June 14, 2016
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Fighting the War on HCV Within the Veterans Health Administration System

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Hepatitis C virus challenges the Veterans Health Administration in much the same way it challenges others, but with the added burden of post-traumatic stress disorder and a host of other military-specific hurdles, it presents unique challenges for treatment.

PTSD disproportionately impacts veterans. Substance use also proliferates in this patient population. In the past, the mental health components of both of these complications were exacerbated by interferon used to treat HCV, which kept generations of veterans away from treatment altogether. Variability in VA facilities can be problematic, as can the logistics of dealing with patients who live far from a VA center. Both patients and clinicians have long lamented the bureaucracy of the system.

Then there is the sheer number of patients within the system. David Ross, MD, PhD, MBI, director of HIV, Hepatitis, and Public Health Pathogens Programs at the VA, laid out the scope of the problem.

“We think at this point that we have about 180,000 patients in care with known chronic HCV,” he said in an interview with HCV Next. “When I say known, I mean that we have a national electronic clinical case registry for patients who have been diagnosed and confirmed.”

There is good news, though. About 70% of veterans in the baby boomer birth cohort have been tested in VA facilities, compared with about 50% in that cohort nationally, according to Ross. “That means if we look at everyone who we have treated, we have around 113,000 individuals who we know need treatment,” he said. “Add to that another 41,000 if we reach 100% birth cohort testing.”

It was with these numbers in mind that in December 2015, Congress approved a measure to provide funding to treat all patients with HCV in the VA system, regardless of cirrhosis level, disease state or substance use status. The budget is likely to be around $1 billion in 2016, close to $1.5 billion in 2017. “We can test and treat these patients, and we are not going to run out of money,” Ross said.

Despite these positive steps, there is controversy. With the spotlight on advances in HCV treatment with direct-acting antivirals and their price tags, several members of Congress have taken notice. They have levied accusations of “revenue-driven pricing strategy” against Gilead for pricing of sofosbuvir (Sovaldi, Gilead Sciences) and ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and, specifically, Raymond F. Schinazi, PhD, Hon DSc, Frances Winship Walters Professor of Pediatrics, Director of the Laboratory of Biochemical Pharmacology and the HIV Cure Scientific Working Eradication Group at Emory’s Center for AIDS Research at the Emory University School of Medicine.

“A key consideration in Gilead’s decision-making process to determine the ultimate price of Sovaldi was setting the price such that it would not only maximize revenue, but also prepare the market for Harvoni and its even higher price,” investigators wrote in the report.

Costs Debate

The principal argument raised by Rep. Jeff Miller (R-Fl.), chairman of the House Veterans’ Affairs Committee, is that Schinazi was developing sofosbuvir for his company, Pharmasset, while working for the Atlanta VA Medical Center. During that time, Schinazi also worked at Emory University and operated a research laboratory. Schinazi said that the majority of his time was spent working in the VA, and that the VA approved his non-VA activities. In an interview with HCV Next, Schinazi explained his VA work was primarily on HIV and he did not work on HCV within the health system.

In the hearing held in February 2016, Miller also expressed concern that Schinazi made a large profit when he sold Pharmasset Inc., a company he founded with three other scientists, to Gilead Sciences, and further raised questions as to why the VA was not given a larger discount for sofosbuvir-based therapies.

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“Gilead has provided discounts that — when coupled with the new funding levels provided by Congress — allow the VA to maximize access to treatment for veterans with HCV. The VA receives the steepest discounts (in excess of 50% for Harvoni), but we also have extended deep discounts to other federal programs, and we hope that funding will be prioritized for those programs to facilitate broad access to treatment,” Cara Miller, a media relations representative for Gilead, told HCV Next.

Schinazi also addressed these questions head-on in his interview. “I was one of the first to publish on the cost issue,” he said. “I realized very early that it may become an obstacle to access. But considering the costs of interferon/ribavirin — which worked a fraction of the time and took more than 1 year to work, if at all, plus all of the side effects — I realized that anything that is safe and highly effective and can cure a person in 6 to 12 weeks is better than interferon/ribavirin.”

The once-daily formulation, high barriers to resistance and vast improvement over early HCV protease inhibitors are also strong features of the sofosbuvir-based therapies, according to Schinazi. “Any way you look at it, it is much more cost effective than earlier lousy treatments,” he said. “I also realized that with time there would be more competition and the price would fall to a more reasonable price in the U.S.A. and Europe. This is now happening.”

Raymond F. Schinazi

Schinazi cited a number of cost-effectiveness studies he conducted, including one with Hagan and colleagues that was published as early as 2013 before the price of sovaldi was set by Gilead.

