Serious Non-AIDS Conditions in HIV: Benefit of Early ART
- 321 Downloads
Purpose of review
Optimal control of HIV can be achieved by early diagnosis followed by the initiation of antiretroviral therapy (ART). Two large randomised trials (TEMPRANO and START) have recently been published documenting the clinical benefits to HIV-positive adults of early ART initiation. Main findings are reviewed with a focus on serious non-AIDS (SNA) conditions.
Data from the two trials demonstrated that initiating ART early in the course of HIV infection resulted in marked reductions in the risk of opportunistic diseases and invasive bacterial infections. This indicates that HIV causes immune impairment in early infection that is remedied by controlling viral replication. Intriguingly, in START, a marked reduction in risk of cancers, both infection-related and unrelated types of cancers, was observed. Like the findings for opportunistic infections, this anti-cancer effect of early ART shows how the immune system influences important pro-oncogenic processes. In START, there was also some evidence suggesting that early ART initiation preserved kidney function, although the clinical consequence of this remains unclear. Conversely, while no adverse effects were evident, the trials did not demonstrate a clear effect on metabolic-related disease outcomes, pulmonary disease, or neurocognitive function.
HIV causes immune impairment soon after acquisition of infection. ART reverses this harm at least partially. The biological nature of the immune impairment needs further elucidation, as well as mechanisms and clinical impact of innate immune activation. Based on the findings from TEMPRANO and START, and because ART lowers the risk of onward transmission, ART initiation should be offered to all persons following their diagnosis of HIV.
KeywordsSerious non-AIDS events HIV Antiretroviral therapy Inflammation
The authors would like to thank the INSIGHT (International Network for Strategic Initiatives in Global HIV Trials), its leadership including Drs. F Gordin, A Babiker, A Phillips, J Baker and B Grund, and main funder division of AIDS, National Institutes of Allergy and Infectious Diseases, USA.
This work was supported by the Danish National Research Foundation [grant 126].
Compliance with Ethical Standards
Conflict of Interest
Alvaro H Borges is supported by Lundbeckfonden (grant R219-2016-762). James D. Neaton reports grants from NIH and NIAID. Jens D. Lundgren declares no conflict of interest.
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.• Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014;384(9939):241–8. International cohort collaboration demonstrating marked reduction in last 15 years in fatal AIDS and SNA-related events incl those caused by cardiovascular and liver pathologies but not non-AIDS cancers. Whereas reduction in AIDS conditions were associated with gradually increasing CD4+ lymphocyte count, this was not the case for the SNA conditions, but perhaps better quality of care . CrossRefPubMedGoogle Scholar
- 5.May MT, Vehreschild J, Trickey A, Obel N, Reiss P, Bonnet F, et al. Mortality according to CD4 count at start of combination antiretroviral therapy among HIV-infected patient followed for up to 15 years after start of treatment: collaborative cohort study. Clin Infect Dis. 2016;62:1571–7.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.•• Grund B, Baker JV, Deeks SG, et al. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS One. 2016;11:e0155100. Combined cohort analysis demonstrating persisting prognostic impact from initial levels of interleukin-& and D-dimer. These observations were confirmed in the START cohort (Baker JV, Sharma S, Grund B, et al. Association of inflammation and coagulation with clinical risk in the START Trial. Abstract, Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, Washington, 2017) . CrossRefPubMedPubMedCentralGoogle Scholar
- 13.• The HIV-Causal Collaboration, Lodi S, Phillips A, Logan R, Olson A, Costagliola D, et al. Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study. Lancet HIV. 2015;2:e335-e-345. Most recent report to address whether statistical analysis of observational studies can predict the benefit from earlier initiation of ART. The predicted benefit (3–20%) was smaller than what was observed in the START study . Google Scholar
- 16.•• TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, Gabillard D, Badje A, Le Carrou J, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373(9):808–22. Single country (Ivory Coast) randomised controlled trial demonstrating clinical benefit from starting ART earlier rather than later in course of early HIV infection. Benefit was due to reduced risk of tuberculosis and invasive bacterial infections (44% reduction) . CrossRefGoogle Scholar
- 17.•• The INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795–807. Large, geographical diverse randomised controlled trial demonstrating clinical benefit from starting ART earlier rather than later in course of early HIV infection. Benefit was due to reduced risk of opportunistic infections and cancer (57%) . CrossRefPubMedCentralGoogle Scholar
