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1.  Prognosis of schizophrenia in persons with and without a history of cannabis use 
Psychological Medicine  2014;44(12):2513-2521.
The aim of the study was to determinate whether schizophrenia patients with a history of cannabis use have a different prognosis, with regards to readmission and hospital duration, compared with those without a history of cannabis use.
The present investigation was a cohort study of 50 087 Swedish men with data on cannabis use at the ages of 18–20 years. A total of 357 cases of schizophrenia were identified from in-patient care and followed up from 1973 to 2007.
Schizophrenia patients with a history of cannabis use had a higher median duration of first hospital episode (59 days v. 30 days). Patients with a history of cannabis use had a higher median rate of readmission (10 times v. four times). Also, total number of hospital days was higher in patients with a history of cannabis use compared with those without (547 days v. 184 days). Patients with a history of cannabis use had an increased odds of having more than 20 hospital readmissions compared with non-users [3.1, 95% confidence interval (CI) 1.3–7.3] as well as an increased odds of hospital admission lasting more than 2 years (2.4, 95% CI 1.1–7.4) after controlling for diagnosis of personality disorders, family socio-economic position, IQ score, civil status, place of residence, risky use of alcohol and use of other drugs. Patients with a history of cannabis use were less likely to have paranoid schizophrenia compared with never users (8% v. 17%) in the first admission.
Schizophrenia patients with a history of cannabis use had a significantly higher burden of lifetime in-patient care than non-cannabis users. Not only does cannabis increase the risk of schizophrenia, but also our findings indicate that the course and prognosis of schizophrenia may be more severe than schizophrenia cases in general.
PMCID: PMC4108251  PMID: 25055170
Cannabis; prognosis; psychosis; schizophrenia
2.  HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease 
Annals of internal medicine  2013;158(9):658-666.
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.
To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.
Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.
Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.
1176 current and former injection drug users with antibodies to HCV.
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.
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.
The process of liver fibrosis began before the study in most persons.
In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.
PMCID: PMC3708651  PMID: 23440167
3.  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.
PMCID: PMC1773967  PMID: 14960533
hepatitis C virus; fibrosis; hepatic fibrosis
4.  Factors associated with the progression of fibrosis on liver biopsy in Alaska Native and American Indian persons with chronic hepatitis C 
Various factors influence the development and rate of fibrosis progression in chronic hepatitis C virus (HCV) infection.
To examine factors associated with fibrosis in a long-term outcomes study of Alaska Native/American Indian persons who underwent liver biopsy, and to examine the rate of fibrosis progression in persons with subsequent biopsies.
A cross-sectional analysis of the demographic, inflammatory and viral characteristics of persons undergoing liver biopsy compared individuals with early (Ishak fibrosis score of lower than 3) with those with advanced (Ishak score of 3 or greater) fibrosis. Persons who underwent two or more biopsies were analyzed for factors associated with fibrosis progression.
Of 253 HCV RNA-positive persons who underwent at least one liver biopsy, 76 (30%) had advanced fibrosis. On multivariate analysis, a Knodell histological activity index score of 10 to 14 and an alpha-fetoprotein level of 8 ng/mL or higher were found to be independent predictors of advanced liver fibrosis (P<0.0001 for each). When surrogate markers of liver inflammation (alanine aminotransferase, aspartate aminotransferase/alanine aminotransferase ratio and alpha-fetoprotein) were removed from the model, type 2 diabetes mellitus (P=0.001), steatosis (P=0.03) and duration of HCV infection by 10-year intervals (P=0.02) were associated with advanced fibrosis. Among 52 persons who underwent two or more biopsies a mean of 6.2 years apart, the mean Ishak fibrosis score increased between biopsies (P=0.002), with progression associated with older age at initial biopsy and HCV risk factors.
The presence of type 2 diabetes mellitus, steatosis and duration of HCV infection were independent predictors of advanced fibrosis in the present cohort, with significant fibrosis progression demonstrated in persons who underwent serial biopsies.