Hagan and colleagues created a decision-analytic Markov model with a lifetime societal perspective to evaluate whether an all-oral drug regimen would be cost-effective compared to standard of care at the time. The analysis was based on the progression of a cohort of patients aged 50 years. Results indicated that an all-oral regimen bested 2013 standard-of-care treatments across a range of willingness-to-pay thresholds. The researchers noted an incremental cost-effectiveness ratio of $44,514 per quality-adjusted life year (QALY). The regimen was most cost-effective for genotype 1 disease, but remained cost-effective for genotypes 2 and 3 at thresholds greater than or equal to $80,000 per QALY, according to the researchers.

“Using this model, the degree of cost-effectiveness depended on the [willing-to-pay] threshold and the final cost set for approved drug combinations,” the researchers wrote.

“The VA is currently doing a great job with regard to HCV in terms of treatment and education,” Schinazi said. “They have treated about one-third of our Veterans infected with HCV and cured the great majority (more than 90%). In the next 2 years, all U.S. veterans will be free of HCV — cured. This will save millions of dollars long term, but most importantly will provide significant additional lifespans and less morbidity, mortality and suffering to our deserving veterans. After serving the VA for over 30 years, I am very proud of all these accomplishments in curing HCV through the efforts of Pharmasset and now Gilead Sciences.”

The debate about the cost of DAA therapies, in all of its iterations and with all of its myriad facets, is likely to continue into the foreseeable future. In the meantime, the research and clinical communities continue to study these drugs in all populations, including VA cohorts.

Novel Therapy Outcomes

Backus and colleagues investigated SVR rates associated with sofosbuvir-based regimens in a cohort of 4,026 veterans with genotypes 1 and 2 disease. The intention-to-treat analysis included 3,202 patients with genotype 1 and 823 patients with genotype 2 HCV. Results indicated a 66.8% SVR rate for patients with genotype 1 disease treated with sofosbuvir and pegylated interferon and ribavirin (PEG-riba), 75.3% for genotype 1 patients treated with sofosbuvir and simeprevir, 74.1% for those with genotype 1 HCV treated with sofosbuvir, simeprevir and ribavirin and 79% for patients with genotype 2 HCV treated with sofosbuvir and ribavirin.

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Reduced SVR was reported among genotype 1 patients with a number of comorbid conditions, including BMI greater than or equal to 30 (OR = 0.64; 95% CI, 0.49-0.84), a history of decompensated liver disease (OR = 0.51; 95% CI, 0.36-0.71), treatment experience (OR = 0.58; 95% CI, 0.48-0.71), APRI score greater than 2 (OR = 0.44; 95% CI, 0.36-0.55) and with sofosbuvir with PEG-riba compared with sofosbuvir/simeprevir (OR = 0.5; 95% CI, 0.4-0.62). Other factors failed to predict SVR12, including age, sex, race/ethnicity, diabetes and genotype subtype. No difference was reported for SVR in patients treated with sofosbuvir, simeprevir and ribavirin compared with sofosbuvir and simeprevir (OR = 1.03; 95% CI, 0.75-1.44). Among patients with genotype 2 disease, treatment experience (OR = 0.55; 95% CI, 0.35-0.88) and APRI score greater than 2 (OR = 0.39; 95% CI, 0.25-0.62) predicted lower SVR. “In this real-world cohort, SVR rates were lower than in clinical trials,” the researchers concluded.

A key to achieving these outcomes is simply adherence, according to Ross. “Historically, relatively few veterans have been treated,” he said. “The main reason was the toxicity of peginterferon and ribavirin, along with the treatment duration of 48 weeks.”

When the new drugs became available in 2014, most providers like Ross jumped at the opportunity to treat as many patients as possible. “Since January of 2014, we have treated about 48,000 vets,” he said. The exact rate varies depending on how much money we had at any given time, but we increased from 7% to 10% in 2014 to over 20% in 2015.”

Active injection drug or alcohol use, along with use of dialysis, have been obstacles to treatment initiation. However, Ross cited another obstacle to getting patients into treatment with these drugs. “There are not enough clinicians who are capable of dealing with the number of patients we have,” he said. “There are relatively few hepatologists. Now in the VA, we are actively trying to train clinicians, including primary care providers, to be prescribers. We have trained hundreds of them, but we still have an imbalance between the number of patients needing treatment and our clinical resources.”

