The Oncogenic Hepatitis C Virus and Direct-Acting Antivirals: Economic Implications for Hepatocellular Carcinoma in Medicaid Beneficiaries With Cirrhosis

Evidence-Based Oncology, April 2017, Volume 23, Issue SP5

The oncogenic effects of the hepatitis C virus can impact patient outcomes for hepatocellular carcinoma (HCC) and have economic implications for medical spending. This study underscores the importance of treating patients early in the disease process for savings associated with reducing the risks of HCC.


Background: The hepatitis C virus (HCV) is an oncogenic virus that is the primary risk factor for hepatocellular carcinoma (HCC), illustrating the relative importance of tertiary prevention of liver cancer.1,2 Health disparities in HCV indicate its disproportionate prevalence among low-income populations. Due to low efficacy rates, predominant treatment regimens do not significantly prevent disease progression toward HCC among all populations—although the risk of HCV is higher in the Medicaid population. Direct-acting antivirals (DAAs) result in improved efficacy and ease of administration compared with current hepatitis treatment options.

Methods: Published literature and the Medicaid National Average Drug Acquisition Cost were used to estimate treatment costs, and averted medical HCC costs were modeled for DAAs and prevailing treatment options for HCV.

Results: Approximately $14,473 in medical expenses related to HCC treatment per person can be avoided over the next 10 years with the sofosbuvir-ledipasvir combination treatment for cirrhotic Medicaid beneficiaries infected with HCV genotype 1a. The DAAs result in lower HCC-related medical spending costs than peginterferon-ribavirin and watch-and-wait regimens.


Conclusions: The oncogenic effects of HCV can impact patient outcomes for HCC and have economic implications for medical spending. The study provides evidence that underscores the importance of treating patients early in the disease process to reap savings related to reduced risks of HCC.

The hepatitis C virus (HCV) is an oncogenic virus that can lead to variable degrees of liver fibrosis and damage (cirrhosis). HCV and associated cirrhosis are the leading causes of hepatocellular carcinoma (HCC).1,3 Most cases of HCC are HCV related; treatment of HCV can reduce the risk of HCC by 50%.1 The risk of HCC increases by 2-6% annually.4 The lag time between acute phase and the development of chronic HCV infection can be 20 to 30 years,5 thus creating a silent epidemic of patients infected with HCV who are at risk for HCC.6

Several groups are at an increased risk for HCV. Disease prevalence is higher in the population under age 55, and it disproportionally affects the poor.7,8 This places the Medicaid population at greater risk and makes the treatment of HCV a priority for Medicaid. The number of Medicaid beneficiaries with oncogenic HCV is high and is only rising.9,10

Reaching sustained virologic response (SVR) has been shown to reduce the imminent risk of HCC; however, the predominant treatment regimen for HCV has only had modest efficacy. Although treatment has been noted to delay development of HCV-related HCC,2 the lack of ease of administration and the associated adverse effects result in high percentages of treatment discontinuation, thereby reducing the absolute effect of peginterferon-ribavirin treatment. A new form of treatment, direct-acting antivirals (DAAs), has emerged to overcome the notable limitations of interferon-based regimens. These medications are expensive, with treatment costs averaging $80,000 for a 12-week regimen, but they do have a much greater success rate over the established interferon-ribavirin regimen, especially for patients with cirrhosis and they reduce the potential risks for HCC. Due to the high prevalence of HCV in the under 55-years group and low-income populations, Medicaid programs are facing the economic burden of efficacious, yet expensive, DAA treatments for HCV.11-15 The cost:benefit ratio of DAAs is being considered, particularly in the context of greater efficacy, reduced risk of HCC, averted HCC treatment—related expenses, and unnecessary future healthcare utilization.

Patients with HCV and cirrhosis face several complications with liver and nonliver-related cancers therapies.3 The prognosis and treatment decisions for HCC depend on the extent of fibrosis in the liver,3 illustrating the importance of efficacious HCV treatments. The increased SVR rate/ “cure” associated with interferon-free DAA treatments lowers the need for HCV-related HCC treatments.3 However, specific data on the number of cases and associated reduction in HCC costs with the use of DAAs have not been fully researched.

To evaluate changes and economic implications for HCC savings, this study modeled HCV-infected genotype 1a Medicaid beneficiaries with cirrhosis undergoing current FDA-approved and American Association for the Study of Liver Diseases (AASLD) and Infectious Disease Society of America (IDSA)—recommended treatments compared with the prevailing options of interferon-ribavirin regimen and watch-and-wait (no treatment for oncogenic disease) over a 10-year time span.


