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  • September 2015
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Hepatitis C

The New Frontier

  • Dr. Daniel D. Zimmerman
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In Brief
Since 2011, great strides have been made in the treatment of Hepatitis C. This article will update the reader on these treatments and the implications for both life and living benefits insurance products and claims.

During that time, the pathophysiology and sequelae of chronic HCV infection, including extra-hepatic manifestations, cirrhosis, end-stage liver disease and hepatocellular carcinoma, were described. In general, treatments have improved incrementally over those years. 

Since 2011, great strides have been made therapeutically and most individuals with HCV may now be considered curable. This article will update the reader on these treatments and the implications for both life and living benefits insurance products and claims.

Global Epidemiology

Hepatitis C is a major global health issue. The main burdens of morbidity and mortality come from the sequelae of chronic infection.

It is estimated that approximately 170 million people are infected worldwide, and that 350,000 deaths occur annually due to all HCV-related causes. Current high prevalence areas (> 3.5%) include Central and East Asia, and North Africa/Middle East. Moderate prevalence areas (1.5-3.5%) include: South and Southeast Asia; Andean, Central, and Southern Latin America; Australasia (including Australia and New Zealand), the Caribbean, Oceania (the Pacific islands); Central, Eastern, and Western Europe; and sub-Saharan Africa. The lowest prevalence areas (< 1.5%) are Asia Pacific (encompassing Brunei, Japan, South Korea and Singapore), tropical Latin America and North America.1

The causes of high prevalence are several. Egypt for example, has the highest prevalence rate (~10%) in the world due to inadequate infection control during medical and dental procedures. The mass campaigns to control schistosomiasis, which generally spreads through contaminated water, may have also exposed many to the HCV via improperly sterilized glass syringes.2

Risk factors for hepatitis C transmission vary among the world’s developed and developing regions. Prior to 1992, most hepatitis C infections in developed countries were acquired through blood transfusions and blood products. In developing countries, blood products and unsafe medical practices continue to play a major role in transmission. HCV is also transmitted via injecting drug use, body piercing, tattooing, religious scarification, and sharing of personal care items such as razors, toothbrushes and manicure tools. Worldwide, there is also little doubt that sexual transmission can occur, and the risk increases for individuals who have had multiple partners, in the presence of sexually transmitted infections, and for men who have sex with men. 

After epidemiologic investigation, no risk factors can be identified in up to 20% of those infected with hepatitis C.4, 5

Extra-Hepatic Manifestations

While hepatitis C primarily affects the liver, it is well recognized that the infection can also cause up to 40% of infected individuals to also develop at least one extra-hepatic condition, such as:

  • Cryoglobulinemia
  • Membranoproliferative glomerulonephritis
  • Hypertension (related to renal disease)
  • Leukocytoclastic vasculitis
  • Neuropathy
  • Porphyria cutanea tarda
  • Lichen planus
  • Increased risk of DM-2
  • Increased risk of lymphoma

These conditions – or the risk of developing these conditions – may or may not be completely mitigated by successful eradication of hepatitis C. The astute underwriter should also consider the possible presence of hepatitis C when any of these conditions are encountered during underwriting and no hepatitis C test results are in the file.

Sustained Viral Response (SVR)

SVR is a desired endpoint of HCV therapy. According to the European Association for the Study of the Liver (EASL), SVR is defined as HCV RNA being undetectable in a sensitive assay (<15 IU/ml) 12 weeks (SVR12) and 24 weeks (SVR24) after completion of treatment.7 SVR is associated with a 97-100% chance of being HCV RNA-negative during long-term follow-up and can therefore be considered a sign that an HCV infection has been cured.

Until the recent introduction of direct-acting antivirals (DAA), SVR was defined as an undetectable viral level at 24 weeks post-treatment. However, as undetectable levels at 12 weeks post-treatment are currently usually maintained through week 24, many clinical studies now report and define SVR at 12 weeks (SVR12).

Treatment Advances

Significant advances occurred in 2011 with regard to the treatment of HCV when two DAAs were licensed for use in combination with pegylated interferon-alpha and ribavirin. Both boceprevir and telaprevir were approved by the Food and Drug Administration (FDA) in May 2011 and resulted in significantly improved SVR in HCV genotype 1 individuals over pegylated interferon and ribavirin therapy alone.6

However, both therapies quickly became obsolete due to the release of newer, more effective agents. Telaprevir was removed from the market in October 2014 and boceprevir will no longer be available after December 2015.

