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1.  Hepatic Steatosis at One Year is an Additional Predictor of Subsequent Fibrosis Severity in Liver Transplantation Recipients with Recurrent Hepatitis C Virus 
Recurrent hepatitis C virus (HCV) is the most common cause of graft loss among HCV-infected liver transplant (LT) recipients. Diabetes (DM) has been associated with increased rates of fibrosis progression but whether steatosis affects post-LT outcomes, independent of DM, is unclear. Using a retrospective cohort of HCV-infected LT recipients, we determined the prevalence of hepatic steatosis and evaluated the relationship between steatosis on index biopsy at one year post-LT (±6 months) and severity of subsequent fibrosis. A total of 152 HCV LT recipients were followed for a median follow-up after the index biopsy of 2.09 (range 0.13–6.17) years, with a median number of biopsies/patient after the index biopsy of 2 (range 1–6). Steatosis (≥5%) was present in 45 (29.6%) individuals in the 1-year index biopsy post-LT; steatosis was mild (grade 1) in 80%. In multivariate analysis, presence of steatosis at 1-year post-LT was positively associated with genotype 3 (OR= 3.60, p=0.02), older donor age (OR= 1.03, p=0.04), and pre-LT hypertension (OR= 3.29, p=0.009). At 3 years post-LT, the cumulative rate of significant fibrosis (F2-4 Ludwig-Batts scale) was 49% in those with steatosis at 1 year versus 24% in those without steatosis (p=0.003). In multivariable analysis, steatosis at 1-year was an independent predictor of subsequent F2-4 fibrosis (OR= 2.20, p=0.008). Steatosis was a stronger predictor of fibrosis in the setting of sirolimus use (HR 9.38, 95% CI 1.37, 64.16; p=0.02). We conclude that steatosis is frequent in the early post-LT period, and that steatosis within the 1 year post-LT is a marker of higher risk of fibrosis progression in HCV-infected patients.
doi:10.1002/lt.22389
PMCID: PMC3712627  PMID: 21770018
2.  Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients 
Gut  2003;52(7):1035-1040.
Objectives: To compare the rate of hepatic fibrosis progression in hepatitis C virus (HCV) infected and human immunodeficiency virus (HIV)-HCV coinfected patients, and to identify factors that may influence fibrosis progression.
Patients and methods: A total of 153 HCV infected and 55 HCV-HIV coinfected patients were identified from two London hospitals. Eligible patients had known dates of HCV acquisition, were HCV-RNA positive, and had undergone a liver biopsy, which was graded using the Ishak score. Univariate and multivariate logistic regression analyses were used to identify factors associated with fibrosis progression rate and the development of advanced fibrosis (stages 3 and 4).
Results: The estimated median fibrosis progression rate was 0.17 units/year (interquartile range (IQR) 0.10–0.25) in HIV-HCV coinfected and 0.13 (IQR 0.07–0.17) in HCV monoinfected patients (p=0.01), equating to an estimated time from HCV infection to cirrhosis of 23 and 32 years, respectively. Older age at infection (p<0.001), HIV positivity (p=0.019), higher alanine aminotransferase (ALT) level (p=0.039), and higher inflammatory activity (p<0.001) on first biopsy were all independently associated with more rapid fibrosis progression. ALT was correlated with histological index (r=0.35, p<0.001). A CD4 cell count ⩽250×106/l was independently associated with advanced liver fibrosis (odds ratio 5.36 (95% confidence interval 1.26–22.79)) and was also correlated with a higher histological index (r=−0.42, p=0.002).
Conclusion: HIV infection modifies the natural history of HCV by accelerating the rate of fibrosis progression by 1.4 fold, and the development of advanced fibrosis threefold. A low CD4 cell count was independently associated with advanced disease and correlated with higher histological index, which suggests that early antiretroviral therapy may be of benefit in slowing HCV progression in coinfected patients.
PMCID: PMC1773713  PMID: 12801963
human immunodeficiency virus; liver fibrosis; hepatitis C virus
3.  HIV Mono-infection Is Associated With FIB-4 – A Noninvasive Index of Liver Fibrosis – in Women 
Predictors of liver fibrosis were evaluated in women using a noninvasive index (FIB-4). HIV RNA levels were associated with increased FIB-4 in the absence of viral hepatitis, alcohol use, or antiretroviral therapy. These data complement evidence suggesting a potential relationship between HIV infection and hepatic fibrosis.
Background. FIB-4 represents a noninvasive, composite index that is a validated measure of hepatic fibrosis, which is an important indicator of liver disease. To date, there are limited data regarding hepatic fibrosis in women.
Methods. FIB-4 was evaluated in a cohort of 1227 women, and associations were evaluated in univariate and multivariate regression models among 4 groups of subjects classified by their human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection status.
Results. The median FIB-4 scores were 0.60 in HIV-/HCV- women, 0.83 in HIV-/HCV+ women, 0.86 in HIV+/HCV- women, and 1.30 in HIV+/HCV+ women. In the HIV/HCV co-infected group, multivariate analysis showed that CD4+ cell count and albumin level were negatively associated with FIB-4 (P <.0001), whereas antiretroviral therapy (ART) was positively associated with FIB-4 score (P =.0008). For the HIV mono-infected group, multivariate analysis showed that CD4+ cell count (P <.0001) and albumin level (P =.0019) were negatively correlated with FIB-4 score, ART was positively associated with FIB-4 score (P =.0008), and plasma HIV RNA level was marginally associated with FIB-4 score (P =.080). In 72 HIV mono-infected women who were also hepatitis B surface antigen negative, ART naive, and reported no recent alcohol intake, plasma HIV RNA level was associated with increased FIB-4 score (P =.030).