PMCID: PMC2918486  PMID: 20652161
Hepatitis C; Liver fibrosis; Liver steatosis
5.  The Effect of Cannabis Use and Cognitive Reserve on Age at Onset and Psychosis Outcomes in First-Episode Schizophrenia 
Schizophrenia Bulletin  2011;38(4):873-880.
Objective: Cannabis use is associated with a younger age at onset of psychosis, an indicator of poor prognosis, but better cognitive function, a positive prognostic indicator. We aimed to clarify the role of age at onset and cognition on outcomes in cannabis users with first-episode schizophrenia as well as the effect of cannabis dose and cessation of use.
Methods: Ninety-nine patients without alcohol or substance abuse other than cannabis were divided into lifetime users and never-users of cannabis and compared on measures of premorbid function, cognition, and clinical outcome.
Results: Cannabis users demonstrated better cognition at psychosis onset, which was explained by higher premorbid IQ. They also showed better social function and neither measure changed over the subsequent 15 months. Cannabis users had an earlier age at onset of psychosis, and there was a strong linear relationship between age at first cannabis use and age at onset of both prodromal and psychotic symptoms. Cannabis use spontaneously declined over time with 3-quarters of users giving up altogether. Later age at first cannabis use predicted earlier cessation of use and this in turn was linked to fewer positive psychotic symptoms and days in hospital during the first 2 years.
Conclusions: Cannabis use brings forward the onset of psychosis in people who otherwise have good prognostic features indicating that an early age at onset can be due to a toxic action of cannabis rather than an intrinsically more severe illness. Many patients abstain over time, but in those who persist, psychosis is more difficult to treat.
PMCID: PMC3406524  PMID: 21389110
cognition; prognosis; longitudinal
6.  Cannabis Withdrawal Symptoms in Non-Treatment-Seeking Adult Cannabis Smokers 
Drug and alcohol dependence  2010;111(1-2):120-127.
Cannabis withdrawal is not recognized in DSM-IV because of doubts about its clinical significance.
Assess the phenomenon of cannabis withdrawal and its relationship to relapse in non-treatment-seeking adults.
Convenience sample of 469 adult cannabis smokers who had made a quit attempt while not in a controlled environment.
Subjects completed a 176-item Marijuana Quit Questionnaire collecting information on sociodemographic characteristics, cannabis use history, and their “most difficult” cannabis quit attempt.
42.4% of subjects had experienced a lifetime withdrawal syndrome, of whom 70.4% reported using cannabis in response to withdrawal. During the index quit attempt, 95.5% of subjects reported ≥1 individual withdrawal symptom (mean [SD] 9.5 [6.1], median 9.0); 43.1% reported ≥10. Number of withdrawal symptoms was significantly associated with greater frequency and amount of cannabis use, but symptoms occurred even in those using less than weekly. Symptoms were usually of ≥ moderate intensity and often prompted actions to relieve them. Alcohol (41.5 %) and tobacco (48.2%) were used more often than cannabis (33.3%) for this purpose. There was little change during withdrawal in use of other legal or illegal substances.
Cannabis withdrawal is a common syndrome among adults not seeking treatment. The intention to relieve withdrawal symptoms can drive relapse during quit attempts, giving cannabis withdrawal clinical significance as a target of treatment.
PMCID: PMC2930056  PMID: 20510550
cannabis; marijuana; withdrawal; tolerance; relapse
7.  Association of Cannabis Use with Opioid Outcomes among Opioid-Dependent Youth 
Drug and alcohol dependence  2013;132(0):342-345.
Cannabis use is common among opioid-dependent patients, but studies of its association with treatment outcome are mixed. In this secondary analysis, the association of cannabis use with opioid treatment outcome is assessed.
In the main study, participants (N=152) aged 15-21 years were randomized to receive psychosocial treatments and either a 12-week course of buprenorphine-naloxone with a dose taper to zero in weeks 9-12, or a 2-week detoxification with buprenorphine-naloxone. Drug use was assessed by self-report and urine drug screen at baseline and during study weeks 1-12. The association between cannabis and opioid use at weeks 4, 8, and 12 was examined using logistic regression models.
