Chronic hepatitis C increased mortality by approximately 50% in patients with Centers for Disease Control and Prevention–defined AIDS, despite the competing mortality risks in these patients. About 20% of the deaths were liver-related, suggesting that greater hepatitis C virus awareness and treatment could increase survival.
Abstract
Background. Before the introduction of combination antiretroviral therapy (cART), patients infected with the human immunodeficiency virus (HIV) rarely died of liver disease. In resource-rich countries, cART dramatically increased longevity. As patients survived longer, hepatitis C virus (HCV) infection became a leading cause of death; however, because patients with AIDS continue to have 5-fold greater mortality than non-AIDS patients, it is unclear whether HCV infection increases mortality in them.
Methods. In this investigation, which is part of the Longitudinal Studies of the Ocular Complications of AIDS, plasma banked at enrollment from 2025 patients with AIDS as defined by the Centers for Disease Control and Prevention were tested for HCV RNA and antibodies.
Results. Three hundred thirty-seven patients had HCV RNA (chronic infection), 91 had HCV antibodies and no HCV RNA (cleared infection), and 1597 had no HCV markers. Median CD4+ T-cell counts/µL were 200 (chronic), 193 (cleared), and 175 (no markers). There were 558 deaths. At a median follow-up of 6.1 years, patients with chronic HCV had a 50% increased risk of mortality compared with patients with no HCV markers (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2–1.9; P = .001) in an adjusted model that included known risk factors. Mortality was not increased in patients with cleared infection (RR, 0.9; 95% CI, .6–1.5; P = .82). In patients with chronic HCV, 20.4% of deaths were liver related compared with 3.8% in patients without HCV.
Conclusions. Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, despite competing risks. Effective HCV treatment may benefit HIV/HCV-coinfected patients with AIDS.
In the early years of the human immunodeficiency virus (HIV)/AIDS epidemic, few patients died of liver disease because they succumbed to other illnesses before progressing to end-stage liver disease. In the 17 years since the advent of combination antiretroviral therapy (cART), survival of HIV-positive individuals has increased, especially in resource-rich countries, and liver disease has emerged as a major cause of death [1–5]. The majority of liver-related deaths in HIV-positive patients occur in people with chronic hepatitis C virus (HCV) infection [6, 7]. HCV infects about 30% of the HIV-positive individuals in the United States and Europe [8]. A recent meta-analysis showed that the overall mortality risk ratio for HIV/HCV coinfected patients compared with HIV monoinfected patients is increased by about 35% [9]. It is unclear whether these results apply to patients with AIDS as defined by the Centers for Disease Control and Prevention (CDC) in the cART era, however, because their mortality rate continues to be approximately 5 times higher than that of HIV-positive patients without a diagnosis of AIDS [10]. Competing risk factors might eclipse the mortality risk of HCV infection in current patients with AIDS, just as they did in the early years of the epidemic. Outcomes in patients with a diagnosis of AIDS remain an important public health concern. In 2009, almost 35 000 people were diagnosed with AIDS in the United States [11].
To determine the impact of HCV infection on survival, this study compared mortality in a large cohort of AIDS patients. The 2025 study subjects were enrolled in the Longitudinal Studies of the Ocular Complications of AIDS (LSOCA) and were followed prospectively for a median of >6 years. LSOCA is one of only a few cohort studies limited to persons diagnosed with AIDS but without further exclusion criteria. It focuses exclusively on the era following the introduction of cART [12].
METHODS
Study Subjects and Design
Subjects were aged ≥13 years with a diagnosis of AIDS according to the 1993 CDC definition [13]. The LSOCA population is similar in age, race, and sex to the US AIDS population, except it has a lower percentage of patients with a history of injection drug use [14]. At enrollment, data on demographics and past medical history were collected, and physical and ophthalmologic examinations were performed. Cytomegalovirus retinitis (CMV-R) was diagnosed by a LSOCA-certified ophthalmologist [12, 15]. Follow-up occurred every 3 months for patients with an ocular opportunistic infection (eg, CMV-R) and every 6 months otherwise. Plasma samples were collected at baseline and every 6 months thereafter. At a baseline-structured interview subjects were asked, “Have you ever been diagnosed with hepatitis?” Subjects responding “yes” were then asked to identify the type(s), for example, hepatitis A virus (HAV), hepatitis B virus (HBV), HCV, or other. One of the original objectives of LSOCA was to collect information about factors associated with mortality. Information on mortality was collected on an ongoing basis. Immediate and contributing causes of death were recorded in death reports. Combination ART was defined as ≥3 antiretroviral drugs given at therapeutic levels. Most HIV type 1 RNA assays were performed using the Roche Amplicor system. For analysis, viral loads below the lower limit of detection were assigned a value of one-half the lower limit, and values above the assay's upper limit were assigned the upper limit. This study was approved by the institutional review board at each center, and all patients gave written informed consent.