Conclusions. HIV RNA level was associated with increased FIB-4 score in the absence of hepatitis B, hepatitis C, ART, or alcohol use, suggesting a potential relationship between HIV infection and hepatic fibrosis in vivo. A better understanding of the various demographic and virologic variables that contribute to hepatic fibrosis may lead to more effective treatment of HIV infection and its co-morbid conditions.
doi:10.1093/cid/ciq199
PMCID: PMC3106241  PMID: 21248367
4.  Low Rates of Sustained Virologic Response with Peginterferon Plus Ribavirin for Chronic Hepatitis C Virus Infection in HIV Infected Patients in Rio de Janeiro, Brazil 
PLoS ONE  2013;8(7):e67734.
Background
The standard treatment for chronic hepatitis C virus (HCV) infection in HIV-infected subjects is the combination of alfapeginterferon (PEG-IFN) plus ribavirin. We designed this study to evaluate the rate of SVR and predictors of SVR in a public health setting in Rio de Janeiro, Brazil.
Methods
Retrospective cohort study of HCV/HIV co-infected patients treated with PEG-IFN plus ribavirin from 2004 to 2011 in 3 outpatient units in Rio de Janeiro. Exposure variables included age, sex, CD4+ cell count, HCV genotype, HCV and HIV viral loads, liver histology (METAVIR fibrosis scoring system) and previous treatment. The main outcome measurement was SVR.
Results
100 patients were included in this analysis. Median age was 47 years and 68% were male. 80%, 4%, 14% and 2% were infected with HCV genotypes 1, 2, 3 and 4, respectively. At baseline, 77% had HCV viral load greater than 800,000 IU/ml, 99% had CD4+ greater than 200 cells/mm3 and 10% had a diagnosis of cirrhosis. The treatment was withdrawn in 9% of the subjects (5% with adverse effects and 4% dropped out). SVR was observed in 27 (27%) of the 100 patients included. 13 (13%) subjects were classified as null-responders, 33(33%) as non-responders, 9 (9%) as breakthrough and 9(9%) as relapsers. In the multivariate model only being infected with genotype 2 or 3 (p<0.01) and having low levels of gamma glutamyl transferase (GGT) at baseline (p = 0.04), were predictive of SVR.
Conclusion
SVR in HCV/HIV co-infected subjects in a public health setting is similar to that observed in clinical trials, albeit very low. A delay in therapy initiation should be considered until new therapies as direct acting antiviral drugs (DAA) become widely available and tested in coinfected subjects.
doi:10.1371/journal.pone.0067734
PMCID: PMC3706550  PMID: 23874441
5.  Cannabis withdrawal in chronic cannabis users with schizophrenia 
Journal of psychiatric research  2012;47(2):240-245.
Background
Chronic users of cannabis often report withdrawal symptoms after abstinence from use, but little is known about cannabis withdrawal in people with schizophrenia.
Methods
Cannabis use patterns and withdrawal symptoms in adults with schizophrenia who had at least weekly cannabis use before attempting to quit without formal treatment were assessed with the Marijuana Quit Questionnaire (MJQQ), a 176-item, semi-structured questionnaire.
Results
120 participants, predominantly African–American (62.5%) and male (76.7%), met inclusion criteria. 20.1% reported that their first regular cannabis use (median age 15 years [range 8–48]) preceded their age at first psychotic symptoms (20 [4–50] years). Twenty (16.7%) participants met lifetime criteria for cannabis abuse; 98 (81.7%) met surrogate criteria for lifetime cannabis dependence. Withdrawal symptoms were reported by 113 (94.2%) participants, with 74.2% reporting ≥4 symptoms. The most frequently reported withdrawal symptoms were craving for cannabis (59.2%), feeling anxious (52.57%), feeling bored (47.5%), feeling sad or depressed (45.8%), feeling irritable or jumpy (45.0%), feeling restless (43.3%), and trouble failing asleep (33.3%). One hundred-and-four (92.0%) participants took some action to relieve at least one of their withdrawal symptoms during their index-quit attempt, including 26 (23.0%) participants who reported resuming cannabis use.
Conclusion
Cannabis withdrawal is a clinically significant feature of cannabis use among people with schizophrenia, may serve as a negative reinforcer for relapse, and deserves greater attention in treatment and research. Clinical Trials registration NCT00679016.
doi:10.1016/j.jpsychires.2012.10.010
PMCID: PMC3591813  PMID: 23146560
Schizophrenia; Marijuana; Co-morbidity; Cannabis; Withdrawal
6.  Fibrosis Progression in African Americans and Caucasian Americans with Chronic Hepatitis C 
Background & Aims
Prior studies suggest the rate of liver fibrosis progression is slower in African-Americans (AA) than Caucasian-Americans (CA) with chronic hepatitis C virus (HCV) infection.
Methods
Using a multi-state Markov model, fibrosis progression was evaluated in a well-characterized cohort of 143 AA and 157 CA adults with untreated chronic HCV genotype 1 infection. In subjects with a history of injection drug use, duration of infection was imputed from a fitted risk model rather than assumed to be the reported first year of use.
Results
The distribution of Ishak fibrosis stages were 0 (8.7%), 1/2 (55.7%), 3/4 (29.3%) and 5/6 (6.3%), and was similar in AA and CA (p= 0.22). After adjusting for biopsy adequacy, AA had a 10% lower rate of fibrosis progression than did CA, but the difference was not statistically significant (hazard ratio = 0.90, 95% confidence intervals = 0.72, 1.12). The overall 20-year estimates of probabilities of progression from stage 0 to stages 1/2, 3/4 and 5/6 were 59.3%, 28.8% and 4.7%. The estimated median time from no fibrosis to cirrhosis was 79 years for the entire cohort, and 74 and 83 years for CA and AA, respectively. In 3-variable models including race and biopsy adequacy, the factors significantly associated with fibrosis progression were age when infected, steatosis, ALT level, and necroinflammatory score.
