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HCV Impaired CD4 Response to ART, in this study
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The Journal of Infectious Diseases
Jan 15, 2006;193:259-268
"Immunologic Response to Antiretroviral Therapy in Hepatitis C Virus-Coinfected Adults in a Population-Based HIV/AIDS Treatment Program"
Paula Braitstein,1,2,a Carlos Zala,5 Benita Yip,1 Martin W. G. Brinkhof,4 David Moore,1 Robert S. Hogg,1,2 and Julio S. G. Montaner1,3
1British Columbia Centre for Excellence in HIV/AIDS and Departments of 2Health Care and Epidemiology and 3Medicine, University of British Columbia, Vancouver, Canada; 4Institute of Social and Preventive Medicine, University of Berne, Berne, Switzerland; 5Fundacion Huesped, Buenos Aires, Argentina
..... Our results suggest that HCV infection has an independent effect on the immunologic response to ART over time and that the baseline absolute CD4 cell count does not significantly alter the magnitude of the CD4 cell response when measured either in absolute numbers or as a percentage of the T cell population.....
".....The median time to an increase of >75 cells/mm3 in the absolute CD4 cell count was 69 days (interquartile range [IQR], 34-149 days) in HCV antibody-negative patients and 84 days (IQR, 40-171 days) in HCV antibody-positive patients (P = .05).... HCV antibody-positive patients remained less likely than HCV antibody-negative patients to have an increase of >75 cells/mm3 in the absolute CD4 cell count....
.....The damage caused by chronic HCV infection is not believed to be the consequence of direct destruction of hepatic cells by the virus but from an intermediate immune response that is large enough to induce hepatic cell destruction and fibrosis but small enough that the virus is not eradicated from its reservoirs [21]. A blunted immune response in HIV/HCV-coinfected patients may be due to the nonspecific immune stimulation driven by chronic HCV infection, or it may be that infection of immune cells by HCV could favor the depletion of CD4 cells.... The differences found at baseline between absolute and fraction measurements raise the issue of CD4 cell sequestration in HIV/HCV-coinfected patients. What this could mean clinically is unknown, but further research on these issues is needed. We recommend that this future research consider markers of both the absolute CD4 cell count and the CD4 cell fraction.....
.... In the adjusted analysis of the absolute CD4 cell counts, although both HCV antibodypositive and HCV antibodynegative patients had statistically significant increases, HCV antibodypositive patients had an average increase of 20 cells/mm3, compared with an average increase of 75 cells/mm3 in HCV antibodynegative patients. Even after the analysis was restricted to patients who were 95% adherent to ART, HCV antibodypositive patients had an average increase of 70 cells/mm3, compared with an average increase of 104 cells/mm3 in HCV antibodynegative patients. The difference in adjusted increases in the absolute CD4 cell count between HCV antibodypositive and HCV antibodynegative patients remained stable across the baseline absolute CD4 cell count strata....
..... The multivariate mixed-effect linear regression analysis of the CD4 cell fraction showed similar results: HCV antibodypositive patients had an average increase of 1.1%, compared with an average increase of 4.4% in HCV antibodynegative patients. After the analysis was restricted to patients who were 95% adherent to ART, HCV antibodypositive patients had an average increase of 2.8%, and HCV antibodynegative patients had an average increase of 3.8%......
Fig 1. Increases in CD4 cell responses after antiretroviral therapy (ART). A, Time to increase of >75 cells/mm3 in absolute CD4 cell count. B, Time to increase of >75 cells/mm3 in absolute CD4 cell count in patients >95% adherent to ART. C, Time to increase of 10% in CD4 cell fraction. D, Time to increase of 10% in CD4 cell fraction in patients >95% adherent to ART. HCV, hepatitis C virus.
When patients were stratified by baseline absolute CD4 cell count, relatively consistent associations were found with the absolute CD4 cell count (for baseline absolute CD4 cell count <200 cells/mm3, P < .001; for baseline absolute CD4 cell count <350 cells/mm3, P < .001; and for baseline absolute CD4 cell count >350 cells/mm3, P = .006), but more variable associations were found with the CD4 cell fraction (for baseline absolute CD4 cell count <200 cells/mm3, P = .41; for baseline absolute CD4 cell count <350 cells/mm3, P = .70; and for baseline absolute CD4 cell count >350 cells/mm3, P = .001).
