Review
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Nov 8, 2016; 8(31): 1295-1308
Published online Nov 8, 2016. doi: 10.4254/wjh.v8.i31.1295
Alcohol use disorder and its impact on chronic hepatitis C virus and human immunodeficiency virus infections
Daniel Fuster, Arantza Sanvisens, Ferran Bolao, Inmaculada Rivas, Jordi Tor, Robert Muga
Daniel Fuster, Arantza Sanvisens, Jordi Tor, Robert Muga, Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
Ferran Bolao, Department of Internal Medicine, Hospital Universitari de Bellvitge, IDIBELL, 08907 L’Hospitalet de Llobregat, Spain
Inmaculada Rivas, Municipal Center for Substance Abuse Treatment (Centro Delta), IMSP, 08916 Badalona, Spain
Author contributions: Fuster D performed the literature search and drafted the first version of the manuscript; Sanvisens A and Muga R provided feedback for the first version and suggested additional references; all authors edited and provided feedback around the updated version of the review and approved the final version of the manuscript.
Supported by Ministry of Economy and Competitiveness, Institute of Health Carlos, ISCIII: European fund for regional development (FEDER), Nos. RETICS RD 12/0028/0006 and RD16/0017/0003; Ministry of Health, Social Services, and Equality, Nos. PNSD 2014/042 and PNSD 2015/027.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Daniel Fuster, MD, PhD, Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, S/N, 08916 Badalona, Spain. dfuster.germanstrias@gencat.cat
Telephone: +34-934-978908 Fax: +34-934-978768
Received: May 4, 2016
Peer-review started: May 6, 2016
First decision: July 4, 2016
Revised: August 4, 2016
Accepted: August 27, 2016
Article in press: August 29, 2016
Published online: November 8, 2016

Abstract

Alcohol use disorder (AUD) and hepatitis C virus (HCV) infection frequently co-occur. AUD is associated with greater exposure to HCV infection, increased HCV infection persistence, and more extensive liver damage due to interactions between AUD and HCV on immune responses, cytotoxicity, and oxidative stress. Although AUD and HCV infection are associated with increased morbidity and mortality, HCV antiviral therapy is less commonly prescribed in individuals with both conditions. AUD is also common in human immunodeficiency virus (HIV) infection, which negatively impacts proper HIV care and adherence to antiretroviral therapy, and liver disease. In addition, AUD and HCV infection are also frequent within a proportion of patients with HIV infection, which negatively impacts liver disease. This review summarizes the current knowledge regarding pathological interactions of AUD with hepatitis C infection, HIV infection, and HCV/HIV co-infection, as well as relating to AUD treatment interventions in these individuals.

Key Words: Hepatitis C virus, Human immunodeficiency virus, Hepatitis C virus/human immunodeficiency virus co-infection, Liver, Alcohol

Core tip: The present review is focused on alcohol use disorder and hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, as well as HCV/HIV co-infection.



INTRODUCTION

Alcohol abuse is a major cause of preventable liver disease worldwide, and alcohol use disorder (AUD) is associated with substantial disease burden in western countries[1]. According to 5th edition of the Diagnostic and Statistical Manual of Mental Disorders[2], AUD encompasses both alcohol abuse and alcohol dependence. Table 1 presents the diagnostic criteria for AUD and other definitions of unhealthy alcohol use, such as the recommendations of the United States National Institute on Alcohol Abuse and Alcoholism.

Table 1 Diagnostic criteria for alcohol use disorder and other definitions of unhealthy alcohol use.
AUD (DSM-5)
In the past year[2], have you1
Had times when you ended up drinking more, or longer than you intended?
More than once wanted to cut down or stop drinking, or tried to, but couldn’t?
Spent a lot of time drinking? Or being sick or getting over the aftereffects?
Experienced craving - a strong need, or urge, to drink?
Found that drinking or being sick from drinking often interfered with taking care of your home or family? Or caused job troubles? Or school problems?
Continued to drink even though it was causing trouble with your family or friends?
Given up or cut back on activities that were important or interesting to you, or gave you pleasure, in order to drink?
More than once gotten into situations while or after drinking that increased your chances of getting hurt (such as driving, swimming, using machinery, walking in a dangerous area, or having unsafe sex)?
Continued to drink even though it was making you feel depressed or anxious or adding to another health problem? Or after having had a memory blackout?
Had to drink much more than you once did to get the effect you want? Or found that your usual number of drinks had much less effect than before?
Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping, shakiness, irritability, anxiety, depression, restlessness, nausea, or sweating? Or sensed things that were not there?
Risky alcohol use[178]
Drinking more than the recommended amount by the National Institute on Alcohol Abuse and Alcoholism
> 14 drinks per week of > 4 drinks on any day for men
> 7 drinks per week or > 3 drinks on any day for women or men > 65 yr
Problem drinking
Use of alcohol accompanied by alcohol-related consequences but not meeting criteria for AUD

In the United States, almost 9% of the adult pop-ulation meets the AUD criteria and alcohol contributes to 79000 deaths annually[3]. Within the European Union, alcohol misuse causes 14% of deaths in men and nearly 8% of deaths in women, with alcohol-related mortality disproportionally impacting young people[4]. In Spain, unhealthy alcohol use is exhibited by 5% of the population between 15 and 64 years old, and 15% report at least one binge drinking episode within the prior year[5]. Moreover, the pattern of binge drinking is becoming increasingly prevalent, mainly among young individuals.

Per capita alcohol consumption is strongly correlated with liver cirrhosis mortality rates globally[6]. However, the short- and long-term impacts of binge drinking with regards to the development and severity of alcoholic liver disease (ALD) are not yet known. Per capita alcohol consumption is strongly correlated with liver cirrhosis mortality rates across countries[5]. Notably, the medical literature reveals wide heterogeneity in the methods used to assess alcohol exposure, and it can be challenging to analyze time-varying exposures like alcohol consumption over time[7].

Epidemiology of AUD in hepatitis C virus and human immunodeficiency virus infection

Addressing alcohol use is critical in the management of hepatitis C virus (HCV)-infected patients, as AUD is associated with poor clinical outcomes and liver-related deaths in this patient group[8]. Compared to the general population, HCV-infected adults tend to consume greater amounts of ethanol[9], being over twice as likely to consume more than one alcoholic drink per day (34% vs 14%) and almost 8 times more likely to consume over three drinks per day (19% vs 2%)[10].

Moreover, alcohol abuse is associated with concomitant use of illegal substances, and 30% to 50% of patients with a history of substance abuse consume alcohol[11]. This is highly important since 2/3 of new HCV infections in the western world are associated with drug injection[12]. Accordingly, the prevalence of HCV infection is higher among patients with AUD who are current or past injecting drug users[13]. Within a cohort of patients with AUD admitted for hospital detoxification in the Barcelona area, HCV prevalence was as high as 20%[14]. However, other researchers in Spain reported a much lower prevalence of 3.5%[13], possibly due to differences in patient selection.

The prevalence of HCV infection is confounded by the degree of liver disease. Cross-sectional studies performed in hepatology clinics showed that HCV prevalence was higher among patients with advanced liver fibrosis, and almost universal among HCV-infected patients with hepatocellular carcinoma[15,16]. On the other hand, HCV prevalence ranged from 1% to 10% in community-oriented studies of individuals with AUD but without clinically apparent liver disease[17,18]. A recent meta-analysis including 24 studies reported that the average weighted prevalence of HCV infection among patients with AUD was 16.3%[13].

AUD may also be common among human immunodeficiency virus (HIV)/AIDS patients, with a prevalence ranging from 30% to 50%[19]. High prevalences of alcohol consumption have been reported in HIV/AIDS cohort studies from the United States[20,21], Europe[22-24], South Africa[25], and other parts of the world[26]. In the Women’s Interagency HIV Study, 14%-24% of female HIV/AIDS participants reported hazardous alcohol use within the past year[27]. On the other hand, patients with AUD show a lower prevalence of HIV infection than HCV infection[14], which is confounded by prevalence of injection drug use.

AUD AND CHRONIC HCV INFECTION
Effect of alcohol on HCV replication

Alcohol metabolites apparently enhance viral protein expression as well as the heterogeneity of HCV quasispecies[28]. Some authors describe RNA-HCV increases among patients who use alcohol[29]. However, a meta-analysis performed by Anand et al[30] in 2005 showed no association between RNA-HCV and alcohol consumption.

Impact of alcohol on HCV infection persistence

Spontaneous resolution of HCV infection requires an early and wide immune response against HCV viral proteins[31]. Once acute HCV infection is controlled, the presence of memory T-cell populations is associated with reduced persistence of infection in re-exposed individuals[32]. HCV infection persistence is also associated with loss of specific T-cell proliferation, and reduced migration of effector T cells to the liver[33]. HCV-infected patients with AUD show functional impairment of dendritic cells[34], which partly explains the association between alcohol use and lower odds of spontaneous HCV resolution[35,36].

Effect of alcohol on HCV-related immunity

Mice that are chronically exposed to ethanol exhibit diminished immune responses to HCV-core protein, mainly due to impaired maturation of dendritic cells[34]. In HCV-infected patients, dendritic cells present impaired allostimulation capacity, which is more apparent in the presence of alcohol[34]. Alcohol and HCV infection exert synergistic effects, suppressing major histocompatibility complex class II[37] via functional impairment of the proteasome (intracellular protein complexes that degrade unnecessary or damaged proteins) and alterations in interferon signaling[38]. This could partly explain the lower efficacy of interferon-based HCV treatment regimens among patients with AUD[39].

Effect of alcohol on cytotoxicity

Enhanced hepatocyte apoptosis is observed in HCV infection, which is apparently associated with impaired immune responses rather than directly attributable to the viral infection[40]. Hepatocyte apoptosis is mediated by cytotoxic T cells and natural killer cells via caspase activity[40]. BCL-2 protein is associated with mitochondrial permeability, and its expression is reduced in HCV-infected hepatocytes[41]. Alcohol seems to enhance hepatocyte apoptosis through down-regulation of BCL-2 expression[40].

