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Hepatitis C and Progression of HIV Disease
Mark S. Sulkowski, MD;
Richard D. Moore, MD;
Shruti H. Mehta, PhD, MPH;
Richard E. Chaisson, MD;
David L. Thomas, MD
JAMA. 2002;288:199-206.
ABSTRACT
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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/µL; 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/µL through 200/µL
(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.
INTRODUCTION
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.
METHODS
Subjects
The outcomes of HIV disease progression, survival, and CD4 cell recoverywere
analyzed in a cohort of patients receiving medical care from January 1995
to January 2001 in the Johns Hopkins Hospital HIV Clinic. In this urban, university-based
setting, all patients undergo a comprehensive evaluation as previously described.19 The Johns Hopkins HIV observational cohort study
was approved by the Johns Hopkins University Joint Committee on Clinical Investigation
in 1990 with waiver of written informed consent. Since 1995, written informed
consent has been obtained from all cohort participants, including those represented
in the analyses herein using consent forms approved by the committee. The
participation rate of patients in the Johns Hopkins HIV cohort exceeded 99%.
The use of the Johns Hopkins HIV Clinical Database in an identity-unlinked
manner for this analysis had been approved by the committee.
Data regarding patient demographics, social practices such as sexual
risk behavior and injection drug use, clinical variables, and laboratory testing
were abstracted from the patient charts (data on demographic and social practices
had been obtained via written or computerized questionnaires) and the Johns
Hopkins Hospital laboratory database at enrollment and every 6 months by trained
personnel using standard data collection forms. Abstracted data included information
regarding clinical outcomes, such as new illnesses, hospitalization, and records
of prescribed medications. The AIDS-defining illnesses were recorded according
to the US Centers for Disease Control and Prevention 1993 revised classification
system.20 Information on death is obtained
from clinic and hospital records as well as the Maryland Bureau of Vital Records
and the national Social Security Death Index; deaths due to any cause were
recorded.
Recorded medication prescription information included drug name, dose,
and number dispensed in the patient chart. This is updated at each clinical
encounter and includes information on telephoned and mailed prescriptions.
Validity checks are done cumulatively on a 5% sample of abstracted variable
fields, including medication prescription and clinical outcome fields, and
data captured via direct computer interface (eg, laboratory data); to date,
errors have been found in 0.2% of variable fields. Patients were classified
as receiving HAART if a protease inhibitor or a nonnucleoside reverse transcriptase
inhibitor was prescribed.
Patients had clinic visits and laboratory evaluations performed at regular
intervals according to written practice guidelines. The standard clinic visit
schedule for patients prescribed antiretroviral therapy was 4 weeks after
initiation of therapy and subsequently every 12 weeks. At each visit, standard
laboratory assessments, performed by licensed clinical laboratories, included
a complete blood cell count; serum chemistry panels; alanine aminotransferase,
aspartate aminotransferase, and total bilirubin levels; CD4 cell count; and
plasma HIV RNA level (reverse transcriptase-polymerase chain reaction used
for viral load determination). According to the practice guidelines of the
clinic and the United States Public Health Service (http://www.hivatis.org/trtgdlns.html), HCV testing is routinely performed on all cohort participants by
a licensed clinical laboratory using a second- or third-version enzyme immunoassay
(EIA) (EIA 2.0, Abbott Laboratories, Abbott Park, Ill; EIA 3.0, Ortho Diagnostics,
Raritan, NJ). Persons who had a repeatedly reactive HCV antibody EIA were
considered to have HCV infection.21 In the
absence of definitive guidelines for the standard of care in the management
of HCV infection in HIV-infected patients, coinfected patients in this cohort
were infrequently treated (<2%) for HCV infection. Treatment consisted
of interferon alfa (standard or pegylated) with or without ribavirin.22-23 Because HCV treatment was infrequent
and ineffective among patients in this cohort, the analysis was not adjusted
for treatment of HCV infection.
