David Nunes

Alcohol Consumption and HIV Disease Progression

Objective:To assess the relation between alcohol consumption and laboratory markers of HIV disease progression. Methods:We prospectively assessed CD4 cell counts, HIV RNA levels, and alcohol consumption for up to 7 years in 595 HIV-infected persons with alcohol problems recruited between 1997 and 2003. We investigated the relation of these markers of HIV disease progression to alcohol consumption using longitudinal regression models controlling for known prognostic factors, including adherence and depressive symptoms, and stratified by antiretroviral therapy (ART) use. Results:Among subjects who were not on ART, heavy alcohol consumption was associated with a lower CD4 cell count (adjusted mean decrease of 48.6 cells/μL compared with abstinence; P = 0.03) but not with higher log10 HIV RNA. Among subjects who were on ART, heavy alcohol consumption was not associated with a lower CD4 cell count or higher log10 HIV RNA. Conclusions:Heavy alcohol consumption has a negative impact on the CD4 cell count in HIV-infected persons not receiving ART. In addition to the known deleterious effects of alcohol on ART adherence, these findings suggest that avoiding heavy alcohol consumption in patients not on ART may have a beneficial effect on HIV disease progression.

Hepatitis C Virus and Human Immunodeficiency Virus Coinfection in an Urban Population: Low Eligibility for Interferon Treatment

One hundred eighty human immunodeficiency virus (HIV)- and hepatitis C virus (HCV)-coinfected patients were prospectively evaluated for suitability for interferon and ribavirin therapy. Of the 149 patients with chronic HCV infection who completed the evaluation, 44 (30%) were eligible for treatment and 105 (70%) were ineligible, with the main barriers being missed clinic visits, active psychiatric illness, active drug or alcohol use, decompensated liver disease, or medical illness.

Noninvasive Markers of Liver Fibrosis Are Highly Predictive of Liver-Related Death in a Cohort of HCV-Infected Individuals With and Without HIV Infection

OBJECTIVES:Noninvasive markers of liver fibrosis correlate with the stage of liver fibrosis, but have not been widely applied to predict liver-related mortality.METHODS:We assessed the ability of two indices of liver fibrosis, aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and Fib-4, and two markers of extracellular matrix metabolism, hyaluronic acid (HA) and YKL40, to predict liver mortality in a prospective cohort of hepatitis C virus (HCV)-infected individuals with and without HIV coinfection. These were compared with two established prognostic scores, the Child–Pugh–Turcotte (CPT) and model of end-stage liver disease (MELD) scores.RESULTS:A total of 303 subjects, of whom 207 were HIV positive at study entry, were followed up for a mean period of 3.1 years. There were 33 deaths due to liver disease. The ability of each test and score to predict 3-year liver mortality was expressed as the area under the receiver operator curve. The area under the receiver operator curve 95% confidence intervals were: HA 0.92 (0.86–0.96), CPT 0.91 (0.79–0.96), APRI 0.88 (0.80–0.93), Fib-4 0.87 (0.77–0.92), MELD 0.84 (71–0.91). In multivariate analyses HA, APRI, and fib-4 were independent predictors of mortality when included in models with MELD or CPT.CONCLUSION:Noninvasive markers of liver fibrosis are highly predictive of liver outcome in HCV-infected individuals with and without HIV coinfection. These markers seem to have a prognostic value independent of CPT and MELD.

HIV infection does not affect the performance of noninvasive markers of fibrosis for the diagnosis of hepatitis C virus-related liver disease.

Background:Noninvasive markers of hepatic fibrosis hold great promise to stage liver fibrosis and to monitor disease progression. To date, few studies have assessed the performance of the currently available markers of hepatic fibrosis in HIV-infected cohorts. The aim of the current study was to compare the diagnostic performance and characteristics of a number of noninvasive markers of hepatic fibrosis in populations of hepatitis C virus (HCV)-infected patients with and without HIV infection. Methods:A sample of 97 subjects (40 HCV/HIV-coinfected, 57 HCV-infected) undergoing liver biopsy as part of an ongoing prospective cohort study was evaluated. Liver biopsies were assessed by a single hepatopathologist and scored according to Ishak criteria. Noninvasive markers of fibrosis studied included international normalized ratio, platelet count, aspartate aminotransferase (AST)/alanine aminotransferase ratio, AST platelet ratio index (APRI), Forns index, procollagen III N peptide, hyaluronic acid, and YKL-40. Results:The correlations between fibrosis markers with the stage of fibrosis and the diagnostic performance of each of the tests were similar in the groups with and without HIV infection. Although a trend to improved diagnostic performance in the HCV/HIV-coinfected group was observed, this may be related to the small sample size. Conclusions:The diagnostic performance of the evaluated noninvasive markers of liver fibrosis is equivalent in HCV/HIV-coinfected and HCV-infected subjects. These tests may be of value for the clinical evaluation of HCV/HIV-coinfected patients and warrant further study.