Rena Johnson, FNP, of the Wilmington VA Medical Center in Delaware, tells a slightly different story. “Currently, I have 101 patients in treatment since January of this year, and primary care is still referring patients to us,” she said. “There is one other provider managing patients who are coinfected with HIV. But the volume is not overwhelming. Primary care handles a lot of the preliminary work-up of the patients, so when I see them in the clinic, it is just a matter of going over the treatments and initiating therapy.”

Screening and Diagnosis

Ross said that EMR are in place for doctors working in VA facilities to perform an HCV test. “If the patient agrees and then the test turns up a positive, under VA policy, we will automatically do confirmatory testing,” he said, noting that around 95% of positive results undergo reflex testing. “We still do not have comprehensive national data, but I would estimate about a 50% rate of confirmation in reflex testing in the general U.S. population.”

Patients are then automatically referred to a registry. “What happens from there is one of the targets for improvement,” Ross said. “Patients should be evaluated with regard to stage of liver disease — whether they are cirrhotic or not — and do they have any risk factors such as alcohol use, HIV or other issues.”

There are two over-arching goals to this approach, according to Ross. “We are trying to achieve antiviral treatment and risk reduction,” he said. “Everyone is focusing on antivirals now, and that’s good, but we also shouldn’t ignore these other risks. If they have alcohol use, we should get them into treatment. If they have active HIV disease, they should get their HIV RNA levels down.”

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Sanjeev Arora, MD, is the director of Project ECHO and Distinguished Professor of Medicine at the University of New Mexico Endoscopy Center. In 2012, Project ECHO joined with the VA in an initiative to better treat patients with complex chronic diseases.

“Project ECHO links expert specialist teams at an academic hub with primary care clinicians in local communities,” Arora told HCV Next. “We have 21 centers of excellence, which are the hubs, reaching out to thousands of patients at centers that are the spokes. It is a large knowledge network to help manage patients.”

Arora said that screening is a cornerstone of the Project ECHO approach. “When we set up a spoke, we implement a screening program first,” he said. “A lot of primary care providers are not experts in screening, particularly because they have so much else to do.”

Rather than trying to teach every clinician at a particular center to screen patients, one of the PCPs in each center becomes the screening expert. This can streamline the process, according to Arora.

For Johnson, it may be even simpler. “We screen everyone that comes through the door,” she said.

PTSD

Groessl and colleagues suggested that mental health and substance abuse issues are critical barriers to treatment with antiviral therapy in patients with HCV. They conducted a prospective, randomized controlled trial in 364 patients at several VA facilities. The parallel-designed study involved patients randomly assigned to integrated care or usual care. Patients in the integrated care group were given a mental health provider who performed brief interventions to address risk factors, collaborative consultation with the HCV treatment clinicians case management before and during antiviral treatment. The researchers assessed outcomes using medical records and self-report questionnaires administered at baseline, 4 months, 16 months and 22 months after enrollment. In addition to SVR12, they assessed for substance use, depression, PTSD symptoms, quality of life, health care satisfaction and health care use. “The Integrated Care intervention has the potential to transform HCV antiviral treatment by increasing the number of HCV-infected individuals that can be successfully treated,” they concluded.

Frankie Phillips, PhD, clinical assistant professor and AP lead instructor at the College of Nursing & Health Innovation at the University of Texas at Arlington, said that evaluating patients for depression, PTSD and other mental aspects of surviving combat is critical to these interventions. “We talk to them about their environment, how they are getting along in general,” she said.

In the interferon era, many patients with these symptoms and comorbid mental health conditions were not candidates for treatment, she said. “Interferon could exacerbate homicidal tendencies.”

PTSD can take over a patient’s life, become a defining characteristic, according to Phillips. “It can dictate how they react to situations, but they often don’t want to tell anything to anyone,” she said. “It presents a lot of barriers to treatment.”

Ross agreed. “PTSD certainly is a huge issue for us,” he said, with the prevalence of veterans with HCV in the VA system around 30%. “PTSD is a huge problem in its own right, but it is also directly linked to a number of other things related to HCV care.”

One of these includes the ability to show up for treatment. But he urged clinicians to not simply view these patients in terms of their HCV or goals regarding treatment adherence and SVR12. “They are not just a virus with a patient attached,” he said. “We are trying very hard to have specialized mental health services, in addition to physically co-locating them.”

Because he is in a position of influence, Ross is able to refer patients to mental health services. “There is a clinical psychologist down the hall from me,” he said. “The idea is to train all providers to recognize the signals and get the patient into appropriate care.”