Alcohol and oxidative stress

The HCV core viral protein is associated with higher oxidative stress. It binds the mitochondrial wall, facilitating calcium entrance, electron transport, and increased reactive oxygen species, which results in increased oxidative stress that damages the cell[42]. This protein also targets microsomal triglyceride transfer protein activity, thus modifying hepatic very-low-density lipoprotein particle assembly and secretion, which leads to liver steatosis[43]. Moreover, the HCV core viral protein alters the oxidant/antioxidant state of the liver in the absence of inflammation, consequently producing mitochondrial DNA damage[44].

In HCV-core transgenic mice, chronic ethanol administration is associated with higher lipid peroxidation and synergic induction of TGF-β1 and hepatic stellate cells[45]. The HCV-core protein cooperates with ethanol to activate some p38 mitogen-activated protein kinase pathways, resulting in polygene modulation, and contributing to liver disease pathogenesis[46]. In alcohol-fed NS5A transgenic mice, the synergistic effect between HCV infection and alcohol is dependent on mechanisms involving Toll-like receptor 4, which belongs to the innate immune system[47]. Alcohol consumption and HCV infection impact FOXO3 expression, thus impairing antioxidant capacity in the liver[48].

In humans, indirect evidence suggests that oxidative stress is associated with more extensive liver injury in patients with AUD and HCV infection, as they tend to show higher serum levels of malondialdehyde (a lipid peroxidation product), poor glutathione peroxidase activity, and stimulation of Th1 response cytokines[49]. Moreover, patients with AUD present major lipid peroxidation, and the loss of antioxidant capacity is associated with liver fibrosis[50]. Among HCV-infected patients who drink alcohol, liver fibrosis is independently associated with liver steatosis, oxidative stress, age, and iron deposits in the liver[51].

Alcohol and progression of HCV-related liver disease

Alcohol consumption is associated with more extensive progression of HCV-related liver damage[52,53]. No safe level of alcohol consumption has been described, as even HCV-infected patients who drink moderate amounts of alcohol (30 g/d) experience progressive liver fibrosis[54-56]. A meta-analysis assessed 20 studies that were published between 1995 and 2004, and found that the relative risk of progression to liver cirrhosis or decompensated liver disease among HCV-infected patients was 2.3 times higher, with a 95%CI of 1.7-3.3, among those who drank alcohol compared to abstainers[52]. However, the majority of included studies were performed in liver units, and thus might be biased towards patients with more severe forms of liver disease[52]. Alcohol consumption is also associated with higher risks of cirrhosis decompensation and liver-related death[57]. Moreover, alcohol consumption has a synergistic effect with chronic hepatitis C, increasing the risk of liver cancer[58].

Assessment of liver disease in patients with AUD and HCV infection

In both HCV infection and ALD, liver fibrosis is the main prognostic factor of liver disease progression[59,60]. Although liver biopsy is the gold standard for liver fibrosis assessment[61], it is associated with several rare complications and is not usually performed in patients with substance use disorders[62]. Recent reports describe the estimation of liver fibrosis using several non-invasive biological markers derived from laboratory parameters routinely used in clinical practice, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count.

Of these potential markers, FIB-4[63] and the aspartate aminotransferase/platelet ratio index (APRI)[64] have been validated against the gold standard of liver biopsy in HCV-monoinfected patients as well as HCV/HIV-coinfected patients[65-68]. These markers perform better for detecting either the absence of liver fibrosis or the presence of advanced liver fibrosis[63,64]. However, clinical experience using these markers in patients with AUD is limited[69], and concerns have been raised about the possibility of overestimating liver fibrosis in patients with alcoholic steatohepatitis. Moreover, ALD is a formal contraindication for the use of Pohl’s score[70]-an index that uses aminotransferase levels and platelet count. Transient elastography has also been used to assess liver fibrosis in ALD[71], but the presence of severe liver steatosis may distort results, leading to overestimation of advanced liver fibrosis[72].

In prior studies, we have defined alcohol-related liver disease (ARLD) as the presence of any two of the following criteria: Elevated AST to between 74 and 300 U/L, AST/ALT ≥ 2, and total bilirubin > 1.2 mg/dL[73,74]. Within a cohort of AUD patients admitted for hospital detoxification in metropolitan Barcelona, Spain, 14.6% met those criteria, and ARLD was associated with mid-term mortality[75].

Impact of HCV infection on hospitalizations and mortality of patients with AUD

As previously mentioned, alcohol use is associated with worse prognosis in HCV-related liver disease. It is estimated that 36% of liver cirrhosis among HCV-infected individuals is attributable to alcohol use[76]. HCV infection also has a deleterious impact on clinical outcomes among patients with AUD[77-80]. Tsui et al[77] identified 6354 AUD-related hospital admissions, and reported that the HCV-positive patients were twice as likely to die (4.4% vs 2.4%, P < 0.01), and showed significantly longer hospital stays (19% longer, 95%CI: 12%-27%). Another study included patients from the United States Nationwide Inpatient Sample Dataset who had a primary or a secondary discharge diagnosis of alcoholic hepatitis, and reported that HCV-positive patients had higher mortality with an odds ratio (OR) of 1.29 (95%CI: 1.12-1.49, P < 0.01)[78].

Patients with AUD who are exposed to HCV infection probably differ from those who are not exposed with regards to co-morbidities or behaviors associated with poorer survival, such as the use of illicit drugs[81]. However, even in studies that have accounted for various lifestyle factors, HCV infection remains associated with both overall mortality, showing a hazard ratio (HR) of 2.55 (95%CI: 1.50-4.33, P < 0.01), and liver-related mortality (HR = 3.24, 95%CI: 1.18-8.94, P = 0.02)[79].

In our study of 675 AUD patients admitted for hospital detoxification, we examined the impact of HCV infection on mortality. Our results showed that HCV infection was associated with higher mortality, and that this effect was more apparent in patients with younger ages at admission (HR = 3.1, 95%CI: 1.3-7.3, P < 0.01) and those who were co-infected with HCV/HIV (HR = 3.9, 95%CI: 2.1-7.1, P < 0.01)[80]. In the same Barcelona cohort, we recently reported that AUD patients with HCV mono-infection showed an increased risk of liver-related death in comparison to AUD patients without HCV-infection (HR = 3.92, 95%CI: 2.03-7.59)[82].

Interferon-based treatment of HCV infection in patients with AUD

In the era of HCV antiviral therapy including interferon, infection treatment was challenging in individuals who consumed alcohol[8]. In fact, alcohol use was a major reason for a lack of HCV treatment[83,84]. Several researchers analyzed strategies to extend HCV treatment to patients with unhealthy alcohol use. Le Lan et al[85] performed an observational study of HCV treatment in alcohol-drinking patients, in which drinking in moderation was encouraged but not required. Of the study population, 30% continuously abstained, 34% consumed low-risk amounts of alcohol, and 36% continued to drink risky amounts. The overall sustained viral response (SVR) rate was 48% with no difference observed between abstainers and low-risk drinkers[85], confirming prior results in a Swiss HCV cohort[86].

Evon et al[87] performed a randomized clinical trial in the United States, which included 9-mo intervention comprising counseling, case management, and motivational interviewing for patients ineligible for HCV treatment (31% due to alcohol abuse). The intervention was associated with a 2.38 relative risk of being deemed eligible (95%CI: 1.21-4.68). The groups did not differ with regards to the proportion of patients that eventually received HCV antiviral therapy[87].

Interferon-free treatment of HCV infection in patients with AUD

The advent of direct-acting antivirals and interferon-free regimens has dramatically changed the landscape of HCV treatment, with most registration trials and pilot real-life experiences reporting SVR rates of over 90%[88]. Although treatment is now more feasible for patients with substance use disorders[89,90], to date, very few patients with AUD have been included in clinical trials[91-93].

The current American Association for the Study of Liver Diseases - Infectious Diseases of America guidelines for HCV treatment advocate abstinence from alcohol[94]. When appropriate, these guidelines suggest interventions to facilitate the cessation of alcohol consumption, ranging from brief interventions for patients with low alcohol intake[94], to referral to mutual help groups and specialty treatment for patients with established AUD[94]. While alcohol consumption is not a formal contraindication for HCV treatment, a year of abstinence from alcohol is thought to be necessary to achieve adequate treatment adherence[95].

There remains a need for a change in the provision of HCV treatment such that patients with AUD and HCV infection can benefit from viral eradication. Expansion of the capacity of primary care clinics or addiction clinics to provide HCV treatment has been successfully tested in several areas of the United States[96] and Australia[90]. These experiences should be replicated worldwide to more effectively treat difficult-to-reach populations[97].

AUD treatment in patients with HCV infection

Brief interventions involving feedback and discussion of the negative consequences of alcohol abuse are efficacious at motivating reduced alcohol consumption among among patients with unhealthy alcohol use[98], but not patients with alcohol dependence. Such brief interventions can be targeted towards patients with HCV infection, with delivery at the primary care level or in hepatology clinics[94,99]. More intensive treatments, such as motivational enhancement therapy, can also reduce the number of drinking days among patients with chronic HCV infection[100]. Other type of interventions, such as group therapy, can reportedly motivate abstinence from alcohol in 44% of patients in an HCV clinic[101].

Table 2 summarizes the various treatment strategies for patients with AUD. Specialty treatment should be favored in such cases, and patients should be offered detoxification; specific pharmacotherapy including disulfiram, acamprosate, naltrexone, or nalmefene; and psychosocial support[3]. Some researchers have reported satisfactory results with baclofene in patients with overt end-stage liver disease[102].