Participants reported a median of 3.0 days (range=0-30) cannabis use in the past month; half (50.3%; n=77) reported occasional use, one-third reported no use (33.1%; n=50), and one-sixth reported daily cannabis use (16.6%; n=25). Median lifetime cannabis use was 4.0 years (range=0-11) and median age of initiation of use was 15.0 years (range 9-21). Neither past cannabis use (age of initiation and use in the month prior to baseline) nor concurrent use was associated with level of opioid use.
Overall, cannabis use had no association with opioid use over 12 weeks in this sample of opioid-dependent youth. While cannabis use remains potentially harmful, it was not a predictor of poor opioid treatment outcome.
PMCID: PMC3724203  PMID: 23528523
cannabis use; opioid dependence; buprenorphine; adolescent substance abuse
8.  Association between age at onset of psychosis and age at onset of cannabis use in non-affective psychosis 
Schizophrenia research  2012;139(1-3):157-160.
Several studies have associated cannabis use with the development of schizophrenia. However, it has been difficult to disentangle the effects of cannabis from that of other illicit drugs, as previous studies have not evaluated pure cannabis users. To test whether the onset of cannabis use had an effect on the initiation of psychosis, we examined the time relationship between onset of use and onset of psychosis, restricting our analysis to a cohort of individuals who only used cannabis and no other street drugs.
Fifty seven subjects with non-affective psychoses who used cannabis prior to developing a psychosis were interviewed using the Diagnostic Interview for Genetic Studies (DIGS). The Family Interview for Genetic Studies (FIGS) was also used to interview a family informant about psychiatric illness in the patient and the entire family. Multiple linear regression techniques were used to estimate the association between variables.
After adjusting for potential confounding factors such as sex, age, lifetime diagnosis of alcohol abuse or dependence, and family history of schizophrenia, the age at onset of cannabis was significantly associated with age at onset of psychosis (β=0.4, 95% CI=0.1–0.7, p=0.004) and age at first hospitalization (β=0.4, 95% CI=0.1–0.8, p=0.008). The mean time between beginning to use cannabis and onset of psychosis was 7.0±4.3. Age at onset of alcohol use was not associated with age at onset of psychosis or age at first hospitalization.
Age at onset of cannabis is directly associated with age at onset of psychosis and age at first hospitalization. These associations remain significant after adjusting for potential confounding factors and are consistent with the hypothesis that cannabis could cause or precipitate the onset of psychosis after a prolonged period of time.
PMCID: PMC3415971  PMID: 22727454
cannabis; psychosis; age; sex; schizophrenia
9.  Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study 
PLoS ONE  2012;7(9):e42394.
A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.
PMCID: PMC3434213  PMID: 22957019
10.  Laser Captured Hepatocytes Show Association of BCHE Loss and Fibrosis Progression in Hepatitis C Infected Drug Users 
Hepatology (Baltimore, Md.)  2012;56(2):544-554.
Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with pre-cirrhotic liver fibrosis (Ishak fibrosis 3–5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in pre-cirrhotic fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity were already decreased at study inception in 19 fibrosis progressors compared to 20 fibrosis non-progressors (p<0.05). Non-progressors also had decreased BCHE activity over time compared to initial values, but these evolved a median (range) 8.6 (7.8–11.4) years after the study period inception(p<0.05). Laser captured portal tracts were enriched for immune related genes when compared to hepatocytes but pre-cirrhotic livers lost this enrichment.
Overall, we found that chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.
PMCID: PMC3388175  PMID: 22331678
butyrylcholinesterase; Hepacivirus; chronic HCV infection; laser capture microdissection; portal tract
11.  Hepatitis C Virus Infection in San Francisco's HIV-infected Urban Poor 
To measure Hepatitis C Virus (HCV) prevalence, incidence, and initiation of HCV therapy in a representative HIV-infected cohort of the urban poor.
Cohort analysis.
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.
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.
We measured HCV testing and treatment history with structured interviews; additionally, participants were tested for HCV antibodies (EIA-2) with RNA viral load confirmation.
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.
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.