Conclusions
The rates of fibrosis progression were slow and did not appear to differ substantially between AA and CA.
doi:10.1016/j.cgh.2008.08.006
PMCID: PMC3166617  PMID: 19081528
7.  Pathological evolution of hepatitis C virus-“Healthy carriers” 
AIM: To determine factors associated with fibrosis progression in hepatitis C virus (HCV)-infected patients without significant initial pathological lesions.
METHODS: Seventy six untreated HCV-infected patients with initially normal liver as defined by a Knodell score ≤ 3, with 2 liver biopsies and detectable HCV-RNA were included. Markers of fibrosis progression were assessed.
RESULTS: Median duration of infection and time between paired biopsies was 13 (95% CI: 1-28) and 4 (95% CI: 2-16) years respectively. Alanine-transaminase (ALT) activity was normal in 43.4% of cases. 50% demonstrated progression of the necro-inflammation and 34% of fibrosis after a median time evolution of 4 years (95% CI: 2-16). The median difference in the necro-inflammation and fibrosis score between biopsies was low, 1.5 and 0.0 respectively. Univariate analysis showed there was no difference between fibrosis activity or evolution according to genotype or viral load. A higher fibrosis progression (P = 0.03) was observed in patients with body mass index (BMI) > 25. Fibrosis progression correlated with the time interval between biopsies (P = 0.01). A significant progression of activity (1.7 vs 0.4, P < 0.05) or fibrosis (0.9 vs 0.0, P < 0.01) was observed in patients with elevated ALT. There was a significant correlation between activity progression and fibrosis progression (P = 0.003). Multivariate analysis demonstrated that fibrosis progression was associated with elevated ALT, BMI > 25 and the time interval between 2 biopsies.
CONCLUSION: There is no fibrosis progression in 66% of patients without significant initial histopathological lesion. Fibrosis progression is associated with elevated ALT and BMI > 25.
doi:10.3748/wjg.14.3861
PMCID: PMC2721443  PMID: 18609710
Hepatitis C virus; Liver fibrosis; Liver biopsy; Alanine-transaminase; Body mass index
8.  Puberty and the Onset of Substance Use and Abuse 
Pediatrics  2004;114(3):e300-e306.
Objective
Substance abuse remains one of the major threats to adolescent health in Western cultures. The study aim was to ascertain the extent of association between pubertal development and early adolescent substance use.
Methods
The design was a cross-sectional survey of 10- to 15-year-old subjects in the states of Washington, United States, and Victoria, Australia. Participants were 5769 students in grades 5, 7, and 9, drawn as a 2-stage cluster sample in each state, and the questionnaire was completed in the school classrooms. The main outcomes of the study were lifetime substance use (tobacco use, having been drunk, or cannabis use), recent substance use (tobacco, alcohol, or cannabis use in the previous month), and substance abuse (daily smoking, any binge drinking, drinking at least weekly, or cannabis use at least weekly).
Results
The odds of lifetime substance use were almost twofold higher (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.4-2.1) in midpuberty (Tanner stage III) and were threefold higher (OR: 3.1; 95% CI: 2.4-4.2) in late puberty (Tanner stage IV/V), after adjustment for age and school grade level. Recent substance use was moderately higher (OR: 1.4; 95% CI: 1.0-1.9) in midpuberty and more than twofold higher (OR: 2.3; 95% CI: 1.7-3.3) in late puberty. The odds of substance abuse were twofold higher (OR: 2.0; 95% CI: 1.2-3.2) in midpuberty and more than threefold higher (OR: 3.5; 95% CI: 2.2-5.4) in late puberty. Reporting most friends as substance users was more likely in the later stages of pubertal development, a relationship that accounted in part for the association found between later pubertal stage and substance abuse.
Conclusions
Pubertal stage was associated with higher rates of substance use and abuse independent of age and school grade level. Early maturers had higher levels of substance use because they entered the risk period at an earlier point than did late maturers. The study findings support prevention strategies and policies that decrease recreational substance use within the peer social group in the early teens.
doi:10.1542/peds.2003-0626-F
PMCID: PMC1892192  PMID: 15342890
puberty; substance abuse; smoking; alcohol consumption; cannabis; adolescence
9.  Isolated Hepatitis B Core Antibody Is Associated with HIV and Ongoing but Not Resolved Hepatitis C Virus Infection in a Cohort of US Women 
The Journal of infectious diseases  2007;195(10):1437-1442.
To characterize predictors of isolated hepatitis B core antibody (anti-HBc) among human immunodeficiency virus (HIV)–infected and HIV-uninfected women, we compared 702 women with anti-HBc and hepatitis B surface antibody (anti-HBs) with 490 women with isolated anti-HBc (1.8% of whom had detectable hepatitis B virus [HBV] DNA). Factors independently associated with isolated anti-HBc without viremia were detectable hepatitis C virus (HCV) RNA, HIV positivity, history of injection drug use, >10 lifetime sex partners, and HIV RNA level >100,000 copies/mL. Anti-HBs levels were lower among anti-HCV–positive women. Isolated anti-HBc was rarely explained by occult HBV in this cohort but may be explained by the influence of viral coinfections on anti-HBs level or durability.
doi:10.1086/515578
PMCID: PMC3133731  PMID: 17436223
10.  Hepatitis C Virus Infection in San Francisco's HIV-infected Urban Poor 
OBJECTIVE
To measure Hepatitis C Virus (HCV) prevalence, incidence, and initiation of HCV therapy in a representative HIV-infected cohort of the urban poor.
