Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller. Sci Transl Med. 2017;9(373):eaal2144.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rosseau CM, Lockhart DW, Listgarten J, et al. Rare HLA drive additional HIV evolution compared to more frequent alleles. AIDS Res Hum Retrovir. 2009;25(3):297–303.CrossRefGoogle Scholar
  17. 17.
    Shasha D, Karel D, Angiuli O, et al. Elite controller CD8+ T cell exhibit comparable viral inhibition capacity, but better sustained effector properties compared to chronic progressors. J Leukoc Biol. 2016;100(6):1425–33.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ferre AL, Hunt PW, Critchfield JW, Young DH, Morris MM, Garcia JC, et al. Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood. 2009;113:3978–89.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nowak P, Troseid M, Avershina E, Barqasho B, Neogi U, Holm K, et al. Gut microbiota diversity predicts immune status in HIV-1 infection. AIDS. 2015;29(18):2409–18.CrossRefPubMedGoogle Scholar
  20. 20.
    Martin-Gayo E, Buzon MJ, Ouyang Z, Hickman T, Cronin J, Pimenova D, et al. Potent cell-intrinsic immune responses in dendritic cells facilitate HIV-1-specific T cell immunity in HIV-1 elite controllers. PLoS Pathog. 2015;11(6):e1004930.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Marras F, Nicco E, Bozzano F, di Biagio A, Dentone C, Pontali E, et al. Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation. Proc Natl Acad Sci U S A. 2013;110(29):11970–5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    O’Connell KA, Brennan TP, Bailey JR, et al. Control of HIV-1 in elite suppressors despite ongoing replication and evolution in plasma virus. J Virol. 2010;84(14):7018–28.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Li JZ, Arnold KB, Lo J, et al. Differential levels of soluble inflammatory markers by human immunodeficiency virus controller status and demographics. Open Forum Infect Dis. 2015;2(1):ofu117.CrossRefPubMedGoogle Scholar
  24. 24.
    Hunt PW, Benchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable HIV RNA levels in the absence of therapy. JID. 2008;197:126–33.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chun T-W, Shawn Justement J, Murray D, Kim CJ, Blazkova J, Hallahan CW, et al. Effect of antiretroviral therapy on HIV reservoirs in elite controllers. J Infect Dis. 2013;208(9):1443–7.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kandathil AJ, Sugawawa S, Balagopal A. Are T-cells the only HIV-1 reservoir? Retrovirology. 2016;13(1):86.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sedaghat AR, Rastegar DA, O’Connell KA, Dinoso JB, Wilke CO, Blankson JN. T cell dynamics and the response to HAART in a cohort of HIV-1 infected elite suppressors. Clin Infect Dis. 2009;49(11):1763–6.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Okulicz JF, Grandits GA, Weintrob AC, Landrum ML, Ganesan A, Crum-Cianflone NF, et al. CD4 T cell count reconstitution in HIV controllers after highly active antiretroviral therapy. Clin Infect Dis. 2010;50(8):1187–91.CrossRefPubMedGoogle Scholar
  29. 29.
    Boufassa F, Lechenadec J, Meyer L, Costagliola D, Hunt PW, Pereyra F, et al. Blunted response to combination antiretroviral therapy in HIV elite controllers: an international HIV controller collaboration. PLoS One. 2014;9(1):e85516.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    • Dominguez-Molina B, Tarancon-Diez L, Hua S, et al. HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers. Clin Infect Dis. 2017;64(5):621–8. This genotypic analysis identified polymorphisms that correlated with elite control.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Karris MY, Haubrich RH. Antiretroviral therapy in the elite controller: justified or premature? J Infect Dis. 2015;211(11):1689–91.CrossRefPubMedGoogle Scholar
  32. 32.
    Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506–12.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mdodo R, Frazier EL, Dube SR, Mattson CL, Sutton MY, Brooks JT, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys. Ann Intern Med. 2015;162(5):335–44.CrossRefPubMedGoogle Scholar
  34. 34.
    Hsue PY, Hunter PW, Schnell A, et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS. 2009;23(9):1059–67.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Tawakol A, Ishai A, Li D, Takx RAP, Hur S, Kaiser Y, et al. Association of arterial and lymph node inflammation with distinct inflammatory pathways in human immunodeficiency virus infection. JAMA Cardiol. 2017;2(2):163–71.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pereyra F, Lo J, Triant VA, Wei J, Buzon MJ, Fitch KV, et al. Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS. 2012;26(18):2409–12.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Platt L, Easterbrook P, Grower E, et al. Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis. Lancet Infect Dis. 2016;16(7):797–808.CrossRefPubMedGoogle Scholar
  38. 38.
    Desai SN, Dodge JL, Landay AL, Glesby MJ, Latham PS, Villacres MC, et al. Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: a Women’s Interagency HIV study. Medicine (Baltimore). 2016;95(33):e4483.CrossRefGoogle Scholar
  39. 39.
    Sajadi MM, Redfield RR, Talwani R. Altered T-cell subsets in HIV-1 natural viral suppressors (elite controllers) with hepatitis C infection. AIDS. 2013;27(12):1989–92.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Stafford KA, Rikhtegaran Tehrani Z, Saadat S, Ebadi M, Redfield RR, Sajadi MM. Long-term follow-up of elite controllers: higher risk of complications with HCV coinfection, no associated with HIV disease progression. Medicine (Baltimore). 2017;96(26):e7348.CrossRefGoogle Scholar
  41. 41.
    •• Dominguez-Molina B, Leon A, Rodriguez C, et al. Analysis of non-AIDS-defining events in HIV controllers. Clin Infect Dis. 2016;62(10):1304–9. This observational study identified HIV/HCV co-infection as the major factor associated with intra-hepatic and extra-hepatic non-AIDS-defining events in elite controllers.CrossRefPubMedGoogle Scholar
  42. 42.
    Gaillard S, Dinoso JB, Marsh JA, DeZern AE, et al. Sustained elite suppression of replication competent HIV-1 in a patient treated with rituximab based chemotherapy. J Clin Virol. 2011;51(3):195–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lambotte O, Lecuroux C, Saez-Cirion A, et al. Kidney transplantation in an elite HIV controller: limited impact of immunosuppressive therapy on therapy on viro-immunological status. J Inf Secur. 2012;64(6):630–3.Google Scholar
  44. 44.
    Smith NMG, Mlcochova P, Watters SA, Aasa-Chapman MMI, Rabin N, Moore S, et al. Proof-of-principle for immune control of global HIV-1 reactivation in vivo. Clin Infect Dis. 2015;61(1):120–8.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    •• NIH. Elite controller and ART-treated HIV+ statin vs. ASA treatment intervention study. Available from https://clinicaltrials.gov/ct/show/NCT02081638. Accessed Aug 8, 2017. This clinical trial currently underway is investigating the effect of aspirin and statins on inflammation in patients living with HIV, including elite controllers.
  46. 46.
    • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/Adul-tandAdolescentGL.pdf. Accessed Sept 8, 2017. The DHHS guidelines state that there is inadequate evidence to adequately compare risks and benefits of ART in elite controllers.
  47. 47.
    • Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society–USA Panel. JAMA. 2016;316(2):191–210. The International Antiviral Society USA panel states that ART may address increased immune activation but overall remains controversial in elite controllers.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of California San DiegoSan DiegoUSA

Personalised recommendations