Adherence to ART, as expected, had a significant effect on outcome. There were 255 HCV antibody-positive patients (42%) and 420 HCV antibody-negative patients (72%) who were >95% adherent to ART (P < .001). After we restricted the Kaplan-Meier analysis to patients >95% adherent to ART, HCV infection had a smaller but statistically significant effect on the absolute CD4 cell count (P = .024), whereas the effect on the CD4 cell fraction was not statistically significant (P = .73). When patients were stratified by baseline absolute CD4 cell count, there was no clear trend in the effect that HCV infection had on either the absolute CD4 cell count (for baseline absolute CD4 cell count <200 cells/mm3, P = .30; for baseline absolute CD4 cell count <350 cells/mm3, P = .04; and for baseline absolute CD4 cell count >350 cells/mm3, P = .34) or the CD4 cell fraction (for baseline absolute CD4 cell count <200 cells/mm3, P = .61; for baseline absolute CD4 cell count <350 cells/mm3, P = .31; and for baseline absolute CD4 cell count >350 cells/mm3, P = .07).
Most studies have found that HCV infection has no effect on the virologic response to ART [811], but, in the literature, there are conflicting reports regarding the immunologic response. The data on the immunologic response to ART may be inconsistent for several reasons. First, it can take up to 24 months of treatment for a complete CD4 cell response to occur [13], which is beyond the time frame of many studies. How an increase in the CD4 cell response is measured and defined is another key factor. Indeed, T cells may become sequestered secondary to HCV infection, and this may potentially affect the consistency between and the interpretability of data on the absolute and fraction T cell populations [14, 15]. Immune dysregulation due to both HIV and HCV infection may also lead to an impaired immunologic response, primarily in patients with low baseline CD4 cell counts.
Table 2 summarizes the results of unadjusted and adjusted Cox proportional hazards analyses of the probability of having an immunologic event (table 2). After we controlled for age at baseline (per 10-year increase), sex (male vs. female), having an AIDS diagnosis at baseline (yes vs. no), baseline absolute CD4 cell count (per 100-cell/mm3 increase), pVL (per log10 copies/mL), adherence to ART (>95% vs. <95%), type of ART initiated (PI vs. NNRTI), and number of CD4 cell measurements, HCV antibody-positive patients remained less likely than HCV antibody-negative patients to have an increase of >75 cells/mm3 in the absolute CD4 cell count (overall AHR, 0.84 [95% CI, 0.72-0.98]; P = .030). The effect that HCV infection had on the probability of having an increase of >10% in the CD4 cell fraction was less pronounced, although this difference may have been related to the smaller number of events (AHR, 0.89 [95% CI, 0.70-1.14]; P = .36). The effect that the baseline absolute CD4 cell count had on the AHRs by absolute CD4 cell count (baseline absolute CD4 cell count <200 cells/mm3: AHR, 1.00 [95% CI, 0.66-1.51] [P = .98]; baseline absolute CD4 cell count <350 cells/mm3: AHR, 1.12 [95% CI, 0.81-1.53] [P = .50]; baseline absolute CD4 cell count >350 cells/mm3: AHR, 0.64 [95% CI, 0.43-0.96] [P = .031]) and the CD4 cell fraction (baseline absolute CD4 cell count <200 cells/mm3: AHR, 0.68 [95% CI, 0.46-1.01] [P = .13]; baseline absolute CD4 cell count <350 cells/mm3: AHR, 0.77 [95% CI, 0.561.05] [P = .056]; baseline absolute CD4 cell count >350 cells/mm3: AHR, 0.97 [95% CI, 0.62-1.50] [P = .87]) was limited.
In a subanalysis, the effect that HCV infection had on the probability of having an increase of 75 cells/mm3 in the absolute CD4 cell count or an increase of 10% in the CD4 cell fraction was examined in Cox proportional hazards analysis using time-updated pVL. pVL over time was, as expected, a very strong predictor of having an increase in either the absolute CD4 cell count (AHR, 0.33 [95% CI, 0.300.37]; P < .001) or the CD4 cell fraction (AHR, 0.36 [95% CI, 0.300.44]; P < .001). However, after adjustment for this factor, the effect of HCV infection on having an increase in either the absolute CD4 cell count (AHR, 1.00 [95% CI, 0.861.17]) or the CD4 cell fraction (AHR, 1.04 [95% CI, 0.811.33]) became nonsignificant.
The effects of outcomes in both the absolute CD4 cell count and the CD4 cell fraction examined as continuous repeated measures in the multivariate mixed-effects linear regression analysis are summarized in tables 3 and 4. Table 3 displays the results (coefficients, SEs, and P values) of the model, whereas table 4 provides the interpreted results from the adjusted analyses, calculated using the coefficient estimates presented in table 3. Table 4 also presents the unadjusted median changes.
