From the time of first presentation for care to the end of the study period, 16 patients lost elite controller status (29%) (Table 1). There was moderate evidence that patients who lost their elite controller status were younger than patients who maintained elite controller status and were more likely to have sexual contact as their primary risk factor. There were no significant differences in other baseline characteristics between those who maintained elite controller status compared with those who lost viral control. There was some evidence that patients who lost elite controller status had higher levels of cellular immune activation (Table 3).
Time to loss of NVS status did not differ significantly by HCV coinfection status (P = .57) (Fig. 1B). There was no difference in the hazard for loss of elite controller status when comparing HCV coinfected patients to HIV monoinfected patients (HR 0.75, 95% confidence interval [CI] 0.27–2.06, P = .57) (Table 2). None of the baseline characteristics changed the crude association between HCV coinfection and loss of elite controller status or improved model fit. The prevalence of HCV coinfection status did not differ between patients who maintained elite controller status compared with those who lost elite controller status. After individually controlling for markers of immune activation, the prevalence of HCV coinfection status was not significantly different among those who lost elite controller status compared with those who maintained it (Table 3).
The median log HCV viral load of coinfected patients at baseline was 6.27 (IQR 5.63–6.54). Twenty-four of the HCV coinfected patients had genotype 1a or 1b, and 1 had 3a. There was no difference in the median log HCV viral load among HCV coinfected patients who developed a complication or who lost their NVS status compared with the coinfected patients who did not develop a complication or maintained natural viral suppression (data not shown).
The 9 patients excluded from analysis due to missing immune activation levels did not differ significantly from patients included with regards to the prevalence of HCV coinfection, incidence of complications, or loss of elite controller status (data not shown). The crude and adjusted estimates of effect did not significantly differ when the patient with liver failure was excluded (data not shown). All results presented include the patient with liver failure.
In this study, HCV coinfection was significantly associated with the risk of complications, even after controlling for CD4+ T-cell level, sex, and older age. Chronic inflammation is thought to be associated with CD4+ T-cell depletion and higher levels of immune activation.[21,26] Similarly, HCV coinfection remained significantly associated with a higher prevalence of complications when individual immune activation markers were controlled for. This study found that HCV coinfected patients had higher levels of cellular activation while also having similar levels of LPS and soluble CD14.[21,26]
Our study has several limitations. Not all patients had measures of immune activation documented in their study records and were therefore excluded introducing the potential for selection bias. However, when we compared the available baseline covariates, and also the distribution of exposure and outcomes between patients included and excluded from the study, we found them to be similar indicating that had they been included our inferences would most likely not have been affected. The measures of immune activation were not assessed at enrollment into the study cohort, and we therefore cannot make temporal inferences of a causal nature nor could we control for them in the multivariable Cox models. We used prevalence rate ratios (PRRs) to estimate the associations of interest as risk was our parameter of interest. We chose PRRs as both the prevalence of HCV coinfection and the outcomes (complications and loss of elite controller status) were fairly common (>10%), and prevalence odds ratios (ORs) would be further away from the null, thus potentially overestimating the strength of the associations of interest.
Continued follow-up will be needed to determine whether HCV cure through the use of direct-acting antivirals among HIV/HCV coinfected elite controllers will make the risk for complications among these patients similar to their HIV monoinfected counterparts. Further studies will also be needed to determine the effects of antiretroviral therapy in this group of patients coupled to its risk/benefit ratio. Whereas HIV patients coinfected with HCV are at significantly increased risk for the development of complications, HCV coinfection does not appear to impact the likelihood of HIV disease progression in this population.
The authors would like to thank Dr John Sorkin for his important contributions to the statistical methods used in this study.
. Solomon SS, Srikrishnan AK, Mehta SH, et al. High prevalence of HIV
/hepatitis C virus co-infection and risk behaviors among IDUs in Chennai, India: a cause for concern. J Acquir Immune Defic Syndr 2008;49:327.
. Law WP, Duncombe CJ, Mahanontharit A, et al. Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV
disease progression in the HIV
-NAT cohort. AIDS 2004;18:1169–77.
. Macias J, Pineda JA, Lozano F, et al. Impaired recovery of CD4+ cell counts following highly active antiretroviral therapy in drug-naive patients coinfected with human immunodeficiency virus and hepatitis C virus. Eur J Clin Microbiol Infect Dis 2003;22:675–80.
. Santin M, Mestre M, Shaw E, et al. Impact of hepatitis C virus coinfection on immune restoration during successful antiretroviral therapy in chronic human immunodeficiency virus type 1 disease. Eur J Clin Microbiol Infect Dis 2008;27:65–73.
