HCV and Alcoholism: How Two Diseases and Their Treatments Go Hand-In-Hand

The question of whether and when to treat patients with hepatitis C who also have uncontrolled alcohol use disorder has plagued clinicians for nearly 30 years . There are a number of arguments for and against. For example, those in favor of treating immediately might suggest, simply, that if a patient has a disease, and if there is an available cure for that disease, it should be cured. Conversely, other clinicians might argue that even if a patient is cured of HCV, excessive alcohol use may lead to high-risk behaviors that predispose the patient to reinfection.

One of the central arguments is whether a period of abstinence from alcohol should be required before initiating therapy. In the interferon era, with mediocre response rates and a host of adverse events — including mental health effects that could exacerbate addiction — there was ample reason to demand control of alcohol intake before therapy. But with the overwhelming efficacy and safety of direct-acting antivirals, many believe that there is no need to wait.

Hashem B. El-Serag, MD, MPH, professor of Medicine and Chief of Gastroenterology and Hepatology at the Michael E. DeBakey VA Medical Center and Baylor College of Medicine in Houston Tex., commented on this aspect of the discussion. “The availability of highly efficacious treatments with minimum side effects has infused a lot of enthusiasm to providers as well as patients who are active alcoholics to overcome the obstacles delaying treatment,” he said. “Therefore, the discussion of adverse effects of drinking, including the discussion of withholding treatment and rehabilitation, at least temporarily, is happening more frequently and more vigorously.”

He acknowledged that the idea of a set period of abstinence before initiating therapy — an approach that is declining in popularity — is still a reasonable option to consider. However, there is flexibility. “There are more methods and avenues to stop drinking than there were previously,” he said. “Some providers, including me, are more compromising about the duration or strictness of non-drinking. Full completed rehab is ideal, but a considerable reduction in alcohol intake or active enrollment in rehab are acceptable alternatives.”

A unique by-product of the efficacy and safety of DAAs is that patients are more willing than ever to get their drinking under control. “They know there is a high benefit awaiting them with DAA therapies,” El-Serag said.

At the moment, however, the effectiveness data on DAAs in this patient population are inconclusive, simply because not enough time has elapsed since their debut. And there are also other gray areas, including the various stigmas associated with HCV and alcohol use, and the role of addiction and mental health specialists in treating these patients.

Because of this complexity, many experts believe that a multidisciplinary approach may be most effective in caring for patients with HCV who also have active alcohol use disorders. However, despite the proliferation comprehensive care programs in other specialties, the gastroenterologists, hepatologists and primary care providers who deal with HCV do not routinely work with addiction specialists in treating patients. When mental health needs are factored into the equation, patient management becomes more complicated.

Lorenzo Leggio, MD, PhD, MSc, clinical investigator, chief of the Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Institute on Drug Abuse (NIDA) Intramural Research Programs (IRPs), and associate director for Clinical Research, NIDA IRP Medication Development Program, said that the question may not be so complex. “The short answer is that you can treat patients for HCV as long as you also treat the addiction,” he said in an interview. “Of course the data are very good for the new treatments, but we still do not have enough data to really fully understand the picture.”

Leggio acknowledged these alternatives, as well, but offered a much more definitive word. “In the end, we simply have to treat these people for hep C,” he said.

Arguments for Treating

“There are patient-related reasons for treating and curing patients of HCV, such as reducing the risks for end stage liver disease and liver cancer,” El-Serag said. “There are also societal reasons, such as reducing the risk of transmission.”

Christine Hsu, MD, assistant professor of Clinical Medicine at the University of Pennsylvania, laid out the arguments in an interview. “The pros of treating a patient with chronic alcoholism would be to eliminate an additional hepatotoxin and to reduce their risks of developing cirrhosis and complications of cirrhosis that may necessitate a liver transplant in the future,” she said. “Additionally, many patients with alcohol abuse may also have drug abuse. Treating their hepatitis C could prevent further transmission and spread of hepatitis C in patients who engage in IV drug use who engage in unsafe needle practices.”