Methods to Determine HCV Serostatus
Plasma samples collected at enrollment were analyzed. All samples were tested for anti-HCV antibodies using the third-generation enzyme immunoassay (EIA) version 2.0 (Abbott). HCV RNA testing was performed on all samples with anti-HCV antibodies and/or an EIA signal-to-noise ratio ≥0.7 and on all samples from injection drug users (IDUs), regardless of the HCV antibody test results, using the Roche Cobas Amplicor Hepatitis C Virus Test, version 2.0 (lower limit of detection, 50 IU/mL). Eighteen subjects with HCV antibody–positive plasma were missing HCV RNA results, 5 were classified as having cleared a past HCV infection because the HCV antibody signal-to-noise ratio was <3.8. HCV serological testing was performed in 2008–2009. Results were sent to participating clinics with the advice that local guidelines be followed for communicating the results to patients. Patients with HCV RNA were considered to have chronic infection, and patients with anti-HCV antibodies and no HCV RNA were considered to have cleared a previous infection. It is possible that some people in the latter group had a false-positive antibody test and never had an HCV infection.
Data Analysis
Data available as of 31 December 2009 were included. The χ2 test was used for categorical variables, and the Kruskal-Wallis test was used for continuous variables. Cox regression analysis was used for factors associated with mortality. Unless otherwise noted, values of samples collected at enrollment were included in the analysis. The variables included HCV serostatus, self-reported diagnosis of HAV and/or HBV, sex, race, age, birth cohort, education, IDU status, time since AIDS diagnosis, diagnosis of CMV-R, cART, AIDS-defining condition, CD4+ T-cell count (at enrollment and nadir), CD8+ T-cell count, HIV RNA (at enrollment and maximum), platelet count, and year of enrollment. Three adjusted models were developed: (1) forward selection was used and only variables with P values ≤ .05 in the adjusted model were retained; (2) backward selection was used; (3) all the variables were entered into a fully adjusted model. Maximum HIV RNA was excluded from multivariable analyses because 6% of subjects had missing data. Follow-up time was calculated as the time from study entry to death, to 31 December 2009, or to the date of the last study contact for patients who were lost to follow-up. Univariate and forward selection multiple logistic regressions were used to identify factors associated with lack of awareness of chronic infection and HCV clearance. Analyses were performed with SAS (version 9.2) [16, 17] and Stata software (version 12.1) [17].
RESULTS
Baseline Characteristics
Among the 2025 subjects, 428 (21%) had evidence of past or current HCV infection. Of these, 337 (79%) were HCV RNA positive, indicating chronic infection, and 91 (21%) had HCV antibodies but no HCV RNA, indicating past infection. Subjects with HCV infection (combined group of cleared plus chronic) were more likely to be female, black, older at the time of enrollment, part of the 1945–1964 (baby boomer) birth cohort, to have a history of injection drug use, and to have higher CD4+ T-cell counts (enrollment and nadir) and lower platelets. They were less likely to have a college education, a diagnosis of CMV-R, to use cART, and to enroll during 1998–2000 (Table 1). A CD4+ T-cell count <200 cells/µL was the AIDS-defining condition in the majority of patients, regardless of HCV serostatus. The rise in CD4+ T cells from the nadir did not differ between patients with and without markers of HCV exposure (P = .91; Table 1). Compared to the group with chronic HCV, the group with past infection had a lower percentage of blacks and IDUs and patients were younger and had higher platelets (Table 1). In an adjusted multiple logistic regression model, failure to clear HCV was associated with black race, injection drug use, higher nadir CD4+ T-cell counts, and lower platelets (Supplemental Table 1).
Table 1.
