Treatment

Diagnosis

The CDC has outlined a series of recommendations on frequency of testing for individuals at-risk for contracting HCV. Current CDC guidelines recommend that anyone born between 1945-1965 be tested at least once for HCV [4]. More rigorous testing schedules are recommended for people who inject drugs and HIV-seropositive men who have unprotected sex with men. Data, aligned with current recommendations, suggest that the incidence of infection is largest among people who inject drugs. Currently, the process for diagnosing HCV is a multistep (multi-visit) process that requires several laboratory diagnostic tests.

Even as diagnosis tools have improved, researchers estimate that up to half of people living with HCV are living undiagnosed [1]. In the past, campaigns have relied on passive testing or only testing those who reported risk factors; however, many of the behaviors associated with HCV transmission are considered socially taboo, leading individuals to under report such behaviors. Attempting to capture these underreported populations, by utilizing “opt-out” testing, Galbraith et al. (2015) adapted the method used to test the baby boom population at emergency room departments. The research- ers integrated HCV antibody testing into the standard clinical care for anyone who came to the emergency department who did not choose to decline the test. The study concluded that there was high prevalence level of unknown HCV in emergency departments that would not have normally been diagnosed or recognized [10]. In total, the researchers found a prevalence rate three times higher in the “opt-out” screened population in the emergency department than the estimated general population prevalence. This spike may be explained by the type of patient who utilizes emergency departments. However, it is important to note that without integrating the HCV testing into the standard of care, many of these infections would have continued to be undiagnosed.


Historical Treatments

Sufferers of HCV should be able to find relief in that this condition can be considered a treatable disease. Successful treatment of HCV is termed a sustained viral response (SVR), indicated by an undetectable HCV RNA level [11]. Those patients who undergo treatment and achieve SVR can expect a life span similar to those without HCV [8]. Treatment of HCV has continuously evolved since the diseases discovery in 1989 [5]. The first standard of care was a combination therapy of peginterferon alfa (PEG) and ribavirin (RBV), which led to SVR rate of approximately 50% [11]. Unfortunately, SVR was not achieved at rates across all ethnic populations. While minorities have a history of being underrepresented in clinical research, a review by Lisker-Malman & Walewski (2013) contained almost identical sample sizes of Caucasian and African American patients, and the African American patients achieved a SVR at rates much lower than their Caucasian counterparts (52% vs. 28%). The same disparity existed in other studies between Caucasians and Latinos. The researchers were careful to explain that some of the difference in treatment response was more than likely due to social, economic, and co-morbidities. However, the most interesting finding pertains to single nucleotide polymorphisms (SNP). In the review, the team found that patients with a particular SNP were more likely to achieve SVR. The data was supported in that minorities with the same genetic SNP achieved SVR at the same rates as their Caucasian counterparts. The PEG/RBV therapy works by activating the innate immune system, but such a treatment program favors certain SNP variants that predominate in certain ethnicities due to global dispersal [12].

In 2011, a new class of drugs called direct acting antivirals (DAAs) was introduced to treat HCV. The DDAs act directly on the virus, instead of relying on the innate immune system. The introduction and future development of additional DAAs will eventually eliminate the disparities faced by those who possess SNPs associated with lower abilities to achieve SVR on the PEG/RBV combination therapy [1] . The first generation of DAAs introduced to the market was telaprevir and boceprevirl which were recommended to be used in combination with the standard PEG/RBV therapy. The first generation DAAs had lengthy treatment plans that lasted a minimum of 24 weeks. In addition to the lengthy treatment regimens, the use of a PEG/RBV therapy is associated with adverse side effects such as impairment in concentration, depression, insomnia, and irritability [13]. Gree- bly et al. (2007) attempted to ascertain if directly observed therapy (DOT) would improve rates at which of patients who inject drugs were able to achieve SVR. The relevant finding are that even with DOT a considerable percentage of the cohort dropped out of the study due to the adverse side-effects of the PEG/RBV therapy [14]. Similar to the PEG/RBV therapy, the first generation DAAs were found to have increased adverse side effects and had to be used in combination with the PEG/RBV therapy, but they were also able to improve SVR rates to 63-75% in certain strains of HCV [5].


