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Original Research |

HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease: A Cohort Study

Gregory D. Kirk, MD, MPH, PhD; Shruti H. Mehta, PhD, MPH; Jacquie Astemborski, MS; Noya Galai, PhD; Jonathan Washington, BA; Yvonne Higgins, PA; Ashwin Balagopal, MD; and David L. Thomas, MD, MPH
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 26 February 2013.

From Johns Hopkins Bloomberg School of Public Health and John Hopkins School of Medicine, Baltimore, Maryland.

Acknowledgment: All persons who have contributed substantially to this work have been recognized.

Grant Support: By United States Public Health Service, National Institute of Drug Abuse (R01-DA-016078, R01-DA-04334, and R01-DA-12568). Dr. Kirk was supported by the American Cancer Society (MRSG-07-284-01-CCE). Support of reagents for HCV RNA testing was generously provided by Abbott Molecular.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1085.

Reproducible Research Statement: Study protocol and data set: Not available. Statistical code: Available from Dr. Kirk (address below).

Requests for Single Reprints: David L. Thomas, MD, Stanhope Bayne Jones Professor of Medicine, Chief, Division of Infectious Diseases, Johns Hopkins School of Medicine, Room 437, 1830 Monument Street, Baltimore, MD 21205.

Current Author Addresses: Dr. Kirk: 615 North Wolfe Street, E-6533, Baltimore, MD 21205.

Dr. Mehta: 615 North Wolfe Street, E-6535, Baltimore, MD 21205.

Ms. Astemborski: 2213 McElderry Street, 1st Floor, Baltimore, MD 21205.

Dr. Galai: 615 North Wolfe Street, E-6529, Baltimore, MD 21205, and University of Haifa, Department of Statistics, Haifa, Israel.

Mr. Washington, Ms. Higgins, and Drs. Balagopal and Thomas: Division of Infectious Diseases, Johns Hopkins School of Medicine, Room 437, 1830 Monument Street, Baltimore, MD 21205.

Author Contributions: Conception and design: G.D. Kirk, S.H. Mehta, D.L. Thomas.

Analysis and interpretation of data: G.D. Kirk, S.H. Mehta, J. Astemborski, N. Galai, D.L. Thomas.

Drafting of the article: G.D. Kirk, J. Astemborski, D.L. Thomas.

Critical revision of the article for important intellectual content: G.D. Kirk, S.H. Mehta, N. Galai, A. Balagopal, D.L. Thomas.

Final approval of the article: G.D. Kirk, S.H. Mehta, J. Astemborski, D.L. Thomas.

Provision of study materials or patients: G.D. Kirk, S.H. Mehta, D.L. Thomas.

Statistical expertise: G.D. Kirk, S.H. Mehta.

Obtaining of funding: G.D. Kirk, S.H. Mehta, D.L. Thomas.

Administrative, technical, or logistic support: G.D. Kirk, Y. Higgins, D.L. Thomas.

Collection and assembly of data: G.D. Kirk, S.H. Mehta, J. Astemborski, Y. Higgins, J. Washington, D.L. Thomas.

Ann Intern Med. 2013;158(9):658-666. doi:10.7326/0003-4819-158-9-201305070-00604
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Chinese translation

Background: Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.

Objective: To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.

Design: Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.

Setting: Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.

Participants: 1176 current and former injection drug users with antibodies to HCV.

Measurements: Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.

Results: Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.

Limitation: The process of liver fibrosis began before the study in most persons.

Conclusion: In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.

Primary Funding Source: National Institute on Drug Abuse.


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Figure 1.

Liver fibrosis increases with greater HCV RNA levels.

In this scatterplot of liver fibrosis scores by HCV RNA levels, each dot represents a participant with measurement of HCV RNA level and liver fibrosis measured by elastography. The solid line (based on Lowess regression) illustrates increasing HCV RNA levels in relation to greater liver fibrosis scores. HCV RNA levels that were not detectable were plotted at the limit of detection of the assay. HCV = hepatitis C virus.

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Figure 2.

Sensitivity analysis of the effect of an unmeasured confounder on the association between HIV status and liver fibrosis.

In our primary analysis of liver fibrosis scores, the β-coefficient for HIV positivity was 0.18. To evaluate the effect of an unmeasured confounder (U) for potentially attenuating this β-coefficient for HIV, we generated U as a continuous variable with a range of association with both the primary exposure of HIV status and the outcome of liver fibrosis measured continuously as FibroScan score. The strength of correlation of U with HIV status was measured as a standardized difference in mean U between groups with and without HIV ranging from 0.1 to 0.6 (x-axis). The strength of association of U with FibroScan score was measured as a Pearson correlation coefficient ranging from 0.2 to 0.6 (y-axis). U was generated for the first study visit for all participants with values carried forward during follow-up. The goal was to assess whether adjustment for U attenuates the estimated β-coefficient for HIV in the regression model. For each combination of correlation coefficient and standardized difference in means, 200 replicates of the β-coefficient were generated and averaged. Results are presented as a contour plot that summarizes the range for values of the β-coefficient across combinations of correlation with the outcome and standardized difference in means between the HIV exposure groups. As illustrated, an unmeasured confounder would need to be both strongly associated with HIV status (for example, difference in means approaching 0.5 SDs) and moderately correlated with liver fibrosis (correlation coefficient >0.35) to substantially attenuate the observed HIV association with liver fibrosis. Because no known exposure met those thresholds, it is exceptionally unlikely that an as-yet unrecognized or incompletely measured factor would substantially alter the results. For example, HCV RNA level is known to be associated with HIV and, in our analysis, was found to be one of the strongest factors associated with liver fibrosis; however, the correlation between log10 HCV RNA level and fibrosis was only 0.13, and the standardized difference in mean HCV RNA levels by HIV status was 0.31. HCV = hepatitis C virus.

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Figure 3.

Liver fibrosis and age among persons coinfected with HIV and HCV (dashed line) and those with only HCV (solid line).

For each age, predicted liver fibrosis scores were calculated using a regression equation that included the race, sex, alcohol use, body mass index, hepatitis B virus surface antigen level status, and HCV RNA level values for a representative participant (overweight black male who has no regular alcohol use, is hepatitis B virus surface antigen–negative, and has high HCV viral load) for persons coinfected with HIV and HCV (dashed line) and for persons with only HCV (solid line). For example, a 40-year-old HIV- and HCV-coinfected person with these characteristics was calculated to have a predicted FibroScan score of 9.04 kPa. For this same degree of fibrosis, the predicted age in a similar person but with only HCV was 49.2 years. Over the entire age range, the average difference in estimated age between persons coinfected with HIV and HCV and those with only HCV was 9.2 years (90% coverage limit, 5.2 to 14.3 years). HCV = hepatitis C virus.

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