The immunologic response to ART in patients coinfected with HIV and HCV is important because of its implications for when to initiate ART. HCV-related hepatic fibrosis progression in HIV-infected patients is strongly associated with a weakened immune system [16], and delaying ART for too long may result in a more-rapid progression of HCV diseaseparticularly if a patient's immunologic recovery will be only partial. Although treatments for HCV infection are becoming more effective, unfavorable genotypes [17, 18], as well as concomitant anemia, depression [16, 19], or HIV infection [2022], mean that only a limited number of HIV/HCV-coinfected patients can expect to successfully complete HCV treatment. Thus, ART for HIV is paramount to the health management of these coinfected patients.
The primary objective of the present study was to examine outcomes in the absolute CD4 cell count and the percentage of CD4 cells in the total T cell population during the first 48 weeks of ART in previously ART-naive HCV antibodypositive and HCV antibodynegative HIV-infected patients in a population-based HIV/AIDS treatment program. Our secondary objective was to describe the contribution of the baseline absolute CD4 cell count to this response.
Outcome measures. The primary outcome measure for this analysis was the CD4 cell response, measured using both absolute CD4 cell counts and CD4 cells as a percentage of the total T cell population (referred to throughout this article as "the CD4 cell fraction" and expressed as a percentage), comparing HCV antibodypositive and HCV antibodynegative HIV-1-infected patients. Events were defined, respectively, as an increase of >75 cells/mm3 in the absolute CD4 cell count or an increase of >10% in the CD4 cell fraction within the first 48 weeks of treatment. We also examined both absolute and CD4 cell fraction measurements as continuous repeated outcomes throughout the first 48 weeks of ART.
ABSTRACT
Background. We sought to characterize the impact that hepatitis C virus (HCV) infection has on CD4 cells during the first 48 weeks of antiretroviral therapy (ART) in previously ART-naive human immunodeficiency virus (HIV)infected patients.
Methods. The HIV/AIDS Drug Treatment Programme at the British Columbia Centre for Excellence in HIV/AIDS distributes all ART in this Canadian province. Eligible individuals were those whose first-ever ART included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor and who had a documented positive result for HCV antibody testing. Outcomes were binary events (time to an increase of 75 CD4 cells/mm3 or an increase of 10% in the percentage of CD4 cells in the total T cell population [CD4 cell fraction]) and continuous repeated measures. Statistical analyses used parametric and nonparametric methods, including multivariate mixed-effects linear regression analysis and Cox proportional hazards analysis.
Results. Of 1186 eligible patients, 606 (51%) were positive and 580 (49%) were negative for HCV antibodies.
HCV antibody-positive patients were slower to have an absolute (P < .001) and a fraction (P = .02) CD4 cell event.
In adjusted Cox proportional hazards analysis (controlling for age, sex, baseline absolute CD4 cell count, baseline pVL, type of ART initiated, AIDS diagnosis at baseline, adherence to ART regimen, and number of CD4 cell measurements), HCV antibody-positive patients were less likely to have an absolute CD4 cell event (adjusted hazard ratio [AHR], 0.84 [95% confidence interval {CI}, 0.720.98]) and somewhat less likely to have a CD4 cell fraction event (AHR, 0.89 [95% CI, 0.701.14]) than HCV antibody-negative patients.
In multivariate mixed-effects linear regression analysis, HCV antibody-negative patients had increases of an average of 75 cells in the absolute CD4 cell count and 4.4% in the CD4 cell fraction, compared with 20 cells and 1.1% in HCV antibody-positive patients, during the first 48 weeks of ART, after adjustment for time-updated pVL, number of CD4 cell measurements, and other factors.
Conclusion. HCV antibody-positive HIV-infected patients may have an altered immunologic response to ART.
RESULTS
Of the 1388 patients in the HOMER cohort, 1186 were available for the present analysis, including 606 (51%) who were HCV antibody positive and 580 (49%) who were HCV antibody negative. Those with HCV serological data available were more likely to be male (86% vs. 75%; P < .001), but there was no difference in history of injection drug use (27% vs. 27%; P = .92), having an AIDS diagnosis at baseline (13% vs. 14%; P = .68) (TABLE SAYS: AIDS diagnosis, no. (%): 65 (11) HCV+, 87 (15) (HCV-, p=.028), median age at baseline (37 vs. 37 years; P = .51), median baseline absolute CD4 cell count (260 vs. 270 cells/mm3; P = .14), and baseline pVL (5.1 vs. 5.1 log10 copies/mL; P = .36) between the groups.