An Assessment of Digital Image Analysis to Measure Fibrosis in Liver Biopsy Specimens of Patients With Chronic Hepatitis C

The aim was to assess the validity of a digitally computed fibrosis ratio as a measure of fibrosis stage in liver biopsy specimens. We scored 230 liver biopsy specimens from patients with chronic hepatitis C for fibrosis using modified Knodell criteria; fibrosis ratios were computed from digital images that encompassed the complete trichrome-stained section of each case. Although an overall correlation between fibrosis ratio and ordinal score was present, subset analysis showed that this correlation existed only among biopsy specimens with high scores (3-6, early bridging fibrosis to established cirrhosis). There was no correlation or difference between category means found among biopsy specimens with low scores (0-3, normal to early bridging fibrosis). Furthermore, concordance by both estimates in direction of fibrosis change among serial liver biopsy specimens was found in only 11 (30%) of 37 pairs compared. The findings suggest that a qualitative assessment of the computerized fibrosis pattern is necessary for the interpretation of computerized fibrosis ratio measurements, particularly in patients with early stage fibrosis.

Health-Related Quality of Life of Patients with HIV Disease: Impact of Hepatitis C Coinfection

Health-related quality of life (HRQOL) is diminished in patients infected with both hepatitis C virus (HCV) and human immunodeficiency virus (HIV), but the effect of HIV/HCV coinfection on HRQOL is unknown. We compared the HRQOL of urban HIV/HCV coinfected patients with that of patients infected with either HCV or HIV alone. We then compared the 3 groups with a US population sample, adjusting for demographic characteristics. HRQOL for the group of HIV/HCV coinfected patients was statistically similar to that of HRQOL in patients with either HCV or HIV alone, but the 3 groups had a significantly decreased HRQOL than did the adjusted US population. Using multivariate techniques, we determined that age, unemployment, injection drug use, and depression were associated with impaired HRQOL. These findings underscore the importance of a multidisciplinary approach to the treatment of these patient populations.

Comparison of HCV-specific intrahepatic CD4+ T cells in HIV/HCV versus HCV.

Persons with human immunodeficiency virus (HIV) and hepatits C virus (HCV) coinfection are at increased risk for progression to cirrhosis compared with persons with HCV alone, but the reasons for this are unclear. In chronic HCV, the mechanism of liver injury is presumed to be due to HCV‐specific T cell destruction of hepatocytes, so it is paradoxical that immunosuppressed hosts have higher rates of fibrosis progression. We examined intrahepatic cellular immune responses to HCV antigens to determine whether there were qualitative or quantitative differences in subjects with and without HIV. Expanded, CD4‐enriched, liver‐infiltrating lymphocytes from 18 subjects with chronic HCV and 12 subjects with HIV/HCV were cultured in the presence of HCV core protein, nonstructural proteins NS3 and NS5, and recall antigens tetanus toxoid and Candida. Secretion of interferon γ (IFN‐γ), tumor necrosis factor α (TNF‐α), and interleukin (IL) 10 was determined using enzyme‐linked immunosorbent spot assay. There were no significant differences in liver biopsy grade or stage for HIV/HCV versus HCV groups. There were no significant differences between groups in the secretion of IFN‐γ or TNF‐α in response to HCV or recall antigens. However, there was a significant increase in IL‐10 secretion in response to NS3 and NS5 in subjects with HCV compared with HIV and HCV coinfection. In conclusion, subjects with coinfection have an alteration of intrahepatic HCV‐specific IL‐10 cytokine response that may have implications for HCV‐related disease progression. (HEPATOLOGY 2004;40:125–132.)

