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Hepatitis C and Progression of HIV Disease
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Mark S. Sulkowski, MD; Richard D. Moore, MD; Shruti H. Mehta, PhD, MPH; Richard E. Chaisson, MD; David L. Thomas, MD
Summary: This study found different results from other recently reported
studies on the effect of HCV in HIV coinfected patients. I think an important
limitation of this study is the short average follow-up of just over 2 years.
The authors said they examined patients with 4 years follow-up and found the
same results but I think 4 years follow-up is also limited. The authors in
this study found differently than the Swiss Cohort findings reported first at
the Durban Intl AIDS Conference. The Swiss Cohort Study found HCV increased
the risk of developing AIDS and death in HIV coinfected patients, and the
average follow-up of patients was also only 28 months. This current study
found HCV did not result in increased risk of dying due to HIV related
causes, or to developing AIDS. However, if you read through the study you'll
see that death certificates did not list the cause of death-whether it is due
to liver disease or not. This study also found differently than observed in
several other studies reported over the past year-- this Sulkowski study
found that the CD4 increase from HAART was not blunted in HCV coinfected
patients while several studies have found HCV can blunt CD4 response to
HAART.
ABSTRACT
Context Conflicting reports exist regarding the effect of hepatitis C virus (HCV) on the progression of human immunodeficiency virus (HIV) disease.
Objective To assess the effect of HCV infection on clinical and immunologic progression of HIV disease and immunologic response to highly active antiretroviral therapy (HAART).
Design Prospective cohort study.
Setting University-based, urban HIV clinic in the United States.
Patients There were 1955 patients enrolled between January 1995 and January 2001 who were eligible for analysis because of having at least 1 return visit to the clinic and being free of acquired immunodeficiency syndrome (AIDS) at enrollment. Median (interquartile range) length of follow-up was 2.19 (1.00-3.50) years for HCV-infected and 2.00 (1.00-3.00) years for HCV-uninfected patients.
Main Outcome Measures Progression to an AIDS-defining illness, survival, and progression to a CD4 cell count below 200/無; CD4 cell count change following initiation of effective HAART (resulting in a viral load of <400 copies/mL recorded at 75% of measurements).
Results No difference was detected in the risk of acquiring an AIDS-defining illness (HCV-infected patients, 231 events [26.4%] and HCV-uninfected patients, 264 events [24.4%]; relative hazard [RH], 1.03; 95% confidence interval [CI], 0.86-1.23) or in the risk of death (HCV-infected patients, 153 deaths [17.5%] and HCV-uninfected patients, 168 deaths [15.5%]; RH, 1.05; 95% CI, 0.85 -1.30). Although an increased risk of death was detected in the subgroup of 429 HCV-infected patients with a baseline CD4 cell count of 50/無 through 200/無 (RH, 1.51; 95% CI, 1.01-2.27), after adjustment for exposure to HAART and its effectiveness in a multivariate Cox regression analysis, death was not independently associated with HCV infection in this subgroup (RH, 1.01; 95% CI, 0.65-1.56). Similarly, in those receiving effective HAART (n = 208), there was no difference in the increase in CD4 cell count or CD4 percentage during HAART in HCV-infected compared with HCV-uninfected patients.
Conclusions Among patients in this urban US cohort, we did not detect evidence that HCV infection substantially alters the risk of dying, developing AIDS, or responding immunologically to HAART, especially after accounting for differences in its administration and effectiveness.
JAMA. 2002;288:199-206
Due to shared routes of transmission, an estimated 15% to 30% of human immunodeficiency virus (HIV)-infected persons are coinfected with hepatitis C virus (HCV) in the United States and Europe.1, 2 Human immunodeficiency virus infection appears to increase the persistence of the hepatitis C virus, the level of HCV RNA, and, in most studies, progression of HCV-related liver disease.3-9 However, there are conflicting reports regarding the effect of HCV on the natural history of HIV disease. Prior to the availability of highly active antiretroviral therapy (HAART), increased rates of progression of HIV disease were detected in some studies5, 10, 11 but not others.12-17 Recently, Greub et al18 reported that, in a study involving HIV-infected patients in Switzerland, among patients receiving HAART, HCV-coinfected patients had decreased survival rates, increased risk of progression to acquired immunodeficiency syndrome (AIDS), and impaired CD4 cell recovery.