Table 2 Treatment interventions for unhealthy alcohol use and alcohol use disorder.
ConditionIntervention
Unhealthy alcohol useBrief intervention
Motivational interviewing
AUDHospital detoxification
Individual and group therapy
Approved pharmacological treatments:
Disulfiram
Acamprosate
Naltrexone
Nalmefene
Investigational treatments:
Baclofene
Topiramate
Gabapentin
AUD AND HIV INFECTION
Effect of alcohol on the immune system

The combined effects of alcohol and HIV on the immune system have been investigated in simian models[103]. Alcohol and HIV infection show a synergistic impact on gastrointestinal tract integrity, causing initial depletion of intestinal CD4 cells[104,105]. Loss of intestinal wall integrity is associated with increased permeability, microbial translocation, and immune activation[106]. Immune activation is crucial for HIV disease progression[107], and is reportedly a better predictor of disease progression than HIV viral load[106,108]. While alcohol seems to impact the adaptive immune responses to HIV infection in animal models, the results in humans are mixed[103]. In a study of HIV-infected patients, blood alcohol levels relative to alcohol intake were higher before antiretroviral treatment compared to after treatment[109].

Alcohol and HIV disease progression

Prior to widespread use of antiretroviral therapy (ART), epidemiological data suggested that alcohol use was not associated with HIV disease progression[110,111]. However, following the advent of ART, several authors have reported reduced ART effectiveness among patients with AUD[19,112]. In 2003, Samet et al[113] investigated a cohort of HIV-infected patients, and reported cross-sectional data suggesting that alcohol consumption negatively impacted HIV disease progression. Alcohol consumption was associated with lower CD4 cell counts and higher HIV viral loads in patients receiving ART. A later longitudinal study of the same cohort demonstrated that heavy alcohol use in patients not receiving ART was associated with lower CD4 cell counts but not with HIV viral load[114].

Chander et al[115] at John Hopkins University reported that heavy alcohol consumption was associated with reduced viral suppression of HIV infection and lower treatment adherence. Wu et al[116] investigated 325 subjects receiving ART and found that, after adjusting for adherence, daily drinkers showed a nearly four-fold increase in the odds of detectable HIV viral load. This association was non-significant for regular drinkers. Their results further showed that alcohol use was not associated with CD4 cell count, and that alcohol consumption was not associated with HIV viral load among patients not receiving ART[116]. On the other hand, Baum et al[117] investigated HIV-infected patients receiving ART, and reported that alcohol use was associated with lower CD4 cell counts, greater risk of showing a CD4 cell count of < 200, and an increased HIV viral load over time.

More recent studies indicate that the benefits of ART seem to outweigh the detrimental effects of alcohol use, reinforcing the importance of initiating ART and ensuring adequate treatment adherence[118]. A study in a Swiss HIV cohort revealed no effect of alcohol consumption on either virological failure or CD4 cell count, both among ART-receiving and ART-naïve patients[119]. That study also demonstrated that heavy drinkers were more likely to interrupt ART; however, only 2.8% of participants were heavy drinkers[119]. A recent French study of HIV/AIDS patients reported that low levels of alcohol consumption (< 10 g/d) were associated with higher CD4 counts compared to in abstainers[120]. However, the beneficial effects of such low levels of alcohol consumption may be confounded by other healthier behaviors exhibited by moderate drinkers[121].

Overall, evidence acquired during the first decade of ART use suggested that AUD may impact HIV disease progression; however, more recent studies do not support those findings. These contradictory results may be partly explained by poor adherence to treatment and barriers to proper medical care associated with AUD.

Alcohol and comorbidities

Alcohol use is associated with unprotected sex and syringe sharing, thus elevating the risks of HIV acquisition and transmission[122-124]. Moreover, alcohol use is associated with higher prevalence of depressive symptoms[125], which can influence ART initiation[126], treatment adherence[127], treatment discontinuation[128], and disease progression[129,130]. Other substance use disorders frequently co-exist in patients who exhibit alcohol abuse[11], which is also associated with poorer treatment adherence, reduced HIV viral suppression, and lower retention in care[112,131].

Heavy alcohol use is related to liver disease among patients with HIV infection[132,133], and is also associated with cardiovascular disease[134] and exacerbations of chronic obstructive pulmonary disease[135]. A systematic review of 13 studies reported that heavy alcohol use was associated with elevated risk of cardiovascular disease, with a risk ratio of 1.78 (95%CI: 1.09-2.93)[134].

Alcohol and mortality in HIV infection

Alcohol is commonly regarded as an underappreciated modifiable risk factor in individuals with HIV infection, with or without HCV co-infection[116]. A retrospective study from northern California evaluated data from between 1996 and 2005, and found that higher mortality rates were associated with diagnosis of a substance use disorder (alcohol only, drug only, or alcohol and drug)[136]. In the HIV-LIVE cohort of HIV-positive patients with alcohol problems, short-term mortality was associated with homelessness and drug use[137], and long-term mortality was associated with HCV infection and high levels of inflammation markers[79,138]. A study from the VACS cohort revealed that even non-hazardous levels of alcohol consumption were associated with decreased survival[139]. Recent data from the same VACS cohort shows that among HIV-positive participants, alcohol use was associated with greater physiological injury. Moreover, within this cohort, a greater risk of mortality was associated with an Alcohol Use Disorders Identification Test value of ≥ 4 drinks/mo (HR = 1.25, 95%CI: 1.09-1.44), and of ≥ 30 drinks/mo (HR = 1.30, 95%CI: 1.14-1.50)[140].

HIV treatment in patients with AUD

Alcohol use co-existing with other substance use is associated with lower quality of HIV care[141] and poor retention in care[131]. A systematic review of 53 studies published between 2010 and 2015 showed that 77% of studies revealed that alcohol use was negatively associated with the HIV treatment cascade, i.e., access to care, ART prescription, and treatment adherence[142]. This suggests that unhealthy alcohol use should be targeted to increase the proportion of HIV/AIDS patients who achieve viral suppression.

Even modest alcohol consumption has been associated with poor ART adherence[139]. Hendershot et al[143] performed a meta-analysis of 40 studies, and showed that patients who drank relatively more were 50%-60% less likely to adhere to ART compared with those who abstained or drank relatively less. Alcohol consumption appears to be dose-dependently related to ART adherence[115], and shows a temporal relationship to missed ART treatments[144].

AUD treatment in HIV-infected patients

Among HIV/AIDS patients who drink alcohol, brief interventions are reportedly efficacious for reducing the frequency of alcohol use and the frequency of unprotected sex[145,146]. However, patients abusing alcohol might need more intensive treatment. Some authors report that the addition of motivational interviewing[147] and problem solving therapy may be necessary to improve ART adherence[148]. An intervention called retention through enhanced personal contact has also been tested to improve retention among HIV-positive patients with alcohol use or mental illness[149].

Chander et al[150] recently performed a cross-sectional survey among HIV care providers, and found that although the majority reported that they usually screen for alcohol use, only 10% used a formal screening tool. Moreover, knowledge of pharmacotherapy for AUD was low, and most care providers referred patients to outside resources for treatment[150].

AUD AND HCV/HIV CO-INFECTION

A proportion of patients with both AUD and HCV infection also have HIV infection. In fact, HCV/HIV co-infection is clinically relevant among individuals with history of injection drug use[151]. HIV infection is associated with faster progression of HCV-related liver fibrosis[152,153] as well as earlier occurrence of decompensated liver disease[154,155], liver cancer[156], and liver-related death[157]. During the interferon era, co-infection with HIV compromised HCV treatment response[158,159]. However, interferon-free regimens have greatly increased the efficacy of HCV antiviral treatment among co-infected patients, both in clinical trials[160] and in real-life scenarios[161,162]. On the other hand, HCV infection is associated with increased risk of ART-related liver toxicity[163], which is even higher with concurrent alcohol use[164]. In cases of HCV/HIV co-infection, alcohol use is also associated with poorer treatment adherence[165], and seems to increase HCV RNA levels[166,167].

Until recently, the impact of alcohol use on HCV-related liver disease in HIV-infected patients had not received much attention in the literature. Older studies suggest that alcohol use is associated with biopsy-proven liver fibrosis in cases of co-infection[152,168]. However, studies using non-invasive methods have produced mixed results, highlighting the shortcomings of non-invasive methods-including methods relying on ALT, AST, and platelets-in patients with ALD[70,69]. Table 3 summarizes the different studies that have used non-invasive methods to evaluate liver fibrosis in patients with AUD and HCV infection or HCV/HIV co-infection.