DESIGN
Cohort analysis.
SETTING
The Research and Access to Care for the Homeless (REACH) Cohort is a systematic sample of HIV-infected marginally housed individuals identified from single-room occupancy hotels, homeless shelters, and free lunch programs in San Francisco.
PARTICIPANTS
Two hundred forty-nine participants with 28.9 months (median) of follow-up were studied. Mean age was 44 (range 24 to 75, standard deviation 8.4) years. Eighty-two percent were male, 43% were African-American, 64% were lifetime injection drug users, and 24% had been on the street or in a shelter in the prior month.
INTERVENTIONS
We measured HCV testing and treatment history with structured interviews; additionally, participants were tested for HCV antibodies (EIA-2) with RNA viral load confirmation.
MAIN RESULTS
At baseline, 172 (69.1%) were HCV-positive and 182 (73.1%) were HCV-positive at follow-up, including 155 (62.2%) with viremia. HCV-positive status was associated with having injected drugs, elevated serum alanine aminotransferase, homelessness in the last 1 year, and more severe depressive symptoms. The incidence of new HCV infection was 4.63% per person-year (ppy; 95% confidence interval, 2.31 to 8.13) in the entire cohort and 16.77% ppy among injection drug users. The prevalence of HCV antibody-negative HCV-viremia was 13.2% (10/76). Nonwhites were less likely to receive HCV testing and subspecialty referral, controlled for drug use and other confounders. Sixty-eight percent (123/182) were aware treatment was available; however, only 3.8% (7/182) or 1.16% ppy received HCV treatment.
CONCLUSIONS
While HCV infection is common, HCV treatment is rare in the HIV-HCV coinfected urban poor. Urban poor, nonwhite individuals are less likely to receive HCV testing and subspecialty referral than their white counterparts. Antibody-negative infection may complicate screening and diagnosis in HIV-infected persons.
doi:10.1111/j.1525-1497.2004.30613.x
PMCID: PMC1492202  PMID: 15061745
hepatitis C; HIV infection; HIV/HCV coinfection; HCV treatment; homelessness
11.  Hepatitis B and C infection and liver disease trends among human immunodeficiency virus-infected individuals 
AIM: To examine trends in and correlates of liver disease and viral hepatitis in an human immunodeficiency virus (HIV)-infected cohort.
METHODS: The multi-site adult/adolescent spectrum of HIV-related diseases (ASD) followed 29 490 HIV-infected individuals receiving medical care in 11 U.S. metropolitan areas for an average of 2.4 years, and a total of 69 487 person-years, between 1998 and 2004. ASD collected data on the presentation, treatment, and outcomes of HIV, including liver disease, hepatitis screening, and hepatitis diagnoses.
RESULTS: Incident liver disease, chronic hepatitis B virus (HBV), and hepatitis C virus (HCV) were diagnosed in 0.9, 1.8, and 4.7 per 100 person-years. HBV and HCV screening increased from fewer than 20% to over 60% during this period of observation (P < 0.001). Deaths occurred in 57% of those diagnosed with liver disease relative to 15% overall (P < 0.001). Overall 10% of deaths occurred among individuals with a diagnosis of liver disease. Despite care guidelines promoting screening and vaccination for HBV and screening for HCV, screening and vaccination were not universally conducted or, if conducted, not documented.
CONCLUSION: Due to high rates of incident liver disease, viral hepatitis screening, vaccination, and treatment among HIV-infected individuals should be a priority.
doi:10.3748/wjg.v17.i14.1807
PMCID: PMC3080714  PMID: 21528052
Human immunodeficiency virus; Hepatitis B; Hepatitis C; Liver disease
12.  Lower Liver-Related Death in African American Women With HIV/HCV Co-Infection Compared to Caucasian and Hispanic Women 
Hepatology (Baltimore, Md.)  2012;56(5):1699-1705.
Among individuals with and without concurrent human immunodeficiency virus (HIV), racial/ethnic differences in the natural history of hepatitis C virus (HCV) have been described. African-Americans have lower spontaneous HCV clearance than Caucasians, yet slower rates of liver fibrosis once chronically infected. It is not clear how these differences in the natural history of hepatitis C affect mortality, in either HIV positive or negative individuals. We conducted a cohort study of HIV/HCV co-infected women followed in the multicenter, NIH-funded Women’s Interagency HIV Study (WIHS) to determine the association of self-reported race/ethnicity with all-cause and liver-related mortality. Survival analyses were performed using Cox proportional hazards models. The eligible cohort (n=794) included 140 Caucasians, 159 Hispanics, and 495 African Americans. There were 438 deaths and 49 liver-related deaths during a median follow-up of 8.9 years and maximum follow-up of 16 years. African American co-infected women had significantly lower liver-related mortality compared to Caucasian (HR 0.41 95% CI 0.19–0.88, p=0.022) and Hispanic co-infected women (HR 0.38 95% CI 0.19–0.76, p=0.006). All-cause mortality was similar between racial/ethnic groups (HRs for all comparisons 0.82–1.03, logrank p=0.8).