Statistical Methods
Baseline characteristics were compared according to HCV serostatus using
the  2 test for categorical variables and the Mann-Whitney test
for continuous variables. Time-to-event analysis was performed using Kaplan-Meier
survival curves, the log-rank test (another method used to compare survival
curves [P values obtained using the log-rank test
were similar to those derived from the univariate Cox model; thus, only those
from the Cox analysis are reported herein]), and Cox proportional hazards
regression. Assumptions of the Cox proportional hazard analysis were tested
and met. Three sets of outcomes were analyzed: the development of an AIDS-defining
illness, death from any cause, and CD4 cell count below 200/µL. Individuals
were censored at their last follow-up visit. Variables considered in all Cox
multivariate analyses included HCV serostatus, age, sex, race, baseline CD4
cell count, and baseline HIV viral load. The CD4 cell count and viral load
were also analyzed as time-dependent covariates for which the change from
baseline at the time of each event was incorporated into the model.
In order to account for the use of antiretroviral therapy, measures
of the total exposure time to HAART and of the effectiveness of HAART were
included. Total exposure time was calculated as the maximum number of years
receiving either a protease inhibitor or a nonnucleoside reverse transcriptase
inhibitor. Assessment of HAART effectiveness was based on the percentage of
total visits in which HIV RNA was detectable. Well-controlled
HIV replication was defined as a viral load below 400 HIV RNA copies/mL
recorded at 75% or more of measurements. The subset of patients with well-controlled
HIV infection represents the most appropriate group to assess the effect of
HCV infection on the progression of HIV disease, since these individuals are
more homogeneous with respect to the administration of and adherence to HAART,
allowing focus on the variable of interest, HCV infection. Patients without
well-controlled HIV infection represent a more heterogeneous group regarding
antiretroviral administration and adherence, which may confound the relationship
of HCV infection and HIV progression.
We also examined the effect of HCV infection on CD4 cell response to
HAART among persons who received effective HAART. For this analysis, effective
HAART was defined as a viral load below 400 HIV RNA copies/mL recorded at
75% or more of measurements for patients receiving HAART for at least 90 days
(n = 1042) and having at least 2 HIV RNA determinations (n = 872). Using the
Mann-Whitney test, we compared the median change in CD4 cell count at 1 year,
2 years, and 3 years in subjects who had at least 1 year of follow-up derived
from the subset of 208 HAART recipients with well-controlled HIV replication
following the initiation of HAART. Stepwise multivariate logistic regression
was used to analyze factors associated with well-controlled HIV replication
(the event [HIV suppression] was considered a dichotomous non–time-dependent
event for this analysis). Because the outcome of interest was common (>10%),
we used the method of Zhang and Yu24 to assess
whether correction of calculated adjusted odds ratios (ORs) was necessary
to avoid the overestimation or underestimation of the risk ratio (RR) in this
cohort study. For each variable, we found that the calculated adjusted ORs
closely approximated the corrected RR (M.S.S., unpublished data, April 2002).
It should be noted that ORs should not be interpreted as RRs in the setting
of common outcomes.24 Statistical analyses
were performed using STATA v6.0 (Stata Corp, College Station, Tex) and SAS
v6.12 (SAS Institute Inc, Cary, NC).
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/µL, 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).
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Table 1. Patient Clinical and Demographic
Characteristics at Enrollment in the Johns Hopkins HIV Clinical Cohort*
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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/µL (RH, 0.95; 95% CI, 0.73-1.24),
from 50/µL through 200/µL (RH, 1.35; 95% CI, 0.93-1.88), or above
200/µL (RH, 1.25; 95% CI, 0.87-1.79).
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Figure 1. Probability of Developing an AIDS-Defining
Illness in HIV-Infected Patients, by HCV Antibody Status
Curves represent Kaplan-Meier time-to-event analyses. AIDS indicates
acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; HCV,
hepatitis C virus. There was no difference detected in the risk of progression
to an AIDS-defining illness among HCV-infected and HCV-uninfected patients
(relative hazard, 1.03; 95% confidence interval, 0.86-1.23).