Characteristics of the Population at Enrollment by Hepatitis C Virus Serostatus
| HCV Serostatusa |
||||||
|---|---|---|---|---|---|---|
| With HCV Markers |
P Valueb |
|||||
| Characteristics at Enrollment | Without HCV Markers (n = 1597) | Clearedc (n = 91) | Chronicd (n = 337) | Total (N = 2025) | With vs Without HCV Markers | Cleared vs Chronic |
| Demographics | ||||||
| Female (%) | 17 | 30 | 26 | 19 | <.0001 | .53 |
| Black race (%) | 30 | 40 | 55 | 35 | <.0001 | .01 |
| Age, y (median ± SDe) | 42 | 43 | 45 | 43 ± 9 | <.0001 | .03 |
| Birth cohort (%) | <.0001 | .60 | ||||
| <1945 | 6 | 7 | 5 | 6 | ||
| 1945–1964 | 68 | 76 | 80 | 71 | ||
| ≥1965 | 25 | 18 | 15 | 23 | ||
| College graduate (%) | 36 | 16 | 12 | 31 | <.0001 | .28 |
| HIV/AIDS history | ||||||
| Intravenous drug user (%) | 4 | 33 | 47 | 13 | <.0001 | .02 |
| Time since AIDS diagnosis, y (median ± SD) | 4.4 | 4.9 | 4.3 | 4.4 ± 4.1 | .79 | .48 |
| Diagnosis with CMV retinitis (%) | 22 | 12 | 12 | 20 | <.0001 | .92 |
| Currently on cART (%) | 84 | 84 | 80 | 84 | .05 | .40 |
| CD4+ T-cell count <200 µL as AIDS-defining illness (%) | 62 | 63 | 66 | 63 | .17 | .64 |
| Self-reported hepatitis history | ||||||
| HCV exposed (%) | 3 | 35 | 71 | 16 | <.0001 | <.0001 |
| HBV exposed (%) | 16 | 21 | 19 | 16 | .08 | .64 |
| HAV exposed (%) | 8 | 9 | 9 | 8 | .37 | .97 |
| Exposed, type unknown (%) | 8 | 8 | 5 | 7 | .12 | .33 |
| Immunology/virology | ||||||
| CD4+ T cells/μL (median ± SD) | 175 | 193 | 200 | 182 ± 207 | .03 | .80 |
| Nadir CD4+ T cells/μL (median ± SD) | 30 | 24 | 57 | 32 ± 62 | <.0001 | .003 |
| Change from nadir CD4+ T cells/µL (median ± SD) | 114 | 128 | 130 | 117 ± 177 | .91 | .60 |
| CD8+ T cells/μL (median ± SD) | 736 | 800 | 734 | 739 ± 473 | .47 | .38 |
| HIV RNA, log copies/mL (median ± SD) | 2.8 | 2.8 | 2.6 | 2.8 ± 2.0 | .25 | .50 |
| Max HIV RNA, log copies/mL (median ± SD) | 5.3 | 5.4 | 5.3 | 5.3 ± 0.8 | .57 | .27 |
| Hematology | ||||||
| Platelets, 100 000 cells/μL (median ± SD) | 2.14 | 2.18 | 1.96 | 2.12 ± 0.68 | <.0001 | .01 |
| Year of enrollment (%) | .02 | .86 | ||||
| 1998–2000 | 43 | 37 | 35 | 41 | ||
| 2001–2005 | 38 | 42 | 45 | 40 | ||
| 2006–2009 | 19 | 21 | 20 | 19 | ||
There were no statistically significant (P < .01) interactions of characteristics of the population with HCV status by injection drug use status.
Abbreviations: cART, combination antiretroviral therapy; CMV, cytomegalovirus retinitis; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; SD, standard deviation.
a Eighteen observations with positive HCV antibody and missing HCV RNA results were imputed to cleared HCV if HCV antibody signal-to-noise cutoff <3.8 (n = 5), otherwise imputed to chronic (n = 13).
b P value based on χ2 test for categorical variables or Kruskal-Wallis test for continuous variables.
c Cleared defined as positive HCV antibody and undetectable HCV RNA.
d Chronic defined as detectable HCV RNA.
e SD estimated using pseudo-Σ.
