DOES ANTIRETROVIRAL TREATMENT AT HIGH CD4 COUNTS REDUCE DISEASE RISK FOR HIV-POSITIVE PATIENTS?: Edited by Jason V. Baker and Caroline A. Sabin
Currently available antiretroviral therapy (ART) is highly efficacious at suppressing HIV replication, is durable over many years of follow-up and is well tolerated with relatively low rates of toxicity . Randomized controlled trial data have now established the potential public health benefits of ART treatment through viral suppression, in terms of reducing risk for HIV transmission, and have also shown that clinical event risk increases when ART initiation is deferred until CD4 cell counts less than 350 cells/μl [2,3]. This has contributed to a movement in public policy and treatment guidelines to call for expanded use of ART to the point that potentially all individuals with HIV infection would receive treatment immediately upon diagnosis [4,5]. Some cohort analyses suggest that individual disease risk would be decreased by starting ART earlier (even at very high CD4 cell counts) . However, these findings have not been substantiated in other cohorts and clinical outcome data from a randomized trial are currently lacking to establish whether ART treatment reduces clinical risk that exceeds drug toxicity, when started at high CD4 cell counts (e.g. >500 cells/μl) wherein absolute clinical event rates remain modest or very low . The purpose of this issue of Current Opinion in HIV and AIDS is therefore to explore the implications of starting ART at high CD4 cell counts in terms of the benefit to individual patients.
In situations in which access to ART exists and it is freely available, risk for AIDS progression has declined and the spectrum of morbidity and mortality seen in such populations now more commonly reflects non-AIDS defining long-term complications . The most relevant, serious, non-AIDS related diseases in current clinical practice include atherosclerotic cardiovascular disease (CVD), cancer, liver disease, end-stage renal disease, bone disease, lung disease and subclinical neurocognitive dysfunction. Articles dedicated to each of these end-organ diseases are included in this issue, exploring what is known about the influence of HIV infection, immune suppression and ART on the disease pathogenesis of each. In general, there is a paucity of randomized data to determine whether ART at high CD4 cell counts would reduce clinical event risk for any of these events. We also include an article focused on ART in young HIV-positive children, which highlights the clear benefits among infants with more conflicting data for children at least 1 year of age.
The prevalence, if not the true incidence, of most serious non-AIDS defining complications has been reported to be higher among HIV-positive adults than among uninfected populations [9–14]. Other large comparative studies have reported a similar risk in HIV-positive and HIV-negative individuals when analyses are restricted to HIV-positive individuals with high CD4 cell counts (e.g. >500 cells/μl) [15,16]. Limitations of all such comparisons, however, include the difficulty in identifying appropriate uninfected control groups, the lack of ascertainment of all potential confounders and the selection of HIV patients with higher health-seeking behaviour when using data from cohorts and trials. An important observation in all these studies is that the rates of non-AIDS defining complications remain low, such that any benefits from ART (or other interventions) on these outcomes would be expected to be correspondingly modest in absolute terms. These uncertainties aside, two HIV-specific mechanisms are widely hypothesized to contribute to premature development of long-term complications (such as CVD and cancer) and receive special attention throughout this issue.
The first is the influence of immune depletion on disease risk. An inverse association between the CD4 cell count and the risk of non-AIDS conditions has been observed for some time , and immune recovery can be slow and even incomplete for some patients starting ART despite effective suppression of viral replication . These observations have motivated claims that earlier initiation of ART will reduce individual disease risk by maintaining and achieving higher CD4 cell counts. However, event rates are most striking for very low CD4 cell counts (e.g. <200 cells/μl) with relatively sparse data among patients with high CD4 cell counts, raising questions about how informative current data are for decisions around starting ART at CD4 cell counts above versus below 500 cells/μl. Furthermore, as noted in the article on immune depletion and clinical risk (Achhra, Petoumenos and Law) and the review of cancer risk specifically (Humberto Borges, Dubrow and Silverberg), the potential impact of immune depletion is likely more relevant for some conditions (e.g. cancer) than others (e.g. CVD). The HIV population is ageing and as people age their immune systems will gradually deteriorate, regardless of HIV status. Evidence generally suggests slightly poorer immunological responses to ART in older individuals despite similar, if not improved, virologic responses. The potential impact of this interaction between age and immune status on the risk of non-AIDS events remains to be clarified. Such an interaction, if present, may have implications for ART initiation in older HIV-positive people.
The other HIV-specific mechanism discussed throughout this issue is systemic inflammation and associated biology related to immune activation and coagulation. Recent epidemiologic data show that key biomarkers of inflammation (e.g. IL-6) and coagulation activation (e.g. D-dimer) predict risk for CVD, cancer, a composite outcome of non-AIDS conditions and all-cause mortality over years of follow-up [19–22]. Importantly, the degree of inflammation during treated HIV disease appears to be independent of CD4 cell counts in blood (at least at moderate to higher CD4 cell count levels) in these studies, suggesting that separate pathways may be at play. Two themed articles in this issue by Sandler/Sereti and Funderburg explore HIV mechanisms contributing to inflammation and coagulation abnormalities, respectively. They discuss the consequences of HIV infection on cellular activation and coagulation biology, and attempt to make the case that ART may be clinically beneficial through reductions in inflammation and coagulation. Important limitations include the heavy reliance on observational data, and the uncertainty surrounding which of the diverse immunologic markers (e.g. T-cell or monocyte activation) are clearly on the causal pathway for a given disease (e.g. CVD versus cancer, and so on). Furthermore, there are also multiple factors that appear to contribute to persistent inflammation and coagulation abnormalities, which implies that the potential for ART to mitigate this disease for a given individual may vary on the basis of (currently unmeasured) disease characteristics specific to that individual.