The objective of this study was to assess the effect of HCV coinfection on clinical and immunologic progression of HIV-1 disease and immunologic response to HAART in a large, urban US patient cohort observed before and during the advent of HAART.
RESULTS
In multivariate logistic regression analysis of baseline variables associated with HCV exposure at entry into the cohort, age older than 30 years (OR, 2.05; 95% confidence interval [CI], 1.42-2.95), African American race (OR, 1.93; 95% CI, 1.39-2.67), and a history of injection drug use (OR, 33.67; 95% CI, 25.93-43.71) were independently associated with HCV status. The median (interquartile range) length of follow-up was 2.19 (1.00-3.50) years for HCV-infected and 2.00 (1.00-3.00) years for HCV-uninfected patients. We did not exclude patients based on a minimum duration of follow-up. Of 1955 patients included in the analysis, 29 (1.5%) had fewer than 90 days of follow-up, of whom 12 (41%) and 17 (59%) were HCV-infected and HCV-uninfected, respectively. When these 29 individuals were removed from analyses of progression to AIDS, death, or CD4 cell count below 200/無, in the 1926 patients with more than 90 days of follow-up we found no significant changes from the reported findings (M.S.S, unpublished data, January 2002).
Progression to AIDS-Defining Illness
No difference was detected in the risk of acquiring an AIDS-defining illness among HCV-infected patients (231 events [26.4%]) and HCV-uninfected patients (264 events [24.4%]) (relative hazard [RH] by Cox proportional hazards regression, 1.03; 95% CI, 0.86-1.23). Figure 1 shows the Kaplan-Meier curves for probability of developing an AIDS-defining illness (conditional probability based on number of events per number of patients surviving to a given time point, giving cumulative incidence). Similarly, no difference was detected in the risk of progression to an AIDS-defining illness among HCV-infected patients compared with HCV-uninfected patients in the subgroup of 1199 patients who ultimately received HAART (RH, 1.09; 95% CI, 0.88-1.34) and in the subgroup of 250 patients with well-controlled HIV replication (RH, 0.57; 95% CI, 0.29-1.13). After stratification by baseline CD4 cell count category, no significant difference was detected in the risk of acquiring an AIDS-defining illness among HCV-infected and HCV-uninfected patients with CD4 cell counts below 50/無 (RH, 0.95; 95% CI, 0.73-1.24), from 50/無 through 200/無 (RH, 1.35; 95% CI, 0.93-1.88), or above 200/無 (RH, 1.25; 95% CI, 0.87-1.79).
Survival
No difference was detected in the risk of death among HCV-infected (153 deaths [17.5%]) compared with HCV-uninfected (168 deaths [15.5%]) patients (RH, 1.05; 95% CI, 0.85-1.30) (Figure 2A). Similarly, no difference was detected in the risk of death among HCV-infected compared with HCV-uninfected patients in the subgroup of 1199 patients who ultimately received HAART (RH, 1.22; 95% CI, 0.22-1.61) and in the subgroup of 250 patients with well-controlled HIV replication (RH, 1.49; 95% CI, 0.33-6.68). After stratification by baseline CD4 cell count category, no significant difference was detected in the risk of death among HCV-infected and HCV-uninfected patients with CD4 cell counts below 50/無 (RH, 1.13; 95% CI, 0.82-1.56) or above 200/無 (RH, 0.89; 95% CI, 0.56-1.42).