Ashwani Singal, MD, associate professor in the Department of Medicine and the Division of Gastroenterology and Hepatology at the University of Alabama at Birmingham, cited meta-analysis data from his own group dating back to 2007 that showed that the risk for advanced fibrosis and cirrhosis was increased 2.5 times and the risk for decompensated cirrhosis was four fold among drinkers with HCV compared to patients with either alcohol abuse or with HCV alone. “Similarly, the outcome of patients with alcoholic hepatitis, another phenotype of alcoholic liver disease, is much poorer within 6 months of presentation in the presence of concomitant HCV infection,” he added, citing more data from his group. “Data from observational studies, post-hoc analysis of randomized controlled trials, and prospective natural history studies have consistently shown that successful treatment of HCV with development of SVR improves outcomes, including mortality and development of cirrhosis, decompensation, and HCC.”

The advances in DAA therapies clearly shift the landscape, according to Singal. “For example, when we see a patient with active alcohol addiction in the clinic with hypertension or diabetes mellitus, we do not hesitate treating these diseases,” he said. “Active alcohol addiction is not considered a contraindication for prescribing treatments for other diseases. Similarly, HCV treatment in patients with active alcohol addiction may be considered, given that the treatment is safe, highly potent and is needed for short-term of 2-6 months. Further, treatment of HCV infection in patients with active alcohol addiction will reduce the risk of HCV transmission to others in the community.”

For Singal, the issue is clear. “The goal of treatment of HCV infection is to reduce the overall as well as liver-related mortality and morbidity from hepatitis C,” he said. “Specifically the goal is to reduce the risk for development of cirrhosis, decompensation with complications of cirrhosis, and HCC. Prevalence of HCV infection is higher in individuals with alcohol addiction compared to the general population in the US. Alcohol and HCV infection act in synergy in causing rapid fibrosis progression, with more frequent development of cirrhosis and advanced liver disease including HCC, compared to when either of these factors is present alone.”

Arguments Against

There are, however, arguments in favor of a more measured approach. Charlet and Heinz conducted a systematic review of 63 studies to determine whether reducing alcohol intake can minimize health risks, including liver injury and HCV outcomes. Results indicated that interventions targeting alcohol reduction — including abstinence as a therapeutic aim — yielded positive responses, including major benefits in terms of body weight reduction, histological improvement in pre-cirrhotic liver disease associated with alcohol and “slowed progression of an already existing alcohol-attributable liver fibrosis,” according to the researchers. A number of non-hepatic results that may benefit patients with HCV also were observed, including reduction in withdrawal symptoms, frequency of psychiatric episodes, duration of in-patient hospital stays, improvements in barometers of mental health such as anxiety, depression, self-confidence and stress, better social functioning and fewer alcohol-related adverse consequences. The researchers added that patients with “heightened vulnerability,” including patients with HCV, would also benefit from significant reduction in alcohol use. “The reviewed studies strongly support and emphasize the importance and benefits of early initial screening for problematic alcohol use followed by brief and other interventions in first contact medical health-care facilities to reduce alcohol intake,” they concluded.

“Although there is strong rationale to treat an HCV-infected drinker, traditionally active alcohol addiction is considered a relative contraindication for HCV treatment,” Singal said. “This is likely due to lack of evidence of benefit in these patients given that traditionally active drinkers and patients with alcohol addiction are excluded from randomized controlled studies.”

Singal pointed out that while safety concerns associated with the combination of interferon and alcohol are largely no longer relevant, the data on the safety of DAA in the specific population with active alcohol addiction remain sparse.

But perhaps the most compelling argument pertains to adherence, according to Hsu. “I would have concerns that patients who do not have control over their addiction would be non-compliant with the HCV regimen,” she said. “Cure rates can be greater than 90% if patients are adherent to the medication regimen. However, if they are not taking their medication daily, I would be concerned for increased viral resistance and lower cure rates.”

El-Serag echoed this point. “While there is little evidence to indicate that the overall effectiveness of HCV treatment is affected by alcohol use in terms of cure rates, a big challenge is adherence to daily treatment in addition to independent liver damage related to alcohol,” he said.

