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The Lo Re Research Group: Bringing new data to the forefront of HCV

When Vincent Lo Re III, MD, MSCE, first entered the clinical epidemiology field, he did not know the rewarding career path on which it would lead him several years later.

The opportunity for longstanding patient relationships, the ability to cure a chronic viral illness such as hepatitis C and help patients improve their quality of life, along with the critical thought process that comes with various research opportunities, have challenged Lo Re and his colleagues to transform the status quo of HCV. Healio spoke with Lo Re, associate professor of medicine and epidemiology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, about his career, his research group and the contributions he has made in the HCV setting.

Vincent Lo Re III

Discuss your background as it relates to epidemiology and infectious diseases, particularly to hepatitis C research and treatment.

I am clinically trained in internal medicine and infectious diseases, with additional research training in clinical epidemiology — the study of determinants and distribution of diseases across populations — and pharmacoepidemiology, which focuses on the effects of drugs and other medical products on disease states.

My interest in hepatitis C developed during my infectious disease training in 2001. At the time, we were approximately 5 years into the highly active antiretroviral therapy era, and I had developed an interest in chronic HCV infection after caring for patients coinfected with HIV/HCV, as well as those monoinfected with HCV. I had observed that the coinfected patients were more commonly developing liver complications and dying from chronic HCV infection compared with those with chronic HCV alone. In an attempt to prevent the development of liver-related morbidity and mortality, I initiated treatment for chronic HCV with pegylated interferon and ribavirin for as many patients as were eligible. However, this combination therapy caused more frequent and severe adverse effects in coinfected patients, particularly influenza-like symptoms, weight loss and anemia.

Unfortunately, few research studies and limited epidemiologic data existed that evaluated adverse effects or adherence to HCV treatment and HCV-related liver complications in HIV. Because of this and my clinical interest in HCV and HIV/HCV coinfection, I decided to focus my clinical and epidemiological research career on viral hepatitis and HIV/viral hepatitis coinfection, evaluating important health outcomes, particularly liver-related disease progression.

Discuss the Lo Re Research Group. What significant contributions has your team made in the study of HCV?

The Lo Re Research Group, founded in 2005, conducts population-based studies using large electronic health data sources. Our team bridges infectious diseases and gastrointestinal epidemiology by developing new epidemiological and biostatistical methods to ascertain various liver events, including hepatic decompensation, hepatocellular carcinoma, severe acute liver injury and acute liver failure. These methods have helped us to examine hepatic and extrahepatic complications of chronic HCV infection and their risk factors, and to study the pharmacoepidemiology of chronic HCV treatments among patients infected with HIV.

One such extrahepatic complication of coinfection is metabolic bone disease, and our work in this area has been particularly novel in that we have combined population-based and mechanistic research studies to identify the structural underpinnings of skeletal fragility. We were the first to demonstrate that chronic hepatitis B virus/HCV coinfection reduces bone mineral density in the setting of HIV, that chronic HBV or HCV monoinfection increases fracture rates and that HIV/HBV/HCV coinfection is associated with the highest risk for fractures compared with those who are viral hepatitis monoinfected, HIV monoinfected or uninfected.^1,2 In addition, we have identified significant structural bone deficits in patients coinfected with HIV and HCV, suggesting that chronic inflammation may be a key contributor to these deficits.

Although we once had a lack of data to guide our treatment protocols, the Lo Re Research Group’s findings have significantly enhanced our understanding of HCV-related liver disease progression in coinfected patients, including identifying potential risk factors such as nonhazardous alcohol use, metabolic comorbidities and the use of specific antiretroviral medications.

What are the motivating factors behind your research? What do you hope to achieve?

My studies and research program are mostly driven by the questions I have faced as a health care provider in clinical practice. We have done extensive work to evaluate the importance of antiviral treatment in reducing the risk for liver complications to prolong survival of coinfected patients. However, these therapies are only effective if patients adhere to their treatment regimens. The Lo Re Research Group has capitalized on my pharmacoepidemiology background by developing and validating ways to measure adherence by tracking pharmacy refills in an effort to improve patient compliance. We are now conducting studies on adherence to direct-acting antiviral regimens to evaluate differences in adherence based on regimens (for example, number of pills per day, with vs. without ribavirin), to evaluate change in adherence over time and to determine whether there is a threshold level of adherence acceptable for achieving a viral cure.

Now that HCV can be cured, what are some remaining challenges in the treatment of HCV that keep you up at night, and what steps must be taken to help mitigate HCV’s prevalence?

Current epidemiologic data suggest approximately half of individuals infected with HCV are unaware of their infection. In addition, we have seen the impact of the opioid epidemic on rising HCV incidence over the last 2 years because of unsafe injection practices and needle sharing. Therefore, key remaining challenges include preventing HCV infection among high-risk groups, testing patients for HCV infection and, if diagnosed, then linking them into care. Diagnosis of HCV infection remains the most important step along the HCV care continuum if we want to eliminate HCV as a public health problem.