Effect of Antiretroviral Therapy by HCV Antibody Status
During the follow-up period, 1199 patients were prescribed HAART, including 54% of HCV-infected patients and 67% of HCV-uninfected patients (P<.001). The duration of exposure to HAART was significantly shorter for HCV-infected patients compared with HCV-uninfected patients except among the subgroup of patients with baseline CD4 cell count below 50/無 (Table 2). In univariate analysis, no difference was detected in the percentage of HCV-infected patients who had well-controlled HIV replication during HAART compared with HCV-uninfected patients receiving HAART in the entire cohort (29% for both groups; P = .89, 2 test) or among the subsets of patients with different baseline CD4 cell counts (above 200/無: 38.4% for HCV-infected and 37.2% for HCV-uninfected patients, P = .37; 50/無 through 200/無: 23.3% for HCV-infected and 25.6% for HCV-uninfected patients, P = .66; below 50/無: 21.3% for HCV-infected and 16.9% for HCV-uninfected patients, P = .80). In a multivariate logistic regression model, well-controlled HIV replication was independently associated with older age (OR, 1.03 per year; 95% CI, 1.01-1.05), white race (OR, 1.57; 95% CI, 1.14-2.17), and baseline HIV-1 RNA category (OR for 400-10 000 copies/mL, 0.22; 95% CI, 0.14-0.35; OR for >10 000 copies/mL, 0.14; 95% CI, 0.09-0.21), but not HCV infection (OR, 1.17; 95% CI, 0.86-1.60).
Among 208 subjects receiving effective HAART, defined as undetectable HIV RNA level at 75% or more of visits, no difference was detected between HCV-infected and HCV-uninfected patients in the increase in absolute CD4 cell count and CD4 cell percentage at 1, 2, and 3 years following the start of HAART (Table 3). In addition, at 1, 2, and 3 years after the start of HAART, no difference was detected in the probability of experiencing a CD4 cell count increase of at least 50/無 or 100/無 among HCV-infected and HCV-uninfected patients receiving effective HAART (Table 4).
Due to shared routes of transmission, an estimated 15% to 30% of human immunodeficiency virus (HIV)-infected persons are coinfected with hepatitis C virus (HCV) in the United States and Europe.1, 2 Human immunodeficiency virus infection appears to increase the persistence of the hepatitis C virus, the level of HCV RNA, and, in most studies, progression of HCV-related liver disease.3-9 However, there are conflicting reports regarding the effect of HCV on the natural history of HIV disease. Prior to the availability of highly active antiretroviral therapy (HAART), increased rates of progression of HIV disease were detected in some studies5, 10, 11 but not others.12-17 Recently, Greub et al18 reported that, in a study involving HIV-infected patients in Switzerland, among patients receiving HAART, HCV-coinfected patients had decreased survival rates, increased risk of progression to acquired immunodeficiency syndrome (AIDS), and impaired CD4 cell recovery.
The objective of this study was to assess the effect of HCV coinfection on clinical and immunologic progression of HIV-1 disease and immunologic response to HAART in a large, urban US patient cohort observed before and during the advent of HAART.
RESULTS
Of 2237 cohort participants enrolled between January 1995 and January 2001, 1955 patients who had at least 1 return visit to the clinic and who had not developed an AIDS-defining illness prior to enrollment were eligible for analysis. The clinical and demographic characteristics at cohort entry (baseline) are shown in Table 1. A total of 873 (44.6%) patients were HCV-infected, and compared with those without HCV infection, were older and more likely to be African American, and to use or have used injection drugs. No significant differences were detected between groups with respect to sex, hepatitis B surface antigen reactivity, and HIV RNA level. The HCV-infected patients had a lower absolute CD4 cell count but a higher CD4 cell percentage at entry compared with HCV-uninfected persons. While the majority of both HCV-infected and HCV-uninfected individuals were not receiving antiretroviral drug therapy at study entry, HCV-infected persons were less likely to have been prescribed antiretroviral drugs than those not infected with HCV (24% and 28%, respectively; P<.001). In multivariate logistic regression analysis of baseline variables associated with HCV exposure at entry into the cohort, age older than 30 years (OR, 2.05; 95% confidence interval [CI], 1.42-2.95), African American race (OR, 1.93; 95% CI, 1.39-2.67), and a history of injection drug use (OR, 33.67; 95% CI, 25.93-43.71) were independently associated with HCV status. The median (interquartile range) length of follow-up was 2.19 (1.00-3.50) years for HCV-infected and 2.00 (1.00-3.00) years for HCV-uninfected patients. We did not exclude patients based on a minimum duration of follow-up. Of 1955 patients included in the analysis, 29 (1.5%) had fewer than 90 days of follow-up, of whom 12 (41%) and 17 (59%) were HCV-infected and HCV-uninfected, respectively. When these 29 individuals were removed from analyses of progression to AIDS, death, or CD4 cell count below 200/無, in the 1926 patients with more than 90 days of follow-up we found no significant changes from the reported findings (M.S.S, unpublished data, January 2002).