There are also more clinical arguments to refrain from treating, according to El-Serag. “There may be less overall benefit for reducing liver complications given that heavy alcohol use continues to damage the liver,” he said. He added that there may be a lower benefit to overall mortality and morbidity in patients who are treated simply because of the overwhelmingly damaging effects of alcohol.

Hsu built on this point. “Additionally, similar to alcohol, many of the hepatitis C medications are metabolized through the liver,” she said. “I would have concerns for drug toxicities and decreased efficacy if alcohol is used concomitantly.”

Regarding societal reasons to refrain from treating, El-Serag said that a lower cost-effectiveness ratio of HCV therapy in patients with alcohol use disorder may be something to consider and evaluate.

“Treatment decisions in patients with alcohol use disorder should be individualized,” El-Serag said. “Overall, I believe that most providers still withhold treatment among patients with evidence of continued heavy alcohol drinking.”

Collaborative Effort

While there is still some debate about when and how to treat patients with active alcohol use disorder, there is less debate that these patients require intervention on multiple fronts, according to Singal. “Hospitals and academic centers need to provide clinical services integrated with addiction team to these patients, so as to target HCV and alcohol use disorder in tandem. At an individual level, clinicians should be vigilant and proactive in screening liver disease patients, including those with chronic HCV infection, for alcohol use. We need to better understand how to identify those patients with alcohol addiction who can potentially benefit from simultaneous consult and management by the addition specialists.”

Morasco and colleagues aimed to develop an integrated cognitive behavior therapy for HCV patients with alcohol use disorder. They suggested that patients with HCV have elevated rates of chronic pain and substance use disorder. Their study population included those in a VA setting. The intervention was comprised of an eight-session integrated group therapy program. Participants completed an evaluation of pain, function, severity of depression and alcohol and substance use at baseline, post-treatment and 3 months of follow-up. Results indicated improvements in pain interference, cravings for alcohol and other substances and decreased use of alcohol and substances during the previous month. The ratio of participants who met diagnostic criteria for current substance use disorder decreased four fold in terms of current substance use, from 24% at baseline to 15% after treatment and 6% at 3 months. Overall, 94% of participants reported improvement from baseline. “Results from this pilot study suggest that a customized [cognitive behavior therapy] for patients with both chronic pain and [substance use disorder] may be beneficial in improving important pain and addiction-related outcomes in patients with HCV,” the researchers concluded. “Larger scale investigations of this intervention appear warranted.”

“Unfortunately, it is unusual to find people who have expertise in both hepatitis treatment and substance use disorders,” Leggio said. “Therefore, it has to be a team effort including a gastroenterologist, hepatologist, mental health specialist and addition specialist working together. It is not easy and requires a lot of coordination to mount this interdisciplinary effort and create real patient-centered care. Nonetheless, it is key to develop these multi-disciplinary teams”

Few such teams exist, according to Leggio. “We simply don’t have enough physicians who specialize in addiction,” he said.

With this in mind, professional organizations may need to play a larger role. “NIAAA, part of the National Institutes of Health, already does a lot of work to fund and support research on the diagnosis and treatment of alcohol use disorder and of alcohol-related consequences including alcoholic liver disease,” Leggio said. “An equally important goal and mission is to translate these efforts into real practice for doctors and other practitioners.”

Education has to be a cornerstone, according to Leggio. “We need to shift the paradigm in medical school to include training on how to treat addiction,” he said. “It needs to be on the radar of every clinician. They need to know how to identify it and who to send the patient to for referral.”

Some steps are being taken by professional societies. “Associations like AASLD and ASAM are strong representations and spokespersons for the physician community,” Singal said. “They work toward the goal of advancing the health of patients with liver diseases or with substance abuse, respectively.”

Singal noted that the public policy committees within these organizations champion causes, including HCV and alcohol use disorder, in Washington. Moreover, he added that the joint guidelines for HCV published by the AASLD and the IDSA offer recommendations for the treatment of patients with alcohol use disorder. “However, they are interim guidelines on treatment in this setting until evidence-based data are available,” he said.

