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Hepatitis C Virus Infection in HIV Type 1-Infected Individuals Does Not Accelerate a Decrease in the CD4+ Cell Count but Does Increase the Likelihood of AIDS-Defining Events
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....coinfected individuals were associated with an increased likelihood of experiencing an AIDS-defining illness for the first time or developing a CD4+ cell count of <200 cells/mm3.....
Clinical Infectious Diseases Sept 15 2005;41:000
Note from Jules Levin: None of the 3 studies of coinfection I reported today made note of the HAART regimens patients in the studies were taking & the possible effect of the regimens regarding hepatotoxicity & liver disease. As well, baseline liver disease of the patients were not considered. Perhaps, the NRTIs used previously, the presence of fatty liver, and the status of an individual's liver disease before HAART & during HAART would be relevant to the findings of these 3 studies. Nonetheless, it is apparent that HCV positivity plays a significant role id the morbidity and mortality of coinfected patients. Clearly, having HCV & HIV results in greater risk of HIV or HCV related disease complications and death.
Authors; Justin Stebbing, Laura Waters, Sundhiya Mandalia, Mark Bower, Mark Nelson, and Brian Gazzard
Department of HIV Medicine, Chelsea and Westminster Hospital, London, United Kingdom
ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) appears to adversely affect hepatitis C, but it remains a point of controversy whether hepatitis C virus (HCV) has a reciprocal effect on HIV-1 infection.
In a multivariate analysis of a cohort of 5832 individuals, we found that individuals coinfected with HCV and HIV-1 (prevalence of coinfection, 5.8%) had a CD4+ cell count that decreased at a rate similar to that for individuals infected with HIV-1 alone.
However, coinfection was associated with a statistically significant increased likelihood of onset of an acquired immunodeficiency syndrome-defining illness or developing a CD4+ cell count of <200 cells/mm3, compared with infection with HIV-1 alone (hazard ratio, 1.52; 95% confidence interval, 1.07-2.17).
Patients who were naive to highly active antiretroviral therapy were significantly less likely to progress to either end point, because of their higher CD4+ cell counts.
In conclusion, there was an increased number of adverse events in coinfected individuals, compared with individuals infected with HIV-1 alone.
Although antiretroviral therapy has significantly reduced morbidity and mortality due to HIV-1 infection [1], liver disease is an increasingly common cause of death among persons infected with HIV-1 [2-4]. Many of the -200 million individuals infected with hepatitis C virus (HCV) and the -50 million individuals infected with HIV-1 are coinfected with both viruses [5-9]. In addition to shared routes of transmission, there are many interactions between these small RNA viruses in which infection is characterized by parenteral transmission followed by seroconversion illness and a long asymptomatic period lasting many years. HIV-1 infection appears to increase the persistence of HCV and the level of HCV RNA, and in a number of studies, it accelerates the progression of HCV-related disease [4, 10-13]. Thus, exploration of potential therapies for HCV infection in coinfected patients is a priority.
There are conflicting reports concerning whether HCV infection alters the course of HIV-1 disease [3]. Some studies before the advent of HAART suggested that data on survival duration and time to progression to AIDS for patients with HIV-1-HCV coinfection were the same as those for patients with HIV-1 infection alone [14-16], whereas other studies suggested that coinfection had adverse effects [11, 17]. During the pre-HAART era, HCV infection was deemed to be irrelevant, because it was HIV-1 disease that affected morbidity and mortality [18].
However, as the life expectancy for individuals infected with HIV-1 has increased, HCV infection has emerged as a problem that adversely affects the survival duration for these individuals [4, 5]. The hepatotoxicities associated with different HAART regimens also appear to be more severe in patients with underlying HCV disease, potentially confounding the ability to provide patients with effective antiviral therapies [19-23].
Therefore, we aimed, in our prospectively observed cohort, to compare HIV-1 disease progression in HIV-1-infected individuals with that in individuals with HIV-1-HCV coinfection. We found no statistically significant differences in the rate of disease progression between these groups, according to analysis of CD4+ cell count parameters. Interestingly, coinfected individuals were associated with an increased likelihood of experiencing an AIDS-defining illness for the first time or developing a CD4+ cell count of <200 cells/mm3.