Factors Associated With Mortality
There were 558 deaths at a median follow-up of 6.1 years (interquartile range, 3.0–8.7). Kaplan-Meier estimates of mortality for patients with chronic hepatitis C, past hepatitis C, and no markers of HCV infection are presented in Figure 1. Cox regression analysis was used to identify factors associated with mortality (Table 2). Three adjusted models were analyzed. All gave similar results concerning the increased mortality risk of HCV infection.
Figure 1.
Kaplan-Meier survival curves indicate that chronic hepatitis C virus infection was associated with an increased mortality risk. Abbreviation: HCV, hepatitis C virus.
Table 2.
Cox Regression Analysis of Factors Associated With Mortality Among 2025 Patients
| Crude |
Adjusteda |
|||||
|---|---|---|---|---|---|---|
| Characteristics at Enrollment | RR | 95% CI | P Value | RR | 95% CI | P Value |
| HCV serostatus | .008 | .004 | ||||
| Cleared vs without HCV markers | 1.1 | .7–1.6 | .68 | 0.9 | .6–1.5 | .82 |
| Chronic vs without HCV markers | 1.4 | 1.1–1.7 | .002 | 1.5 | 1.2–1.9 | .001 |
| Self-reported hepatitis | ||||||
| HBV (yes vs no) | 0.8 | .6–1.0 | .04 | |||
| HAV (yes vs no) | 1.1 | .8–1.5 | .46 | 1.5 | 1.1–2.1 | .02 |
| Demographics | ||||||
| Female vs male | 1.2 | 1.0–1.4 | .12 | |||
| Black vs nonblack | 1.3 | 1.1–1.5 | .002 | |||
| Age (per y) | 1.00 | .99–1.01 | .97 | 1.01 | 1.00–1.02 | .02 |
| Birth cohort | .35 | |||||
| <1945 vs ≥1965 | 1.2 | .9–1.7 | …b | |||
| 1945–1964 vs ≥ 1965 | 1.0 | .8–1.2 | …b | |||
| Not college grad vs college grad | 1.3 | 1.0–1.5 | .02 | |||
| HIV/AIDS history | ||||||
| IDU vs no IDU | 1.3 | 1.0–1.6 | .05 | |||
| Time since AIDS diagnosis (per y) | 1.01 | .99–1.03 | .48 | 1.02 | 1.00–1.05 | .04 |
| Diagnosis vs not diagnosis with CMV retinitis | 1.8 | 1.5–2.2 | <.0001 | 1.9 | 1.6–2.3 | <.0001 |
| On vs not on cART | 0.5 | .4–.6 | <.0001 | |||
| CD4+ T-cell count <200 µL vs other AIDS-defining illness | 1.0 | .8–1.1 | .65 | |||
| Immunology and virology | ||||||
| CD4+ T cells (per 100 cells/µL) | 0.70 | .66–.74 | <.0001 | 0.82 | .77–.88 | <.0001 |
| Nadir CD4+ T cells (per 100 cells/µL) | 0.71 | .62–.82 | <.0001 | |||
| CD8+ T cells (per 100 cells/µL) | 0.93 | .91–.94 | <.0001 | |||
| HIV RNA (per log copies/mL) | 1.63 | 1.53–1.74 | <.0001 | 1.47 | 1.37–1.58 | <.0001 |
| Max HIV RNA (per log copies/µL) | 1.51 | 1.35–1.70 | <.0001 | |||
| Hematology | ||||||
| Platelet count (per 100 K cells/µL) | 0.67 | .60–.76 | <.0001 | 0.87 | .77–.99 | .04 |
| Year of enrollment | .0007 | .008 | ||||
| 1998–2000 vs 2006–2009 | 1.7 | 1.2–2.3 | .002 | 1.5 | 1.0–2.1 | .03 |
| 2001–2005 vs 2006–2009 | 1.3 | .9–1.8 | .12 | 1.1 | .8–1.6 | .47 |
Abbreviations: cART, combination antiretroviral therapy; CI, confidence interval; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, intravenous drug use; RR, relative risk.
a Variables selected from multiple Cox regression model regressing time to death on all variables listed above (except max HIV RNA because of 6% with missing data) using forward selection entry criterion P < .05. There were 1833 complete cases.
b Not shown since overall P value is not significant.
