| |
Impact of Hepatitis C Virus on Immune Restoration in HIV-Infected Patients Who Start Highly Active Antiretroviral Therapy: A Meta-analysis
|
| |
| |
Clinical Infectious Diseases Sept 1 2005 vol 41, Number 5
Melissa Farmer Miller,1 Clinton Haley,2 Margaret James Koziel,3 and Christopher F. Rowley3
1Division of Cancer Prevention, Cancer Prevention Fellowship Program, National Cancer Institute, Bethesda, Maryland; 2Austin Medical Education Programs, Austin, Texas; and 3Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Numerous studies have reported on the CD4 response to HAART by HCV coinfected patients, finding conflicting results. some studies find no difference in CD4 response or in clinical HIV progression while other studies do. Here is a meta-analysis still trying but not succeeding in my mind in answering the question:
--Patients with HIV-HCV coinfection had a mean increase in the CD4 cell count that was 33.4 cells/mm3 (95% CI, 23.5-43.3 cells/mm3) less than that for HIV-infected patients without HCV infection
--The clinical consequences of a blunted CD4 cell count response are not yet known in this context.
-- The clinical significance of an impaired increase in the CD4 cell count may be different for someone who initiates HAART with a CD4 cell count of 100 cells/mm3, compared with someone who initiates it with a CD4 cell count of 300 cells/mm3. Whether immune reconstitution differs in these subgroups of patients with HCV-HIV coinfection and the clinical significance of this, in terms of the frequencies of opportunistic infections, should be explored in prospective studies.
-- there is benefit for earlier treatment of hepatitis C in HIV-coinfected patients in the hope of eradicating this infection before the initiation of HAART, to allow optimal immune reconstitution
--This meta-analysis is dependent on the published literature, and the studies reviewed are very different in their design. In all of the studies, the increase in the CD4 cell count was a secondary outcome..... This population often has less access to health care and typically has worse adherence to HIV regimens, compared with the population of patients who contracted HIV infection by other means....see Author Discussion below
ABSTRACT
Background. There are conflicting data in the medical literature regarding the degree of immune restoration (as measured by CD4 cell count) in patients who commence highly active antiretroviral therapy (HAART) when coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), compared with those with HIV infection alone.
We conducted a meta-analysis to examine the difference in the increases in the CD4 cell count at least 12 months after HAART initiation in HCV-negative and HCV-positive patients who are infected with HIV. The objective of the meta-analysis was to determine whether there is a blunted increase in the CD4 cell count after initiation of HAART in HIV-HCV-coinfected patients relative to patients with HIV infection alone.
Methods. We performed a meta-analysis that compared CD4 cell count increases after HAART initiation in HCV-negative and HCV-positive patients who were infected with HIV. Published studies in the English-language medical literature that involved cohorts of HCV-negative and HCV-positive patients who were coinfected with HIV were obtained by searching the Medline, Embase Drugs and Pharmacology, and EBM Review-Cochrane Central Register of Controlled Trials databases. Data were extracted independently from relevant studies by 3 investigators and were used in a fixed-effects meta-analysis to determine the mean difference in the expected CD4 count change in the 2 groups.
Results. Eight trials involving 6216 patients were analyzed. Patients with HIV-HCV coinfection had a mean increase in the CD4 cell count that was 33.4 cells/mm3 (95% CI, 23.5-43.3 cells/mm3) less than that for HIV-infected patients without HCV infection. The results of the meta-analysis were independent of any one study and were not influenced by the year in which HAART was started.
The 95% CI for the mean difference is -43.3 to -23.5 cells/mm3, indicating a less robust increase in the CD4 cell count among HCV-HIV-coinfected subjects when analyzed >48 weeks after the initiation of HAART.
The clinical consequences of a blunted CD4 cell count response are not yet known in this context.
This result was statistically significant and suggests that HIV-infected patients are likely to have a better immunological response to antiretroviral therapy if they are not coinfected with HCV.
Treatment of hepatitis C with pegylated IFN and ribavirin results in viral eradication in a substantial fraction of patients with HCV-HIV coinfection [18, 19]. The result of this study should prompt further investigations designed to determine whether there is benefit for earlier treatment of hepatitis C in HIV-coinfected patients in the hope of eradicating this infection before the initiation of HAART, to allow optimal immune reconstitution. In addition to preventing a weakened CD4 cell response to HAART, earlier therapy for HCV infection may help reduce potential liver toxicity associated with antiretroviral therapy.
Conclusions. This meta-analysis shows that patients with HIV-HCV coinfection do, in fact, have less immune reconstitution, as determined by CD4 cell count after 48 weeks of HAART, than do patients with HCV infection alone.
Future research should examine whether an impaired immunologic response corresponds with meaningful virologic and clinical outcomes.
The discrepancy in the CD4 cell count increase with HAART between these 2 groups may have implications for HIV care, particularly for subjects who initiate HAART at lower CD4 cell counts. Current HIV guidelines published by the US Department of Health and Human Services suggest that HAART should commence when the CD4 cell count decreases to <350 cells/mm3 or when the patient has an HIV load of >55,000 copies/mL [17]. Additionally, clinical decisions regarding chemoprophylaxis for the prevention of opportunistic infections in patients with HIV infection, such as Pneumocystis jiroveci pneumonia and disseminated Mycobacterium avium complex infections, are based largely on CD4 cell count.