PMCID: PMC1492202  PMID: 15061745
hepatitis C; HIV infection; HIV/HCV coinfection; HCV treatment; homelessness
12.  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.
PMCID: PMC3106241  PMID: 21248367
13.  Relations of Pre-Onset Cannabis, Alcohol, and Tobacco Use with the Age at Onset of Prodrome and Age at Onset of Psychosis in First-Episode Patients 
The American journal of psychiatry  2009;166(11):1251-1257.
Several reports suggest that cannabis use is associated with an earlier age at onset of psychosis, though not all studies have operationalized cannabis use as occurring prior to onset of symptoms. This study addressed whether pre-onset cannabis use (and alcohol and tobacco use) is associated with an earlier age at onset of prodromal and psychotic symptoms. Additionally, effects of the progression of frequency of use were examined through time-dependent covariates in survival analyses.
First-episode patients (n=109) hospitalized in two public-sector inpatient psychiatric units underwent in-depth cross-sectional/retrospective assessments. Prior substance use and ages at onset of prodromal and psychotic symptoms were determined using standardized methods. Cox regression modeling was conducted.
Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of onset, analysis of change in frequency of use prior to onset indicated that progression to daily cannabis and tobacco use was associated with increased risk of onset of psychotic symptoms. Similar or even stronger effects were observed when onset of illness/prodromal symptoms was the outcome. A gender by daily cannabis use interaction was observed—progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than males.
Pre-onset cannabis use may hasten the onset of psychotic as well as prodromal symptoms. Age at onset is a key prognostic factor in schizophrenia, and discovering modifiable predictors of age at onset is crucial.
PMCID: PMC3662470  PMID: 19797432
Alcohol; Cannabis; First-episode psychosis; Marijuana; Nicotine; Prodrome; Schizophrenia; Substance abuse; Tobacco
14.  Steatohepatitis: Risk Factors and Impact on Disease Severity in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection 
Hepatology (Baltimore, Md.)  2008;47(4):1118-1127.
Hepatic steatosis has been reported in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. However, the features of steatohepatitis, including cytologic ballooning and pericellular fibrosis, its risk factors, and the impact on disease severity in such patients are unknown. To assess this, we prospectively reviewed liver histology in consecutive coinfected patients to define the prevalence and severity of the features of steatohepatitis, its risk factors, and its impact on the severity of liver disease. A total of 222 subjects (74% male, mean age 45, 78% African American, 90% genotype 1) were studied. The mean body mass index (BMI) was 26, and 18% had a BMI >30. The prevalence of risk factors for steatosis were: diabetes (31%), hypertension (15%), dyslipidemia (8%), metabolic syndrome (9%), and alcohol abuse (21%). Steatosis was present in 23% and steatohepatitis was present in 17%. The steatosis was mild (5%–33%) in 19%, and moderate to severe (>33%) in 4%. Cytologic ballooning and pericellular fibrosis were present in 30% and 13%, respectively. The mean Ishak score was 6.9, and 33% had bridging fibrosis or cirrhosis. Both steatosis and cytologic ballooning were associated with BMI, metabolic syndrome, and insulin resistance, and presence of either was strongly associated with advanced fibrosis (P < 0.0001). By multiple logistic regressions, the following associations were identified: increased BMI, diabetes, and genotype 3 with steatosis; diabetes with cytologic ballooning; and longer duration of infection with steatohepatitis.
Steatosis and steatohepatitis are present in 23% and 30%, respectively, of patients with HIV/HCV coinfection, and both are associated with an increased risk of having advanced fibrosis. Although we did identify genotype 3, increased BMI, and diabetes as risk factors, we found no independent association with antiretroviral therapy.
PMCID: PMC2394857  PMID: 18366118
15.  Depression Symptoms Associated with Cannabis Dependence in an Adolescent American Indian Community Sample 
Depression and substance use disorders, including cannabis dependence, arise during adolescence, are frequently co-morbid, and represent major health burdens in the general U.S. population. Yet little is known about the association of depression symptoms with cannabis and other substance use and use disorders in Native American adolescents.
To investigate the comorbidity of cannabis use and depression symptoms in Native American adolescents.