Without concrete data to support them, then, individual clinicians are forced to make day-to-day decisions at the doctor–patient level on their own. “Studies have shown that patients with any substance use addiction, including alcohol, can complete therapy successfully with efficacy comparable to patients without addiction, if these patients are simultaneously enrolled in substance abuse program,” Singal said. “In the case of alcohol addiction, this becomes more relevant. Abstinence to alcohol use is the single most important determinant of the long-term outcomes of patients with severe liver disease from alcohol, including alcoholic hepatitis and alcoholic cirrhosis.”

For El-Serag, counseling patients on the adverse effects of alcohol on the efficacy of HCV therapy is critical. “I also emphasize that we could start treatment for HCV while they are in the ambulatory portion of the rehab program, as opposed to waiting until the end of the program or for a 6-month abstinence period,” he said. “If possible, I try to involve their caretaker or a close family member in the discussion.”

Comorbidity, Tri-morbidity

Chereji and colleagues investigated the trimorbidity of depression, substance abuse disorders and chronic pain in a review paper. They suggested a synergistic acceleration of liver injury, particularly between alcohol use and HCV, even when alcohol intake is a moderate (20 to 80 grams per day) or lower (1 to 30 grams per day) amounts. Reducing or abstaining from alcohol consumption can slow the progression of liver disease and reduce or eliminate the negative health consequences of alcohol use in HCV-infected individuals,” they wrote.

Jennifer M. Loftis, PhD, research scientist at the VA Portland Health Care System and professor in the Department of Psychiatry at Oregon Health & Science University, said, “Until very recently, treatment of HCV was challenging because of low viral clearance rates, significant medication toxicity, and other barriers, including, in some cases, the presence of co-occurring substance use and/or mental health disorders,” referring to them as comorbid or tri-morbid diagnoses. “Patients with HCV and ongoing substance use and/or mental health disorders are increasingly being treated with DAA therapies, and although prospective, longitudinal studies are needed, initial reports indicate that patients with active tri-morbidity can initiate and complete DAA therapy with comparable successes to those patients without co-existing substance use or mental health disorders.”

Leggio echoed the sentiment that until data on DAAs mature, it is important for clinicians to continue to hammer home the messages that alcohol use can put patients at risk for any number of further complications.

For Loftis, the mental health disorders that often go hand-in-hand with alcohol use and HCV should not be ignored. “Multidisciplinary, collaborative care models that combine HCV treatment with mental health and substance use treatment services can further facilitate successful DAA therapy outcomes,” she said. “Attaining viral clearance may be particularly critical for patients with active tri-morbidity, as research suggests that mental health disorder and substance abuse symptoms such as depression and cognitive impairments may be related to the presence of chronic HCV infection.”

One way to handle this is to reduce the stigmas that surround HCV, alcohol use and mental health disorders. “We have reacwhed a place where mental health disorders like depression are much more recognized and accepted,” Leggio said. “The majority of primary care providers know that there are medications to prescribe for depression. But many still don’t know how to deal with addiction. It is not their fault because they have not been trained in these interventions and therapies. This is something we need to fix because it will help to reduce stigma.”

Leggio also believes that perceptions surrounding liver transplant tie in with stigma. “Here is a parallel,” he said. “If you have a patient with heart failure who is diabetic and a patient with heart failure who is not diabetic, would you treat the patient without diabetes and not the patient with diabetes because the patient without diabetes is more likely to survive? No, you would treat both patients. It is important to understand that alcohol use is a medical disorder the same as hepatitis C. It is a disorder in the brain. Denying treatments (including liver transplant) to a patient with alcohol use disorder is the same as denying treatment to a patient with diabetes. It is reinforcing the stigma.”

He added that more people in the general public know that alcohol use disorder is a legitimate medical problem, but there are still gaps in understanding how to approach it. “Compared with our understanding of diabetes, hypertension, cancer, etc., we still have work to do,” he said. “Stigma is still present. There is still a lot of work to be done because many people still don’t know that alcohol use disorder is a medical problem.”