Conclusions
African American co-infected women were much less likely to die from liver disease as compared to Caucasians and Hispanics, independent of other causes of death. Future studies are needed to investigate the reasons for this marked racial/ethnic discrepancy in liver-related mortality.
doi:10.1002/hep.25859
PMCID: PMC3440547  PMID: 22618868
race; ethnicity; viral hepatitis; mortality; gender
13.  Relationship of Liver Disease Stage and Antiviral Therapy With Liver-Related Events and Death in Adults Coinfected With HIV/HCV 
JAMA : the journal of the American Medical Association  2012;308(4):10.1001/jama.2012.7844.
Context
Human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV) disease progression; however, the effect of liver disease stage and antiviral therapy on the risk of clinical outcomes is incompletely understood.
Objective
To determine the incidence of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), or death according to baseline hepatic fibrosis and antiviral treatment for HIV/HCV coinfected individuals.
Design, Setting, and Participants
Prospective cohort of 638 coinfected adults (80% black, 66% men) receiving care at the Johns Hopkins HIV clinic and receiving a liver biopsy and who were prospectively monitored for clinical events between July 1993 and August 2011 (median follow-up, 5.82 years; interquartile range, 3.42–8.85 years). Histological specimens were scored for hepatic fibrosis stage according to the METAVIR scoring system.
Main Outcome Measure
Incidence of composite outcome of ESLD, HCC, or death.
Results
Patients experienced a graded increased risk in incidence of clinical outcomes based on baseline hepatic fibrosis stage (classification range, F0-F4): F0, 23.63 (95% CI, 16.80–33.24); F1, 36.33 (95% CI, 28.03–47.10); F2, 53.40 (95% CI, 33.65–84.76); F3, 56.14 (95% CI, 31.09–101.38); and F4, 79.43 (95% CI, 55.86–112.95) per 1000 person-years (P<.001). In multivariable negative binomial regression, fibrosis stages F2 through F4 and antiretroviral therapy were independently associated with composite ESLD, HCC, or all-cause mortality after adjustment for demographic characteristics, injection drug use, and CD4 cell count. Compared with F0, the incidence rate ratio (RR) for F2 was 2.31 (95% CI, 1.23–4.34; P=.009); F3, 3.18 (95% CI, 1.47–6.88; P=.003); and F4, 3.57 (95% CI, 2.06–6.19; P<.001). Human immunodeficiency virus treatment was associated with fewer clinical events (incidence RR, 0.27; 95% CI, 0.19–0.38; P<.001). For the 226 patients who underwent HCV treatment, the incidence of clinical events did not significantly differ between treatment nonresponders and untreated patients (incidence RR, 1.27; 95% CI, 0.86–1.86; P=.23). In contrast, no events were observed in the 51 patients with sustained virologic response (n= 36) and relapse (n= 15), including 19 with significant fibrosis.
Conclusion
In this cohort of patients with HIV/HCV coinfection, hepatic fibrosis stage was independently associated with a composite outcome of ESLD, HCC, or death.
doi:10.1001/jama.2012.7844
PMCID: PMC3807214  PMID: 22820790
14.  Rapid Progression to Decompensated Cirrhosis, Liver Transplant, and Death in HIV-Infected Men After Primary Hepatitis C Virus Infection 
Four men from a cohort of HIV-infected men who did not achieve cure after primary hepatitis C virus infection developed decompensated cirrhosis within 17 months to 6 years after infection, with subsequent rapid progression to liver transplant and death.
Background. We and others have shown that primary hepatitis C (HCV) infection in men infected with human immunodeficiency virus (HIV) causes early-onset liver fibrosis; however, little is known about the long-term natural history of the liver disease in these HIV-infected men.
Methods. We followed a cohort of HIV-infected men with primary HCV infection in New York City.
Results. Four men who were not cured after their primary HCV infection developed decompensated cirrhosis within 17 months to 6 years after primary HCV infection. Three died within 8 years of primary HCV infection, and 1 survived after liver transplant done 2 years after primary HCV infection. Three of the 4 men had AIDS at the time of primary HCV infection, and the most rapid progression occurred in the 2 men with the lowest CD4 counts at the time of HCV infection. Liver histopathology was most consistent with HCV-induced damage even though some had exposures to other potential hepatotoxins.
Conclusions. Primary HCV infection resulted in decompensated cirrhosis and death within 2–8 years in 4 HIV-infected men. The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign. The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.
doi:10.1093/cid/cis1206
PMCID: PMC3588118  PMID: 23264364
liver failure; primary acute hepatitis C infection; HIV infection/AIDS; immunocompromise; men who have sex with men
15.  Prospective Study of Cannabis Use in Adolescents at Clinical High-Risk for Psychosis: Impact on Conversion to Psychosis and Functional Outcome 
Psychological medicine  2012;42(12):2485-2497.
Background
Clinical and epidemiological studies suggest an association between cannabis use and psychosis, but this relationship remains controversial.
Methods
Clinical High-Risk (CHR) subjects (age 12–22) with attenuated positive symptoms of psychosis (CHR+, n=101) were compared to healthy controls (HC, n=59) on rates of substance use, including cannabis. CHR+ subjects with and without lifetime cannabis use (and abuse) were compared on prodromal symptoms and social/role functioning at baseline. Participants were followed an average of 2.97 years to determine psychosis conversion status and functional outcome.
Results
At baseline, CHR+ subjects had significantly higher rates of lifetime cannabis use than HC subjects. CHR+ lifetime cannabis users (N=35) were older (p=0.015, trend), more likely Caucasian (p=0.002), less socially anhedonic (p<0.001), and had higher Global Functioning (GF):Social scores (p<0.001) than non-users (N=61). CHR+ cannabis users continued to have higher social functioning than non-users at follow-up (p<0.001), but no differences on role functioning. A small sample of CHR+ cannabis abusers (N=10) showed similar results in that abusers were older (p=0.008), less socially anhedonic (p=0.017, trend), and had higher baseline GF:Social scores (p=0.006) than non-abusers. Logistic regression analyses revealed that conversion to psychosis in CHR+ subjects (N=15) was not related to lifetime cannabis use or abuse.