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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/µL (RH, 1.13; 95% CI, 0.82-1.56) or above
200/µL (RH, 0.89; 95% CI, 0.56-1.42).
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Figure 2. Probability of Death in HIV-Infected
Patients, by HCV Antibody Status
Curves represent Kaplan-Meier time-to-event analyses. HIV indicates
human immunodeficiency virus; HCV, hepatitis C virus. A, Survival of all 1955
patients. There was no difference detected in the risk of death in HCV-infected
and HCV-uninfected patients (relative hazard [RH], 1.05; 95% confidence interval
[CI], 0.85-1.30). B, Survival of the subset of 429 patients with baseline
CD4 cell count from 50/µL through 200/µL at entry. In this subset,
HCV-infected patients had an increased risk of death compared with HCV-uninfected
patients (RH, 1.51; 95% CI, 1.01-2.27). However, the significant difference
in survival detected among those with baseline CD4 cell count of 50/µL
through 200/µL (panel B) was not sustained in a multivariate model adjusted
for the use of highly active antiretroviral therapy and for HIV suppression
(adjusted RH, 1.01; 95% CI, 0.65-1.56).
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Among the 429 patients with baseline CD4 cell counts from 50/µL
through 200/µL, 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/µL through 200/µL,
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/µL; 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/µL
Among all persons with a baseline CD4 cell count above 200/µL
(n = 1073), HCV-infected patients had a greater but statistically nonsignificant
probability of progression to CD4 cell count below 200/µL (RH, 1.28;
95% CI, 0.98-1.68) (Figure 3). However,
in multivariate Cox regression analysis, progression to CD4 cell count below
200/µL 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/µL; 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/µL
was 336 (243-476) cells/µL and 373 (272-489) cells/µL for HCV-infected
and HCV-uninfected patients, respectively (P = .09,
Mann-Whitney test).
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Figure 3. Probability of Maintaining CD4 Cell
Count Above 200/µL in HIV-Infected Patients With Baseline CD4 Cell Count
Above 200/µL, by HCV Antibody Status
Curves represent Kaplan-Meier time-to-event analyses. HIV indicates
human immunodeficiency virus; HCV, hepatitis C virus. Compared with HCV-uninfected
patients, HCV-infected patients had a greater but statistically nonsignificant
probability of progression to CD4 cell count below 200/µL (relative
hazard, 1.28; 95% confidence interval, 0.98-1.68).
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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/µL (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/µL: 38.4% for HCV-infected and 37.2%
for HCV-uninfected patients, P = .37; 50/µL
through 200/µL: 23.3% for HCV-infected and 25.6% for HCV-uninfected
patients, P = .66; below 50/µL: 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).
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Table 2. Exposure Time for HAART, by HCV Antibody
Status and CD4 Cell Count Category*
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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/µL
or 100/µL among HCV-infected and HCV-uninfected patients receiving effective
HAART (Table 4).
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Table 3. Change in Absolute CD4 Cell Count
and CD4 Cell Percentage in HCV-Infected and HCV-Uninfected Patients Receiving
Effective HAART*
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Table 4. Probability of Increasing CD4 Cell
Count in Patients Receiving Effective HAART*
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COMMENT
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/µL, 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/µL.
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–positive 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/µL 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/µL 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.
AUTHOR INFORMATION
Author Contributions: Study
concept and design: Sulkowski, Chaisson, Thomas.
Acquisition of data: Sulkowski, Moore.
Analysis and interpretation of data: Sulkowski,
Moore, Mehta, Chaisson, Thomas.
Drafting of the manuscript: Sulkowski, Thomas.
Critical revision of the manuscript for important
intellectual content: Sulkowski, Moore, Mehta, Chaisson, Thomas.