Table 3 Non-invasive methods for analyzing liver fibrosis in patients with alcohol use disorder, hepatitis C virus infection and hepatitis C virus - human immunodeficiency virus co-infection.
Ref.SettingNon-invasive methodMethod for detecting alcohol consumptionFinding
Lieber et al[69]VA studies (2) of alcoholic liver diseaseAPRI1Average alcohol intakeLow sensitivity and specificity of APRI in comparison to liver biopsy, especially in subjects with HCV
Chaudhry et al[169]HIV Hopkins clinical cohortAPRIPast 6-mo hazardous drinkingNo effect of alcohol on APRI values in HCV/HIV co-infection
Blackard et al[170]WIHS cohortFIB-42Recent drinkingNo association between alcohol intake and FIB-4 values in HCV/HIV co-infection
Muga et al[171]AUD patients admitted for detoxificationFIB-4Past 6-mo unhealthy drinkingNo association between FIB-4 and alcohol use in HCV/HIV co-infection
Fuster et al[173]HIV-live cohortFIB-4 and APRILDHNo association between LDH and liver fibrosis measured with FIB-4 or APRI
Lim et al[174]VACS cohortFIB-4AUDIT-C3Advanced liver fibrosis correlated with alcohol use

A cross-sectional study in an urban HIV/AIDS cohort revealed that heavy alcohol use was associated with advanced liver fibrosis measured using the APRI score[169]. However, when the patients were stratified by HCV infection, high APRI score was associated with hazardous alcohol use only among patients without HCV infection[169]. Blackard et al[170] investigated a cohort of women, and demonstrated that alcohol use was not associated with FIB-4 values among HCV/HIV co-infected patients. Within our cohort of AUD patients, FIB-4 was significantly higher among HCV/HIV co-infected patients compared to in HCV monoinfected patients[171]. In the HIV-LIVE cohort, lifetime alcohol consumption[172] was not associated with the absence of liver fibrosis (FIB-4 < 1.45), and similar results were found for the presence of advanced liver fibrosis (FIB-4 ≥ 3.25) and among patients with HCV infection[173]. A study in the VACS cohort-which included a larger number of patients and a different measure of alcohol consumption-reported greater risks of advanced liver fibrosis (measured based on FIB-4) among co-infected patients who exhibited nonhazardous drinking (OR = 14.2, 95%CI: 5.91-34.0) or hazardous/binge drinking (OR = 18.9, 95%CI: 7.98-44.8), or who had alcohol-related diagnoses (OR = 25.2, 95%CI: 10.6-59.7) relative to uninfected individuals who were nonhazardous drinkers[174]. The somewhat discordant results among studies may be partly due to differences in the methods used to describe alcohol use and other characteristics of the study population[169-174].

French researchers investigating HCV/HIV co-infected patients recently found that advanced liver fibrosis (measured with transient elastography) was more common among those with an alcohol-related diagnosis (OR = 3.06, 95%CI: 1.42-6.60) compared to non-hazardous drinkers[175]. Elastography may be more reliable than laboratory markers for assessing liver fibrosis in HCV/HIV co-infected patients with AUD. Additionally, the combination of HCV infection and alcohol use is associated with greater mortality within HIV/AIDS cohorts[79,176], highlighting the need to further address alcohol use in co-infection. Although it can be challenging, it is feasible to reduce alcohol use in the setting of HCV/HIV co-infection[177].

CONCLUSION

To reduce the impact of HCV, HIV and ethanol on liver disease, patients with AUD should be screened for HCV and HIV infection, and interventions should focus on both reducing alcohol consumption and treating viral infections. Moreover, patients with HCV infection or HCV/HIV co-infection should be screened for unhealthy alcohol use to prevent end-stage liver disease. Several treatment interventions are efficacious for reducing alcohol consumption among individuals with HCV infection or HCV/HIV co-infection.

In settings where AUD often coexists with other substance use and viral co-infections, higher levels of co-morbidities are expected. Health care facilities for treatment interventions and multidisciplinary approaches must be widely accessible for managing AUD and associated diseases.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Spain

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P- Reviewer: Chen YD, Kawasaki H, Liu HF S- Editor: Qi Y L- Editor: A E- Editor: Li D