Progression to AIDS-Defining Illness
No difference was detected in the risk of acquiring an AIDS-defining illness among HCV-infected patients (231 events [26.4%]) and HCV-uninfected patients (264 events [24.4%]) (relative hazard [RH] by Cox proportional hazards regression, 1.03; 95% CI, 0.86-1.23). Figure 1 shows the Kaplan-Meier curves for probability of developing an AIDS-defining illness (conditional probability based on number of events per number of patients surviving to a given time point, giving cumulative incidence). Similarly, no difference was detected in the risk of progression to an AIDS-defining illness among HCV-infected patients compared with HCV-uninfected patients in the subgroup of 1199 patients who ultimately received HAART (RH, 1.09; 95% CI, 0.88-1.34) and in the subgroup of 250 patients with well-controlled HIV replication (RH, 0.57; 95% CI, 0.29-1.13). After stratification by baseline CD4 cell count category, no significant difference was detected in the risk of acquiring an AIDS-defining illness among HCV-infected and HCV-uninfected patients with CD4 cell counts below 50/無 (RH, 0.95; 95% CI, 0.73-1.24), from 50/無 through 200/無 (RH, 1.35; 95% CI, 0.93-1.88), or above 200/無 (RH, 1.25; 95% CI, 0.87-1.79).
Survival
No difference was detected in the risk of death among HCV-infected (153 deaths [17.5%]) compared with HCV-uninfected (168 deaths [15.5%]) patients (RH, 1.05; 95% CI, 0.85-1.30) (Figure 2A). Similarly, no difference was detected in the risk of death among HCV-infected compared with HCV-uninfected patients in the subgroup of 1199 patients who ultimately received HAART (RH, 1.22; 95% CI, 0.22-1.61) and in the subgroup of 250 patients with well-controlled HIV replication (RH, 1.49; 95% CI, 0.33-6.68). After stratification by baseline CD4 cell count category, no significant difference was detected in the risk of death among HCV-infected and HCV-uninfected patients with CD4 cell counts below 50/無 (RH, 1.13; 95% CI, 0.82-1.56) or above 200/無 (RH, 0.89; 95% CI, 0.56-1.42).
Among the 429 patients with baseline CD4 cell counts from 50/無 through 200/無, the risk of death was higher among HCV-infected patients compared with HCV-uninfected patients (RH, 1.51; 95% CI, 1.01-2.27) (Figure 2B) and among the subset in this CD4 strata who received HAART (RH, 1.85; 95% CI, 1.11-3.07). However, among this group of patients with baseline CD4 cell counts from 50/無 through 200/無, multivariate Cox regression analysis revealed that death was independently associated with total exposure time (years) to HAART (RH, 0.47; 95% CI, 0.36-0.63), percentage of clinic visits with detectable HIV RNA level (RH, 7.96; 95% CI, 2.00-31.66), older age (RH, 1.05; 95% CI, 1.03-1.08), and baseline CD4 cell count (RH, 0.71 per 50 cells/無; 95% CI, 0.56-0.91), but not HCV infection (RH, 1.01; 95% CI, 0.65-1.56).