Patients and methods. HIV-1-infected patients in the Chelsea and Westminster Hospital (London, United Kingdom) cohort are seen at regular intervals for clinical assessment, trial follow up, and immunologic assessment. All HIV-1-infected patients who have attended Chelsea and Westminster Hospital since routine prospective data collection commenced in 1989 were identified. We defined HAART as therapy consisting of at least 3 antiretroviral drugs, in accordance with published guidelines (dual nucleoside analogues alone are not considered to be HAART). This study focuses on a cohort of individuals who have been followed up since commencement of the HAART era, which we defined as beginning on 1 January 1996, when HAART became routinely available at our institution (and at others). Since 1998, staged HCV antibody testing with the IMX system (Abbot) has been performed. Clinical use of this test has been routine since 2003 for all new HIV-1-infected individuals presenting to our hospital. Because our cohort has very low rate of hepatitis B virus infection, the prevalence of this infection was not measured [24]. CD4+ cell subset analysis was performed using whole blood specimens stained with murine anti-human monoclonal antibodies to CD4+ cells (TetraOne; Beckman Coulter) evaluated by means of an Epics XL-MCL multiparametric flow cytometer (Beckman Coulter).
We identified individuals who presented during the HAART era and then excluded those who had a baseline CD4+ cell count of <200 cells/mm3. The end points in our small cohort study (considered to be events in this study) were development of a CD4+ cell count of <200 cells/mm3 or onset of an AIDS-defining opportunistic illness, as clinically defined by the Centers for Disease Control and Prevention classification (including Pneumocystis jiroveci [formerly P. carinii] pneumonia, cytomegalovirus infection, candidiasis, Kaposi sarcoma, any lymphoma, toxoplasmosis, and AIDS-associated diarrheas) [25].
Statistical analyses were performed using SAS, version 8.0 (SAS Institute), using parametric tests. The MIXED procedure in SAS was used to calculate the difference in averages (DAVG), which represent the time-weighted difference between the CD4+ cell count at baseline and the CD4+ cell count at each time point. A univariate and multivariable Cox proportional hazards regression method was used to estimate the likelihood of developing a CD4+ cell count of <200 cells/mm3 or developing the first AIDS-defining illness since entry into the cohort of HIV-1-infected patients during the HAART era. Time to event was defined as the time to development of a CD4+ cell count of <200 cells/mm3 or onset of the patient's first AIDS-defining illness. Data were censored at the time of the last clinic visit, and the final multivariate model was tested for its distributional assumptions using Cox-Snell residual plots, adjusting for sex and for age at study entry, stratified by baseline CD4+ cell count for possible confounding or residual effects. Variables that were found to be statistically significant (P < .15) in the univariate model were selected to build a multivariable model. All P values were determined by means of 2-tailed tests.
Results
A total of 5832 patients followed up during the HAART era were eligible for analysis, representing 34,133 patient-years of follow-up. A total of 2049 persons met our eligibility criteria, and the majority were male (86.6%). The mean age of this subgroup was 34.2 years, similar to that for the entire cohort. Of these 2049 individuals, 1467 underwent testing for detection of HCV, and 1382 were HCV antibody negative. The prevalence of HIV-1-HCV coinfection in our study cohort was 5.8% (85 of 1467 patients).
Table 1 shows the results of the univariate model. Patients naive to antiretrovirals were significantly less likely to experience an event than were antiretroviral-experienced patients, because their higher CD4+ cell counts did not necessitate therapy. This was found to be true for every individual drug component of HAART that we examined (P < .001). Women were significantly more likely to experience an event than were men (P = .034), and use of a continuous variable for age revealed that the likelihood of experiencing an event increased by 1% for each 1-year increase in age (P = .044).