Expression of Membrane-associated Mucins MUC1 and MUC4 in Major Human Salivary Glands

Mucins are high molecular weight glycoproteins secreted by salivary glands and epithelial cells lining the digestive, respiratory, and reproductive tracts. These glyco-proteins, encoded in at least 13 distinct human genes, can be subdivided into gel-forming and membrane-associated forms. The gel-forming mucin MUC5B is secreted by mucous acinar cells in major and minor salivary glands, but little is known about the expression pattern of membrane-associated mucins. In this study, RT-PCR and Northern blotting demonstrated the presence of transcripts for MUC1 and MUC4 in both parotid and submandibular glands, and in situ hybridization localized these transcripts to epithelial cells lining striated and excretory ducts and in some serous acinar cells. The same cellular distribution was observed by immunohistochemistry. Soluble forms of both mucins were detected in parotid secretion after immunoprecipitation with mucin-specific antibodies. These studies have shown that membrane-associated mucins are produced in both parotid and submandibular glands and that they are expressed in different cell types than gel-forming mucins. Although the function of these mucins in the oral cavity remains to be elucidated, it is possible that they both contribute to the epithelial protective mucin layer and act as receptors initiating one or more intracellular signal transduction pathways.

Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C

Although recurrent hepatitis C virus (HCV) after liver transplantation (LT) is universal, a minority of patients will develop cirrhosis within 5 years of surgery, which places them at risk for allograft failure. This retrospective study investigated whether 2 serum fibrosis markers, serum hyaluronic acid (HA) and YKL‐40, could be used to predict rapid fibrosis progression (RFP) post‐LT. These markers were compared with conventional laboratory tests, histological assessment, and hepatic stellate cell activity (HSCA), a key step in fibrogenesis, as assessed by immunohistochemical staining for alpha‐smooth muscle actin. Serum and protocol liver biopsy samples were obtained from 46 LT recipients at means of 5 ± 2 (biopsy 1) and 39 ± 6 (biopsy 2) months post‐LT, respectively. RFP was defined as an increase in the fibrosis score ≥ 2 from biopsy 1 to biopsy 2 (a mean interval of 33 ± 6 months). The ability of parameters at biopsy 1 to predict RFP was compared with the areas under receiver operating characteristic curves (AUROCs). Of the 46 subjects, 15 developed RFP. Serum HA and YKL‐40 performed significantly better than conventional parameters and HSCA in predicting RFP post‐LT for HCV at biopsy 1, with AUROCs of 0.89 and 0.92, respectively. The accuracy of serum HA ≥ 90 μg/L and YKL‐40 ≥ 200 μg/L in predicting RFP at biopsy 1 was 80% and 96%, respectively. In conclusion, we found that elevated levels of serum HA and YKL‐40 within the first 6 months after LT accurately predicted RFP. Larger studies evaluating the role of serum HA and YKL‐40 in post‐LT management are warranted. Liver Transpl 14:1294–1302, 2008.

Recent drug use, homelessness and increased short-term mortality in HIV-infected persons with alcohol problems

Objective:To assess the impact of recent heavy alcohol use, heroin/cocaine use, and homelessness on short-term mortality in HIV-infected persons. Methods:Survival in a longitudinal cohort of 595 HIV-infected persons with alcohol problems was assessed at 6-month intervals in 1996–2005. The time-varying main independent variables were heavy alcohol use (past 30 days), heroin/cocaine use (past 6 months), and homelessness (past 6 months). Date of death was determined using the Social Security Death Index. Outcomes were limited to deaths occurring within 6 months of last assessment to ensure recent assessments of the main independent variables. Cox proportional hazards models were fit to the data. Results:Death within 6 months of their last assessment occurred in 31 subjects (5.2%). Characteristics at study entry included mean age 41 years, 25% female, 41% African-American, 24% with CD4 cell count < 200 cells/μl; 41% taking antiretroviral therapy, 30% heavy alcohol use, 57% heroin or cocaine use, and 28% homelessness. Heroin or cocaine use [hazard ratio (HR), 2.43; 95% confidence interval (CI), 1.12–5.30)] and homelessness (HR, 2.92; 95% CI, 1.32–6.44), but not heavy alcohol use (HR, 0.57; 95% CI, 0.23–1.44), were associated with increased mortality in analyses adjusted for age, injection drug use ever, CD4 cell count, and current antiretroviral therapy. Conclusions:Recent heroin or cocaine use and homelessness are associated with increased short-term mortality in HIV-infected patients with alcohol problems. Optimal management of HIV-infected patients requires regular assessments for drug use and homelessness and improved access to drug treatment and housing.