Table 2 presents the model developed using forward selection. Patients with chronic HCV infection had a 50% increased mortality risk (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2–1.9; P = .001) compared to patients with no markers of HCV infection, whereas patients with prior HCV infection did not have increased risk (RR, 0.9; 95% CI, .6–1.5; P = .82). In addition to chronic HCV infection, increased risk was associated with a prior diagnosis of HAV, older age at enrollment, a diagnosis of CMV-R, higher HIV RNA, and enrollment during 1998–2000 vs 2006–2009. Decreased risk was associated with higher CD4+ T-cell counts and platelets. Neither the time since a diagnosis of AIDS (Table 2) nor the number of interruptions of cART during follow-up (data not shown) was related to mortality in the adjusted model.
In a backward selection model and in a fully adjusted model that included all the variables in the univariate analysis, the RR of chronic HCV infection was 1.5, identical to the RR estimated in the forward selection model. In the backward selection model, the 95% CI was 1.2–1.9 (P = .0007), and in the fully adjusted model, the 95% CI was 1.2–2.0 (P = .003). In all 3 models, in addition to chronic HCV infection, increased mortality was associated with HAV, CMV-R, higher HIV RNA, and the year of enrollment; decreased mortality was associated with higher CD4+ T-cell counts (Table 2 and data not shown). All 3 models showed that mortality risk was approximately 50% higher in patients with chronic hepatitis C than in patients with prior hepatitis C, but the increase was not statistically significant: 95% CIs were 1.0–1.5 in all 3 adjusted models and P values were .07.
Of the 113 deaths in patients with chronic HCV, 20.4% were liver related, compared to only 3.8% of the 420 deaths in patients with no markers of HCV exposure. Patients with chronic infection were >5 times more likely to die of liver-related causes than patients with no markers of HCV (P < .0001). Liver-related deaths contributed to 12.0% of the 25 deaths in patients with cleared HCV. Alcohol use and HBV infection may have contributed to these liver-related deaths. The proportion of deaths related to cardiovascular disease, AIDS, and non-AIDS-related cancer were similar between patients with and without HCV infection (Supplementary Table 2).
Lack of Awareness of HCV Status
Because HCV infection decreases longevity and is both transmissible and potentially curable, we investigated patient awareness of HCV. Almost one-third (100 of 337) of the subjects with chronic hepatitis C reported that they had never received a diagnosis of HCV infection. In a logistic regression model, this lack of awareness was positively associated with enrollment during 1998–2000 vs 2006–2009; it was not associated with self-reported HBV infection, and it was negatively associated with self-reported HAV infection (Table 3).
Table 3.
Logistic Regression Analysis of Factors Associated With Failure to Accurately Self-report Positive Hepatitis C Virus (HCV) Status Among 337 Patients With Chronic HCV Infection
| Crude |
Adjusteda |
|||||
|---|---|---|---|---|---|---|
| Characteristics at Enrollment | OR | 95% CI | P Value | OR | 95% CI | P Value |
| Demographics | ||||||
| Female vs male | 0.8 | .5–1.4 | .39 | |||
| Black vs nonblack | 1.1 | .7–1.7 | .82 | |||
| Age (per y) | 0.97 | .94–1.00 | .05 | |||
| Birth cohort | .39 | |||||
| <1945 vs ≥1965 | 0.7 | .2–3.0 | …b | |||
| 1945–1964 vs ≥1965 | 1.4 | .7–2.9 | …b | |||
| Not college grad vs college grad | 0.6 | .3–1.2 | .15 | |||
| Self-reported hepatitis | ||||||
| HBV (yes vs no) | 0.6 | .3–1.1 | .09 | |||
| HAV (yes vs no) | 0.2 | .1–.8 | .02 | 0.3 | .1–.9 | .03 |
| HIV/AIDS history | ||||||
| IDU vs no IDU | 0.6 | .4–1.0 | .08 | |||
| Time since AIDS diagnosis (per yr) | 0.99 | .93–1.04 | .63 | |||
| On vs not on cART | 0.9 | .5–1.5 | .61 | |||
| Year of enrollment | .0001 | .0002 | ||||
| 1998–2000 vs 2006–2009 | 3.7 | 1.8–7.6 | .0004 | 3.2 | 1.6–6.8 | .002 |
| 2001–2005 vs 2006–2009 | 1.5 | .7–3.1 | .28 | 1.3 | .6–2.7 | .48 |
Abbreviations: cART, combination antiretroviral therapy; CI, confidence interval; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatic C virus; HIV, human immunodeficiency virus; IDU, intravenous drug use; OR, odds ratio.
a Multiple logistic regression model regressing probability of self-reported negative HCV on all variables listed above using forward selection entry criterion P < .05. There were 329 complete cases.
b Not shown because overall P value is not significant.