Because all antiretroviral-naive patients were less likely to experience an event than were antiretroviral-experienced patients, we compared the groups as a whole (table 2). After adjusting for age, sex, and antiretroviral use (naive vs. experienced) and stratifying the analysis according to baseline CD4+ cell count, the factors remaining significantly and independently predictive of an event were HCV positivity and no antiretroviral experience. Patients who were HCV positive were 52% as likely to experience an event than were patients who were HCV negative (hazard ratio, 1.52; 95% CI, 1.07-2.17). Results of DAVG analysis showing the differences between baseline and subsequent CD4+ cell counts for HIV-1-infected patients and patients with HIV-1-HCV coinfection appear in figure 1. The differences were similar at nearly all time points for both groups. and 95% CIs were widely overlapping.
Discussion
We demonstrated that individuals with HIV-1-HCV coinfection have an increased likelihood of developing a CD4+ cell count of <200 cells/mm3 or their first AIDS-defining illness, compared with HIV-1-infected individuals. The rate at which the CD4+ cell count decreased was not significantly different between the 2 groups. The clinical data on whether HCV infection alters the natural history of HIV-1 infection are conflicting. In a large cohort study of HIV-1-infected individuals in Switzerland, Greub et al. [26] reported that, during a median follow-up period of 28 months, HCV seropositivity increased the likelihood of progression to a new AIDS-defining clinical event or to death. However, this decrease in survival duration did not appear to be due to a reduced responsiveness to HAART by patients with coinfection, because there was no association between HCV seropositivity and the probability of reaching an HIV-1 RNA load of <400 copies/mL. The increase in CD4+ cell count in response to antiretroviral therapy did, however, appear to be less in patients with HIV-1-HCV coinfection, compared with patients with HIV-1 infection alone. The authors hypothesized that HCV could have a direct pathogenic effect on lymphocytes, impairing the recovery of HIV-1-related immune function with antiretroviral therapy, thus explaining both the progression to AIDS and the delay in the CD4+ cell count recovery in patients infected with HCV [26].
Results of other smaller studies during the HAART era agreed with these findings and showed faster disease progression in the context of coinfection [27, 28], which was especially marked in injection drug users (a group constituting <5% of our cohort) [29, 30]. However, additional longitudinal studies have shown no significant increases in the rate of progression during coinfection [31-34], although patients infected with HCV genotype 1 were shown to have a faster rate of progression [35] (HCV genotypes in our cohort have been determined in <20% of infected patients).
Although DAVG analyses did not show any differences in CD4+ cell count decreases between HIV-1-infected patients and patients with HIV-1-HCV coinfection, the groups differed with respect to the likelihood of having an event, suggesting that HCV infection is having an effect on HIV-1 disease progression that is not reflected by a change in CD4+ cell count. For example, it is conceivable that our data may be explained by an effect of HCV on CD8+ cytotoxic T cells [36] or dendritic cells [37], although interestingly, immune responses in patients coinfected with HIV-1 and HCV do not appear be more compromised than those in patients with HIV-1 monoinfection [37].
More recently, Sulkowski et al. [38] showed no difference in the risk of death or in the risk of developing a new AIDS-defining illness between patients with and patients without HCV infection. However, survival duration was reduced in HCV-infected patients with baseline CD4+ cell counts of 50-200 cells/mm3, but this difference was not observed in a multivariate model that adjusted for HAART use. Patients with HCV infection had an increased but nonsignificant likelihood of progression to a CD4+ cell count of <200 cells/mm3; this association between CD4+ cell count and HCV infection was not demonstrated in a multivariate regression analysis.
Differences in survival duration between HCV-positive patients and HCV-negative patients observed in the European study [26] were likely not due to differences in antiretroviral therapy, because the adverse effect of HCV infection was even seen in patients who had well-controlled HIV-1 infection and were receiving therapy [38]. Different outcomes observed may simply be due to differences in the demographic characteristics of the study populations. However, in other cohorts, the interval between the time of HIV-1 infection diagnosis and the onset of AIDS has been shown to be similar between HIV-1-infected patients and patients with HIV-1-HCV coinfection, supporting the lack of a direct effect of HCV infection on HIV-1 immune progression, as measured by CD4+ cell count [39]. Further effects of HCV infection on HIV-1 disease progression require additional clarification in large epidemiologic studies.
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