References
1.  Saitz R. Clinical practice. Unhealthy alcohol use. N Engl J Med. 2005;352:596-607.  [PubMed]  [DOI]
2.  American Psychiatric Association  Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, USA: American Psychiatric Association Publishing.  [PubMed]  [DOI]
3.  Friedmann PD. Clinical practice. Alcohol use in adults. N Engl J Med. 2013;368:365-373.  [PubMed]  [DOI]
4.  World Health Organization. Alcohol in the European Union. Consumption, harm and policy approaches. Copenhagen, Denmark: World Health Organization; 2012.  Available from: http://www.euro.who.int/__data/assets/pdf_file/0003/160680/e96457.pdf.  [PubMed]  [DOI]
5.  Ministerio de Sanidad, Servicios Sociales e Igualdad. Estudio Edades. Encuesta sobre alcoholy drogas en España. Plan Nacional sobre Drogas; 2013.  Available from: http://www.pnsd.msssi.gob.es/profesionales/sistemasInformacion/sistemaInformacion/pdf/EDADES2013.pdf.  [PubMed]  [DOI]
6.  Rehm J, Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, Roerecke M. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev. 2010;29:437-445.  [PubMed]  [DOI]
7.  Cook RL, Kelso NE, Brumback BA, Chen X. Analytic strategies to evaluate the association of time-varying exposures to HIV-related outcomes: Alcohol consumption as an example. Curr HIV Res. 2016;14:85-92.  [PubMed]  [DOI]
8.  Fuster D, Tor J, Rey-Joly C, Muga R. [Pathogenic interactions between alcohol and hepatitis C]. Med Clin (Barc). 2012;138:627-632.  [PubMed]  [DOI]
9.  Stoller EP, Hund AJ, Webster NJ, Bixen CE, Perzynski AT, McCormick RA, Kanuch SW, Dawson NV. Alcohol consumption within the context of hepatitis C: a qualitative study of non-problematic drinkers. Alcohol Alcohol. 2006;41:546-552.  [PubMed]  [DOI]
10.  Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714.  [PubMed]  [DOI]
11.  Campbell JV, Hagan H, Latka MH, Garfein RS, Golub ET, Coady MH, Thomas DL, Strathdee SA. High prevalence of alcohol use among hepatitis C virus antibody positive injection drug users in three US cities. Drug Alcohol Depend. 2006;81:259-265.  [PubMed]  [DOI]
12.  Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007;13:2436-2441.  [PubMed]  [DOI]
13.  Novo-Veleiro I, Calle Cde L, Domínguez-Quibén S, Pastor I, Marcos M, Laso FJ. Prevalence of hepatitis C virus infection in alcoholic patients: cohort study and systematic review. Alcohol Alcohol. 2013;48:564-569.  [PubMed]  [DOI]
14.  Rivas I, Sanvisens A, Bolao F, Fuster D, Tor J, Pujol R, Torrens M, Rey-Joly C, Muga R. Impact of medical comorbidity and risk of death in 680 patients with alcohol use disorders. Alcohol Clin Exp Res. 2013;37 Suppl 1:E221-E227.  [PubMed]  [DOI]
15.  Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Tapias JM, Ventura M, Vall M, Bruguera M, Bru C. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet. 1989;2:1004-1006.  [PubMed]  [DOI]
16.  Rosman AS, Paronetto F, Galvin K, Williams RJ, Lieber CS. Hepatitis C virus antibody in alcoholic patients. Association with the presence of portal and/or lobular hepatitis. Arch Intern Med. 1993;153:965-969.  [PubMed]  [DOI]
17.  Rosman AS, Waraich A, Galvin K, Casiano J, Paronetto F, Lieber CS. Alcoholism is associated with hepatitis C but not hepatitis B in an urban population. Am J Gastroenterol. 1996;91:498-505.  [PubMed]  [DOI]
18.  Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, Saveria Crocè L, Sasso F, Pozzato G, Cristianini G. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut. 1997;41:845-850.  [PubMed]  [DOI]
19.  Hahn JA, Samet JH. Alcohol and HIV disease progression: weighing the evidence. Curr HIV/AIDS Rep. 2010;7:226-233.  [PubMed]  [DOI]
20.  Samet JH, Walley AY, Bridden C. Illicit drugs, alcohol, and addiction in human immunodeficiency virus. Panminerva Med. 2007;49:67-77.  [PubMed]  [DOI]
21.  Chander G, Josephs J, Fleishman JA, Korthuis PT, Gaist P, Hellinger J, Gebo K. Alcohol use among HIV-infected persons in care: results of a multi-site survey. HIV Med. 2008;9:196-202.  [PubMed]  [DOI]
22.  Rosenthal E, Salmon-Ceron D, Lewden C, Bouteloup V, Pialoux G, Bonnet F, Karmochkine M, May T, François M, Burty C. Liver-related deaths in HIV-infected patients between 1995 and 2005 in the French GERMIVIC Joint Study Group Network (Mortavic 2005 study in collaboration with the Mortalite 2005 survey, ANRS EN19). HIV Med. 2009;10:282-289.  [PubMed]  [DOI]
23.  Krupitsky EM, Horton NJ, Williams EC, Lioznov D, Kuznetsova M, Zvartau E, Samet JH. Alcohol use and HIV risk behaviors among HIV-infected hospitalized patients in St. Petersburg, Russia. Drug Alcohol Depend. 2005;79:251-256.  [PubMed]  [DOI]
24.  Conen A, Fehr J, Glass TR, Furrer H, Weber R, Vernazza P, Hirschel B, Cavassini M, Bernasconi E, Bucher HC. Self-reported alcohol consumption and its association with adherence and outcome of antiretroviral therapy in the Swiss HIV Cohort Study. Antivir Ther. 2009;14:349-357.  [PubMed]  [DOI]
25.  Scott-Sheldon LA, Carey KB, Carey MP, Cain D, Simbayi LC, Kalichman SC. Alcohol use disorder, contexts of alcohol use, and the risk of HIV transmission among South African male patrons of shebeens. Drug Alcohol Depend. 2014;140:198-204.  [PubMed]  [DOI]
26.  Soboka M, Tesfaye M, Feyissa GT, Hanlon C. Alcohol use disorders and associated factors among people living with HIV who are attending services in south west Ethiopia. BMC Res Notes. 2014;7:828.  [PubMed]  [DOI]
27.  Cook RL, Zhu F, Belnap BH, Weber K, Cook JA, Vlahov D, Wilson TE, Hessol NA, Plankey M, Howard AA. Longitudinal trends in hazardous alcohol consumption among women with human immunodeficiency virus infection, 1995-2006. Am J Epidemiol. 2009;169:1025-1032.  [PubMed]  [DOI]
28.  Seronello S, Montanez J, Presleigh K, Barlow M, Park SB, Choi J. Ethanol and reactive species increase basal sequence heterogeneity of hepatitis C virus and produce variants with reduced susceptibility to antivirals. PLoS One. 2011;6:e27436.  [PubMed]  [DOI]
29.  Siu L, Foont J, Wands JR. Hepatitis C virus and alcohol. Semin Liver Dis. 2009;29:188-199.  [PubMed]  [DOI]
30.  Anand BS, Thornby J. Alcohol has no effect on hepatitis C virus replication: a meta-analysis. Gut. 2005;54:1468-1472.  [PubMed]  [DOI]
31.  Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001;194:1395-1406.  [PubMed]  [DOI]
32.  Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, Strathdee SA, Vlahov D, Thomas DL. Protection against persistence of hepatitis C. Lancet. 2002;359:1478-1483.  [PubMed]  [DOI]
33.  Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C, Govindarajan S, Purcell RH, Chisari FV. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci USA. 2002;99:15661-15668.  [PubMed]  [DOI]
34.  Dolganiuc A, Kodys K, Kopasz A, Marshall C, Mandrekar P, Szabo G. Additive inhibition of dendritic cell allostimulatory capacity by alcohol and hepatitis C is not restored by DC maturation and involves abnormal IL-10 and IL-2 induction. Alcohol Clin Exp Res. 2003;27:1023-1031.  [PubMed]  [DOI]
35.  Piasecki BA, Lewis JD, Reddy KR, Bellamy SL, Porter SB, Weinrieb RM, Stieritz DD, Chang KM. Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population. Hepatology. 2004;40:892-899.  [PubMed]  [DOI]
36.  Grebely J, Grady B, Hajarizadeh B, Page K, Dore GJ. Disease progression during advanced fibrosis: IL28B genotype or HCV RNA levels? Hepatology. 2014;59:1650-1651.  [PubMed]  [DOI]
37.  Osna NA. Hepatitis C virus and ethanol alter antigen presentation in liver cells. World J Gastroenterol. 2009;15:1201-1208.  [PubMed]  [DOI]
38.  McCartney EM, Beard MR. Impact of alcohol on hepatitis C virus replication and interferon signaling. World J Gastroenterol. 2010;16:1337-1343.  [PubMed]  [DOI]
39.  Anand BS, Currie S, Dieperink E, Bini EJ, Shen H, Ho SB, Wright T. Alcohol use and treatment of hepatitis C virus: results of a national multicenter study. Gastroenterology. 2006;130:1607-1616.  [PubMed]  [DOI]
40.  Kountouras J, Zavos C, Chatzopoulos D. Apoptosis in hepatitis C. J Viral Hepat. 2003;10:335-342.  [PubMed]  [DOI]
41.  Nakamoto Y, Kaneko S, Kobayashi K. Increased susceptibility to apoptosis and attenuated Bcl-2 expression in T lymphocytes and monocytes from patients with advanced chronic hepatitis C. J Leukoc Biol. 2002;72:49-55.  [PubMed]  [DOI]
42.  Szabo G, Wands JR, Eken A, Osna NA, Weinman SA, Machida K, Joe Wang H. Alcohol and hepatitis C virus--interactions in immune dysfunctions and liver damage. Alcohol Clin Exp Res. 2010;34:1675-1686.  [PubMed]  [DOI]
43.  Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chrétien Y, Koike K, Pessayre D, Chapman J, Barba G. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002;16:185-194.  [PubMed]  [DOI]
44.  Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Miyazawa T, Ishibashi K, Horie T. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res. 2001;61:4365-4370.  [PubMed]  [DOI]
45.  Perlemuter G, Lettéron P, Carnot F, Zavala F, Pessayre D, Nalpas B, Bréchot C. Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model. J Hepatol. 2003;39:1020-1027.  [PubMed]  [DOI]
46.  Tsutsumi T, Suzuki T, Moriya K, Shintani Y, Fujie H, Miyoshi H, Matsuura Y, Koike K, Miyamura T. Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice. Hepatology. 2003;38:820-828.  [PubMed]  [DOI]
47.  Machida K, Tsukamoto H, Mkrtchyan H, Duan L, Dynnyk A, Liu HM, Asahina K, Govindarajan S, Ray R, Ou JH. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci USA. 2009;106:1548-1553.  [PubMed]  [DOI]
48.  Tikhanovich I, Kuravi S, Campbell RV, Kharbanda KK, Artigues A, Villar MT, Weinman SA. Regulation of FOXO3 by phosphorylation and methylation in hepatitis C virus infection and alcohol exposure. Hepatology. 2014;59:58-70.  [PubMed]  [DOI]