Effectiveness of the Approach Used to Identify Cases of Chronic HCV
HCV RNA testing was carried out on all samples with HCV antibodies and all samples from subjects with a history of injection drug use, 25% of the total. This approach identified 337 HCV RNA–positive samples. We performed HCV RNA testing on 60 representative samples from low-risk patients (non-IDUs who self-reported HCV negative status) and used the results to estimate the percentage of HCV RNA–positive samples (and cases of chronic infection) that we likely missed by not testing all antibody-negative samples for HCV RNA. HCV RNA was present in 3 of 60 samples (5%); 2 of the 3 had HCV antibodies. At a 5% positivity rate, the low-risk group should contain about 86 chronic cases, but only 61 samples were anti–HCV antibody positive. This suggests that about 25 cases were missed, and that the actual number of HCV RNA–positive samples in the entire study group was about 362. Of these, we identified 337, which is 93% (337 of 362) of the estimated chronic cases.
DISCUSSION
This study of patients with a diagnosis of AIDS established that chronic HCV infection increased mortality risk by about 50% after adjustment for demographic factors, HIV status, CMV-R, and injection drug use. It also revealed that almost 30% of the subjects with chronic HCV infection reported that they had never been given a diagnosis of this disease. In addition, and in keeping with previous investigations, this study showed that black patients and patients with a history of injection drug use were less likely to clear HCV than other patients [18, 19].
Strikingly, liver disease was the immediate or contributing cause in 20.4% of the deaths that occurred in patients with chronic hepatitis C. Liver disease was the only cause of death reported more frequently in patients with HCV than in patients without HCV. The negative impact of liver disease on survival emphasizes the need for patients with AIDS to be aware of their HCV status so that they can fully participate in their healthcare and risk reduction. Although current HCV treatments lead to a sustained virological response (SVR) in only 25%–50% of HIV/HCV coinfected patients [20–22], SVR rates are expected to rise soon as direct-acting antiviral drugs for HCV enter the clinic. SVR increases survival in HIV/HCV coinfected patients [23] and reduces the risk of subsequent antiretroviral-related toxicities [24]. Heightened HCV awareness may increase the proportion of patients seeking treatment and achieving an SVR; however, optimizing treatment and managing drug-drug interactions will be significant challenges in the years ahead.
HCV-mediated liver disease was only one of the mortality risks in the patients with chronic HCV infection. AIDS-related conditions were immediate or contributing factors in 58.4% of the deaths. This percentage is similar to that of patients without HCV. We did not find any evidence that HCV increased the immunological deficits caused by HIV. The relationship between HCV infection and immune dysfunction is unresolved in the literature. HCV infection is reported to blunt the CD4+ T-cell response to cART, leading to smaller increases in CD4+ T-cell counts [1, 25–27]; however, maximal viral suppression is reported to mitigate this effect [28]. We did not observe a blunted CD4+ T-cell response; however, HCV might have adverse effects on immune function that are not reflected in CD4+ T-cell counts. HCV impairs dendritic cell function and alters CD8+ T-cell phenotype [29, 30]. It is possible that subtle immunological effects of HCV reduced the resilience of patients with chronic infection and rendered them more susceptible to a variety of comorbid conditions, contributing to their increased overall mortality.
In addition to HCV-mediated liver damage and immune dysfunction, high-risk behaviors, including injection drug use and heavy alcohol consumption, add significantly to excess morbidity and mortality in many groups of HIV/HCV-coinfected individuals [5, 31, 32]. However, none of the 3 models of mortality risk in our study group showed an association between injection drug use and mortality. Death due to trauma, which is often a marker of high-risk behavior, was not increased in patients with chronic hepatitis C. These results suggest that injection drug use and accidents did not contribute significantly to the excess mortality we observed in patients with chronic HCV. Although high-risk behaviors account for most HCV transmissions, it is significant that past HCV infection was not associated with increased mortality risk in our study group. It thus appears that the high-risk activities associated with HCV acquisition did not reduce longevity in our cohort.