Progression to CD4 Cell Count Below 200/無
Among all persons with a baseline CD4 cell count above 200/無 (n = 1073), HCV-infected patients had a greater but statistically nonsignificant probability of progression to CD4 cell count below 200/無 (RH, 1.28; 95% CI, 0.98-1.68) (Figure 3). However, in multivariate Cox regression analysis, progression to CD4 cell count below 200/無 was independently associated with percentage of clinic visits with detectable HIV RNA level (RH, 2.80; 95% CI, 1.67-4.70), baseline CD4 cell count (RH, 0.74 per 50 cells/無; 95% CI, 0.70-0.79), and log baseline HIV RNA level (RH, 1.09; 95% CI, 1.03-1.16), but not HCV infection (RH, 1.13; 95% CI, 0.83-1.50). The median (interquartile range) CD4 cell count at time of HAART initiation for those with a baseline CD4 cell count above 200/無 was 336 (243-476) cells/無 and 373 (272-489) cells/無 for HCV-infected and HCV-uninfected patients, respectively (P = .09, Mann-Whitney test).
Effect of Antiretroviral Therapy by HCV Antibody Status
During the follow-up period, 1199 patients were prescribed HAART, including 54% of HCV-infected patients and 67% of HCV-uninfected patients (P<.001). The duration of exposure to HAART was significantly shorter for HCV-infected patients compared with HCV-uninfected patients except among the subgroup of patients with baseline CD4 cell count below 50/無 (Table 2). In univariate analysis, no difference was detected in the percentage of HCV-infected patients who had well-controlled HIV replication during HAART compared with HCV-uninfected patients receiving HAART in the entire cohort (29% for both groups; P = .89, 2 test) or among the subsets of patients with different baseline CD4 cell counts (above 200/無: 38.4% for HCV-infected and 37.2% for HCV-uninfected patients, P = .37; 50/無 through 200/無: 23.3% for HCV-infected and 25.6% for HCV-uninfected patients, P = .66; below 50/無: 21.3% for HCV-infected and 16.9% for HCV-uninfected patients, P = .80). In a multivariate logistic regression model, well-controlled HIV replication was independently associated with older age (OR, 1.03 per year; 95% CI, 1.01-1.05), white race (OR, 1.57; 95% CI, 1.14-2.17), and baseline HIV-1 RNA category (OR for 400-10 000 copies/mL, 0.22; 95% CI, 0.14-0.35; OR for >10 000 copies/mL, 0.14; 95% CI, 0.09-0.21), but not HCV infection (OR, 1.17; 95% CI, 0.86-1.60).
Among 208 subjects receiving effective HAART, defined as undetectable HIV RNA level at 75% or more of visits, no difference was detected between HCV-infected and HCV-uninfected patients in the increase in absolute CD4 cell count and CD4 cell percentage at 1, 2, and 3 years following the start of HAART. In addition, at 1, 2, and 3 years after the start of HAART, no difference was detected in the probability of experiencing a CD4 cell count increase of at least 50/無 or 100/無 among HCV-infected and HCV-uninfected patients receiving effective HAART.
COMMENTS BY AUTHORS
In this large, urban US HIV cohort, relatively high incidence of AIDS and death was observed, principally in persons not receiving HAART. However, when HCV-infected patients were compared with those without HCV infection, no differences were observed in the incidence of AIDS-defining illness, death, CD4 cell count decline to below 200/無, or CD4 cell count increase following effective HAART, especially after accounting for differences in the use of HAART by multivariate adjustment and by subgroup analysis of those with well-controlled HIV replication.