The baseline characteristics of HCV antibodypositive and HCV antibodynegative patients are summarized in table 1. There were no statistical differences at baseline in the median age, median absolute CD4 cell count, pVL, or type of ART initiated. However, HCV antibody-positive patients were less likely to be male (78% vs. 93%; P < .001), more likely to have a history of injection drug use (47% vs. 6%; P < .001), and less likely to have an AIDS diagnosis at baseline (11% vs. 15%; P = .028) than HCV antibody-negative patients. In addition, in spite of having the same median absolute CD4 cell count as HCV antibody-negative patients, they had a significantly higher baseline median CD4 cell fraction (19% vs. 16%; P < .001).
The median time to an increase of >75 cells/mm3 in the absolute CD4 cell count was 69 days (interquartile range [IQR], 34-149 days) in HCV antibody-negative patients and 84 days (IQR, 40-171 days) in HCV antibody-positive patients (P = .05). The median time to censoring in the absolute CD4 cell count time-to-event analysis was 197 days (IQR, 0.5-282 days) in HCV antibody-negative patients and 199.5 days (IQR, 0.5279 days) in HCV antibody-positive patients (P = .93). The median time to a CD4 cell fraction event (>10% increase) was 151 days (IQR, 58-235 days) in HCV antibody-negative patients and 89.5 days (IQR, 49207 days) in HCV antibody-positive patients (P = .05). The median time to censoring in the CD4 cell fraction analysis was 269.5 days (IQR, 206.5307 days) in HCV antibody-negative patients and 244.5 days (IQR, 145-294 days) in HCV antibodypositive patients (P < .001). HCV antibody-positive patients had fewer CD4 cell measurements (median, 3 tests [IQR, 24 tests]) performed than did HCV antibodynegative patients (median, 4 tests [IQR, 35 tests]), and this was controlled for in adjusted analyses.
More Author Discussion
Our results suggest that HCV infection has an independent effect on the immunologic response to ART over time and that the baseline absolute CD4 cell count does not significantly alter the magnitude of the CD4 cell response when measured either in absolute numbers or as a percentage of the T cell population. Our findings support those of others [8, 30, 31]. The Swiss HIV Cohort Study reported that HCV infection predicted a longer time to an increase of at least 50 cells/mm3 in the CD4 cell count after initiation of ART [8]. Using linear regression analysis, an Italian cohort found that HCV-positive patients had a smaller increase in the CD4 cell count than did HCV-negative patients [30]. Our data are in contrast with those from studies that found that HCV infection had little or no effect on the CD4 cell response after initiation of ART [9-12, 32]. Sulkowski et al. found that HIV/HCV-coinfected patients had a statistically higher median CD4 cell fraction at baseline than did HCV-negative patients but found no evidence that HCV infection altered either the absolute CD4 cell count or the CD4 cell fraction [11]. A study of the HIV-Netherlands Australia Thailand cohort found that mean increases in the CD4 cell count were significantly lower in HCV-positive patients than in HCV-negative patients at week 4 but that the differences were not present by week 48 [33].
Our analysis has several strengths. First, our sample was drawn from a large population-based program, making our data more generalizable than those from clinic-based studies, cohort studies, or clinical trials. Second, we were able to account for the confounding effect of adherence to ART, through statistical adjustment and restriction based on our adherence measure, as well as through controlling for pVL response over time. This enabled us to adjust for any differences in pVL trajectories between HCV antibody-positive and HCV antibody-negative patients. Our finding that using time-updated pVL removed the effect of HCV infection in Cox proportional hazards analysis but not in multivariate mixed-effects linear regression analysis suggests that Cox models may be insufficiently sensitive for detecting differences in a continuous outcome (CD4 cells) that is artificially dichotomized, as is required in time-to-event analyses, and may explain, in part, some of the disparity in the findings in the literature. Third, by using both repeated measures and time-to-event analyses and by studying outcomes in both absolute CD4 cell counts and CD4 cell fractions, we were able to elucidate some of the complexities in analyzing the immunologic response to ART in HIV/HCV-coinfected patients. Our results were robust to different random effects (patient ID, time since initiation of ART, and baseline absolute CD4 cell count) and were independent of the number of CD4 cell measurements in HCV antibody-positive and HCV antibody-negative patients. Finally, our analyses were based on previously ART-naive patients initiating ART with highly potent regimens and did not include patients initiating triple-nucleoside regimens.
SUBJECTS, MATERIALS, AND METHODS
Data source: HIV/AIDS Drug Treatment Programme. Since 1986, antiretroviral drugs have been centrally distributed in British Columbia at no cost to eligible HIV-infected patients. In October 1992, the distribution of antiretroviral drugs became the responsibility of the HIV/AIDS Drug Treatment Programme of the British Columbia Centre for Excellence in HIV/AIDS. This distribution program remains the only free source of antiretroviral drugs in this Canadian province (and it is a unique program in Canada). The HIV/AIDS Drug Treatment Programme has received ethics approval from the University of British Columbia Ethics Review Committee at its St. Paul's Hospital site, and the program conforms with the province's Freedom of Information and Protection of Privacy Act.