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The endgame is to ensure that patients are not denied care specifically because of PTSD, according to Ross. A big issue is trust. “We need to have a cohort of experienced HCV providers who are sensitive to the needs of these patients,” he said. “We need to let them know that when they reach SVR, they are going to feel better.”

Arora was pointed in his comments on the topic. “Depression has to be tackled if we want high cure rates,” he said. “If these patients believe that life isn’t worth living, they are not going to show up for doctor visits.”

There is reason for hope with existing and developing DAAs, according to Johnson. “These therapies have much fewer side effects on patients with PTSD and substance use issues,” she said. “Also, the clinicians in our mental health department are more knowledgeable about HCV today than they were in the past.”

Substance Abuse

Although substance abuse is not a problem only in the VA, the prevalence rates among veterans may be worth noting, according to Ross. “Over half of the patients we see at our facility have alcohol use disorders,” he said. “We have to make sure they get linked to appropriate care.”

Ross suggested that a team approach is critical to dealing with substance use. “The ideal setup is that you have some sort of mental health provider,” he said. “It doesn’t need to be a psychiatrist, it can be a social worker, a clinical nurse specialist or even a peer support counselor. The main point is that if you leave this up to an MD, it’s not going to get done because of so many competing priorities.”

For Arora, it is a matter of whether the patient will be adherent to therapy. “We refer them to an addiction person,” he said. “A mental health evaluation will help predict whether they will be adherent. In fact, we often have community hospital outreach people to focus only on adherence.”

Sanjeev Arora

Friends and family are critical to this approach, as is extended follow-up, according to Arora. “SVR is not where it ends,” he added. “We need to ensure that they are getting cancer screenings and not engaging in behaviors that will put them at risk for reinfection.”

Ross stressed that this kind of comprehensive care works, even in the most challenging patients. “We have seen that patients with a host of mental health issues who get these services actually do better in terms of SVR than patients with no mental health issues who receive standard care,” he said, and added that support beyond the clinical community would be helpful to improve and increase these services. “Congress needs to increase funds for these assistance programs.”

Integrated Care

Another key issue is that many veterans live far from VA medical centers or otherwise have access issues. It is because of this that integrated service and outreach programs like Project ECHO have become commonplace around the country.

Access improved and patient satisfaction increased as the program took hold, according to Arora. “Patients felt less isolated, which is a big problem in VA populations,” he said. “We have fundamentally improved linkage to care.”

In another similar program, Phillips and colleagues aimed to describe social support for veterans, and how those support systems impact treatment adherence. The analysis included 21 patients at a single VA facility in Texas. The researchers conducted one in-depth interview and a follow-up phone call with each participant. Results indicated that patients often failed to disclose their diagnosis to certain individuals because of fear of stigma. Consequently, they have a limited number of friends and co-workers who can provide support. Family members can provide support to some veterans, but family relationships also can be burdensome.

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As a result, the researchers reported that some veterans “hibernate,” whereas others become more social. Some members of the cohort found health care providers to be supportive, but others did not. The reaction from friends and family can either help or harm efforts to remain adherent, according to the findings.

“In order to support treatment adherence, health care providers need to assess sources of support, or burden, experienced by military veterans during HCV treatment,” the researchers concluded. “When veterans do not have a supportive network, they need to be encouraged to attend a support group or seek counseling. Support services need to be funded by the Veterans Health Administration. Providers need to practice empathy and caring in order to support adherence during treatment.”

This support needs to be in place regardless of the outcome of therapy, according to Phillips. “One thing we have seen is that patients don’t know how to respond to treatment failure,” she said. “It can be devastating, particularly now that the new therapies are so effective. We have to figure out how to give them hope, to let them know that there may be options.”

This hope needs to continue beyond treatment, because even after cure, damage to the liver can lead to downstream complications. El-Serag and colleagues conducted a retrospective cohort study that included 33,005 patients who were treated for HCV, of whom 10,817 reached SVR12. Eligible participants were treated between October 1999 and August 2009, with follow-up through January 2010. The aim was to assess long-term risk for hepatocellular carcinoma (HCC) in patients who achieved SVR12. Results indicated 100 new cases of HCC during a follow-up of 30,562 person-years. The overall incidence rate was 0.33%. Patients with cirrhosis carried the highest annual risk, at 1.39%, followed by patients cured after age 64 years (0.95%). Diabetes also was associated with increased HCC risk (adjusted HR = 1.88; 1.21-2.91), along with genotype 3 infection (adjusted HR = 1.62; 0.96-2.734). “The risk of HCC after HCV cure, while considerably reduced, remains relatively high,” the researchers concluded.