Statistical expertise: Sulkowski, Mehta.
Obtained funding: Moore, Chaisson, Thomas.
Administrative, technical, or material support:
Moore, Chaisson.
Funding/Support: The study was supported in
part by National Institute on Drug Abuse grants R01 DA-11602, R01 DA-13806,
and K24 DA-00432, and by National Institute on Allergy and Infectious Diseases
grant K24 AI-01637.
Role of the Funding Source: Our funding sources
had no role in the collection, analysis, or interpretation of the data for
this study.
Financial Disclosures: Dr Sulkowski: research
grants or funding/lecture sponsorships/honoraria for continuing medical education
(CME) programs from, or advisor or consultant for Boehringer Ingelheim, Hepatitis
Resource Network, Human Genome Sciences, Ortho-Biotech, Roche, and Schering,
and government grants or research funding (R01 DA13806); Dr Moore: research
grants or funding/lecture sponsorships/honoraria for CME programs from or
consultant for Agency for Healthcare Research and Quality, Bristol-Myers Squibb,
US Centers for Disease Control and Prevention, Health Resources and Services
Administration, Ortho-Biotech, and Glaxo Wellcome, and government grant R01
DA-11602; Dr Chaisson: research grants or funding/honoraria/lecture sponsorships/honoraria
for CME programs from Abbott, Agouron, Bristol-Myers Squibb, and GlaxoSmithKline,
and family members own Merck stock; Dr Thomas: research grants or funding/lecture
sponsorships, honoraria for CME programs from, or consultant for Eli Lilly,
Glaxo Wellcome, Maryland Department of Corrections, Ortho-Biotech, Roche,
and Schering, and government grants or research funding (R01 DA13806, R01
DA10627, U19 AI40035-01, and R01 DA13324).
Corresponding Author and Reprints: Mark
S. Sulkowski, MD, Division of Infectious Diseases, Department of Medicine,
Johns Hopkins University School of Medicine, 1830 E Monument St, Room 448,
Baltimore, MD 21287-0003 (e-mail: msulkows{at}jhmi.edu).
Author Affiliations: Division of Infectious
Diseases (Drs Sulkowski, Chaisson, and Thomas) and Division of General Internal
Medicine (Dr Moore), Department of Medicine, Johns Hopkins University School
of Medicine; and Department of Epidemiology, Johns Hopkins University Bloomberg
School of Public Health (Dr Mehta), Baltimore, Md.
REFERENCES
| |
1. Sulkowski MS, Mast EE, Seeff LB, Thomas DL. Hepatitis C virus infection as an opportunistic disease in persons
infected with human immunodeficiency virus. Clin Infect Dis. 2000;30(suppl 1):S77-S84.
2. Broers B, Junet C, Bourquin M, et al. Prevalence and incidence rate of HIV, hepatitis B and C among drug
users on methadone maintenance treatment in Geneva between 1988 and 1995. AIDS. 1998;12:2059-2066.
ISI
| PUBMED
3. Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in haemophilic men and
boys in UK given blood products contaminated with hepatitis C. Lancet. 1997;350:1425-1431.
FULL TEXT
|
ISI
| PUBMED
4. Monga HK, Rodriguez-Barradas MC, Breaux K, et al. Hepatitis C virus infection-related morbidity and mortality among patients
with human immunodeficiency virus infection. Clin Infect Dis. 2001;33:240-247.
FULL TEXT
|
ISI
| PUBMED
5. Lesens O, Deschenes M, Steben M, et al. Hepatitis C virus is related to progressive liver disease in human
immunodeficiency virus-positive hemophiliacs and should be treated as an opportunistic
infection. J Infect Dis. 1999;179:1254-1258.
FULL TEXT
|
ISI
| PUBMED
6. Eyster ME, Diamondstone LS, Lien JM, et al. Natural history of hepatitis C virus infection in multitransfused hemophiliacs. J Acquir Immune Defic Syndr. 1993;6:602-610.