All 8 studies were cohort studies; 3 were retrospective in design, and 5 were prospective in design. One-half of the studies were conducted in western Europe (n = 4), and the remaining studies were conducted in North America (n = 3) and Australia (n = 1). The years that subjects entered the cohorts ranged between 1992 and 2002. Sample sizes ranged from 68 to 2333 subjects (mean, 777 subjects). The median age of HCV-negative subjects was 36 years, and it was 35 years for HCV-positive subjects. Although actual percentage differences were not available for all studies, there were disproportionate numbers of injection drug users in the HCV-positive subgroups. Of the 4 studies that included mean or median pre-HAART CD4 cell counts, averages of these measurements revealed that the average pre-HAART CD4 cell count was 291 cells/mm3 for HCV-negative subjects and 307 cells/mm3 for HCV-positive subjects. Four of the studies included patients with prior use of antiretroviral therapies. Durations of follow-up ranged from 48 weeks to 4 years, with a mean duration of follow-up of 1 year, 9 months.
AUTHOR DISCUSSION
There are limitations, however, to this type of analysis. Initially, we sought to examine potential effect modification by baseline CD4 cell count, but several studies did not report a baseline measurement for the analytic subgroup. We cannot determine, for example, whether the effect is the same or different for individuals with a baseline CD4 cell count of <100 cells/mm3, compared with patients with higher values. There appeared to be a wide range in baseline CD4 cell counts in those studies that did report their values, and it would have been productive to have been able to stratify the changes in the groups on the basis of the baseline CD4 cell counts. In some studies, only the change was noted, and not the actual starting CD4 cell count, and in 2 instances, crude data were not provided and only adjusted data were given. The clinical significance of an impaired increase in the CD4 cell count may be different for someone who initiates HAART with a CD4 cell count of 100 cells/mm3, compared with someone who initiates it with a CD4 cell count of 300 cells/mm3. Whether immune reconstitution differs in these subgroups of patients with HCV-HIV coinfection and the clinical significance of this, in terms of the frequencies of opportunistic infections, should be explored in prospective studies.
Another limitation of this study is that many of the studies we used in our analysis reported only HCV antibody positivity. However, at least 15% of patients with HCV seropositivity will, in fact, have cleared HCV [18]. If a significant percentage of patients in these studies are, in fact, not viremic, if anything, we would expect the difference in immune reconstitution to be greater when only viremic patients were included. Furthermore, there is no information about the degree of liver dysfunction in the patients in these studies. It is possible that underlying liver dysfunction may be related to the changes in CD4 cell count.
This meta-analysis is dependent on the published literature, and the studies reviewed are very different in their design. In all of the studies, the increase in the CD4 cell count was a secondary outcome, and many of the studies are statistically underpowered to examine the specific question of interest to us. Although the formal tests for heterogeneity among studies did not demonstrate any significant differences, there are clearly differences between populations coinfected with HCV-HIV and those infected with HIV alone. HCV-HIV-coinfected individuals are far more likely to have contracted HIV infection via injection drug use. This population often has less access to health care and typically has worse adherence to HIV regimens, compared with the population of patients who contracted HIV infection by other means. Adherence to HAART in this population may be directly related to improvements in the CD4 cell count [20]. Interestingly, in the large study by Greub et al. [4], there was an equivalent response in the nearly 1600 HCV-positive and HCV-negative patients with respect to their ability to suppress HIV while receiving HAART. Six of the 7 remaining studies commented similarly on this finding, suggesting that adherence to treatment is unlikely to play a role in the findings of this meta-analysis [5, 7-11].
We found no evidence of publication bias, but we recognize that the Begg and Mazumdar's and Egger and colleagues' tests are limited in their ability to indicate publication bias when there are a limited number of studies. We cannot exclude the possibility of reporting bias, in that studies with a negative finding (i.e., no association between CD4 cell count response and HCV infection status) may not have been deemed by study authors or editors to be of sufficient interest to warrant publication.
The clinical consequences of a blunted CD4 cell count response are not yet known in this context. Care of patients with HIV infection is not limited to simply measurements of CD4 cell counts but also depends on knowledge of both clinical and virologic status. This analysis does not attempt to account for the clinical outcome in patients stratified by HCV infection status because of the wide degree of variation in methods of reporting clinical outcomes in the 8 studies. Viral load data, before and after the initiation of HAART, were not provided in all 8 studies and were not further analyzed. As noted above, however, in 7 of the 8 studies, there was no difference in the ability to suppress HIV virologically in the 2 different groups. The clinical consequences of the observed difference in CD4 cell count response described in this analysis should be further explored.
Our meta-analysis showed that the increase in the CD4 cell count in patients who started receiving HAART for HIV infection is significantly lower if they have HCV coinfection. To gain a better understanding of the true nature of the effect of HCV infection on the response to HAART in HIV-infected patients, prospective cohort studies should be conducted that account for multiple variables, such as degree of liver disease, duration of HIV and HCV infection, baseline HIV load, and different treatment regimens. The best time to initiate hepatitis C treatment in HIV-infected individuals remains unknown. Additional prospective studies need to be conducted to provide the definitive answer to patients and clinicians, so that both infections can be treated in the most effective manner.
|
|
| |
| |
|
|
|