49.  Castellano-Higuera A, González-Reimers E, Alemán-Valls MR, Abreu-González P, Santolaria-Fernández F, De La Vega-Prieto MJ, Gómez-Sirvent JL, Pelazas-González R. Cytokines and lipid peroxidation in alcoholics with chronic hepatitis C virus infection. Alcohol Alcohol. 2008;43:137-142.  [PubMed]  [DOI]
50.  Rigamonti C, Mottaran E, Reale E, Rolla R, Cipriani V, Capelli F, Boldorini R, Vidali M, Sartori M, Albano E. Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology. 2003;38:42-49.  [PubMed]  [DOI]
51.  Vidali M, Occhino G, Ivaldi A, Rigamonti C, Sartori M, Albano E. Combination of oxidative stress and steatosis is a risk factor for fibrosis in alcohol-drinking patients with chronic hepatitis C. Am J Gastroenterol. 2008;103:147-153.  [PubMed]  [DOI]
52.  Hutchinson SJ, Bird SM, Goldberg DJ. Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis. Clin Gastroenterol Hepatol. 2005;3:1150-1159.  [PubMed]  [DOI]
53.  Pace CA, Samet JH. In the Clinic. Substance Use Disorders. Ann Intern Med. 2016;164:ITC49-ITC64.  [PubMed]  [DOI]
54.  Hézode C, Lonjon I, Roudot-Thoraval F, Pawlotsky JM, Zafrani ES, Dhumeaux D. Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study. Aliment Pharmacol Ther. 2003;17:1031-1037.  [PubMed]  [DOI]
55.  Brogniez V, Nyssen-Behets C, Grégoire V, Reychler H, Lengelé B. Implant osseointegration in the irradiated mandible. A comparative study in dogs with a microradiographic and histologic assessment. Clin Oral Implants Res. 2002;13:234-242.  [PubMed]  [DOI]
56.  Monto A, Patel K, Bostrom A, Pianko S, Pockros P, McHutchison JG, Wright TL. Risks of a range of alcohol intake on hepatitis C-related fibrosis. Hepatology. 2004;39:826-834.  [PubMed]  [DOI]
57.  Harris HE, Ramsay ME, Andrews N, Eldridge KP. Clinical course of hepatitis C virus during the first decade of infection: cohort study. BMJ. 2002;324:450-453.  [PubMed]  [DOI]
58.  Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36:1206-1213.  [PubMed]  [DOI]
59.  Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209-218.  [PubMed]  [DOI]
60.  Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-1374.  [PubMed]  [DOI]
61.  Gebo KA, Herlong HF, Torbenson MS, Jenckes MW, Chander G, Ghanem KG, El-Kamary SS, Sulkowski M, Bass EB. Role of liver biopsy in management of chronic hepatitis C: a systematic review. Hepatology. 2002;36:S161-S172.  [PubMed]  [DOI]
62.  Sanvisens A, Fuster D, Serra I, Tor J, Tural C, Rey-Joly C, Muga R. Estimated liver fibrosis and its impact on all-cause mortality of HCV-monoinfected and HCV/HIV-coinfected drug users. Curr HIV Res. 2011;9:256-262.  [PubMed]  [DOI]
63.  Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317-1325.  [PubMed]  [DOI]
64.  Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518-526.  [PubMed]  [DOI]
65.  Loko MA, Castera L, Dabis F, Le Bail B, Winnock M, Coureau G, Bioulac-Sage P, de Ledinghen V, Neau D. Validation and comparison of simple noninvasive indexes for predicting liver fibrosis in HIV-HCV-coinfected patients: ANRS CO3 Aquitaine cohort. Am J Gastroenterol. 2008;103:1973-1980.  [PubMed]  [DOI]
66.  Nunes D, Fleming C, Offner G, O'Brien M, Tumilty S, Fix O, Heeren T, Koziel M, Graham C, Craven DE. HIV infection does not affect the performance of noninvasive markers of fibrosis for the diagnosis of hepatitis C virus-related liver disease. J Acquir Immune Defic Syndr. 2005;40:538-544.  [PubMed]  [DOI]
67.  Sebastiani G, Halfon P, Castera L, Pol S, Thomas DL, Mangia A, Di Marco V, Pirisi M, Voiculescu M, Guido M. SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology. 2009;49:1821-1827.  [PubMed]  [DOI]
68.  Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, Fontaine H, Pol S. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology. 2007;46:32-36.  [PubMed]  [DOI]
69.  Lieber CS, Weiss DG, Morgan TR, Paronetto F. Aspartate aminotransferase to platelet ratio index in patients with alcoholic liver fibrosis. Am J Gastroenterol. 2006;101:1500-1508.  [PubMed]  [DOI]
70.  Pohl A, Behling C, Oliver D, Kilani M, Monson P, Hassanein T. Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection. Am J Gastroenterol. 2001;96:3142-3146.  [PubMed]  [DOI]
71.  Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, Eisele S, Stickel F, Longerich T, Schirmacher P. Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol. 2010;16:966-972.  [PubMed]  [DOI]
72.  Mueller S, Englert S, Seitz HK, Badea RI, Erhardt A, Bozaari B, Beaugrand M, Lupșor-Platon M. Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease. Liver Int. 2015;35:2514-2521.  [PubMed]  [DOI]
73.  O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2010;51:307-328.  [PubMed]  [DOI]
74.  Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360:2758-2769.  [PubMed]  [DOI]
75.  Fuster D, Sanvisens A, Bolao F, Zuluaga P, Rivas I, Tor J, Muga R. Markers of inflammation and mortality in a cohort of patients with alcohol dependence. Medicine (Baltimore). 2015;94:e607.  [PubMed]  [DOI]
76.  Innes HA, Hutchinson SJ, Barclay S, Cadzow E, Dillon JF, Fraser A, Goldberg DJ, Mills PR, McDonald SA, Morris J. Quantifying the fraction of cirrhosis attributable to alcohol among chronic hepatitis C virus patients: implications for treatment cost-effectiveness. Hepatology. 2013;57:451-460.  [PubMed]  [DOI]
77.  Tsui JI, Pletcher MJ, Vittinghoff E, Seal K, Gonzales R. Hepatitis C and hospital outcomes in patients admitted with alcohol-related problems. J Hepatol. 2006;44:262-266.  [PubMed]  [DOI]
78.  Singal AK, Kuo YF, Anand BS. Hepatitis C virus infection in alcoholic hepatitis: prevalence patterns and impact on in-hospital mortality. Eur J Gastroenterol Hepatol. 2012;24:1178-1184.  [PubMed]  [DOI]
79.  Fuster D, Cheng DM, Quinn EK, Nunes D, Saitz R, Samet JH, Tsui JI. Chronic hepatitis C virus infection is associated with all-cause and liver-related mortality in a cohort of HIV-infected patients with alcohol problems. Addiction. 2014;109:62-70.  [PubMed]  [DOI]
80.  Fuster D, Sanvisens A, Bolao F, Serra I, Rivas I, Tor J, Muga R. Impact of hepatitis C virus infection on the risk of death of alcohol-dependent patients. J Viral Hepat. 2015;22:18-24.  [PubMed]  [DOI]
81.  Grebely J, Dore GJ. What is killing people with hepatitis C virus infection? Semin Liver Dis. 2011;31:331-339.  [PubMed]  [DOI]
82.  Sanvisens A, Bolao F, Jarrin I, Fuster D, Zuluaga P, Tor J, Muga R. Impact of Hepatitis C Virus infection in the liver-related mortality of patients with alcohol use disorder. In: International Liver Congress. 2016 April 13-17; Barcelona, Spain. .  [PubMed]  [DOI]
83.  Grebely J, Haire B, Taylor LE, Macneill P, Litwin AH, Swan T, Byrne J, Levin J, Bruggmann P, Dore GJ. Excluding people who use drugs or alcohol from access to hepatitis C treatments - Is this fair, given the available data? J Hepatol. 2015;63:779-782.  [PubMed]  [DOI]
84.  Okazaki T, Yoshihara H, Suzuki K, Yamada Y, Tsujimura T, Kawano K, Yamada Y, Abe H. Efficacy of interferon therapy in patients with chronic hepatitis C. Comparison between non-drinkers and drinkers. Scand J Gastroenterol. 1994;29:1039-1043.  [PubMed]  [DOI]
85.  Le Lan C, Guillygomarc'h A, Danielou H, Le Dréau G, Lainé F, Védeilhié C, Deugnier Y, Brissot P, Guyader D, Moirand R. A multi-disciplinary approach to treating hepatitis C with interferon and ribavirin in alcohol-dependent patients with ongoing abuse. J Hepatol. 2012;56:334-340.  [PubMed]  [DOI]
86.  Bruggmann P, Dampz M, Gerlach T, Kravecz L, Falcato L. Treatment outcome in relation to alcohol consumption during hepatitis C therapy: an analysis of the Swiss Hepatitis C Cohort Study. Drug Alcohol Depend. 2010;110:167-171.  [PubMed]  [DOI]
87.  Evon DM, Simpson K, Kixmiller S, Galanko J, Dougherty K, Golin C, Fried MW. A randomized controlled trial of an integrated care intervention to increase eligibility for chronic hepatitis C treatment. Am J Gastroenterol. 2011;106:1777-1786.  [PubMed]  [DOI]
88.  Afdhal NH, Zeuzem S, Schooley RT, Thomas DL, Ward JW, Litwin AH, Razavi H, Castera L, Poynard T, Muir A. The new paradigm of hepatitis C therapy: integration of oral therapies into best practices. J Viral Hepat. 2013;20:745-760.  [PubMed]  [DOI]
89.  Lalezari J, Sullivan JG, Varunok P, Galen E, Kowdley KV, Rustgi V, Aguilar H, Felizarta F, McGovern B, King M. Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine. J Hepatol. 2015;63:364-369.  [PubMed]  [DOI]
90.  Grebely J, Alavi M, Micallef M, Dunlop AJ, Balcomb AC, Phung N, Weltman MD, Day CA, Treloar C, Bath N. Treatment for hepatitis C virus infection among people who inject drugs attending opioid substitution treatment and community health clinics: the ETHOS Study. Addiction. 2016;111:311-319.  [PubMed]  [DOI]
91.  Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, Abergel A, Mangia A, Lai CL, Chan HL. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015;373:2599-2607.  [PubMed]  [DOI]
92.  Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, Brown RS, Fried MW, Terrault NA, O'Leary JG, Vargas HE. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterology. 2015;149:649-659.  [PubMed]  [DOI]
93.  Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.  [PubMed]  [DOI]
94.  American Association for the Study of Liver Diseases-Infectious Diseases Society of America (AASLD-IDSA). HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. 2016.  Available from: http://www.hcvguidelines.org.  [PubMed]  [DOI]
95.  North CS, Sims O, Hong BA, Jain MK, Brown G, Lisker-Melman M, Pollio DE. An empirical study of alcohol consumption by patients considering HCV treatment. Am J Drug Alcohol Abuse. 2014;40:484-489.  [PubMed]  [DOI]