Conclusions
The current data do not support low to moderate lifetime cannabis use to be a major contributor to psychosis or poor social and role functioning in high-risk youth.
doi:10.1017/S0033291712000803
PMCID: PMC3459073  PMID: 22716931
Cannabis use; high-risk; prodrome; social functioning; conversion; psychosis
16.  Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study 
Gut  2004;53(3):451-455.
Background: The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment.
Patients: We studied 214 HCV infected patients (126 male; median age 36 years (range 5–8)) with predominantly mild liver disease who were prospectively followed without treatment and assessed for risk factors for progression of liver disease. Interbiopsy interval was a median of 2.5 years. Paired biopsies from the same patient were scored by the same pathologist.
Results: Seventy of 219 (33%) patients showed progression of at least 1 fibrosis point in the Ishak score; 23 progressed at least 2 points. Independent predictors of progression were age at first biopsy and any fibrosis on first biopsy. Factors not associated with progression were: necroinflammation, duration of infection, alcohol consumption, alanine aminotransferase levels, current or past hepatitis B virus infection, ferritin, HCV genotype, and steatosis or iron deposition in the initial biopsy.
Conclusions: One third of patients with predominantly mild hepatitis C showed significant fibrosis progression over a median period of 30 months. Histologically, mild hepatitis C is a progressive disease. The overall rate of fibrosis progression in patients with hepatitis C was low but increased in patients who were older or had fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years.
doi:10.1136/gut.2003.021691
PMCID: PMC1773967  PMID: 14960533
hepatitis C virus; fibrosis; hepatic fibrosis
17.  CXCL9 and CXCL10 Chemokines as Predictors of Liver Fibrosis in a Cohort of Primarily African-American Injection Drug Users With Chronic Hepatitis C 
The Journal of Infectious Diseases  2011;204(6):832-836.
CXCL9 (monokine induced by IFN γ [Mig]) and CXCL10 (interferon [IFN] γ−inducible protein 10 [IP-10]) have been associated with hepatic fibrosis in predominantly white hepatitis C virus (HCV)–infected patients. We investigated their potential as noninvasive markers of hepatic fibrosis and fibrosis progression in African-American patients. Peripheral chemokine levels were measured in 115 HCV-infected patients within 4 months of liver biopsy; patients underwent a second biopsy after 3–5 years. CXCL10 levels appeared to be higher in patients with advanced fibrosis on the contemporaneous biopsy and were significantly higher in patients with advanced fibrosis compared with those with minimal fibrosis on the later biopsy (P = .0045). Therefore, CXCL10 has potential as a marker of fibrosis progression in African-American HCV-infected patients.
doi:10.1093/infdis/jir424
PMCID: PMC3156920  PMID: 21849280
18.  Marijuana Smoking Does Not Accelerate Progression of Liver Disease in HIV–Hepatitis C Coinfection: A Longitudinal Cohort Analysis 
In a large human immunodeficiency virus–hepatitis C virus coinfection cohort, we found no evidence that marijuana smoking accelerated progression to significant liver fibrosis, cirrhosis, or end-stage liver disease. Previous studies reporting an association may have been biased by reverse causation due to self-medication.
Background. Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons.
Methods. Data were analyzed for 690 HCV polymerase chain reaction positive (PCR-positive) individuals without significant fibrosis or end-stage liver disease (ESLD) at baseline. Time-updated Cox Proportional Hazards models were used to assess the association between the average number of joints smoked/week and progression to significant liver fibrosis (APRI ≥ 1.5), cirrhosis (APRI ≥ 2) or ESLD.
Results At baseline, 53% had smoked marijuana in the past 6 months, consuming a median of 7 joints/week (IQR, 1–21); 40% smoked daily. There was no evidence that marijuana smoking accelerates progression to significant liver fibrosis (APRI ≥ 1.5) or cirrhosis (APRI ≥ 2; hazard ratio [HR]: 1.02 [0.93–1.12] and 0.99 [0.88–1.12], respectively). Each 10 additional joints/week smoked slightly increased the risk of progression to a clinical diagnosis of cirrhosis and ESLD combined (HR, 1.13 [1.01–1.28]). However, when exposure was lagged to 6–12 months before the diagnosis, marijuana was no longer associated with clinical disease progression (HR, 1.10 [0.95–1.26]).
Conclusions In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection. A slight increase in the hazard of cirrhosis and ESLD with higher intensity of marijuana smoking was attenuated after lagging marijuana exposure, suggesting that reverse causation due to self-medication could explain previous results.
doi:10.1093/cid/cit378
PMCID: PMC3739469  PMID: 23811492
HIV; HCV; cannabis; liver disease; cohort study
19.  Hepatitis C Virus-Specific T cell-Derived Transforming Growth Factor beta is Associated with Slow Hepatic Fibrogenesis 
Hepatology (Baltimore, Md.)  2012;56(6):2094-2105.
Background/Aims
Hepatitis C virus (HCV)-specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are main effectors of liver fibrosis. We previously identified TGFβ, produced by HCV-specific CD8+ T cells, as key regulatory cytokine modulating HCV-specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV-specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis.