Finally, drug toxicity remains an important consideration for decisions to start ART, as it is a potential causal factor in the development of some non-AIDS events despite drastic improvements in side effect profiles over the past decade. Even low levels of end-organ toxicity may manifest clinically when considering a population in which the goal has become life-long treatment with near-normal lifespans. Consistent with this, it took years of follow-up data to quantify myocardial infarction risk for individual antiretrovirals, and concerns associated with abacavir exposure remain [23,24]. Similarly, concerns remain over subtle renal impairment over the long-term with tenofovir and atazanavir exposure, and bone disease with tenofovir or continuous ART use in general [25–27]. Pertinent to assessing long-term risk from antiretroviral drugs in the current era, it is important to note that only recently have HIV studies started to track and adjudicate non-AIDS defining clinical outcomes so that additional risk associations may become apparent over time.
In summary, for patients with high CD4 cell counts at low risk for AIDS progression, the established public health benefits of ART must be considered alongside the implications for individual patients, a balance explored in our opening article on the community perspective by Collins and Geffen. Risk for the current spectrum of non-AIDS defining long-term complications from HIV disease is predicted by the degree of immune depletion and systemic inflammation, and ART improves these abnormalities. However, we currently lack the randomized clinical data necessary to establish whether the timing of ART initiation (i.e. starting at higher CD4 cell counts) has a differential effect on the level of inflammatory markers once steady states are achieved with long-term treatment, whether ART-related treatment effects on immune recovery or inflammatory/coagulation pathways are associated with corresponding changes in clinical event risk for non-AIDS complications and whether any ART effect at high CD4 cell counts is of net benefit in clinical terms. To this last point, the clinical effects of ART may vary by disease (e.g. CVD vs. cancer vs. lung disease vs. bone disease) and may also correspond to very small differences in absolute terms; both points are germane to discussions surrounding cost, resources and whether treatment effects are clinically meaningful for an individual. To further complicate this issue, it may very well be the case that the net effect of ART is to reduce the risk for some non-AIDS events and simultaneously increase the risk for others. Randomized clinical outcome data quantifying benefits of ART treatment started at CD4 cell counts more than 500 cells/μl will be provided by the Strategic Timing of AntiRetroviral Therapy (START) trial in several years (enrolment is completed and follow-up is ongoing). In the meantime, providers should be mindful to separate the established prevention benefits of ART with the hypothesized individual clinical benefits when assessing patients’ readiness and discussing risks and benefits of starting ART at very high CD4 cell counts.
Conflicts of interest
Dr Baker is a member of the Scientific Steering Committee for the INSIGHT Network, which is conducting the START study, an expert member of the Protocol Team for this study and the member of several network sub-committees; Professor Sabin is also a member of the INSIGHT Network.
1. Bansi L, Sabin C, Delpech V, et al. Trends over calendar time in antiretroviral treatment success and failure in HIV clinic populations. HIV Med 2010; 11:432–438.
2. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010; 363:257–265.
3. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493–505.
4. 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; 2013. http://aidsinfo.nih.gov/guidelines
. [Accessed September, 2013]
5. World Health Organization HIV/AIDS Programme. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a Public Health Approach, June 2013. Geneva: WHO; 2013.
6. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009; 360:1815–1826.
7. Sabin CA, Cooper DA, Collins S. Rating evidence in treatment guidelines: a case example of when to initiate combination antiretroviral therapy (cART) in HIV-positive asymptomatic persons. AIDS 2013; 27:1839–1846.
8. Mocroft A, Reiss P, Gasiorowski J, et al. Serious fatal and nonfatal non-AIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr 2010; 55:262–270.
9. Mocroft A, Soriano V, Rockstroh J, et al. Is there evidence for an increase in the death rate from liver-related disease in patients with HIV? AIDS 2005; 19:2117–2125.
10. Schwartz EJ, Szczech LA, Ross MJ, et al. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol 2005; 16:2412–2420.
11. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007; 44:1625–1631.
12. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370:59–67.
13. 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; 92:2506–2512.
14. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med 2013; 173:614–622.
15. Lewden C, Bouteloup V, De Wit S, et al. Collaboration of Observational HIVEREiE 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 2012; 41:433–445.
16. Rodger AJ, Lodwick R, Schechter M, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS 2013; 27:973–979.
17. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS 2008; 22:841–848.
18. Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet 2007; 370:407–413.
19. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 2012; 7:e44454.
20. Borges AH, Silverberg MJ, Wentworth D, et al. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS 2013; 27:1433–1441.
21. Grund B, Baker J, Deeks SG, et al. Combined effect of interleukin-6 and D-dimer on the risk of serious non-AIDS conditions: data from 3 prospective cohorts. 20th Conference on Retroviruses and Opportunistic Infections; 2013; Atlanta, GA 3–6 March 2013.
22. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
23. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003.
24. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis 2010; 201:318–330.
25. Ryom L, Mocroft A, Kirk O, et al. Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study. J Infect Dis 2013; 207:1359–1369.
26. Grund B, Peng G, Gibert CL, et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS 2009; 23:1519–1529.
27. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011; 203:1791–1801.