This study used the Children’s Semi-Structured Assessment for the Genetics of Alcoholism (Adolescent Version) to obtain lifetime DSM-III-R diagnoses from a community sample of 202 (98 boys, 104 girls) American Indian adolescents living on contiguous reservations.
Thirteen percent of boys and 38% of girls had a lifetime DSM-III-R major depression disorder (MDD) independent of substance use. Fifteen percent of boys and 41% of girls had a major depression episode (MDE) either coincident with or independent of cannabis use. MDE and several individual depression symptoms were significantly associated with cannabis dependence in boys but not in girls. The median ages of onset of MDE were the same in the boys and girls who had experienced both depression and cannabis use.
These findings suggest that the association of depression with cannabis dependence is more significant in boys than girls in this population of adolescents.
Scientific Significance
Understanding co-morbidity between depression and cannabis use is important in order to disentangle the etiological relationship between the two and also for designing more effective treatment and prevention strategies, particularly in Native Americans who are at high risk for both disorders.
PMCID: PMC3498983  PMID: 23082832
16.  Impact of lifetime alcohol use on liver fibrosis in a population of HIV-infected patients with and without hepatitis C coinfection 
The effect of alcohol on liver disease in HIV infection has not been well characterized.
We performed a cross-sectional multivariable analysis of the association between lifetime alcohol use and liver fibrosis in a longitudinal cohort of HIV-infected patients with alcohol problems. Liver fibrosis was estimated with two non-invasive indices, “FIB-4”, which includes platelets, liver enzymes, and age; and “APRI”, which includes platelets and liver enzymes. FIB-4<1.45 and APRI<0.5 defined absence of liver fibrosis. FIB-4>3.25 and APRI>1.5 defined advanced liver fibrosis. The main independent variable was lifetime alcohol consumption (<150 kg, 150–600kg, >600 kg).
Subjects (n=308) were 73% male, mean age 43 years, 49% with hepatitis C virus (HCV) infection, 60% on antiretroviral therapy, 49% with an HIV RNA load<1000 copies/mL, and 18.7% with a CD4 count<200 cells/mm3. Forty-five percent had lifetime alcohol consumption >600 kg, 32.7% 150–600 kg, and 22.3% <150 kg; 33% had current heavy alcohol use, and 69% had >9 years of heavy episodic drinking. Sixty-one percent had absence of liver fibrosis and 10% had advanced liver fibrosis based on FIB-4. In logistic regression analyses controlling for age, gender, HCV infection, and CD4 count, no association was detected between lifetime alcohol consumption and absence of liver fibrosis (FIB-4<1.45) [adjusted odds ratio (AOR)=1.12 (95%CI:0.25–2.52) for 150–600 kg versus <150 kg; AOR=1.11 (95%CI:0.52–2.36) for >600 kg vs. <150 kg; global p=0.95]. Additionally, no association was detected between lifetime alcohol use and advanced liver fibrosis (FIB-4>3.25). Results were similar using APRI, and among those with and without HCV infection.
In this cohort of HIV-infected patients with alcohol problems, we found no significant association between lifetime alcohol consumption and absence of liver fibrosis or the presence of advanced liver fibrosis, suggesting that alcohol may be less important than other known factors that promote liver fibrosis in this population.
PMCID: PMC3758457  PMID: 23647488
alcohol; HIV; Hepatitis C virus; liver fibrosis
17.  Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis 
AIDS (London, England)  2012;26(5):599-607.
Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART.
HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women’s Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed.
Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death.
Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV.
PMCID: PMC3698040  PMID: 22156972
fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality
18.  Probability and Predictors of Transition from Abuse to Dependence on Alcohol, Cannabis, and Cocaine: Results from the National Epidemiologic Survey on Alcohol and Related Conditions 
Little is known about the transition from substance abuse to substance dependence. Objectives: This study aims to estimate the cumulative probability of developing dependence and to identify predictors of transition to dependence among individuals with lifetime alcohol, cannabis, or cocaine abuse.