Methods
Cross-sectional study of 2 well-defined groups of HCV-infected subjects with slow (≤0.1 Metavir units/year, n=13) or rapid (n=6) liver fibrosis progression. HCV-specific T cell responses were studied using IFNγ-ELISpot ±mAbs blocking regulatory cytokines, along with multiplex, ELISA and multi-parameter FACS. Effects of IHL stimulated with HCV-core peptides on HSC expression of pro-fibrotic and fibrolytic genes were determined.
Results
Blocking regulatory cytokines significantly raised detection of HCV-specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (p=0.003) and liver (p=0.01). Regulatory cytokine blockade revealed HCV-specific IFNγ responses strongly correlated with HCV-specific TGFβ, measured before blockade (R=0.84, p=0.0003), with only trend to correlation with HCV-specific IL-10. HCV-specific TGFβ was produced by CD8 and CD4 T cells. HCV-specific TGFβ, not IL-10, inversely correlated with liver inflammation (R=-0.63, p=0.008) and, unexpectedly, fibrosis (R=-0.46, p=0.05). In addition, supernatants from HCV-stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti-TGFβ mAb abrogated such expression.
Conclusion
Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV-specific T cells appeared to have a protective role in HCV-infected liver, together with other T-cell derived factors, ameliorating HCV liver disease progression.
doi:10.1002/hep.25951
PMCID: PMC3508175  PMID: 22806830
Treg; IL-17; MMP-1; liver fibrosis
20.  Genome-Wide Association Study Identifies Variants Associated with Progression of Liver Fibrosis from HCV Infection 
Gastroenterology  2012;143(5):1244-52.e1-12.
BACKGROUND & AIMS
Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We carried out a 2-stage GWA study of liver fibrosis progression related to HCV infection.
METHODS
We studied well-characterized HCV-infected patients of European descent who had liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of Metavir scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P-values<5×10−5 from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance.
RESULTS
In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients that received blood transfusions) were associated with fibrosis progression (Pcombined=8.9×10−9 and 1.1×10−9, respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (Pcombined=5.4×10−7), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages.
CONCLUSIONS
Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.
doi:10.1053/j.gastro.2012.07.097
PMCID: PMC3756935  PMID: 22841784
genetic analysis; risk factors; cirrhosis; liver disease
21.  U.S. Multicenter Pilot Study of Daily Consensus Interferon (CIFN) Plus Ribavirin for “Difficult-to-Treat” HCV Genotype 1 Patients 
Digestive Diseases and Sciences  2011;56(3):880-888.
Background
Patients with chronic hepatitis C genotype 1 (HCV-1) and difficult-to-treat characteristics respond poorly to pegylated interferon alfa and ribavirin (RBV), and could benefit from an interferon with increased activity (consensus interferon or CIFN), favorable viral kinetics from daily dosing, and a longer duration of therapy. The purpose of this pilot study was to determine the efficacy and safety of daily CIFN + RBV for initial treatment of patients with HCV-1 infection.
Methods
Patients with difficult-to-treat characteristics (92% male, 33% African American, 78% Veterans Affairs [VA]; 67% high viral load, 59% stage 3–4 fibrosis, and mean weight of 204 lbs) were enrolled at seven VA and two community medical centers. They were randomized to daily CIFN (15 mcg/day SQ) and RBV (1–1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52–72 weeks (from time of viral response +48 weeks) (group B, n = 31).
Results
Intention to treat analysis for treatment groups A and B demonstrated 33% (11/33) and 32% (10/31) sustained virologic response (SVR), respectively. Only 2/31 patients in group B received more than 52 weeks of treatment. The overall group demonstrated a 31% (20/64) rapid virologic response rate (RVR), 54% (34/64) end of treatment virologic response and a 33% (21/64) SVR. Patients with RVR at 4 weeks, early virologic response from 8–12 weeks, and late virologic response from 16–24 weeks demonstrated SVR of 75% (15/20), 31% (4/13), and 22% (2/9), respectively. Overall early non-protocol discontinuation occurred in 26/64 (40%) patients.
Conclusion
Daily CIFN and ribavirin for initial treatment of HCV-1 patients has potential for achieving a relatively high RVR rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence.
doi:10.1007/s10620-010-1504-y
PMCID: PMC3041922  PMID: 21221804
Consensus interferon; Hepatitis C; Ribavirin; Veterans Affairs
22.  Comparison of Hepatitis C Viral Loads in Patients with or without Human Immunodeficiency Virus 
A better understanding of how human immunodeficiency virus (HIV) coinfection affects the course of hepatitis C virus (HCV) infection is required to select patients with HIV who would benefit from current HCV therapy. Between June 1996 and March 2000, HCV RNA levels were quantified for 1,279 patients at the Louisiana State University Health Sciences Center; 28 of these patients were coinfected with HIV. HCV loads were quantified by the Bayer branched-DNA assay with a lower limit of detection of 0.2 Meq/ml. We compared the median HCV RNA levels of for patients coinfected with HIV and HCV and patients infected only with HCV who were in the same age range (23 to 55 years). The median HCV load for the 28 patients coinfected with HCV and HIV (17.8 Meq/ml) was significantly greater (P < 0.05) than that for similarly aged patients infected only with HCV (6.1 Meq/ml). The HCV load did not correlate with age or sex for either group of patients. A significant (R = −0.4; P < 0.05) negative correlation was observed between HCV load and CD4 count in the coinfected group, for whom the CD4 counts at the time of HCV load analysis ranged from 6 to 1,773/mm3. The increased HCV load in patients coinfected with HCV and HIV compared to that in patients infected only with HCV and the inverse relationship of the HCV load to the CD4 count indicate that immunosuppression results in decreased control of HCV replication. In addition, we report significantly higher HCV loads among coinfected African Americans than Caucasians.
doi:10.1128/CDLI.8.4.690-694.2001
PMCID: PMC96128  PMID: 11427412
23.  Association of IL-18 promoter polymorphism with liver disease severity in HCV-infected patients 
Hepatology International  2009;3(2):371-377.