This study modeled a cohort of Medicaid enrollees, including beneficiaries across all states, over a period of 10 years. Published data and reports were used to define the size of the population of patients with Medicaid and HCV genotype 1a infection.16,17 The 10-year time frame is ideal to determine both the short-term and long-term impact of these treatments. To qualify for Medicare, individuals must be 65 years; thus, the modeled cohort was limited to Medicaid beneficiaries 55 years and younger.17 The model considered 28,765 patients with HCV with cirrhosis on Medicaid, as per public literature estimates, age/genotype distributes, and the chronic HCV cohort study.10 This study was exempt from evaluation by an Institutional Review Board as only published literature and existing data were used.

Probabilities of disease progression, obtained from published literature, were included. In the first year, patients with HCV with cirrhosis received a specific treatment regimen (12-to-48 weeks, depending on the regimen) and patients who had not discontinued treatment could reach SVR/“cure” after their HCV treatment ends. The cohort of Medicaid beneficiaries was modeled year-by-year, beginning in the second year, to evaluate changes in the number of patients who would progress to HCC, as well as HCC-related costs. The successive disease progression stages that were modeled were F4-compensated cirrhosis/fibrosis, decompensated cirrhosis (DCC), liver cancer, and liver transplantation.18 During each successive year that the cohort was modeled, the patient progressed toward the endpoint along the disease stages, as per expected probabilities, unless a treatment-related “cure” was documented. At baseline, all patients were assumed to have compensated cirrhosis. If an individual failed to reach SVR/ “cure”, he or she had a 1-time, 50% chance of retreatment with the same regimen (year 2). Each year, an individual might remain in the same disease stage or have disease progression (F4 compensated to DCC or liver cancer, DCC to liver cancer or transplant, liver cancer to transplant).18

For our study, we evaluated elbasvir-grazoprevir, sofosbuvir-ledipasvir, sofosbuvir-velpatasvir, and ribavirin-peginterferon, which are FDA-approved and AASLD-IDSA—recommended treatment regimens for treatment-naïve patients infected with HCV genotype 1a who have cirrhosis.17 These medications were evaluated in the context of a watch-and-wait scenario.

For the treatment regimens considered, efficacy rates from published clinical trial data (NEUTRINO, ION-1, OPTIMIST-2, ALLY, and ASTRAL trials), treatment discontinuation rates from observational studies and meta analyses, and treatment costs from the Medicaid National Average Drug Acquisition Cost and published literature were used.19-23 All-cause healthcare costs for HCV disease progression (F4, DCC, HCC, and liver transplantation) were extracted from published literature.24 Table 1 illustrates the variable inputs used in the model.

The number of patients who progressed to HCC from F4 cirrhosis, as well as their related costs, were tabulated annually. For each treatment, all-cause healthcare/medical costs for HCC that were averted by treatment and medical costs encountered for no treatment/watch-and-wait were accumulated over 10 years. In addition, the number of patients with HCV who progressed to HCC was determined.


As expected, fewer patients who reached SVR developed HCC. In year 3, those who developed HCC with SVR peaked, as this depended on both the number of patients who reached SVR due to retreatment and the presence of patients who progressed to DCC in year 2. Fewer patients who reached SVR developed HCC compared with patients who were not “cured” and continued through disease progression—a key benefit of DAA treatment, as illustrated in Table 2.

In the first year (year 2) of follow-up after treatment, 1232 patients developed HCC. A peak in HCC cases that year was associated with a rise in patients with DCC. Further, an increased number of patients with cirrhosis progressed to DCC, one of the clinical precursors of HCC. Each year thereafter saw a decrease in the number of individuals who developed HCC. In general, as shown in Table 3, of 28,765 patients with HCV who had cirrhosis, 12,887 developed HCC after treatment with sofosbuvir-veltapasvir over a period of 10 years, and peginterferon-ribavirin treatment resulted in approximately 15,000 patients with HCV who had cirrhosis progressing to HCC. Finally, if a watch-and-wait strategy was followed, about 22,000 of 28,765 patients with cirrhosis developed HCC.

Following HCV treatment with elbasvir-grazoprevir, HCC-related costs per person in year 2 were $2633, which increased to $3521 in year 3. As mentioned, this is due to the buildup of DCC from the year before. After year 3, however, HCC costs saw a steady decline and dropped down to $2068 by year 10, as Table 4 shows. Similarly, in year 10, costs associated with HCC were only $2058 per person after treatment with sofosbuvir-velpatasvir.