Phillips said that even SVR can come with unexpected complications and consequences. “Many of these patients have lived their whole life with HCV,” she said. “When they don’t have it, they are unsure how to react. End of treatment care is lacking, when we send these patients back into the world without HCV.”

Facility Variation

Kanwal and colleagues evaluated processes of HCV care in 34,258 patients who sought care in 126 VA centers between 2003 and 2006. They evaluated how processes of care and facilities interact. Some of the factors that underwent analysis included the number of weekly half-day HCV clinics per 1,000 HCV patients, HCV-specific quality-improvement initiatives, and administrative service of the HCV clinic, including gastroenterology, infectious disease and primary care. Twenty-three HCV-specific processes of care were analyzed, including seven pretreatment measures, seven preventive and/or comorbid measures and nine treatment or monitoring of treatment care measures. Patients treated at facilities with more than eight half-day clinics were more likely to receive care that, overall, followed treatment indications (OR = 1.52; 95% CI, 1.13-2.05). Those treated at facilities with more than 3 HCV quality improvement initiatives had an increased chance of receiving better preventive and/or comorbid care (OR = 1.32; 95% CI, 1-1.74). Improved pretreatment care was reported by patients treated at facilities with gastroenterology-based clinics (OR = 1.36; 95% CI, 1.01-1.85) and more antiviral treatment (OR = 1.45; 95% CI, 1.06-1.97) compared with those that had no dedicated HCV clinic. Also in comparison with facilities with no dedicated clinic, improved preventive and/or comorbid care were reported in those with an infectious disease-based clinic (OR = 1.59; 95% CI, 1.06-2.39) or a primary care clinic (OR = 1.84; 95% CI, 1.21-2.79). “Several facility factors affected the process of HCV care,” the researchers concluded. “These factors may serve as targets for quality-improvement efforts.”

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“There are patients in very remote areas where there is no hepatologist,” Ross said. “This can be a barrier.”

Arora is more optimistic, at least for centers that are served by spokes of Project ECHO. “I can say with great confidence that cure rates are identical in rural facilities as those in large centers,” he said. However, a large portion of the VA is not covered by ECHO or any other similar program.

Johnson also feels positive, largely because of the workflow at the Wilmington VA. “We work well together as a team,” she said. “We’ve arranged our own version of integrated care.”

Bureaucracy is part of the flood, according to Phillips. “What worked for me was networking,” she said. “Staying in touch with clinicians in other areas, mental health or pharmacy, can go a long way in understanding how to navigate these systems.”

For Schinazi, it comes down to the user-friendly nature of DAA therapies. “HCV treatment can be done easily in large and small VAs,” he said. “The oral drugs are easy to dispense and the patient needs to be followed up virologically. An infectious disease doctor, trained nurse practitioner or physician associate can be a viable replacement when a gastroenterologist or hepatologist is not available especially in an HCV infected person with limited liver disease and no HIV or HBV co-infections.”

Moving Forward

Ross laid out three things to focus on for 2016 and 2017. “The first is to expand our capacity to treat,” he said. “The undersecretary set a goal of 2,000 new treatment starts per week. At the moment, we are starting about 1,150 on therapy per week.”

The second goal is to make increases in treatment sustainable. “We can’t have people working 24/7, working overtime,” Ross said. He suggested that hiring someone to specifically deal with scheduling can go a long way in keeping patients coming through the system without overwhelming clinicians.

“The third thing is that we want to get veterans to know that they are entitled to this care,” he said. “If they walk in the door, they can get tested and treated, regardless of risk factors.”

Arora is thinking a little bigger. “With our VA system, we have an opportunity to be a model for the world’s HCV treatment,” he said. “It is reasonable to think that we can diagnose every patient and possibly eliminate HCV among veterans in a cost-effective way.”

But even in the face of these broad challenges, clinicians should not lose sight of who these patients are, according to Ross. “People in the military have experiences that most of us don’t have,” he said. “They are wounded and have transfusions at much higher rates than the general population. Their personal experiences as they relate to their disease are unique. The guy in front of you steps on a mine and you are covered in his blood. We need to be sensitive to this as we move forward with our routine of diagnosis and treatment.”

In the end, it may simply come down to the effectiveness of the drugs. “What has changed since DAAs arrived?” Phillips said. “That’s easy: we’re curing everybody.” – by Rob Volanksy

Disclosures: Arora and Philips report no relevant financial disclosures. Johnson and Ross’ disclosures could not be determined at the time of press. Schinazi reports he is the founder, chairman and director of Cocrystal Pharma, Inc