Introduction
Interleukin (IL)-18 plays an important dual role in Th1 polarization and viral clearance, as well as in the development of liver fibrosis. Single-nucleotide promoter polymorphisms influence the transcription of IL-18 mRNA. Promoter polymorphisms are linked to delayed virus clearance and disease susceptibility in many diseases. However, there is no information about their role in hepatitis C virus (HCV) infection.
Aim
To investigate the association between −607 or −137 polymorphism with susceptibility and severity of HCV infection.
Patients and methods
Two hundred and four serologically proven patients with chronic HCV infection and 350 matched healthy controls were included in this study. Patients were segregated in 2 groups: group A with mild liver disease and group B with severe liver disease on the basis of histological activity index (HAI ≤5 or >5) and hepatic fibrosis score (≤2 or >2). IL-18 promoter genotyping was performed with sequence-specific primers.
Results
There was no significant difference in the frequencies of −607 and −137 allelic distribution in patients and controls. The −607 A/A allele was more common in group A patients with mild liver disease than in patients with severe liver disease on the basis of HAI (38.6% vs. 21%, P = 0.05; odds ratio [OR] = 0.424, confidence interval [CI] = 0.233–0.773; R2 = 0.631) and stage of fibrosis (38.7% vs. 16.7%, P = 0.008; OR = 0282, CI = 0.134–0.596; R2 = 0.434).
Conclusions
IL-18 promoter polymorphism at −607 position with A/A allele is a potential protective marker, as it is associated with milder liver disease in patients with chronic HCV infection.
doi:10.1007/s12072-009-9127-0
PMCID: PMC2716760  PMID: 19669363
IL-18; Hepatitis C; Polymorphism; HAI; Fibrosis
24.  Metabolic and cardiovascular risk profiles and hepatitis C virus infection in rural Egypt 
Gut  2006;56(8):1105-1110.
Background and aim
To investigate the relationship between lipid profiles and diabetes with past and chronic hepatitis C virus (HCV) infection among village residents of Egypt.
Patients and methods
Fasting lipids and glucose profiles were compared among adults never infected with HCV (negative HCV antibodies), infected in the past (positive HCV antibodies and negative HCV RNA) and chronically infected (positive HCV antibodies and HCV RNA).
Results
Of the 765 participants, 456 (59.6%) were female, and median age was 40 (range 25–88) years. Chronic HCV infection was present in 113 (14.8%) and past infection in 67 (8.8%). After adjustment for age and sex, participants with chronic HCV infection had lower plasma low density lipoproteins (LDL) cholesterol and triglyceride levels compared with those never infected (age and sex adjusted differences (95% CI) were −19.0 (−26.3 to −11.7) mg/dl and −26.2 (−39.0 to −13.3) mg/dl, respectively). In contrast, participants with cleared HCV infection had higher triglyceride levels compared with those never infected (age and sex adjusted difference (95% CI) was +16.0 (0.03 to 31.9) mg/dl). In multivariate analysis, participants with chronic HCV infection were more likely to have diabetes (OR 3.05, 95% CI 1.19 to 7.81) compared with those never infected, independent of LDL cholesterol levels.
Conclusion
In conclusion, this community based study has shown that in a single population, chronic HCV infection is associated with glucose intolerance and, despite that, a favourable lipid pattern. An intriguing finding was the high triglyceride levels observed among participants with past infection, suggesting that elevated triglycerides at the time of acute infection may facilitate viral clearance.
doi:10.1136/gut.2006.091983
PMCID: PMC1955512  PMID: 16956918
25.  Prospective Follow-Up of Patients with Acute Hepatitis C Virus Infection in Brazil 
Background
The natural outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. However, little is known about host and viral factors associated with a self-limiting or chronic evolution of HCV infection.
Methods
From 1 January 2001 through 31 December 2008, a consecutive series of 65 patients from Rio de Janeiro, Brazil, with a well-documented diagnosis of acute HCV infection, acquired via various routes, were enrolled in this study. Patients were prospectively followed up for a median of 40 months after the estimated date of HCV infection with serial measurements of serum alanine aminotransferase, HCV RNA, and anti-HCV antibodies. Spontaneous viral clearance (SVC) was defined as undetectable levels of HCV RNA in serum, in the absence of treatment, for 3 consecutive HCV polymerase chain reaction tests within the first 6 months of follow-up. Cox proportional hazards regression was used to identify host and viral predictors of SVC.
Results
The cumulative rate of SVC was 44.6% (95% confidence interval, 32.3%–57.5%). Compared with chronic HCV evolution, patients with self-limiting disease had significantly lower peak levels of anti-HCV antibodies (median, 109.0 vs 86.7 optical density–to–cutoff ratio [od/co]; P < .02), experienced disease symptoms more frequently (69.4% vs 100%; P < .001), and had lower viral load at first clinical presentation (median, 4.3 vs 0.0 log copies; P =.01). In multivariate analyses, low peak anti-HCV level (<93.5 od/co) was the only independent predictor for SVC; the hazard ratio compared with high anti-HCV levels (≥93.5 od/co) was 2.62 (95% confidence interval, 1.11–6.19; P =.03).
Conclusion
Our data suggest that low levels of anti-HCV antibodies during the acute phase of HCV infection are independently related to spontaneous viral clearance.
doi:10.1086/651599
PMCID: PMC3860186  PMID: 20235831

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