PUBMED
7. Sherman KE, O'Brien J, Gutierrez G, et al. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent
human immunodeficiency virus infections. J Clin Microbiol. 1993;31:2679-2682.
FREE FULL TEXT
8. Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection. JAMA. 2000;284:450-456.
FREE FULL TEXT
9. Thomas DL, Astemborski J, Vlahov D, et al. Determinants of the quantity of hepatitis C virus RNA. J Infect Dis. 2000;181:844-851.
FULL TEXT
|
ISI
| PUBMED
10. Sabin CA, Telfer P, Phillips AN, et al. The association between hepatitis C virus genotype and human immunodeficiency
virus disease progression in a cohort of hemophilic men. J Infect Dis. 1997;175:164-168.
ISI
| PUBMED
11. Piroth L, Duong M, Quantin C, et al. Does hepatitis C virus co-infection accelerate clinical and immunological
evolution of HIV-infected patients? AIDS. 1998;12:381-388.
ISI
| PUBMED
12. Quan S, Krajden M, Grigoriew GA, Salit IE. Hepatitis C virus infection in patients infected with the human immunodeficiency
virus. Clin Infect Dis. 1993;17:117-119.
ISI
| PUBMED
13. Wright TL, Hollander H, Pu X, et al. Hepatitis C in HIV-infected patients with and without AIDS. Hepatology. 1994;20:1152-1155.
FULL TEXT
|
ISI
14. Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A.
(Veterans Affairs Medical Center) Cohort Study (HAVACS). Clin Infect Dis. 1999;29:150-154.
ISI
| PUBMED
15. Dorrucci M, Pezzotti P, Phillips AN, et al. Coinfection of hepatitis C virus with human immunodeficiency virus
and progression to AIDS. J Infect Dis. 1995;172:1503-1508.
ISI
| PUBMED
16. Macias J, Pineda JA, Leal M, et al. Influence of hepatitis C virus infection on the mortality of antiretroviral-treated
patients with HIV disease. Eur J Clin Microbiol Infect Dis. 1998;17:167-170.
ISI
| PUBMED
17. Haydon GH, Flegg PJ, Blair CS, et al. The impact of chronic hepatitis C virus infection on HIV disease and
progression in intravenous drug users. Eur J Gastroenterol Hepatol. 1998;10:485-489.
ISI
| PUBMED
18. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral
therapy in patients with HIV-1 and hepatitis C virus coinfection. Lancet. 2000;356:1800-1805.
FULL TEXT
|
ISI
| PUBMED
19. Moore RD, Stanton D, Gopalan R, Chaisson RE. Racial differences in the use of drug therapy for HIV disease in an
urban community. N Engl J Med. 1994;330:763-768.
FREE FULL TEXT
20. 1993 revised classification system for HIV infection and expanded surveillance
case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17):1-19.
21. Thio CL, Nolt KR, Astemborski J, et al. Screening for hepatitis C virus in human immunodeficiency virus-infected
individuals. J Clin Microbiol. 2000;38:575-577.
FREE FULL TEXT
22. National Institutes of Health Consensus Development Conference Panel
statement: management of hepatitis C. Hepatology. 1997;26(suppl 1):2S-10S.
23. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b
plus ribavirin for initial treatment of chronic hepatitis C. Lancet. 2001;358:958-965.
FULL TEXT
|
ISI
| PUBMED
24. Zhang J, Yu KF. What's the relative risk? a method of correcting the odds ratio in
cohort studies of common outcomes. JAMA. 1998;280:1690-1691.
FREE FULL TEXT
25. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected
with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283:74-80.
FREE FULL TEXT
26. den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity
of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000;14:2895-2902.
FULL TEXT
|
ISI
| PUBMED
27. Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing
antiretroviral therapy. AIDS. 2001;15:1261-1268.