The HIV/AIDS Drug Treatment Programme distributes antiretroviral drugs on the basis of specific guidelines generated by the Therapeutic Guidelines Committee [23]. These guidelines are consistent with the treatment guidelines published by the International AIDS Society [13, 24-26]. The HIV/AIDS Drug Treatment Programme's guidelines recommend that CD4 cell counts and plasma HIV-1 RNA loads (pVLs) be monitored at baseline, at 4 weeks after initiation of ART, and every 3 months thereafter. In this program, pVLs are measured using the Amplicor HIV-1 Monitor test (Roche Diagnostics). All classes of federally licensed antiretroviral drugs--including all nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs)--are presently available through the program. Tenofovir, atazanavir, and enfuvirtide are also available.
Patients are automatically entered into the HIV/AIDS Drug Treatment Programme when they are first prescribed any antiretroviral drug. At entry into the program and with each subsequent physician visit, the patient's history (if any) of antiretroviral drug use, the absolute CD4 cell count, and pVL are recorded. Typically, patients are followed up at 3-month intervals, at which time prescriptions are renewed or altered on the basis of treatment success and other clinical factors.
Study population. The HAART Observational Medical Evaluation and Research (HOMER) study is a nested cohort within the HIV/AIDS Drug Treatment Programme. It includes all previously ART-naive patients who initiated ART consisting of 2 NRTIs and either a PI or an NNRTI between July 1996 and August 2000. The data used in the present analyses are from patients in the HOMER cohort for whom HCV serological data were available.
Statistical analyses. We used an intent-to-treat approach whereby all eligible patients were included in the study when they were first dispensed antiretroviral drugs, regardless of whether they later discontinued or modified their regimen. HCV antibody-positive and HCV antibody-negative patients were compared using both parametric and distribution-free methods. Categorical data were analyzed using Pearson's x2 test. Fisher's exact test was used for contingency tables in which >25% of the expected cell frequencies were <5. Continuous variables were analyzed using the Wilcoxon rank-sum test.
Kaplan-Meier analysis was used to calculate cumulative rates of a increase of >75 cells/mm3 in the absolute CD4 cell count or an increase of >10% in the CD4 cell fraction. In secondary analyses, we stratified the population by baseline absolute CD4 cell count (<200 cells/mm3, <350 cells/mm3, and >350 cells/mm3). Because of small numbers, the <350 cells/mm3 group included patients with <200 cells/mm3. Cox proportional hazards analysis was used to calculate unadjusted and adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). Possible confounding factors adjusted for were sex (male vs. female), age at baseline (continuous), AIDS diagnosis at baseline (yes vs. no), absolute CD4 cell count (per 100-cell/mm3 increase) or CD4 cell fraction (per 5% increase), log-transformed pVL (continuous, per log10 copies/mL), type of treatment initiated (PI vs. NNRTI based), adherence to ART in the first year of treatment (>95% vs. <95%), and number of CD4 cell measurements (continuous). In a subanalysis, Cox proportional hazards analysis was conducted using time-updated pVL response, in addition to the aforementioned variables. The assumption of proportional hazards was validated by inspection of log10(-log10[survival function]) estimates against log time plots.
Multivariate mixed-effects linear regression analysis was performed to model CD4 cell slopes (absolute and fraction) during the first 48 weeks of ART, primarily for the whole population and secondarily stratified by baseline absolute CD4 cell count (<200 cells/mm3, <350 cells/mm3, and >350 cells/mm3). Independent fixed effects included were HCV antibody status at baseline (positive vs. negative), time since initiation of ART (weeks), sex (male vs. female), age at baseline, and pVL (categorized as <500 copies/mL, 500-20,000 copies/mL, and >20,000 copies/mL), and the latter was updated over time. Random effects included were patient identification (ID), time since initiation of ART (weeks), and baseline absolute CD4 cell count (continuous). All patients were included in the multivariate mixed-effects linear regression analysis, regardless of how many CD4 cell measurements they had. The effect of HCV infection over time was measured by creating an interaction term between HCV antibody status and time. Correlation between repeated outcome measures was assumed to be constant, but we tested whether using a time-decaying correlation structure made a difference (it did not). The data were analyzed using SAS (version 6.2; SAS Institute) and Stata (version 9; StataCorp). All reported P values are 2-tailed.
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