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Influence of Coinfection with Hepatitis C Virus on Morbidity and Mortality Due to Human Immunodeficiency Virus Infection in the Era of Highly Active Antiretroviral Therapy
 
  HIV-HCV coinfected patients receiving HAART had similar durations of survival to patients infected with HIV alone when we adjusted for all of these factors ...Among HIV-HCV coinfected patients, there were significantly more cases of cirrhosis (5% vs 0.4%), yet these patients did not have a greater risk-adjusted mortality rate. It is possible that a longer duration of follow-up would be needed to see a mortality effect.
 
Comments from Jules Levin: This is the second study published in the past few weeks whose findings suggest that HIV does not accelerate HCV progression. The first was a study from Shiffman and this study did not follow patients over a period of time but was a cross-sectional or one-time look at patients. The authors of this study in CID conclude: Although HIV-HCV coinfection is associated with a greater prevalence of liver morbidity, this study suggests that HAART increases the duration of survival for coinfected patients. But I don’t think you can conclude that from this study. The duration of following patients was limited and we don’t know how long patients had liver disease or cirrhosis. As stated above coinfected patients were more likely to have cirrhosis and perhaps if followed longer the patients might be more likely to develop serious complications of liver disease. See the Editorial below where Graham and Koziel discuss limitations of this CID study.
 
There have been a number of studies finding that HIV accelerates HCV from 2 to 5 fold. But this questions remains open until better studies address this. For the time being medical care providers are I think mostly presuming that HIV does accelerate HCV until proven otherwise. In general, care providers often recommend HCV therapy when a coinfected patient has stage 2 disease, based on a biopsy. Some doctors will suggest considering HCV therapy at stage 1 in coinfected patients. To presume otherwise would place patients at risk for accelerated progression. These recommendations are based on a presumption that these patients are at greater risk for acceleration than HCV monoinfected patients. And of course it is always important to consider whether a patient is ready for HCV therapy. The following link is to a review of the Shiffman study and to a meta-analysis of a number of studies all examining whether HIV accelerates HCV progression:
 
Does HIV Accelerate HCV Progression?
http://www.natap.org/2003/Jan/012103_4.htm
 
You should read the Editorial of this study appearing in CID written by Camilia Graham and Margaret Koziel, which is below at the end of the study report. They say: this study excluded patients who had HCV infection diagnosed before 1996; thus, it may have eliminated the patients with the highest likelihood of having advanced liver disease and an impaired ability to tolerate HAART……..The natural history of HCV-related liver disease is one of progressive damage over the course of years, even in patients with HIV coinfection. Estimates vary widely, but severe liver disease is found in 12%50% of patients by 1525 years after presumed infection with HCV [8, 9]. In this cohort, only 4.5% of the patients had cirrhosis diagnosed, suggesting that this cohort was studied earlier in the disease process. However, this is consistent with the findings of another large US cohort studied during a similar time frame [10] in which death was not associated with HCV infection once the authors adjusted for use and effectiveness of HAART. We will need longer-term follow-up of cohorts such as this one to determine whether HCV infection has an impact on mortality in persons living with HIV infection over decades……
 
Abstract summary:
 
To ascertain the impact of hepatitis C virus (HCV) infection on human immunodeficiency virus (HIV) disease progression and associated death in the era of highly active antiretroviral therapy (HAART), we examined mortality rates, the presence of other diseases, and antiretroviral use in an observational cohort of 823 HIV-infected patients with and without HCV coinfection during the period of January 1996 through June 2001. Analyses were used to compare patient characteristics, comorbid conditions, and survival durations in HIV-infected and HIV-HCVcoinfected patients. HIV-HCVcoinfected persons did not have a statistically greater rate of acquired immunodeficiency syndrome or of renal or cardiovascular disease, but they did have more cases of cirrhosis and transaminase elevations. There were proportionately more deaths in the HIV-HCV coinfected group. Age, baseline CD4+ cell count, and duration of HAART were significantly associated with survival, but HCV infection was not. HAART use was a strong predictor of increased duration of survival, suggesting that treatment is more important to survival than is HCV coinfection status.
 