96.  Mitruka K, Thornton K, Cusick S, Orme C, Moore A, Manch RA, Box T, Carroll C, Holtzman D, Ward JW. Expanding primary care capacity to treat hepatitis C virus infection through an evidence-based care model--Arizona and Utah, 2012-2014. MMWR Morb Mortal Wkly Rep. 2014;63:393-398.  [PubMed]  [DOI]
97.  Muga R, Zuluaga P, Sanvisens A, Rivas I, Fuster D, Bolao F, Tor J. Hepatitis C associated to substance abuse: ever closer to a treatment without Interferon. Adicciones. 2015;27:141-149.  [PubMed]  [DOI]
98.  Saitz R. Treatment of alcohol and other drug dependence. Liver Transpl. 2007;13:S59-S64.  [PubMed]  [DOI]
99.  Dieperink E, Ho SB, Heit S, Durfee JM, Thuras P, Willenbring ML. Significant reductions in drinking following brief alcohol treatment provided in a hepatitis C clinic. Psychosomatics. 2010;51:149-156.  [PubMed]  [DOI]
100.  Dieperink E, Fuller B, Isenhart C, McMaken K, Lenox R, Pocha C, Thuras P, Hauser P. Efficacy of motivational enhancement therapy on alcohol use disorders in patients with chronic hepatitis C: a randomized controlled trial. Addiction. 2014;109:1869-1877.  [PubMed]  [DOI]
101.  Proeschold-Bell RJ, Patkar AA, Naggie S, Coward L, Mannelli P, Yao J, Bixby P, Muir AJ. An integrated alcohol abuse and medical treatment model for patients with hepatitis C. Dig Dis Sci. 2012;57:1083-1091.  [PubMed]  [DOI]
102.  Addolorato G, Leggio L, Agabio R, Colombo G, Gasbarrini G. Baclofen: a new drug for the treatment of alcohol dependence. Int J Clin Pract. 2006;60:1003-1008.  [PubMed]  [DOI]
103.  Bagby GJ, Amedee AM, Siggins RW, Molina PE, Nelson S, Veazey RS. Alcohol and HIV Effects on the Immune System. Alcohol Res. 2015;37:287-297.  [PubMed]  [DOI]
104.  Sandler NG, Douek DC. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol. 2012;10:655-666.  [PubMed]  [DOI]
105.  Douek D. HIV disease progression: immune activation, microbes, and a leaky gut. Top HIV Med. 2007;15:114-117.  [PubMed]  [DOI]
106.  Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, Narváez AB, Hunt P, Martin JN, Kahn JO, Levy J. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood. 2004;104:942-947.  [PubMed]  [DOI]
107.  Klatt NR, Harris LD, Vinton CL, Sung H, Briant JA, Tabb B, Morcock D, McGinty JW, Lifson JD, Lafont BA. Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection. Mucosal Immunol. 2010;3:387-398.  [PubMed]  [DOI]
108.  Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funderburg N, Robinson J, Huang Y, Epling L, Martin JN. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis. 2014;210:1228-1238.  [PubMed]  [DOI]
109.  McCance-Katz EF, Lum PJ, Beatty G, Gruber VA, Peters M, Rainey PM. Untreated HIV infection is associated with higher blood alcohol levels. J Acquir Immune Defic Syndr. 2012;60:282-288.  [PubMed]  [DOI]
110.  Kaslow RA, Blackwelder WC, Ostrow DG, Yerg D, Palenicek J, Coulson AH, Valdiserri RO. No evidence for a role of alcohol or other psychoactive drugs in accelerating immunodeficiency in HIV-1-positive individuals. A report from the Multicenter AIDS Cohort Study. JAMA. 1989;261:3424-3429.  [PubMed]  [DOI]
111.  Coates RA, Farewell VT, Raboud J, Read SE, MacFadden DK, Calzavara LM, Johnson JK, Shepherd FA, Fanning MM. Cofactors of progression to acquired immunodeficiency syndrome in a cohort of male sexual contacts of men with human immunodeficiency virus disease. Am J Epidemiol. 1990;132:717-722.  [PubMed]  [DOI]
112.  Lucas GM, Gebo KA, Chaisson RE, Moore RD. Longitudinal assessment of the effects of drug and alcohol abuse on HIV-1 treatment outcomes in an urban clinic. AIDS. 2002;16:767-774.  [PubMed]  [DOI]
113.  Samet JH, Horton NJ, Traphagen ET, Lyon SM, Freedberg KA. Alcohol consumption and HIV disease progression: are they related? Alcohol Clin Exp Res. 2003;27:862-867.  [PubMed]  [DOI]
114.  Samet JH, Cheng DM, Libman H, Nunes DP, Alperen JK, Saitz R. Alcohol consumption and HIV disease progression. J Acquir Immune Defic Syndr. 2007;46:194-199.  [PubMed]  [DOI]
115.  Chander G, Lau B, Moore RD. Hazardous alcohol use: a risk factor for non-adherence and lack of suppression in HIV infection. J Acquir Immune Defic Syndr. 2006;43:411-417.  [PubMed]  [DOI]
116.  Wu ES, Metzger DS, Lynch KG, Douglas SD. Association between alcohol use and HIV viral load. J Acquir Immune Defic Syndr. 2011;56:e129-e130.  [PubMed]  [DOI]
117.  Baum MK, Rafie C, Lai S, Sales S, Page JB, Campa A. Alcohol use accelerates HIV disease progression. AIDS Res Hum Retroviruses. 2010;26:511-518.  [PubMed]  [DOI]
118.  Kowalski S, Colantuoni E, Lau B, Keruly J, McCaul ME, Hutton HE, Moore RD, Chander G. Alcohol consumption and CD4 T-cell count response among persons initiating antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;61:455-461.  [PubMed]  [DOI]
119.  Conen A, Wang Q, Glass TR, Fux CA, Thurnheer MC, Orasch C, Calmy A, Bernasconi E, Vernazza P, Weber R. Association of alcohol consumption and HIV surrogate markers in participants of the swiss HIV cohort study. J Acquir Immune Defic Syndr. 2013;64:472-478.  [PubMed]  [DOI]
120.  Carrieri MP, Protopopescu C, Raffi F, March L, Reboud P, Spire B, Leport C. Low alcohol consumption as a predictor of higher CD4+ cell count in HIV-treated patients: a french paradox or a proxy of healthy behaviors? The ANRS APROCO-COPILOTE CO-08 cohort. J Acquir Immune Defic Syndr. 2014;65:e148-e150.  [PubMed]  [DOI]
121.  Naimi TS, Babor T, Chikritzhs T, Stockwell TR, McCambridge J, Miller P, Xuan Z, Bradley K, Blanchette JG, Kypri K. Let's Not "Relax" Evidence Standards when Recommending Risky Preventive Therapeutic Agents. Alcohol Clin Exp Res. 2015;39:1275-1276.  [PubMed]  [DOI]
122.  Samet JH, Pace CA, Cheng DM, Coleman S, Bridden C, Pardesi M, Saggurti N, Raj A. Alcohol use and sex risk behaviors among HIV-infected female sex workers (FSWs) and HIV-infected male clients of FSWs in India. AIDS Behav. 2010;14:S74-S83.  [PubMed]  [DOI]
123.  Chaudhry AA, Botsko M, Weiss L, Egan JE, Mitty J, Estrada B, Lucas GM, Woodson T, Flanigan TP, Fiellin DA. Participant characteristics and HIV risk behaviors among individuals entering integrated buprenorphine/naloxone and HIV care. J Acquir Immune Defic Syndr. 2011;56 Suppl 1:S14-S21.  [PubMed]  [DOI]
124.  Hasse B, Ledergerber B, Hirschel B, Vernazza P, Glass TR, Jeannin A, Evison JM, Elzi L, Cavassini M, Bernasconi E. Frequency and determinants of unprotected sex among HIV-infected persons: the Swiss HIV cohort study. Clin Infect Dis. 2010;51:1314-1322.  [PubMed]  [DOI]
125.  Sullivan LE, Saitz R, Cheng DM, Libman H, Nunes D, Samet JH. The impact of alcohol use on depressive symptoms in human immunodeficiency virus-infected patients. Addiction. 2008;103:1461-1467.  [PubMed]  [DOI]
126.  Goodness TM, Palfai TP, Cheng DM, Coleman SM, Bridden C, Blokhina E, Krupitsky E, Samet JH. Depressive symptoms and antiretroviral therapy (ART) initiation among HIV-infected Russian drinkers. AIDS Behav. 2014;18:1085-1093.  [PubMed]  [DOI]
127.  Gonzalez JS, Batchelder AW, Psaros C, Safren SA. Depression and HIV/AIDS treatment nonadherence: a review and meta-analysis. J Acquir Immune Defic Syndr. 2011;58:181-187.  [PubMed]  [DOI]
128.  Kim TW, Palepu A, Cheng DM, Libman H, Saitz R, Samet JH. Factors associated with discontinuation of antiretroviral therapy in HIV-infected patients with alcohol problems. AIDS Care. 2007;19:1039-1047.  [PubMed]  [DOI]
129.  Conaty TP. More about March editorial. J Am Dent Assoc. 2008;139:659-660.  [PubMed]  [DOI]
130.  Ghebremichael M, Paintsil E, Ickovics JR, Vlahov D, Schuman P, Boland R, Schoenbaum E, Moore J, Zhang H. Longitudinal association of alcohol use with HIV disease progression and psychological health of women with HIV. AIDS Care. 2009;21:834-841.  [PubMed]  [DOI]
131.  Westergaard RP, Hess T, Astemborski J, Mehta SH, Kirk GD. Longitudinal changes in engagement in care and viral suppression for HIV-infected injection drug users. AIDS. 2013;27:2559-2566.  [PubMed]  [DOI]
132.  Salmon-Ceron D, Lewden C, Morlat P, Bévilacqua S, Jougla E, Bonnet F, Héripret L, Costagliola D, May T, Chêne G. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol. 2005;42:799-805.  [PubMed]  [DOI]
133.  Joshi D, O'Grady J, Dieterich D, Gazzard B, Agarwal K. Increasing burden of liver disease in patients with HIV infection. Lancet. 2011;377:1198-1209.  [PubMed]  [DOI]
134.  Kelso NE, Sheps DS, Cook RL. The association between alcohol use and cardiovascular disease among people living with HIV: a systematic review. Am J Drug Alcohol Abuse. 2015;41:479-488.  [PubMed]  [DOI]
135.  Depp TB, McGinnis KA, Kraemer K, Akgün KM, Edelman EJ, Fiellin DA, Butt AA, Crystal S, Gordon AJ, Freiberg M. Risk factors associated with acute exacerbation of chronic obstructive pulmonary disease in HIV-infected and uninfected patients. AIDS. 2016;30:455-463.  [PubMed]  [DOI]
136.  DeLorenze GN, Weisner C, Tsai AL, Satre DD, Quesenberry CP. Excess mortality among HIV-infected patients diagnosed with substance use dependence or abuse receiving care in a fully integrated medical care program. Alcohol Clin Exp Res. 2011;35:203-210.  [PubMed]  [DOI]
137.  Walley AY, Cheng DM, Libman H, Nunes D, Horsburgh CR, Saitz R, Samet JH. Recent drug use, homelessness and increased short-term mortality in HIV-infected persons with alcohol problems. AIDS. 2008;22:415-420.  [PubMed]  [DOI]
138.  Fuster D, Cheng DM, Quinn EK, Armah KA, Saitz R, Freiberg MS, Samet JH, Tsui JI. Inflammatory cytokines and mortality in a cohort of HIV-infected adults with alcohol problems. AIDS. 2014;28:1059-1064.  [PubMed]  [DOI]
139.  Braithwaite RS, Conigliaro J, Roberts MS, Shechter S, Schaefer A, McGinnis K, Rodriguez MC, Rabeneck L, Bryant K, Justice AC. Estimating the impact of alcohol consumption on survival for HIV+ individuals. AIDS Care. 2007;19:459-466.  [PubMed]  [DOI]