We calculated the 10-year aggregated medical costs for HCC because the medical costs for HCC vary by the number of individuals who progress to HCC each year. For all DAA medications, the 10-year medical costs due to HCC treatment are similar in value and lower than in a watch-and-wait strategy or in peginterferon-ribavirin regimens. The sofosbuvir-ledipasvir regimen resulted in $24,456 in HCC-related medical costs per patient compared with around $29,900 per patient for the prevailing peginterferon-ribavirin regimen.

Treating cirrhotic patients lowers the numbers who develop HCC and thereby the associated costs. Treatment at an earlier stage of the disease reduces the chance of sequela. For example, sofosbuvir-ledipasvir would provide the largest amount of payer savings for averted HCC cases ($17,473) compared with costs for no treatment (following watch-and-wait strategies) over 10 years. These results are presented in Table 5.


Although the probability of liver cancer declines with treatment success, the number of patients with SVR increases, inadvertently increasing the number of patients with HCC, and resulting in higher costs. For patients with cirrhosis, the risks and medical costs for HCC are already higher, as per clinical manifestations of disease progression and regardless of whether the patient is “cured” of HCV.25 A patient with cirrhosis continues to accrue costs related to cirrhosis care and monitoring even with the increased efficacy of DAAs.25

The majority of costs for DAAs come from earlier stages, resulting in lower HCC-related costs with reduced disease stage progression, while for peginterferon-ribavirin, most of the medical costs are driven by liver disease complications (DCC and liver cancer). Treatment with DAAs increases the number of beneficiaries reaching SVR and reduces the risk of HCC. Plus, higher SVR means lower numbers of liver-related outcomes. Thus, as is evident in the model results, most of the HCC cases from HCV infection are observed in patients who did not reach SVR.

The number of cases of HCC in patients who were “cured” following DAA treatment are extremely high (after 10 years, there are less than 200 HCC cases with SVR out of 26,000 plus patients in the model cohort), while HCC cases without SVR are lower. HCC cases with SVR are extremely low among patients treated with peginterferon-ribavirin, and the majority of HCC cases are observed among patients who were not “cured,” due to lowered efficacy of this prevailing treatment. The number of patients with HCC and “cured” are also less likely to continue through disease progression to liver transplantation and so on.

The averted high medical costs of HCC treatment are often thought to be overshadowed by the high costs of the DAAs. Therefore, high SVR rates would result in an increase in HCCrelated savings and less negative liver-related health events would occur in these regimens. Thus, when the probability of SVR increased, as with DAA treatments, the likelihood of negative health outcomes fell and the number of individuals in earlier stages of cirrhosis increased.

This study focused on patients infected with HCV genotype 1a, which is the most common strain of HCV in the United States. The strength of this research is that this model incorporated some of the complexity and uncertainty involved in healthcare decision making pertinent to the ongoing debate over Medicaid coverage for HCV treatment. The key is that DAAs result in lower HCC medical spending costs than peginterferon-ribavirin and watch-and-wait regimens; peginterferon-ribavirin has lower HCC costs than watch-and-wait alone.




S. Mantravadi, PhD, MS, MPH, is clinical assistant professor, University of West Florida.


S. Mantravadi, PhD, MS, MPH

University of West Florida

11000 Univ Pkwy

Pensacola, FL 32514

The lower medical costs and risks for patients with cirrhosis, and improved health outcomes from treating patients without cirrhosis, can offset the cost implications of treatment. The model demonstrates that there is almost a $156 million difference in HCC medical costs between DAAs and peginterferon-ribavirin for Medicaid patients over a 10-year period. The results also emphasize an urgency for providing DAAs as first-line treatment, especially in patients with cirrhosis. The true effectiveness of DAAs becomes evident through the reduction of HCC risk and related medical costs; patients with cirrhosis are already at higher risk for HCC and the high SVR rate associated with DAAs is imperative in improving liver health outcomes. Starting DAA treatment for patients with cirrhosis may additionally reduce the likelihood of future outcomes after development of HCC (liver transplantation, ascites, further complications of cirrhosis, etc) and/or current effects of the virus, and thus the associated costs, as patients begin to reach SVR. Treatment with DAAs holds importance for patients with cirrhosis to prevent HCC associated with HCV.REFERENCES

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