Clinical Infectious Diseases 2003;36:363-367 Ellen M. Tedaldi,1 Rose K. Baker,2 Anne C. Moorman,3 Carlos F. Alzola,2 Jack Furhrer,4 Robert E. McCabe,5 Kathleen C. Wood,2 Scott D. Holmberg,3 and the HIV Outpatient Study (HOPS) Investigators
 
Temple University Hospital, Philadelphia, Pennsylvania; 2Cerner Corporation, Vienna, Virginia; 3Centers for Disease Control and Prevention, Atlanta, Georgia; 4State University at New York, Stony Brook; and 5Fairmont Hospital, San Leandro, California
 
Hepatitis C virus (HCV) coinfection may be found in 30% of HIV-infected patients overall and in 60%90% of HIV-infected injection drug users [13]. HCV coinfection in HIV-infected patients has serious implications for the individual [4] and for the HIV infection epidemic generally. The clinical progression of hepatitis C is reportedly accelerated in persons with HIV infection, with more rapid development of liver fibrosis and cirrhosis [59]. Complications of chronic liver disease increasingly cause hospitalizations and deaths in HIV-infected populations [10-15].
 
Although there have been HAART-related improvements in the mortality rate among patients with HIV disease [16], there have been conflicting reports about clinical experience and outcomes for HIV-HCV coinfection and receipt of HAART [15, 17, 18]. HCV infection itself is associated with extra hepatic manifestations, such as glomerulonephritis, insulin resistance, and cryoglobulinemia [4], which could possibly affect renal- and cardiovascular-associated morbidity and mortality in an HIV-HCVcoinfected population. We analyzed the mortality rates and comorbid diagnoses in an observational cohort of HIV-infected persons to determine whether there was increased morbidity or mortality among those who were coinfected with HCV, adjusting for such factors as receipt of HAART.
 
HIV Outpatient Study (HOPS). The HOPS has been described elsewhere [16, 19]. This dynamic cohort includes HIV-infected persons seen at 8 clinics specializing in the treatment of HIV infection in 7 cities (Philadelphia, PA; Tampa, FL; Oakland, CA [2 sites: San Leandro and Oakland]; Washington, D.C.; Chicago, IL; Stony Brook, NY; and Denver, CO). The physicians at these sites routinely care for >2500 HIV-infected patients every year and are considered experienced HIV caregivers. Data from ongoing physician-patient interactions are electronically collected and submitted for central processing and analysis. This database includes data on demographic characteristics, symptoms, comorbid conditions, treatments, and laboratory values. More than 7000 HIV-infected ambulatory (nonhospitalized) patients have been seen in 120,000 outpatient visits to their HIV clinicians since 1992.
 
The ethical conduct of this study undergoes yearly review by federal (Centers for Disease Control and Prevention; Atlanta, GA) and local institutional research review boards. Appropriate informed consent was obtained and guidelines for human experimentation were followed in the conduct of this clinical research.
 
HIV-HCV coinfected patients. This analysis was restricted to 3 HOPS sites (Philadelphia, Stony Brook, and San Leandro, CA) that each had 50 HIV-HCVcoinfected patients. HIV-HCV coinfected patients were compared with patients infected with HIV only at those same 3 sites. To account for lag times in data entry, observations regarding patient deaths, diagnoses, and laboratory values were censored at 30 June 2001. Length of observation for each patient was calculated as the time from first visit with the HOPS physician to the censoring date, or at the last office visit or date of death if either of these preceded the censoring date. Patients were excluded if they had undergone <6 months of observation.
 
Information from each patient's visit to his or her HIV (HOPS) clinician was entered into a database with a proprietary data entry tool called the "Clinical Practice Analyst" (Cerner). If multiple risk factors were noted (at time of entry to the HOPS cohort) when assigning HIV transmission risk category, the category injection drug use took precedence, followed by male-male sex, and then heterosexual sex.
 
The CD4+ cell count and plasma HIV RNA load obtained closest to the first office visit with the HOPS physician were chosen as baseline measurements. The "current" CD4+ cell count or virus load was the most recent value documented as of the censoring date (30 June 2001). In this analysis, receipt of HAART was defined as the simultaneous use of 3 antiretroviral drugs or 2 full-dose protease inhibitors.
 
For analysis of comorbidities, HIV-HCVcoinfected patients were compared with patients who had HIV infection only for data on cancer (all types), renal disease (renal insufficiency and renal failure), diabetes mellitus, cardiovascular disease (hypertension, congestive heart failure, coronary artery disease, and peripheral vascular disease), cirrhosis, and transaminase elevations (alanine aminotransferase or aspartate aminotransferase levels 2 times greater than the upper limit of normal at any time during study observation). The clinical diagnoses were based on the provider's chart entry without specified diagnostic criteria. Relative risks were calculated after adjusting for age. A survival analysis was performed with use of a Cox proportional hazard model with covariates for HCV coinfection, age, baseline CD4+ cell count, and duration of HAART.
 