Also, despite the acknowledged benefits of DAAs, these therapies are costly, which has led both public and private insurers to restrict access to the medication in the United States. Insurers have established criteria for reimbursement, such as evidence of advanced liver fibrosis, consultation with a specialist and/or abstinence from alcohol or opiate drug use. Reimbursement restrictions are common across insurance plans and have led to denial of DAA treatment. To achieve the goal of HCV elimination, access to antiviral treatment must be improved.

What are the implications of restricted access to DAAs?

Given the Lo Re Research Group’s strong interest in evaluating access to DAAs, we conducted the first-ever prospective cohort study among patients who had a DAA prescription submitted to a regional specialty pharmacy between November 2014 and April 2015. These pharmacies serviced patients in Delaware, Maryland, New Jersey and Pennsylvania, and we defined absolute denial as a lack of approval of prescriptions filled by the insurer — either Medicaid, Medicare or commercial insurance. Among 2,321 patients who were prescribed a DAA regimen during this 6-month period, 16% were absolutely denied their therapy, most commonly because of lack of medical necessity or insufficient information to assess medical need.

Interestingly, absolute denial was more common among patients covered by Medicaid. Forty-six percent of Medicaid beneficiaries were absolutely denied their DAA regimen, compared with 5% covered by Medicare and 10% on commercial insurance. According to our multivariable modeling, Medicaid insurance and the absence of cirrhosis were independently associated with absolute denial. These findings emphasized the need for Medicaid programs to relax their criteria for reimbursement. In fact, as of January 2018, Medicaid officials in Pennsylvania have declared that access to direct-acting antivirals is no longer reliant on stage of fibrosis, meaning patients can receive DAA treatment with any stage of liver fibrosis.

Absolute treatment denial remains a significant issue, however, and its implications are troubling. Patients denied coverage will experience continued progression of hepatic fibrosis and remain at risk for cirrhosis, end-stage liver disease and hepatocellular carcinoma. Furthermore, recent data from the Veterans Health Administration suggest that deferring HCV treatment until the development of advanced hepatic fibrosis or cirrhosis reduces treatment effectiveness and increases the risk for liver-related complications and death. Lack of treatment can also lead to continued chronic HCV-associated inflammation, which may increase the risk for extrahepatic complications, including bone, kidney, cardiovascular and neuropsychiatric diseases.

You recently attended the 2018 Conference on Retroviruses and Opportunistic Infections. Which HCV-related study findings did you present?

As a follow-up to the regional study on absolute denials, our group presented a nationwide prospective cohort study among patients who were denied DAA therapy. Prescriptions were submitted between January 2016 and April 2017 to Diplomat Pharmacy, a specialty pharmacy that services patients across 45 states. We again calculated the incidence of insurer denials from Medicaid, Medicare and commercial insurers over the entire study period and for quarters of time. Of the 9,025 patients who were prescribed DAA therapy, 35.5% were absolutely denied treatment. On a national level, absolute denial was more common among patients covered by commercial insurers (52.4%) than among those covered by Medicaid (34.5%) or Medicare (14.7%). Notably, the incidence of absolute denial increased across each quarter of the study period and across all insurance types, from 27.7% in the first quarter to 43.8% in the last quarter. Therefore, despite the availability of new DAA regimens and changes in restrictions of these therapies, absolute denials of DAA regimens have remained high and have increased over time, regardless of insurance type.

Do you believe HCV will ever be eliminated as a public health risk in the future?

I believe HCV can be eliminated as a public health problem if recommendations from the National Academies of Science, Engineering, and Medicine are implemented and political will is capitalized upon. I was one of 17 members of a Committee for the Elimination of Hepatitis B and Hepatitis C in the United States that was assembled by the National Academies, where my colleagues and I spent 2 years first determining whether HCV elimination as a public health problem was feasible and, having concluded it was possible, identifying the barriers to elimination and formulating concrete recommendations to health care providers. We held stakeholder meetings in Washington and Atlanta, sponsored in part by the CDC, and subsequently published two reports in April 2016 and March 2017, to formulate an action plan and implement the recommendations.

References

• Lo Re V 3rd, Lynn K, Stumm ER, et al. Structural bone deficits in HIV/HCV-coinfected, HCV-monoinfected, and HIV-monoinfected women. J Infect Dis. 2015;212(6):924-933.
• Lo Re V 3rd, Volk J, Newcomb CW, et al. Risk of hip fracture associated with hepatitis C virus infection and hepatitis C/human immunodeficiency virus coinfection. Hepatology. 2012;56(5):1688-1698.
• Lo Re V 3rd, Gowda C, Urick PN, et al. Disparities in absolute denial of modern hepatitis C therapy by type of insurance. Clin Gastroenterol Hepatol. 2016;14(7):1035-1043.

• Gowda C, Lott S, Grigorian M, et al. Increasing incidence of denial of DAA therapy for chronic HCV by insurance type. Presented at: 2018 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston, Mass.