Current Treatment Recommendations.

The EASL and the American Association for the Study of Liver Diseases (AASLD), in conjunction with the Infectious Diseases Society of America (IDSA), recently published detailed treatment guidelines for HCV disease.7, 8 Up-to-date treatment recommendations should be sought from these organizations’ websites, as changes may occur frequently due to the rapid evolution of treatment modalities.

Currently, recommendations are provided for all six HCV sub-types, including for those who are treatment-naïve (have never undergone any form of therapy for the disease) or treatment-experienced. There are many new treatment options which now include sofosbuvir, simeprevir and dasabuvir, and combinations of ledipasivir/sofosbuvir and paritaprevir/ritonavir/ombitasvir. Other agents will likely be released in the near future.8 Additional recommendations are provided for those with other co-morbid conditions, such as co-infection with HIV.

There are multiple advantages of the newer treatment protocols of direct-acting antivirals:

  • They may not require co-administration of pegylated interferon-alpha and/or ribavirin, depending on the indication. Thus, they may be deemed “all oral” regimens. 
  • Most treatment-naïve and treatment-experienced individuals require only 12 weeks of therapy, although some may need up to 24. (Older protocols commonly required 48 weeks.)
  • Tolerance of treatment is much improved over interferonbased protocols.
  • Although long-term experience is still limited, it is anticipated that the new treatment protocols will also lead to as permanent a state of SVR did the older treatment protocols.

However, the cost of the new treatments can range upward from approximately USD85,000 annually, and may therefore not be accessible to many individuals. Various countries and jurisdictions as well as private health insurers will need to assess the cost and the likelihood of curing an HCV infection versus cost of care for end-stage liver disease, liver transplants, and/or treatment of hepatocellular carcinoma or other extra-hepatic condition(s).

Recent Treatment Studies

In addition to the established, approved treatment regimens currently published by EASL and AASLD/IDSA, research and development continues on alternative and novel treatments.

In a JAMA publication from May 2015, Poordad and others9 reported on the outcome of administering a 12-week, all-oral combination of daclatasvir, asunaprevir and beclabuvir to 415 patients with HCV genotype 1 (312 treatment-naïve and 103 treatment-experienced) without cirrhosis. SVR at 12 weeks was 92% for those in the treatment-naïve group and 89.3% of the treatment-experienced group. There was a less than 1% discontinuation rate due to adverse side effects.

In the same issue of JAMA, Muir and colleagues10 presented data from a 12-week all-oral protocol of daclatasvir, asunaprevir and beclabuvir, this time either with or without ribavirin, in patients with compensated cirrhosis and HCV genotype 1 infection. Among this group, 98% of treatmentnaïve patients achieved SVR at 12 weeks with ribavirin and 93% without ribavirin. The treatment-experienced group had a 93% SVR at 12 weeks with ribavirin and 87% without ribavirin. The addition of ribavirin was only of benefit to those in the treatment-experienced group. Even prior null responders (i.e., patients who did not obtain viral suppression with previous treatment) responded very well both with and without ribavirin. An accompanying editorial to this article noted that the high response rates, especially among patients with cirrhosis, is substantial and important clinically, given that viral eradication has been shown to delay or decrease chances of decompensation of liver disease and also hepatocellular carcinoma.11

Treatment of Hepatitis C and HIV Co-Infection

HCV is also present as a co-infection in 25-30% of persons infected with the human immunodeficiency virus (HIV). For HIV-positive individuals, HCV co-infection rates of 72-95% are seen among injection drug users, among 1-12% of men who have sex with men, and among 9-27% of heterosexuals.12

HCV infection causes substantial morbidity and mortality, but those co-infected with HIV are three times more likely to develop cirrhosis or liver decompensation than those only infected with HCV.

Successful achievement of SVR among persons co-infected with HCV and HIV has been demonstrated to lead to a significant decrease in subsequent liver decompensation, liver cancer, and all-cause mortality. Graham13 pointed out that despite this knowledge, HIV specialists have historically been hesitant to prescribe interferon-alpha and hepatologists have been hesitant to treat HCV in individuals with HIV.