Analyses were done for the subsample of individuals with lifetime alcohol abuse (n = 7802), cannabis abuse (n = 2832), or cocaine abuse (n = 815) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Estimated projections of the cumulative probability of transitioning from abuse to dependence were obtained by the standard actuarial method. Discrete-time survival analyses with time-varying covariates were implemented to identify predictors of transition to dependence.
Lifetime cumulative probability estimates indicated that 26.6% of individuals with alcohol abuse, 9.4% of individuals with cannabis abuse, and 15.6% of individuals with cocaine abuse transition from abuse to dependence at some point in their lives. Half of the transitions of alcohol, cannabis, and cocaine dependence occurred approximately 3.16, 1.83, and 1.42 years after abuse onset, respectively. Several sociodemographic, psychopathological, and substance use-related variables predicted transition from abuse to dependence for all of the substances assessed.
The majority of individuals with abuse do not transition to dependence. Lifetime cumulative probability of transition from abuse to dependence was highest for alcohol, followed by cocaine and lastly cannabis. Time from onset of abuse to dependence was shorter for cocaine, followed by cannabis and alcohol. Although some predictors of transition were common across substances, other predictors were specific for certain substances.
PMCID: PMC3755735  PMID: 23721532
transition; abuse; dependence; cannabis; alcohol; cocaine
19.  Hepatic steatosis in patients with HIV-Hepatitis C Virus coinfection: is it associated with antiretroviral therapy and more advanced hepatic fibrosis? 
BMC Research Notes  2008;1:46.
Background and aims
Patients with HIV and hepatitis C virus (HCV) coinfection are at increased risk of developing hepatic steatosis. The aims of this study were to assess the prevalence of steatosis in a cohort with HIV-HCV coinfection, and to determine an association, if any, between steatosis, antiretroviral therapy (ART), and advanced hepatic fibrosis.
Patients and methods
HIV-HCV coinfected patients were retrospectively identified from the HIV clinic. ART was classified as none, nucleoside reverse transcriptase inhibitors (NRTIs) only, highly active antiretroviral therapy (HAART) only, and sequential therapy (initial NRTIs followed by HAART). Fibrosis stage and necroinflammation grade were assessed by the modified HAI (Ishak) scoring method. Steatosis was graded as 0–3.
Sixty patients were identified. The overall prevalence of hepatic steatosis was 58%. Those that received HAART only had a lower prevalence of steatosis (41%) compared to those on NRTIs only (70%) or sequential therapy (82%). Independent predictors of hepatic steatosis were absence of HAART only therapy, OR 2.9, p = 0.09, and presence of cirrhosis, OR 4.6, p = 0.044. Forty five percent of the patients had advanced fibrosis (fibrosis stage ≥ 3). NI grade (OR 1.9, p = 0.030), and steatosis grade (OR 3.6, p = 0.045), were independent predictors of advanced fibrosis.
Hepatic steatosis is associated with more advanced hepatic fibrosis in the HIV-HCV coinfected population. HAART only therapy (rather than NRTIs only or sequential therapy) appears to be associated with a lower prevalence of hepatic steatosis. This may be one of the mechanisms by which HAART could attenuate hepatic fibrosis in such a cohort.
PMCID: PMC2527001  PMID: 18710499
20.  Pathology of Chronic Hepatitis C in Children: Liver Biopsy Findings in the Peds-C Trial 
Hepatology (Baltimore, Md.)  2008;47(3):836-843.