RESULTS
 
Among the 1696 patients seen at the 3 sites during the study period, 873 (51.5%) did not meet study criteria: 476 patients had <6 months of follow-up, data were censored for 128 patients (because of death, last visit, or hepatitis C diagnosis before 1996), and 269 patients had no documented serological testing for hepatitis. Among these 269 patients without HCV serologic testing data, 19.7% were injection drug users (compared with 26.2% of the patients who were included in the analysis), 55.8% were lost to follow-up, and 29.7% had died as of 1 July 2002.
 
Thus, there were 823 HIV-infected patients at the 3 HOPS sites that met the study criteria for this analysis. Of these, 267 (32.4%) were infected with both HIV and HCV, and 556 (67.6%) were seropositive only for HIV. Compared with the 556 patients in the HIV-only group, HIV-HCVcoinfected patients were more likely to have injection drug use as their HIV transmission risk (69.7% vs. 5.4%; P < .001), to be older (median age, 40.5 vs. 35.0 years; P < .01), to be nonwhite (68.9% vs. 62.0% were African American or Hispanic; P = .03), to have received <12 years of education (26.6% vs. 17.8%; P < .001), and to have undergone care with use of public funds, such as Medicaid, Medicare, and Ryan White funding (75.7% vs. 57.7%; P < .001). The median duration of observation was longer in the HIV-only group than it was in the HIV-HCVcoinfected group (3.1 vs. 2.7 years; P = .03); 76% of all years of observation were before 1999. The rate of loss to follow-up was higher in the HIV-HCV coinfection group than in the HIV-only group (19.8% vs. 16.9%), but the difference was not significant (P = .30). HIV-HCV coinfected patients also had lower median baseline CD4+ cell counts (242 vs. 316 cells/mm3; P < .01) but comparable median baseline plasma HIV RNA levels (2414 vs. 4212 copies/mL; P = .21).
 
Two hundred twenty-seven (85%) of the 267 HIV-HCVcoinfected patients and 465 (83.6%) of the 556 patients with HIV infection alone had documented use of HAART. In the HIV-only and HIV-HCV coinfection groups, 82% of the days of receipt of HAART included the use of a protease inhibitor. Although it took HIV-HCVcoinfected patients longer than patients with HIV infection alone to initiate HAART (4.5 vs. 3.2 years; P = .03), both groups continued to receive HAART for a median of 1.9 years during the time they were observed in the HOPS cohort. The median CD4+ cell count during the 6 months before the initiation of HAART was lower among HIV-HCVcoinfected patients (164.5 vs. 231.5 cells/mm3; P < .01). However, CD4+ cell counts before the initiation of HAART could only be ascertained for approximately one-half of the patients who had been receiving HAART, either because the CD4+ cell counts were not available or because the exact date that HAART was started was unknown.
 
Compared with patients in the HIV-only group, HIV-HCV coinfected patients were more likely to have AIDS, renal disease, cardiovascular disease, cirrhosis, and elevated transaminase levels. However, after adjustment for patient age, only the prevalences of cirrhosis (5% vs 0.4%) and transaminase elevations remained significantly higher in the coinfected patients. Only 19 (7.1%) of the 267 HIV-HCV coinfected patients were prescribed IFN- and/or ribavirin, usually late in the observation period of this analysis, for their HCV infection; thus, HCV treatment was not included in further analyses.
 
There were proportionately more deaths in the HIV-HCV coinfection group than in the HIV-only group (29 [10.9%] of 267 vs. 37 [6.7%] of 556 patients died; P = .04, determined by means of Pearson 2 test). An analysis of survival time done with use of a Cox proportional survival model showed that, when baseline CD4+ cell count, number of weeks receiving HAART, and patient age were included, HCV infection was not a significant predictor of survival (hazard ratio, 0.91; 95% CI, 0.551.51): HCV infection (HR 0.91 [0.55-1.51], p=.7129), baseline CD4 cell count (HR 0.12 [0.06-0.27], p<.0001), weeks receiving HAART (HR 0.17 [0.10-0.29], <.0001), patient age, years (HR 1.73 [1.19-2.53], p=.0042). A logistic regression multivariate analysis of mortality rates showed almost identical values ORs, 95% CIs, and P valuesas seen in the survival model (data not shown).
 
DISCUSSION
 
HCV infection presents special problems for the HIV-infected patientnotably, liver disease and associated mortality. However, after controlling for age and baseline CD4+ cell count, this analysis suggests that receipt of HAART decreases the mortality rate among HIV-HCV coinfected patients. HIV-HCV coinfected patients receiving HAART had similar durations of survival to patients infected with HIV alone when we adjusted for all of these factors.
 