In our cohort, HCV-coinfected patients differed from patients without HCV infection in many respects, including the administration of HAART. The reasons for the disparity in the administration of HAART are incompletely understood. The HCV-coinfected patients may be more likely to develop antiretroviral-associated hepatotoxicity, which may influence medical decisions regarding the use of HAART.25-27 In addition, HCV-coinfected patients who are actively using injection drugs may be less likely to be prescribed HAART than are HCV-uninfected patients, who are substantially less likely to use or have used injection drugs.28-32 Nonetheless, among patients prescribed HAART, we found no evidence that HCV infection substantially alters the virological or immunologic response to potent antiretroviral therapy. These findings underscore the importance of the consideration of effective antiretroviral therapy for HIV-infected persons at immediate risk of developing AIDS, including those coinfected with HCV.
These findings are similar to the results of prior studies that found no evidence that HCV coinfection altered HIV disease progression.12-17 Our data contribute substantially to this literature because we prospectively evaluated a large number of patients, included more than 4300 person-years of follow-up after the advent of HAART, and considered a spectrum of HIV-related outcomes among antiretroviral-treated and -untreated patients.
Our findings differ from the results of the Swiss HIV Cohort investigation which found, among 3111 patients receiving HAART, a greater risk of progression to AIDS or death among persons coinfected with HCV (adjusted hazard ratio for combined end point of AIDS or death, 1.70; 95% CI, 1.26-2.30) and, among those who suppressed their HIV virus load, smaller increases in CD4 cell counts.18 We observed 187 deaths in 1199 patients (15.6%) receiving HAART in our cohort but only 6 deaths in 208 patients (2.9%) with well-controlled HIV replication. Our mortality rate was higher than that of the Swiss HIV Cohort study18 in which there were 181 deaths in 3111 patients (5.8%) receiving HAART and 20 deaths in 1596 patients (1.3%) having undetectable HIV RNA levels during the follow-up period. However, our mortality rate was similar to that of other North American studies. In the Multicenter AIDS Cohort Study,33 there were 41 deaths in 2888 men (14.2%) between July 1995 and July 1997, a time in which HAART was available to participants. In British Columbia, Hogg et al34 reported 23 deaths in 227 patients (10.1%) followed up in the HAART era. Finally, in participants in the HIV Outpatient Study,35 there was a death rate of 7.8% to 14.4% in yearly quartiles following HAART availability. While interesting, direct comparisons of these findings are limited by differences in patient populations and duration of follow-up among these patient cohorts. Furthermore, the ability to directly compare our findings with those of Greub and coworkers18 may be somewhat limited by differences in the clinical and sociodemographic characteristics of the respective cohort participants. For example, in our cohort, compared with HCV-uninfected patients, HCV-infected patients were older and more likely to be African American, whereas in the Swiss HIV Cohort, compared with HCV-uninfected patients, HCV-infected patients were younger, more likely to be female, and were principally white. In addition, Greub and coworkers analyzed only the cohort members who were receiving HAART, while in the investigation herein, all cohort members were considered (and HCV-infected patients were less likely to receive HAART).
Nonetheless, our study included data on 1199 patients who were receiving HAART, of whom 208 patients had durable suppression of HIV replication, comprising a subgroup of patients similar to those studied in the Swiss HIV Cohort. Among this subgroup of 1199 HAART recipients, we did not find evidence that HCV infection substantially alters the risk of progression to AIDS (RH, 1.09; 95% CI, 0.88-1.34) or death (RH, 1.22; 95% CI, 0.22-1.61) or the combined end point of AIDS or death (RH, 1.11; 95% CI, 0.92-1.34). Similarly, among those with effective HIV suppression, we did not find evidence that HCV infection substantially diminishes CD4 cell recovery during HAART. In addition, we considered the change in CD4 cell percentage following effective HAART, which may be less subject to within-subject variability over time compared with measurements of the absolute CD4 cell count, and thus may provide a more reliable assessment of the effect of HCV coinfection on immune recovery.36 Interestingly, since the CD4 cell count increase following HAART has been associated with significant reductions in AIDS-related illnesses, the lack of an independent association between HCV infection and HIV disease progression in our cohort may be explained by our finding that, in contrast to the findings of the Swiss HIV Cohort study, HCV infection did not alter CD4 cell recovery.18 Further research is needed to better understand the complex interaction between HCV and HIV infections and the immune system.