. Seminari E, Tinelli C, Ravasi G, et al. Hepatitis C infection
on immune recovery in HIV
-positive patients on successful HAART: the role of genotype 3. Curr HIV
. Sajadi MM, Constantine NT, Mann DL, et al. Epidemiologic characteristics and natural history of HIV
-1 natural viral suppressors. J Acquir Immune Defic Syndr 2009;50:403.
. Lambotte O, Boufassa F, Madec Y, et al. HIV
controllers: a homogeneous group of HIV
-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 2005;41:1053–6.
. Pereyra F, Addo MM, Kaufmann DE, et al. Genetic and immunologic heterogeneity among persons who control HIV
infection in the absence of therapy. J Infect Dis 2008;197:563–71.
. Bailey JR, Lassen KG, Yang HC, et al. Neutralizing antibodies do not mediate suppression of human immunodeficiency virus type 1 in elite suppressors or selection of plasma virus variants in patients on highly active antiretroviral therapy. J Virol 2006;80:4758–70.
. Sajadi MM, Heredia A, Le N, et al. HIV
-1 natural viral suppressors: control of viral replication in the absence of therapy. AIDS 2007;21:517–9.
. Sajadi MM, Pulijala R, Redfield RR, et al. Chronic immune activation and decreased CD4 counts associated with hepatitis C infection
-1 natural viral suppressors. AIDS (London, England) 2012;26:1879.
. Crowell TA, Gebo KA, Blankson JN, et al. Hospitalization rates and reasons among HIV elite controllers
and persons with medically controlled HIV
infection. J Infect Dis 2015;211:1692–702.
. Crowell TA, Gebo KA, Balagopal A, et al. Impact of hepatitis coinfection on hospitalization rates and causes in a multicenter cohort of persons living with HIV
. J Acquir Immune Defic Syndr 2014;65:429–37.
. Katrak S, Park LP, Woods C, et al. Patterns of healthcare utilization among veterans infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV
) and coinfected with HIV
/HCV: unique burdens of disease. Open Forum Infect Dis 2016;3:ofw173.
. Sajadi MM, Shakeri N, Talwani R, et al. Hepatitis C infection
-1 natural viral suppressors. AIDS (London, England) 2010;24:1689.
. Pereyra F, Lo J, Triant VA, et al. Increased coronary atherosclerosis and immune activation in HIV
-1 elite controllers
. AIDS (London, England) 2012;26:2409.
. Okulicz JF, Marconi VC, Landrum ML, et al. Clinical outcomes of elite controllers
, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV
natural history study. J Infect Dis 2009;200:1714–23.
. Hatano H, Yukl SA, Ferre AL, et al. Prospective antiretroviral treatment of asymptomatic, HIV
-1 infected controllers. PLoS Pathog 2013;9:e1003691.
. Chun T-W, Justement JS, Murray D, et al. Effect of antiretroviral therapy on HIV
reservoirs in elite controllers
. J Infect Dis 2013;208:1443–7.
. Krishnan S, Wilson EM, Sheikh V, et al. Evidence for innate immune system activation in HIV
type 1-infected elite controllers
. J Infect Dis 2014;209:931–9.
. Sedaghat AR, Rastegar DA, O’Connell KA, et al. T cell dynamics and the response to HAART in a cohort of HIV
-1-infected elite suppressors. Clin Infect Dis 2009;49:1763–6.
. Boufassa F, Lechenadec J, Meyer L, et al. Blunted response to combination antiretroviral therapy in HIV elite controllers
: an international HIV
controller collaboration. PloS One 2014;9:
. Okulicz JF, Grandits GA, Weintrob AC, et al. CD4 T cell count reconstitution in HIV
controllers after highly active antiretroviral therapy. Clin Infect Dis 2010;50:1187–91.
. Hatano H, Delwart EL, Norris PJ, et al. Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol 2009;83:329–35.
. Hersperger AR, Migueles SA, Betts MR, et al. Qualitative features of the HIV
-specific CD8+ T cell response associated with immunologic control. Curr Opin HIV
. Sousa AE, Carneiro J, Meier-Schellersheim M, et al. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV
-1 and HIV
-2 but only indirectly to the viral load. J Immunol 2002;169:3400–6.
. Zocchetti C, Consonni D, Bertazzi PA. Relationship between prevalence rate ratios and odds ratios in cross-sectional studies. Int J Epidemiol 1997;26:220–3.