FULL TEXT
|
ISI
| PUBMED
28. Escaffre N, Morin M, Bouhnik AD, et al. Injecting drug users' adherence to HIV antiretroviral treatments. AIDS Care. 2000;12:723-730.
FULL TEXT
|
ISI
| PUBMED
29. Celentano DD, Vlahov D, Cohn S, et al. Self-reported antiretroviral therapy in injection drug users. JAMA. 1998;280:544-546.
FREE FULL TEXT
30. Strathdee SA, Palepu A, Cornelisse PG, et al. Barriers to use of free antiretroviral therapy in injection drug users. JAMA. 1998;280:547-549.
FREE FULL TEXT
31. Mocroft A, Madge S, Johnson AM, et al. A comparison of exposure groups in the EuroSIDA study. J Acquir Immune Defic Syndr. 1999;22:369-378.
ISI
| PUBMED
32. Lucas GM, Cheever LW, Chaisson RE, Moore RD. Detrimental effects of continued illicit drug use on the treatment
of HIV-1 infection. J Acquir Immune Defic Syndr. 2001;27:251-259.
ISI
| PUBMED
33. Detels R, Munoz A, McFarlane G, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and
death in men with known HIV infection duration. JAMA. 1998;280:1497-1503.
FREE FULL TEXT
34. Hogg RS, Heath KV, Yip B, et al. Improved survival among HIV-infected individuals following initiation
of antiretroviral therapy. JAMA. 1998;279:450-454.
FREE FULL TEXT
35. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human
immunodeficiency infection. N Engl J Med. 1998;338:853-860.
FREE FULL TEXT
36. Hughes MD, Stein DS, Gundacker HM, et al. Within-subject variation in CD4 lymphocyte count in asymptomatic human
immunodeficiency virus infection. J Infect Dis. 1994;169:28-36.
ISI
| PUBMED
37. Smith Sehdev AE, Hutchins GM. Problems with proper completion and accuracy of the cause-of-death
statement. Arch Intern Med. 2001;161:277-284.
FREE FULL TEXT
38. Goedert JJ, Fung MW, Felton S, et al. Cause-specific mortality associated with HIV and HTLV-II infections
among injecting drug users in the USA. AIDS. 2001;15:1295-1302.
FULL TEXT
|
ISI
| PUBMED
39. Prins M, Hernandez Aguado IH, Brettle RP, et al. Pre-AIDS mortality from natural causes associated with HIV disease
progression. AIDS. 1997;11:1747-1756.
FULL TEXT
|
ISI
| PUBMED
40. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States,
1988 through 1994. N Engl J Med. 1999;341:556-562.
FREE FULL TEXT
41. Lok AS, Gunaratnam NT. Diagnosis of hepatitis C. Hepatology. 1997;26(suppl 1):48S-56S.
42. Tillmann HL, Heiken H, Knapik-Botor A, et al. Infection with GB virus C and reduced mortality among HIV-infected
patients. N Engl J Med. 2001;345:715-724.
FREE FULL TEXT
43. Xiang J, Wunschmann S, Diekema DJ, et al. Effect of coinfection with GB virus C on survival among patients with
HIV infection. N Engl J Med. 2001;345:707-714.
FREE FULL TEXT
44. Thomas DL, Vlahov D, Alter HJ, et al. The association of antibody to GB virus C (hepatitis G virus) with
viral clearance and protection from reinfection. J Infect Dis. 1998;177:539-542.
ISI
| PUBMED
45. Yeo AE, Matsumoto A, Hisada M, et al. Effect of hepatitis G virus infection on progression of HIV infection
in patients with hemophilia. Ann Intern Med. 2000;132:959-963.
FREE FULL TEXT
46. Christensen JK, Eugen-Olsen J, Sorensen M, et al. Prevalence and prognostic significance of infection with TT virus in
patients infected with human immunodeficiency virus. J Infect Dis. 2000;181:1796-1799.
FULL TEXT
|
ISI
| PUBMED
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