140.  Justice AC, McGinnis KA, Tate JP, Braithwaite RS, Bryant KJ, Cook RL, Edelman EJ, Fiellin LE, Freiberg MS, Gordon AJ. Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men. Drug Alcohol Depend. 2016;161:95-103.  [PubMed]  [DOI]
141.  Korthuis PT, Fiellin DA, McGinnis KA, Skanderson M, Justice AC, Gordon AJ, Doebler DA, Asch SM, Fiellin LE, Bryant K. Unhealthy alcohol and illicit drug use are associated with decreased quality of HIV care. J Acquir Immune Defic Syndr. 2012;61:171-178.  [PubMed]  [DOI]
142.  Nagasawa M, Kanbayashi S, Mogi K, Serpell JA, Kikusui T. Comparison of behavioral characteristics of dogs in the United States and Japan. J Vet Med Sci. 2016;78:231-238.  [PubMed]  [DOI]
143.  Hendershot CS, Stoner SA, Pantalone DW, Simoni JM. Alcohol use and antiretroviral adherence: review and meta-analysis. J Acquir Immune Defic Syndr. 2009;52:180-202.  [PubMed]  [DOI]
144.  Braithwaite RS, McGinnis KA, Conigliaro J, Maisto SA, Crystal S, Day N, Cook RL, Gordon A, Bridges MW, Seiler JF. A temporal and dose-response association between alcohol consumption and medication adherence among veterans in care. Alcohol Clin Exp Res. 2005;29:1190-1197.  [PubMed]  [DOI]
145.  Brown JL, DeMartini KS, Sales JM, Swartzendruber AL, DiClemente RJ. Interventions to reduce alcohol use among HIV-infected individuals: a review and critique of the literature. Curr HIV/AIDS Rep. 2013;10:356-370.  [PubMed]  [DOI]
146.  Chander G, Hutton HE, Lau B, Xu X, McCaul ME. Brief Intervention Decreases Drinking Frequency in HIV-Infected, Heavy Drinking Women: Results of a Randomized Controlled Trial. J Acquir Immune Defic Syndr. 2015;70:137-145.  [PubMed]  [DOI]
147.  Hasin DS, Aharonovich E, O'Leary A, Greenstein E, Pavlicova M, Arunajadai S, Waxman R, Wainberg M, Helzer J, Johnston B. Reducing heavy drinking in HIV primary care: a randomized trial of brief intervention, with and without technological enhancement. Addiction. 2013;108:1230-1240.  [PubMed]  [DOI]
148.  Parry CD, Morojele NK, Myers BJ, Kekwaletswe CT, Manda SO, Sorsdahl K, Ramjee G, Hahn JA, Rehm J, Shuper PA. Efficacy of an alcohol-focused intervention for improving adherence to antiretroviral therapy (ART) and HIV treatment outcomes - a randomised controlled trial protocol. BMC Infect Dis. 2014;14:500.  [PubMed]  [DOI]
149.  Gardner LI, Marks G, Shahani L, Giordano TP, Wilson TE, Drainoni ML, Keruly JC, Batey DS, Metsch LR. Assessing efficacy of a retention-in-care intervention among HIV patients with depression, anxiety, heavy alcohol consumption and illicit drug use. AIDS. 2016;30:1111-1119.  [PubMed]  [DOI]
150.  Chander G, Monroe AK, Crane HM, Hutton HE, Saag MS, Cropsey K, Eron JJ, Quinlivan EB, Geng E, Mathews WC. HIV primary care providers--Screening, knowledge, attitudes and behaviors related to alcohol interventions. Drug Alcohol Depend. 2016;161:59-66.  [PubMed]  [DOI]
151.  Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected patient. Clin Liver Dis. 2003;7:179-194.  [PubMed]  [DOI]
152.  Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, Vidaud M, Bricaire F, Opolon P, Katlama C. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30:1054-1058.  [PubMed]  [DOI]
153.  Sulkowski MS, Mehta SH, Torbenson MS, Higgins Y, Brinkley SC, de Oca RM, Moore RD, Afdhal NH, Thomas DL. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS. 2007;21:2209-2216.  [PubMed]  [DOI]
154.  Pineda JA, García-García JA, Aguilar-Guisado M, Ríos-Villegas MJ, Ruiz-Morales J, Rivero A, del Valle J, Luque R, Rodríguez-Baño J, González-Serrano M. Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy. Hepatology. 2007;46:622-630.  [PubMed]  [DOI]
155.  Lo Re V, Kallan MJ, Tate JP, Localio AR, Lim JK, Goetz MB, Klein MB, Rimland D, Rodriguez-Barradas MC, Butt AA. Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: a cohort study. Ann Intern Med. 2014;160:369-379.  [PubMed]  [DOI]
156.  Limketkai BN, Mehta SH, Sutcliffe CG, Higgins YM, Torbenson MS, Brinkley SC, Moore RD, Thomas DL, Sulkowski MS. Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV. JAMA. 2012;308:370-378.  [PubMed]  [DOI]
157.  Gray JW, Carrano AV, Moore DH, Steinmetz LL, Minkler J, Mayall BH, Mendelsohn ML, Van Dilla MA. High-speed quantitative karyotyping by flow microfluorometry. Clin Chem. 1975;21:1258-1262.  [PubMed]  [DOI]
158.  Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M, Mauss S, Bräu N, Hatzakis A, Pol S. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS. 2007;21:1073-1089.  [PubMed]  [DOI]
159.  Nunes D, Saitz R, Libman H, Cheng DM, Vidaver J, Samet JH. Barriers to treatment of hepatitis C in HIV/HCV-coinfected adults with alcohol problems. Alcohol Clin Exp Res. 2006;30:1520-1526.  [PubMed]  [DOI]
160.  Sulkowski MS, Eron JJ, Wyles D, Trinh R, Lalezari J, Wang C, Slim J, Bhatti L, Gathe J, Ruane PJ. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA. 2015;313:1223-1231.  [PubMed]  [DOI]
161.  Christensen S, Mauss S, Hueppe D, Lutz T, Schewe K, Rockstroh JK, Baumgarten A, Simon KG, Busch H, Ingiliz P. Directly acting agents against HCV- Results from the German Hepatitis C cohort (GECCO). In: Conference on Retroviruses and Opportunistic Infections (CROI). 2016 Feb 22-25; Boston, USA. .  [PubMed]  [DOI]
162.  Piroth L, Wittkop L, Lacombe K, Rosenthal E, Gilbert C, Carrieri P, Dabis F, Sogni P, Dominique Salmon-Ceron8 for the the ANRS CO13 HEPAVIH Study Group . Response to DAA-based regimens in HIV-HCV co-infected patients in real-life, France. In: Conference on Retroviruses and Opportunistic Infections (CROI). 2016 Feb 22-25; Boston, USA. .  [PubMed]  [DOI]
163.  Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS. 2004;18:2277-2284.  [PubMed]  [DOI]
164.  Kottilil S, Polis MA, Kovacs JA. HIV Infection, hepatitis C infection, and HAART: hard clinical choices. JAMA. 2004;292:243-250.  [PubMed]  [DOI]
165.  Marcellin F, Lions C, Winnock M, Salmon D, Durant J, Spire B, Mora M, Loko MA, Dabis F, Dominguez S. Self-reported alcohol abuse in HIV-HCV co-infected patients: a better predictor of HIV virological rebound than physician's perceptions (HEPAVIH ARNS CO13 cohort). Addiction. 2013;108:1250-1258.  [PubMed]  [DOI]
166.  Cooper CL, Cameron DW. Effect of alcohol use and highly active antiretroviral therapy on plasma levels of hepatitis C virus (HCV) in patients coinfected with HIV and HCV. Clin Infect Dis. 2005;41 Suppl 1:S105-S109.  [PubMed]  [DOI]
167.  Fishbein DA, Lo Y, Netski D, Thomas DL, Klein RS. Predictors of hepatitis C virus RNA levels in a prospective cohort study of drug users. J Acquir Immune Defic Syndr. 2006;41:471-476.  [PubMed]  [DOI]
168.  Tural C, Fuster D, Tor J, Ojanguren I, Sirera G, Ballesteros A, Lasanta JA, Planas R, Rey-Joly C, Clotet B. Time on antiretroviral therapy is a protective factor for liver fibrosis in HIV and hepatitis C virus (HCV) co-infected patients. J Viral Hepat. 2003;10:118-125.  [PubMed]  [DOI]
169.  Chaudhry AA, Sulkowski MS, Chander G, Moore RD. Hazardous drinking is associated with an elevated aspartate aminotransferase to platelet ratio index in an urban HIV-infected clinical cohort. HIV Med. 2009;10:133-142.  [PubMed]  [DOI]
170.  Blackard JT, Welge JA, Taylor LE, Mayer KH, Klein RS, Celentano DD, Jamieson DJ, Gardner L, Sherman KE. HIV mono-infection is associated with FIB-4 - A noninvasive index of liver fibrosis - in women. Clin Infect Dis. 2011;52:674-680.  [PubMed]  [DOI]
171.  Muga R, Sanvisens A, Fuster D, Tor J, Martínez E, Pérez-Hoyos S, Muñoz A. Unhealthy alcohol use, HIV infection and risk of liver fibrosis in drug users with hepatitis C. PLoS One. 2012;7:e46810.  [PubMed]  [DOI]
172.  Skinner HA, Sheu WJ. Reliability of alcohol use indices. The Lifetime Drinking History and the MAST. J Stud Alcohol. 1982;43:1157-1170.  [PubMed]  [DOI]
173.  Fuster D, Tsui JI, Cheng DM, Quinn EK, Bridden C, Nunes D, Libman H, Saitz R, Samet JH. Impact of lifetime alcohol use on liver fibrosis in a population of HIV-infected patients with and without hepatitis C coinfection. Alcohol Clin Exp Res. 2013;37:1527-1535.  [PubMed]  [DOI]
174.  Lim JK, Tate JP, Fultz SL, Goulet JL, Conigliaro J, Bryant KJ, Gordon AJ, Gibert C, Rimland D, Goetz MB. Relationship between alcohol use categories and noninvasive markers of advanced hepatic fibrosis in HIV-infected, chronic hepatitis C virus-infected, and uninfected patients. Clin Infect Dis. 2014;58:1449-1458.  [PubMed]  [DOI]
175.  Marcellin F, Roux P, Loko MA, Lions C, Caumont-Prim A, Dabis F, Salmon-Ceron D, Spire B, Carrieri MP. High levels of alcohol consumption increase the risk of advanced hepatic fibrosis in HIV/hepatitis C virus-coinfected patients: a sex-based analysis using transient elastography at enrollment in the HEPAVIH ANRS CO13 cohort. Clin Infect Dis. 2014;59:1190-1192.  [PubMed]  [DOI]
176.  Obel N, Omland LH, Kronborg G, Larsen CS, Pedersen C, Pedersen G, Sørensen HT, Gerstoft J. Impact of non-HIV and HIV risk factors on survival in HIV-infected patients on HAART: a population-based nationwide cohort study. PLoS One. 2011;6:e22698.  [PubMed]  [DOI]
177.  Tsui JI, Saitz R, Cheng DM, Nunes D, Libman H, Alperen JK, Samet JH. Awareness of hepatitis C diagnosis is associated with less alcohol use among persons co-infected with HIV. J Gen Intern Med. 2007;22:822-825.  [PubMed]  [DOI]
178.  National Institute on Alcohol Abuse and Alcoholism. Helping patients who drink too much: a clinician¡¯s guide. 2007 ed. Bethesda, MD; 2007. .  [PubMed]  [DOI]
179.  Bush K, Kivlahan DR, McDonell MB, Fihn SD, Bradley KA. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med. 1998;158:1789-1795.  [PubMed]  [DOI]