Considering the impact of end-stage liver disease on mortality and the potential benefits of HCV treatment, it is noteworthy that almost one-third of the chronically infected patients said that they had never been given a diagnosis of HCV. Confusion with HAV or HBV did not account for this underreporting. Research is needed to determine whether the failure to accurately report positive HCV status reflected failure of physicians to test for HCV, lack of communication, miscommunication, or denial. We found that lack of HCV awareness was more likely in patients enrolled during the earliest part of the study. Lack of HCV awareness was not associated with race, injection drug use, or age, in contrast to a previous investigation of HIV-positive women and women at risk for HIV infection. In those women, lack of HCV awareness was associated with black race and younger age [33]. Such disparate results show that the factors contributing to lack of awareness of HCV infection may differ between populations, underscoring the need for broad-based HCV screening. It is estimated that only about half of all the HCV-positive individuals in the United States are aware of the infection [34].
The Department of Health and Human Services guidelines for the prevention of opportunistic infections among HIV-infected persons issued in 2002 advised screening for HCV in all HIV-infected persons [35]. Identifying the most cost-effective screening approach is an important public health objective but is challenging for several reasons: HIV-seropositive patients with chronic HCV have a significant rate of false-negative anti-HCV antibody test results [36]; the more definitive HCV RNA test is more expensive than the antibody test; and ongoing high-risk behaviors may lead to reinfection, resulting in a need for periodic retesting. In this study, HCV RNA tests were performed on about 25% of the study population, with RNA testing directed to high-risk subjects (eg, IDUs) and to subjects with positive antibody tests. Using this targeted approach, an estimated 93% of HCV RNA–positive cases were detected. Our failure to detect all of the cases indicates that HCV RNA testing should be performed on HIV-positive individuals who test HCV antibody negative but have multiple HCV risk factors.
The strengths of this study include the large number of AIDS patients (2025), the large number of HIV/HCV coinfected non-IDUs (179), the prospective collection of data and plasma, the long duration of follow-up (median, 6.1 years), the use of HCV RNA testing to distinguish chronic from previous HCV infection, and the use of a testing algorithm that identified an estimated 93% of the cases of chronic infection. The limitations include the use of baseline data to analyze factors associated with mortality and the lack of data about alcohol use.
Our results underscore the urgency of efforts to screen AIDS patients for HCV and to make sure that the test results and their implications are clearly communicated. A new era of HCV treatment with direct acting antiviral drugs has just begun. More effective treatments for both HIV and HCV will undoubtedly decrease mortality in HCV-positive patients with a diagnosis of AIDS. Early cure of HCV may avoid the costs of liver transplantation, which exceed $123 000 per patient [37]. Broader screening and more patient education are needed to maximize the benefits of new treatments and to reduce liver-related mortality.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online (http://www.oxfordjournals.org/our_journals/cid/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Notes
Financial support. This work was supported by the National Institutes of Health Eye Institute to the Mount Sinai School of Medicine (grant U10 EY 008052); the Johns Hopkins University Bloomberg School of Public Health (grant U10 EY08057); and the University of Wisconsin, Madison (grant U10 EY08067); and by the National Institute on Drug Abuse and the National Institute of Diabetes and Digestive and Kidney Diseases to the Mount Sinai School of Medicine (grants DA031095 and DK090317).
Potential conflicts of interest. D. A. J. has acted as a consultant for Ciba Vision, Bayer Corporation, Centocor, Inc, and SmithKline Beecham; is currently a consultant for Allergan Pharmaceutical Corporation, Genzyme Corporation, Abbott Laboratories, Novartis Pharmaceutical Corp, Roche Pharmaceuticals, GlaxoSmithKline, Alcon Laboratories, Corcept Therapeutics, and Genentech; has received research support from Roche Laboratories in the past; and currently acts as a data and safety monitoring board member for Applied Genetic Technologies Corporation. D. T. D. has acted as a consultant for Gilead, BMS, Roche, Genetech, and BI. He is a board member of Merck and has received speaker's payment from Merck and Vertex. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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