The results of this study could be affected by several potential limitations. First, since we did not differentiate between the causes of death, we were unable to evaluate the effect of HCV infection on the risk of death due to AIDS or liver disease. We do not provide data on cause of death because its ascertainment is not reliable and uniform. Smith et al37 compared clinical and autopsy-based cause-of-death data for 494 autopsies performed at Johns Hopkins Hospital and found that only 59% of certificates were properly completed and, of those, there was substantial disagreement between the clinical and autopsy-derived cause-of-death determinations in 49%. We reviewed records for the 321 observed deaths in this study and identified cause of death in only 60% of patients; we found that the role of contributory factors such as concurrent liver disease were not consistently reported, which could lead to inaccurate estimates of the burden of advanced liver disease in this population (M.S.S., unpublished data, January 2002). However, since deaths due to non-AIDS causes, such as opiate overdose, violence, and liver disease, occur more frequently among HCV-infected persons compared with HCV-uninfected persons, this approach should exaggerate rather than obscure an effect of HCV coinfection on mortality.8, 38, 39 Since we did not find an increased risk of death among HCV-infected patients after adjusting for HAART and its effectiveness, the absence of cause-of-death information should not affect our findings. In addition, we found no difference in HIV progression between HCV-infected and HCV-uninfected patients, measured by time to first opportunistic infection and to CD4 cell decline to below 200/無.
Second, since some persons with HCV antibodies have cleared their infection, the effect of HCV infection could have been underestimated by classifying all HCV antibody計ositive patients as infected.40 However, we have previously found that more than 90% of HIV-infected persons with a reactive HCV antibody test have detectable plasma HCV RNA, suggesting that our case definition is reasonable.8 Third, since some HIV-infected patients may have HCV infection in the absence of a reactive antibody test, some patients could have been misclassified as HCV-uninfected. However, in a similar Baltimore cohort of 559 HIV-infected subjects, the sensitivity and specificity of the EIA 3.0 were both greater than 99%.21 In high-risk populations the EIA versions 2.0 and 3.0 have similar sensitivity and specificity.41 Fourth, the relatively short period of follow-up may limit our ability to assess the effect of HCV coinfection on HIV disease progression. However, we analyzed the subset of 191 persons with follow-up of greater than 4 years duration, and did not detect a significant difference in the risk of progression to AIDS, death, or to CD4 cell count below 200/無 in HCV-infected compared with HCV-uninfected persons (M.S.S., unpublished data, January 2002). Furthermore, it would seem that we observed a sufficient number of persons at risk of HIV disease progression, as there was a large number who experienced a new opportunistic infection (n = 231) or death (n = 321). An analysis of a cohort of 1955 patients who were relatively balanced with respect to proportions having HCV infection should have sufficient precision to detect relatively small differences in HIV progression. Fifth, our findings may not be generalizable to HIV-infected patients receiving care outside of urban settings in which HCV infection and injection drug use may be less prevalent. Finally, we did not evaluate the effect of other potential cofactors such as GB virus C and TT virus infections.42-46 In particular, since GB virus C infection has been associated with reduced progression of HIV disease, the presence of GB virus C infection could mask an adverse effect of HCV if it occurred more often in HCV-infected persons.42, 43, 45 Thus, these and other unmeasured factors may confound the relationship of HCV and HIV progression.
In conclusion, after adjustment for the administration of HAART and its effectiveness, we did not detect an increased risk of development of AIDS-defining illness, death, or CD4 cell count decline to below 200/無 among HCV-infected compared with HCV-uninfected patients. In addition, among patients prescribed HAART, we found no evidence that HCV infection alters the virological or immunologic response to potent antiretroviral therapy. While further research is needed to understand the effect of HCV infection on HIV disease and immune reconstitution in response to HAART, these findings emphasize the importance of the consideration of effective antiretroviral therapy for HCV-infected and HCV-uninfected persons at immediate risk for the development of AIDS.
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