There is relatively little information in the literature on the histopathology of chronic hepatitis C in children. The Peds-C Trial, designed to test the efficacy and safety of peginterferon alfa-2a and ribavirin in children, provided an opportunity to examine liver biopsies from 121 treatment-naïve children, ages 2 to 16 (mean, 9.8 years) infected with the hepatitis C virus (HCV) and with no other identifiable cause for liver disease, signs of hepatic decompensation, or another significant nonhepatic disease. Liver biopsies were scored for inflammation, fibrosis, steatosis, and other histological features. Inflammation in the biopsy was minimal in 42%, mild in 17%, moderate in 38%, and severe in only 3%. Five had bridging fibrosis, and 2 had cirrhosis. Steatosis was absent in 56%, minimal in 34%, and mild in 10%. Inflammation scores correlated with fibrosis scores, serum alanine aminotransferase levels, and duration of infection, but not with age, body mass index z score, or HCV genotype. Fibrosis scores correlated with inflammation but not with age, HCV genotype, body mass index z score, or steatosis parameters. Steatosis correlated with serum alanine aminotransferase levels and body mass index z scores; overweight children had more fibrosis than the non-overweight. In conclusion, in this cohort of HCV-infected children, inflammation, fibrosis, and steatosis were milder than reported for treatment-naïve adults with chronic hepatitis C, but there were several with bridging fibrosis or cirrhosis. The positive correlation of inflammation with duration of infection and fibrosis and of obesity with fibrosis suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors.
PMCID: PMC3755275  PMID: 18167062
21.  Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)* 
Drug and alcohol dependence  2010;115(1-2):120-130.
This study aims to estimate general and racial-ethnic specific cumulative probability of developing dependence among nicotine, alcohol, cannabis or cocaine users, and to identify predictors of transition to substance dependence.
Analyses were done for the subsample of lifetime nicotine (n=15,918), alcohol (n=28,907), cannabis (n=7,389) or cocaine (n=2,259) users who participated in the first and second wave of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Discrete-time survival analyses were implemented to estimate the cumulative probability of transitioning from use to dependence and to identify predictors of transition to dependence.
The cumulative probability estimate of transition to dependence was 67.5% for nicotine users, 22.7% for alcohol users, 20.9% for cocaine users, and 8.9% for cannabis users. Half of the cases of dependence on nicotine, alcohol, cannabis and cocaine were observed approximately 27, 13, 5 and 4 years after use onset, respectively. Significant racial-ethnic differences were observed in the probability of transition to dependence across the four substances. Several predictors of dependence were common across the four substances assessed.
Transition from use to dependence was highest for nicotine users, followed by cocaine, alcohol and cannabis users. Transition to cannabis or cocaine dependence occurred faster than transition to nicotine or alcohol dependence. The existence of common predictors of transition dependence across substances suggests that shared mechanisms are involved. The increased risk of transition to dependence among individuals from minorities or those with psychiatric or dependence comorbidity highlights the importance of promoting outreach and treatment of these populations.
PMCID: PMC3069146  PMID: 21145178
nicotine; alcohol; cannabis; cocaine; dependence; racial-ethnic groups; discrete-time time survival analyses
22.  Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes 
Gut  2013;63(6):1005-1013.
Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA).
103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy.
No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted.
Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone.
—Randomised study for immunosuppression regimen in liver transplantation.
PMCID: PMC4033276  PMID: 24131637
23.  Can reduce - the effects of chat-counseling and web-based self-help, web-based self-help alone and a waiting list control program on cannabis use in problematic cannabis users: a randomized controlled trial 
BMC Psychiatry  2013;13:305.
In European countries, including Switzerland, as well as in many states worldwide, cannabis is the most widely used psychoactive substance after alcohol and tobacco. Although approximately one in ten users develop serious problems of dependency, only a minority attends outpatient addiction counseling centers. The offer of a combined web-based self-help and chat counseling treatment could potentially also reach those users who hesitate to approach such treatment centers and help them to reduce their cannabis use.
This paper presents the protocol for a three-armed randomized controlled trial that will test the effectiveness of a web-based self-help intervention in combination with, or independent of, tailored chat counseling compared to a waiting list in reducing or enabling the abstention from cannabis use in problematic users. The primary outcome will be the weekly quantity of cannabis used. Secondary outcome measures will include the number of days per week on which cannabis is used, the severity of cannabis use disorder, the severity of cannabis dependence, cannabis withdrawal symptoms, cannabis craving, the use of alcohol, tobacco, and other non-cannabis illicit drugs, changes in mental health symptoms, and treatment retention. The self-help intervention will consist of 8 modules designed to reduce cannabis use based on the principles of motivational interviewing, self-control practices, and methods of cognitive behavioral therapy. The two additional individual chat-counseling sessions in the additional chat condition will be based on the same therapy approaches and tailored to participants’ self-help information data and personal problems. The predictive validity of participants’ baseline characteristics on treatment retention and outcomes will be explored.