Professional organizations like the AASLD and the American Association for Addiction Medicine can carry weight in helping to improve the practical consequences of this stigma, according to Hsu. “My patients have often expressed their frustrations with the difficulty of finding a psychiatrist or therapist,” she said. “Certain insurances may cover specific psychiatrists or therapists, and there is often a long wait time to see them. Some psychiatrists may not even accept insurances. As a community, we should try to improve patient access to mental health care as that often affects their medical care and compliance. We should strive to improve equal access to mental health care regardless of socioeconomic class.”

It is with this in mind that Leggio has been outspoken to the media and in other venues. “We never turn down requests to talk about this,” he said. “It is important to get these messages out.”

This message can be spread at the level of professional organizations, but it can also come down to the individual doctor–patient relationship. “Educating patients regarding their liver disease and emphasizing the need to eliminate hepatotoxins such as alcohol is critical,” Hsu said. “Many patients express the interest to pursue alcohol sobriety, but do not have the resources or means to achieve this. They are unfamiliar with the addiction treatment centers available to them or the centers that may be covered by their insurance. Clinicians should be more vigilant and proactive in helping to facilitate or directing these patients to addiction treatment centers, psychiatrists, or counselors.”

For Leggio, even the terminology is important. “This is why we use the term ‘alcohol use disorder,’” he said. “The term ‘alcoholic’ has too many negative associations.”

Understanding Behaviors

Leggio is cautiously optimistic about the current direction in treating these patients. “It depends on your perspective,” he said. “Compared with 30 years ago, we have seen a lot of progress. We know much more about the brain of these patients, what underlies addiction. But there is still much to learn.”

Some experts believe that answers lie in simply understanding why patients drink. Elliott and colleagues conducted a study involving 254 heavy drinkers with HIV, 30.6% of whom also had HCV. They aimed to determine motives for drinking in this patient population. Results indicated that at 12 months, coinfected individuals drank as a way of coping with their disease states, rather than for social reasons.

In another cohort, Elliott and colleagues investigated a cohort of drug and alcohol users with HIV and HCV. They attempted to elucidate the relationships between their substance use and their illnesses. The analysis included 476 patients with HIV and 1,145 with HCV who had been recruited from drug treatment clinics. Drug users with HIV who believed that HIV carried the highest risk for serious outcomes were the most likely to engage in high-risk alcohol-related behaviors compared with patients who had less serious perceptions of their disease (X(2)(6)=14.19; P < .05). By comparison, drug users with HCV who believed that HCV carried moderate risk for serious outcomes were most likely to engage in high-risk drinking (X(2)(6)=12.98; P < .05). “Risky drinking was most common among those with HCV who believed that severe outcomes were somewhat likely,” the researchers wrote. “Further research is needed to understand the mechanisms of these associations.”

Singal agreed that such research is much needed. “Clearly, this is an area of unmet need,” he said. “Well-designed studies are needed as basis for deriving evidence-based guidelines to treat HCV infected patients with active alcohol addiction.”

Post-hoc data analyzing randomized controlled trials on various DAAs can be a starting point, according to Singal. “Prospective studies in HCV infected population with active alcohol addiction may provide initial data on the efficacy and safety on the use of DAA,” he said. “Randomized studies focusing on treating HCV patients with alcohol addiction jointly with addiction specialists — treating both HCV and alcoholism together — would provide useful data on the feasibility and approach to treating these patients. These studies could serve as a basis for improving morbidity and mortality in this population.”

Other Issues

Another area that may require further investigation surrounds the timing of therapy and/or a possible period of intervention prior to liver transplantation. It remains unclear how to optimize outcomes in this particular subset of patients.