- 18.INSIGHT Strategic Timing of AntiRetroviral Treatment (START) Study Group, Lundgren J, Babiker A, Gordin F, Emery S, Fätkenheuer G, et al. Why START? Reflections that led to the conduct of this large long-term strategic HIV trial. HIV Med. 2015;16(Suppl 1):1–9. https://doi.org/10.1111/hiv.12227.CrossRefGoogle Scholar
- 20.• Lodi S, Sharma S, Lundgren JD, Phillips AN, Cole SR, Logan R, et al. The per-protocol effect of immediate versus deferred antiretroviral therapy initiation. AIDS. 2016;30(17):2659–63. Analysis of the START cohort with aim to assess the benefit from earlier ART if all had all the trial participants adhered to the protocol. The ITT effect estimate (as reported in the N Engl J Med main article) may underestimate the benefit of immediate ART initiation by 23%.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Molina JM, Grund B, Gordin F, et al. Who benefited most from immediate treatment in START? A subgroup analysis. Abstract THAB0201, AIDS 2016, Durban, South Africa; 2016.Google Scholar
- 23.• Babiker A, Grund B, Sharma S, et al. The role of HIV RNA and T cell counts, percent and ratio in explaining the benefit of immediate ART initiation in HIV+ individuals with high CD4+ counts. Abstract, AIDS 2016, Durban, South Africa; 2016. Analysis of the START study focusing on which immunological parameters could explain benefit from earlier ART initiation. Whereas changes in absolute CD4 count over follow-up only explained a small fraction of benefit (15%), changes in the CD4:CD8 ratio was a better predictor (45%).Google Scholar
- 25.• O'Connor J, Vjecha MJ, Phillips AN, Angus B, Cooper D, Grinsztejn B, et al. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial. Lancet HIV. 2017;4(3):e105–12. Analysis in START cohort of how earlier ART reduced substantially (61%) the risk of contracting a composite endpoint of severe bacterial infection (including bacterial pneumonia, pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death). This benefit was partially explained by how earlier ART increased CD4+ lymphocyte count.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.• Borges AH, Neuhaus J, Babiker AG, et al. Immediate antiretroviral therapy reduces risk of infection-related cancer during early HIV infection. Clin Infect Dis. 2016;63:1668–76. Detailed analysis of cancer emerging in the START cohort, and how earlier initiation of ART reduced risk of both infectious-related and un-related types of cancers. Intriguingly, adjusted for time-updated HIV-RNA levels (but not CD4+ count) attenuated the observed benefit from earlier initiation of ART, but this effect was not observed for infectious-related, suggesting that the anti-cancer benefit from earlier ART initiation is not solely attributable to suppression of HIV replication.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Mazzuca P, Marsico S, Schulze K, Mitola S, Pils MC, Giagulli C, Guzman CA, Caruso A, Caccuri F. Role of Autophagy in HIV-1 Matrix Protein p17-Driven Lymphangiogenesis. J Virol. 2017;91(16). https://doi.org/10.1128/JVI.00801-17.
- 32.• Friis-Møller N, Ryom L, Smith C, Weber R, Reiss P, Dabis F, et al. An updated prediction model of the global risk of cardiovascular disease in HIV-positive persons: the dData-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study. Eur J Prev Cardiol. 2016;23(2):214–23. Updated version of the D:A:D study predictor of absolute underlying risk of cardiovascular disease in HIV+ populations. This and risk prediction tools for chronic kidney disease are available for online use at http://www.chip.dk/Tools.CrossRefPubMedGoogle Scholar
- 36.Baker JV, Sharma S, Grund B, Rupert A, Metcalf JA, Schechter M, et al.Systemic Inflammation, Coagulation, and Clinical Risk in the START Trial. Open Forum Infect Dis. 2017;4(4):ofx262. http://www.ncbi.nlm.nih.gov/pubmed/29308409
- 37.• Baker JV, Sharma S, Achhra AC, Bernardino JI, Bogner JR, Duprez D, et al. Changes in cardiovascular disease risk factors with immediate versus deferred antiretroviral therapy initiation among HIV-positive participants in the START (Strategic Timing of Antiretroviral Treatment) Trial. J Am Heart Assoc. 2017;6(5). Analysis in START cohort of how earlier ART initiation impact traditional cardiovascular risk factors, iincluding worsening dyslipidaemia (in part depending on type of antiretroviral drug used), but decreased use of blood pressure medications, leading to an overall projected clinically insignificant impact on cardiovascular risk. Risk of new onset diabetes was not affected.Google Scholar
- 38.• Ghehi C, Gabillard D, Moh R, Badje A, Kouamé GM, Oouttara E, et al. High correlation between Framingham equations with BMI and with lipids to estimate cardiovascular risks score at baseline in HIV-infected adults in the Temprano trial, ANRS 12136 in Côte d’Ivoire. PLoS One. 2017;12(6):e0177440. Analysis of the TEMPRANO study using the Framingham equation, assessing temporal trends during follow-up and between the two randomised arms of the trial. No effect of earlier ART initiation affected this outcome.CrossRefPubMedPubMedCentralGoogle Scholar