It is possible that a longer duration of follow-up is needed to observe a significant difference in survival durations between HIV-infected patients with and without HCV coinfection, even after adjusting for factors associated with mortality in HIV-infected patients. Renal morbidity, as well as morbidities associated with cardiovascular disease and diabetes, may also have a great influence on clinical outcomes as these patients age. Another limitation of this analysis is the potential misclassification of patients in the HIV-only patient group. These patients had 1 negative result of an HCV test, but these tests were not performed at the same time that persons were assigned into the patient groups. The 269 patients that did not undergo serological testing for hepatitis C were excluded to avoid this type of misclassification. The characteristics of the 269 patients excluded because of the lack of documented serological tests for HCV were not similar to either the HIV-only or the HIV-HCVcoinfected group; thus, exclusion of these patients may not be a significant source of bias.
 
As reported in a very recent review of HIV-HCVcoinfected patients published in this journal [3], 2.8% of the HCV-seronegative patients had measurable HCV RNA levels, and 91% of patients with positive results of serological tests for HCV had measurable HCV viremia.
 
Although HIV-HCV coinfection is associated with a greater prevalence of liver morbidity, this study suggests that HAART increases the duration of survival for coinfected patients.
 
References
 
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4.Poles MA, Dieterich DT. Hepatitis C/human immunodeficiency virus coinfection: clinical management issues [review]. Clin Infect Dis 2000; 31:15461. First citation in article | Full Text | PubMed
 
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6.Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:5629. First citation in article | Full Text | PubMed
 
7.Ragni MV, Belle SH. Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C infection. J Infect Dis 2001; 183:11125. First citation in article | Full Text | PubMed
 
8.Rodriguez-Rosado R, Garcia-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS 1998; 12:1256. First citation in article | PubMed
 
9.Torre D, Tambini R, Cadario F, Barbarini G, Moroni M, Basilico C. Evolution of coinfection with human immunodeficiency virus and hepatitis C virus in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2001; 33:157985. First citation in article | Full Text | PubMed
 
10.Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32:4927. First citation in article | Full Text | PubMed
 
11.Cacoub P, Geffray L, Rosenthal E, et al. Mortality among human immunodeficiency virusinfected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases, in 1995 and 1997. Clin Infect Dis 2001; 32:120714. First citation in article | Full Text | PubMed
 
12.Soriano V, Garcia-Samaniego J, Valencia E, et al. Impact of chronic liver disease due to hepatitis viruses as cause of hospital admission and death in HIV-infected drug users. Eur J Epidemiol 1999; 15:14. First citation in article | PubMed
 
13.Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in haemophilic men and boys in the UK given blood products contaminated with hepatitis C. Lancet 1997; 350:142531. First citation in article | PubMed
 
14.Puoti M, Spinetti A, Ghezzi A, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr 2000; 24:2117. First citation in article | PubMed
 
15.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 coinfection: the Swiss HIV Cohort Study. Lancet 2000; 356:18005. First citation in article | PubMed
 
16.Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining mortality and morbidity among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:85360. First citation in article | PubMed
 
17.Sulkowski MS, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000; 283:7480. First citation in article | PubMed
 
18.Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002; 288:199206. First citation in article | PubMed
 
19.Moorman AC, Holmberg SD, Marlowe SI, et al. Changing conditions and therapies of ambulatory HIV-infected patients: the HIV Outpatient Study (HOPS). Ann Epidemiol 1999; 9:34957. First citation in article | PubMed
 
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EDITORIAL
 
First Things First: Balancing Hepatitis C and Human Immunodeficiency Virus
 
Camilla S. Graham and Margaret James Koziel Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
 
Persons who are coinfected with HIV and hepatitis C virus (HCV) and their providers face a number of dilemmas. These include understanding how the natural history of each virus is affected by the presence of the other, balancing the risks and benefits of treating each of these viral infections, deciding on the order and timing of treatment, and understanding how medication toxicity may be modified in patients with coinfection. Previous studies have addressed the natural history of HCV in HIV-infected patients, but given the long natural history of HCV infection, many of these studies were conducted before the widespread use of HAART [1, 2]. Several recent studies have suggested that HCV infection is an independent predictor of mortality in HIV infection [35], possibly by impeding immune reconstitution after the initiation of HAART [6]. The article by Tedaldi and colleagues [7] in this issue of Clinical Infectious Diseases addresses whether HCV infection alters the morbidity and mortality associated with HIV infection in a cohort of patients during a period when HAART was available.
 