Cheong and colleagues investigated the association between renal failure at the time of liver transplantation and patient outcome in a large cohort of patients that included 6,920 with alcoholic liver disease and 14,922 with HCV. The full cohort included 24,798 transplant recipients. The presence of renal failure was reported in 23.95% of patients with alcoholic liver disease and 19.38% of those with HCV (P < .001). Multivariable analysis results indicated that renal failure independently predicted survival. However, the effect of renal failure was less pronounced in patients with alcoholic liver disease (HR = 1.31; P < .0001) than it was in patients with NASH (HR = 1.73; P < .0001) or HCV (HR = 1.52; P < .0001). “Despite a higher MELD score at the time of [liver transplantation], [alcoholic liver disease] patients with renal failure had better long-term prognosis than non-[alcoholic liver disease] patients,” the researchers wrote.

The issue, for Leggio, is more practical, and comes back to the period of abstinence. “We see this Catch-22 in liver transplantation, as well,” he said. “We are asking people to be abstinent, but they can’t be abstinent because they have a legitimate medical problem. So this prevents them from dealing with another, potentially more serious legitimate medical problem.”

So it is with this in mind that Leggio would like to address the clinical community. “The mentality about alcohol use disorder has to change,” he said. “We as clinicians treating these patients need to be the bridge. We need to bring these people to a place where they are ready to be treated.”

He once again cited the synergistic effects of HCV and alcohol on the liver. “If you deny HCV treatment because of an alcohol problem, you are leading this patient to die of these two medical problems,” he said. “The question is about how we can build an approach where we treat the disorders together and maximize the chance for people to recover.”

• References:
• Addolorato G, et al. Alcohol Clin Exp Res. 2013; 37: 1601-8.
• Addolorato G, et al. CNS Drugs. 2013; 27: 287-99
• Charlet K and Heinz A. Addict Biol. 2016;doi: 10.1111/adb.12414.
• Cheong J, et al. Liver Int. 2016;doi: 10.1111/liv.13182.
• Chereji E, et al. Open Med J. 2016;doi:10.2174/1874220301603010079.
• Elliott JC, et al. Addict Behav. 2016;doi:10.1016/j.addbeh.2016.06.023.
• Elliott JC, et al. Ann Med. 2016;27:1-7.
• Hutchinson SJ, et al. Clin Gastroenterol Hepatol. 2005;3:1150-1159.
• Lee MR, Leggio L. Am J Psychiatry. 2015; 172: 1182-9.
• Leggio L, et al. Addict Behav. 2012; 37: 561-4
• Morasco BJ, et al. Pain Med. 2016; pii: pnw076.
• Singal AK, et al. J Clin Gastroenterol. 2007; 41:761-72.
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• For more information:
• Hashem B. El-Serag, MD, can be reached at 2002 Holcombe Blvd (152), Houston Texas 77030; email: hasheme@bcm.edu.
• Christine Hsu, MD, can be reached at 3400 Spruce Street, 2 Dulles, Philadelphia, PA 19104; email: Christine.Hsu@uphs.upenn.edu.
• Lorenzo Leggio, MD, PhD, MSc, can be reached at NIAAA and NIDA, NIH, 10 Center Drive (10CRC/15330) Room 1-5429, Bethesda, MD, 20892-1108; email: lorenzo.leggio@nih.gov.
• Jennifer M. Loftis, PhD, can be reached at the VA Portland Health Care System, 3710 SW US Veterans Hospital Road, Portland, OR 97239; email: loftisj@ohsu.edu; Jennifer.loftis2@va.gov.
• Ashwani Singal, MD, can be reached at1808 7th Ave S, BDB 351, Birmingham AL 35294-0012; email: ashwanisingal.com@gmail.com.

Disclosures: El-Serag reports receiving grant funding from Gilead and Merck. He added that although he works for the VA, his views do not necessarily represent the views of the VA. Hsu reports no relevant financial disclosures. Leggio reports no relevant financial disclosures and his views do not necessarily represent the views of the NIH. Loftis wrote that the contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Also, she and Oregon Health & Science University have a significant financial interest in Artielle Immunotherapeutics, a company that may have a commercial interest in the results of her research. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU. Singal reports receiving research funding from ACG, NIAAA, NIDDK, and Intercept Pharmaceutical; honoraria from CLD foundation; royalties from Up-To-Date; and being an advisory board member for Intercept, Gilead, and Recordati.