To the best of our knowledge, this will be the first randomized controlled trial to test the effectiveness of online self-help therapy in combination or without chat counseling in reducing or enabling the abstention from cannabis use. It will also investigate predictors of outcome and retention for these interventions. This trial is registered at Current Controlled Trials and is traceable as ISRCTN59948178.
PMCID: PMC3830542  PMID: 24228630
Cannabis; Internet; Chat; Web-based; Self-help; Cognitive behavioral therapy; Motivational interviewing
24.  Dopamine release in chronic cannabis users: a [11C]raclopride Positron Emission Tomography study 
Biological Psychiatry  2012;71(8):677-683.
Low striatal dopamine 2/3 receptor (D2/3) availability and low ventrostriatal (VST) dopamine (DA) release have been observed in alcoholism, cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D2/3 availability and DA release in abstinent cannabis users compared to controls and explored relationships to parameters of cannabis use history, using [11C]raclopride Positron Emission Tomography (PET) and an amphetamine challenge paradigm.
16 recently abstinent, medically and psychiatrically healthy cannabis-using participants (CD, 27.3 ± 6.1 years, 1 female, 15 males) and 16 matched controls (HC, 28.1 ± 6.7 years, 2 females, 14 males) completed two PET scans, before and after injection of i.v. d-amphetamine (0.3 mg/kg). Percent change in [11C]raclopride binding after amphetamine (ΔBPND) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined.
Cannabis dependent participants had an average consumption of 517± 465 estimated puffs per month, indicating overall mild to moderate cannabis dependence. Neither baseline BPND nor ΔBPND differed from controls in any ROI, including VST. In CD, earlier age of onset of use correlated with lower [ΔBPND] in the associative striatum (AST) when controlling for current age.
Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier use, or longer duration of use, is related to lower DA release in the AST. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.
PMCID: PMC3314125  PMID: 22290115
cannabis; dopamine; PET imaging; addiction; amphetamine challenge; adolescent onset
25.  Liver Fibrosis progression using Fibroscan in HIV/HCV coinfected patients with undetectable HIV viral load 
Journal of the International AIDS Society  2014;17(4Suppl 3):19636.
Several factors such as duration of infection, age, male gender, consumption of alcohol, HIV infection and low CD4 count have been associated with fibrosis progression rate. However, it is relatively scarce, the knowledge about the liver fibrosis progression rate in HIV-infected patients with undetectable HIV viral load (VL). For this reason, we performed the present study.
Materials and Methods
Observational and multicenter study (2008–2012) conducted in four hospitals of the northern Spain. HIV/HCV (hepatitis c) virus coinfected patients ≥18 years on stable combination antiretroviral therapy (cART) (≥6 months) and with a HIV VL <50 copies/mL were selected to analyze their liver fibrosis progression. Fibrosis progression was assessed using a Fibroscan® (502 STEP 3 model) and measuring a basal test and a second one at least 12 months apart from baseline. This evolution was compared with different variables such as duration of HIV/HCV coinfection, gender, age, previous treatment for HCV, HCV genotype, CD4 lymphocyte counts and the cART employed at the basal test.
A total of 608 patients were included (median age 29.4 years, 71.7% men). Of these, 463 patients met the inclusion criteria. In these patients, the liver fibrosis progression was nearly flat and the only variables related to a higher liver fibrosis progression were the increasing age of the patients (p=0.02) and the duration of the coinfection (p=0.001). CD4 lymphocyte counts showed a tendency to improved liver fibrosis (p=0.056).
In HIV/HCV coinfected patients on stable cART and HIV undetectable VL, the increase in liver fibrosis rate progression was nearly flat, although it was significantly associated with the duration of the coinfection and the age of the patient. The beneficial effects of the cART were independent of the antiretroviral drug employed. A tendency to a lower fibrosis progression was observed in those patients with a higher CD4 count.
PMCID: PMC4224865  PMID: 25394140

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