This study found that there were proportionately more deaths among HIV-HCVcoinfected patients than there were among patients infected with HIV alone. However, when the authors adjusted for age, baseline CD4+ cell count, and duration of HAART, HCV infection was not an independent predictor of survival. Several differences between the HIV-HCVcoinfected group and the HIV-monoinfected group were notable. HIV-HCVcoinfected patients were more likely to have injection drug use as their HIV transmission risk (69.7% vs. 5.4% of those with HIV infection alone); to be nonwhite, older, and less educated; and to receive care with use of public funds. HIV-HCVcoinfected patients had lower baseline CD4+ cell counts (242 vs. 316 cells/mm3), a delay in the initiation of HAART of 4.5 years (compared with 3.2 years for patients with HIV infection alone), and lower CD4+ cell counts before the initiation of HAART (164.5 vs. 231.5 cells/mm3 for the one-half of the HIV-only cohort for whom these data were available).
 
This study is reassuring in its finding that, during the relatively short observation period examined, there was not an increase in mortality among HIV-HCVcoinfected patients that was attributable to HCV infection. However, this study excluded patients who had HCV infection diagnosed before 1996; thus, it may have eliminated the patients with the highest likelihood of having advanced liver disease and an impaired ability to tolerate HAART. The natural history of HCV-related liver disease is one of progressive damage over the course of years, even in patients with HIV coinfection. Estimates vary widely, but severe liver disease is found in 12%50% of patients by 1525 years after presumed infection with HCV [8, 9]. In this cohort, only 4.5% of the patients had cirrhosis diagnosed, suggesting that this cohort was studied earlier in the disease process. However, this is consistent with the findings of another large US cohort studied during a similar time frame [10] in which death was not associated with HCV infection once the authors adjusted for use and effectiveness of HAART. We will need longer-term follow-up of cohorts such as this one to determine whether HCV infection has an impact on mortality in persons living with HIV infection over decades.
 
HCV infection has been shown to increase the risk of severe hepatotoxicity associated with HAART [11]. However, a potential source of variability in studies examining the role of HCV infection in progression of HIV disease and tolerability of HAART is that the definition of HCV infection is often limited to HCV antibody seropositivity. This definition of HCV infection encompasses patients who are antibody positive but virus negativeand, thus, who do not have chronic infectionand patients with liver disease of variable severity. It is logical to assume that the ability to tolerate HAART may be quite different between a patient with minimal liver inflammation and a patient with advanced fibrosis. However, this information is often not known, because performing a liver biopsy is the only means to definitively define the extent of liver damage, and there are currently no reliable noninvasive tests that accurately predict the extent of histologic injury [12]. The relationship between HAART tolerability and the extent of liver disease is an important area for future research. As seen in the present study, if a major factor in survival among HIV-HCVcoinfected persons is the tolerability of HAART, another important and still unanswered question is whether treatment of HCV-associated liver disease will improve the tolerability of HAART, thus improving effective and durable control of HIV infection.
 
Studies that compare HIV-HCVcoinfected patients with patients who have HCV infection alone try to answer questions about the role of HIV on progression of severe liver disease due to HCV [8]. These cohorts tend to be relatively homogenous and typically comprise either persons with hemophilia or persons with a history of injection drug use. In contrast, studies that compare HIV-HCVcoinfected patients with HIV-monoinfected patients examine the role of HCV in modifying outcomes in persons with HIV infection. As in the present study, these studies tend to compare patients who had sexual transmission of HIV with those for whom injection drug use is the primary risk factor. The differences seen between patients with and patients without HCV infection in this study brings up a larger question of whether HCV infection status should raise a flag about broader issues related to the care of persons with a history of injection drug use. Injection drug use has also been shown to be a predictor of progression to AIDS-defining illness or death [13, 14]. HCV antibody status may be serving as a marker for poorer access to care and competing problems with addiction that lead to delays in care or failure to implement the standard of care, as suggested by the greater time to initiation of HAART and lower median CD4+ cell count before the initiation of HAART noted in the present study. If we are to improve the health statuses of patients with HIV-HCV coinfection, perhaps we should focus on these issues as well as the presence of 2 viruses.
 
References
 
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6.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: the Swiss HIV Cohort Study. Lancet 2000; 356:18005. First citation in article | PubMed
 
7.Tedaldi EM, Baker RK, Moorman AC, et al. Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2003; 36:3637 (in this issue). First citation in article | Full Text | PubMed
 
8.Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:5629. First citation in article | Full Text | PubMed
 
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10.Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002; 288:199206. First citation in article | PubMed
 
11.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; 283:7480. First citation in article | PubMed
 
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