- 39.• Baker JV, Hullsiek KH, Engen NW, Nelson R, Chetchotisakd P, Gerstoft J, et al. Early antiretroviral therapy at high CD4 counts does not improve arterial elasticity: a substudy of the Strategic Timing of AntiRetroviral Treatment (START) Trial. Open Forum Infect Dis. 2016;3(4):ofw213. Substudy in START assessing whether earlier ART affects changes in arterial elasticity (a marker of arterial wall disease which in general population studies are closely linked with risk of cardiovascular disease). No benefit from earlier ART was observed in this study.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.• Mocroft A, Lundgren JD, Ross M, Fux CA, Reiss P, Moranne O, et al. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study. Lancet HIV. 2016;3(1):e23–32. International cohort study demonstrating dose-response association between duration of tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir usage and gradually increasing risk of developing chronic kidney disease. This finding did in relative terms not interact with patients underlying risk of contracting this outcome, implying that this complication is relatively common in those with elevated predicted underlying risk (i.e. a low number needed to harm).CrossRefPubMedGoogle Scholar
- 45.Achhra AC, Mocroft A, Ross M, Ryom-Nielson L, Avihingsanon A, Bakowska E, et al. Impact of early versus deferred antiretroviral therapy on estimated glomerular filtration rate in HIV-positive individuals in the START trial. Int J Antimicrob Agents. 2017.Google Scholar
- 46.Kunisaki KM, Niewoehner DE, Collins G, Nixon DE, Tedaldi E, Akolo C, et al. Pulmonary function in an international sample of HIV-positive, treatment-naïve adults with CD4 counts > 500 cells/μL: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med. 2015;16(Suppl 1):119–28.CrossRefPubMedPubMedCentralGoogle Scholar
- 47.•• Kunisaki KM, Niewoehner DE, Collins G, Aagaard B, Atako NB, Bakowska E, et al. Pulmonary effects of immediate versus deferred antiretroviral therapy in HIV-positive individuals: a nested substudy within the multicentre, international, randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial. Lancet Respir Med. 2016;4(12):980–9. Substudy from START study, assessing whether earlier ART affects longitudinal pulmonary function over a 2 year period. No such effect was found, irrespective of smoking status, which by itself markedly affected the course of pulmonary function.CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Hoy J, Grund B, Roediger M, Ensrud KE, Brar I, Colebunders R, et al. Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: The SMART body composition substudy. J Bone Miner Res. 2013;28(6):1264–74.CrossRefPubMedPubMedCentralGoogle Scholar
- 49.• Hoy JF, Grund B, Roediger M, Schwartz AV, Shepherd J, Avihingsanon A, et al. Immediate initiation of antiretroviral therapy for HIV infection accelerates bone loss relative to deferring therapy: findings from the START bone mineral density substudy, a randomized trial. J Bone Miner Res. 2017;32:1945–55. https://doi.org/10.1002/jbmr.3183. Substudy from START study, assessing whether earlier ART affects changes in bone mineral density over a 2 year period. Earlier ART reduced density more so in the first but not the second year, and this initial decline was not linked to type of ART used.CrossRefPubMedGoogle Scholar
- 52.Wright E, Grund B, Robertson K, Cysique L, Collins G, Brew B et al. No difference between the effects of immediate versus deferred ART on neuropsychological test performance in HIV-positive adults with CD4+ cell counts > 500 cells/μL. 15th European AIDS Conference (EACS), Barcelona, October 2015.Google Scholar
- 53.•• Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med. 2016;375(9):830–9. Follow-up report to original HPTN 052 report documenting substantial reduction (93%) in risk of linked HIV transmission from placing HIV+ person on ART. Whereas no linked transmission was observed while index HIV+ person was on fully suppressive ART, a total of 8 linked transmissions were observed after initiation of ART stressing that full adherence is required.CrossRefPubMedPubMedCentralGoogle Scholar
- 54.•• Rodger AJ, Cambiano V, Bruun T, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using supportive antiretroviral therapy. JAMA. 2016;316:171–81. International study assessing the risk of HIV transmission in serodiscordant relationships having condom-less sex, and where the initial HIV+ person was on fully suppressive ART. No linked transmissions were observed after 40,000+ sexual intercourses. Supports claim that fully suppressive ART renders the person no longer able to transmit HIV.CrossRefPubMedGoogle Scholar
- 56.• Sereti I, Gulick RM, Krishnan S, et al. ART in HIV persons with pre-treatment viremia ≤ 3000 c/mL: the START study. Abstract 984, Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, Washington, 2017. Subgroup analysis of START cohort, focused on those entering the study with low HIV RNA viral load. Earlier ART raised CD4+ lymphocyte count and reduced risk of HIV viral rebound . No power was available to assess impact on clinical events from earlier initiation of ART. Google Scholar
- 59.Borges AH, Neuhaus J, Sharma S, et al. Benefit of continuous/immediate ART on disease risk: SMART & START combined analysis. Abstract 793, Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, Washington; 2017.Google Scholar
- 60.Mocroft A, Phillips AN, Gatell J, Ledergerber B, Fisher M, Clumeck N, et al. Normalization of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational study. Lancet. 2007;370:407–13.CrossRefPubMedGoogle Scholar