Two very recent studies demonstrated that a very high percentage of those with HIV and HCV can achieve SVR with interferon-free regimens. The first, by Sulkowski14 and colleagues, used an all-oral protocol of three DAAs – ombitasvir, paritaprevir (plus a ritonavir booster) and dasabuvir – with ribavirin, for 12 or 24 weeks, in those with HCV genotype 1 and those on HIV treatment and full HIV suppression. All of the patients in this group were HCV treatment-naïve or may have failed prior interferon-based treatment. SVR post-treatment was 29 of 31 (94%) for 12 weeks of treatment and 29 of 32 (91%) for 24 weeks. The second study, by Osinusi15 and colleagues, studied the effects of a 12-week all-oral fixed-dose combination of ledipasvir and sofosbuvir in HCV treatment-naïve HIV coinfected individuals. At 12 weeks post-treatment, the SVR was 49 of 50 (98%). Neither study reported discontinuation of study medication due to adverse side effects.

Essentially, HCV treatment outcomes now for those coinfected with HCV and HIV are equivalent to those monoinfected with HCV. Professional organizations focused on infectious diseases and liver disorders now provide detailed treatment guidelines for co-infected individuals as well. These are not markedly different for those infected only with HCV, except that they give more attention to drug interactions for the co-infected.

An Insurance Medicine Analysis

A 2012 JAMA article16 presented a study of all-cause mortality among individuals with histologically proven advanced hepatic fibrosis who were treated with interferon-based therapy between 1990 and 2003. The study focused on 530 individuals and compared outcomes of those who achieved SVR with those who did not, and followed the participants for a median of 8.4 years. Compared to those who did not achieve SVR, those who achieved SVR demonstrated significantly reduced all-cause mortality, liver failure, liver-related mortality, need for liver transplantation, and hepatocellular carcinoma.

A 2014 Journal of Insurance Medicine article17 noted that the data from the above article was not especially useful to assess the mortality risk of insurance applicants with a history of hepatitis C that included advanced hepatic fibrosis and successful treatment. The successfully treated group was the comparison population, not the general population. The researcher created a model to translate the documented improvements into relative terms compared with a suitable general population. He concluded that the mortality of those achieving SVR was only slightly worse than the general population but urged caution in reaching definitive conclusions, given limitations in the data and assumptions that were made to develop the model.

Implications for Insurance Products

Successful treatment of individuals with HCV who have access to novel therapies will likely have the following insurance implications:

Life Insurance

  • More applicants will be insurable based on history of cure.
  • If a biopsy is performed and the degree of hepatic fibrosis is known, the likelihood of progression after successful treatment is low. Risk assessments can be based upon last known stage of hepatic fibrosis as well as available information regarding liver function and/or imaging.
  • There will be a longer life expectancy of those with in-force policies due to reduced likelihood of death from end-stage liver disease (or associated complications) and hepatocellular cancer.

Living Benefits

  • Higher upfront costs might be experienced by health insurers to cover new therapies, but they are potentially subject to lower long-term liabilities due to avoidance of health care expenses for liver decompensation and associated complications as well as avoidance of need for liver transplantation.
  • Reduced claims may be experienced by critical illness (fewer liver transplant, cancer, and terminal illness claims), total and permanent disability (TPD), income replacement, and hospital cash products.


Recent advances in the treatment of hepatitis C have led to extremely high rates of sustained viral response and cure. In the short to medium term, accessibility to and affordability of these medications will determine how many of those infected will actually benefit from the advances. For those with access, there will be a much-improved risk assessment profile for both life and living benefits products.

Meet the Authors & Experts

Dan Zimmerman
Dr. Daniel D. Zimmerman
Senior Vice President, Chief Science Advisor


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  2. Mortality and Morbidity Weekly Report (MMWR). July 27, 2012, 61(29);545-549. Progress Toward Prevention and Control of Hepatitis C Virus Infection — Egypt, 2001–2012 (cdc.gov)
  3. Thornton L, et al. Determination of the burden of hepatitis C virus infection in Ireland. Epidemiol Infect 2012 Aug; 140(8), 1461-8. Pubmed link : Determination of the burden of hepatitis C virus infection in Ireland - PubMed (nih.gov)
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  6. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm255390.htm
  7. http://www.easl.eu/research/our-contributions/clinicalpractice-guidelines/detail/recommendations-ontreatment-of-hepatitis-c-2015
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  10. Muir AJ, et al. Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 Infection with compensated cirrhosis. JAMA 2015
    May;313(17):1736-44. Pubmed link: Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis - PubMed (nih.gov)
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  14. Sulkowski MS, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA. 2015 Mar 24-31;313(12):1223-31.
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