Current Treatments

HCV has many biological characteristics, that when combined, make HCV difficult to treat. The virus has a high rate of replication with no DNA replication proofreading mechanisms, which leads to increased genetic variability. The increased genetic variance has led to several different strains of HCV to emerge across the globe. Astonishingly, different variants of HCV can have genetic profiles that vary by as much as 30% [5]. While Genotype 1 accounts for the majority of HCV cases, the prevalence of different strains is not evenly spread across the globe with different strains being concentrated in different populations. Such diversity not only presents challenges to developing effective treatments but also creates challenges for generating accurate epidemiological data [5].

The advent and the subsequent 2013 FDA approval of second generation DAAs made the possibility of treating multiple strains of HCV a reality [7,15]. To reflect the emerging personalized medicine in HCV treatments the American Society for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) then recommended that an assay be performed to determine the genotype of the HCV variant prior to treatment. They consider the genotype recommendation to be a Class I, Level A (the highest possible) recommendation within their prescribed set of guidelines meaning that the genotype determination is now paramount for successful treatment and best outcomes [4].

To attest to the astounding rate at which HCV treatment is evolving, the guidelines published by the Federal Bureau of Prisons recommend consulting the AASLD website before treatment begins. Furthermore, a list of the most common standard of care DAAs is outlined with their potential uses. When looking at the long list, each drug must be used in combination with another to prevent creating resistant strains, and each drug is only approved for treatments of certain genotypes of HCV [5,16]. Moreover, the second-generation DAAs dramatically improved patients’ abilities to achieve SVR. Many clinical trials suggested that the second generation combination therapies were able to achieve SVR in upwards of 90% of patients, and the new DAAs had almost no side-effects, and they found that patients tolerated the new drugs almost as well as the placebo in the control arm of studies [8]. While second-generation DAAs are a miraculous breakthrough that could lead to a tremendous reduction of the prevalence of HCV, there are many barriers to treatment that patients and possibly providers face.


Cost

Undeniably, the most well documented barrier to accessing current standard of care DAAs for HCV treatment are their exorbitant costs. Initially, when second generation DAAs were introduced to the market, some were priced at over $1,000 a pill [17]. It is troubling to know that if the whole-sale acquisition price were paid for Sovoldi, a popular second-generation DAA, to treat everyone in America with HCV, the cost would easily have exceeded the total cost for all prescription medications in 2011 [7]. While it should be noted that drug companies are for-profit organizations that spent enormous sums of money to develop new drugs, the profit ratio that Gilead experienced on the drug Sovoldi was 20:1, a ratio that a Congres- sional panel determined to be excessive [18].

However, while the costs of second generation DAAs such as Sovoldi and Harvoni are large in comparison to the costs for treating other disease, a recent review of the pricing and affordability of DAAs for HCV treatment did observe that the total cost of treatment for DAAs was roughly equivalent to the original PEG/RBV therapies [17]. Therefore, the treatment would be money saving over-time due to the increased cure rates. Unfortunately, the upfront cost of the therapy is still prohibitive of wide scale utilization, and it eliminates the possibility for patients to utilize older more-cost effective drugs since the new drugs are already more cost-effective, albeit with a much larger up-front cost [17,19].

Additionally, many government agencies have worked together to increase buying power in an attempt to secure discounts from the wholesale acquisition price [3]. However, such claims are difficult to verify because of a continued lack of transparency from pharmaceutical companies as they consider the actual price that a consumer pays to be part of a private business contract. Such lack of transparency has led to a great disparity within different organizations ability to afford DAAs [17]. Some claims in various reports show that government agencies such as the Department of Veterans Affairs and the Department of Defense receive discounts of roughly 24% while other agencies such as Medicare and Medicaid receive discounts estimated at 50%, relative to the wholesale acquisition price [3]. Nonetheless, such discounts are not enough to ensure equitable access to all people who are diagnosed with HCV and are recommended to receive DAAs as the standard of care.

Perhaps one main cause of the delay in change is the substantial amount of literature that concludes treating individuals who have F1 and F2 stage liver disease is not cost effective. A review complied by Rosenthal and Graham (2016) shows ample literature that suggests the most cost effective method for treating those with HCV is to prioritize treatment for the youngest individuals with advanced fibrosis [17]. The researchers conclude that it would be more cost effective to wait until liver disease had progressed to moderate to advanced stages; however, the models that make such claims fail to account for factors other than direct medical costs and omitting factors such as treatment or prevention. A person who is at high risk for spreading the disease, such as person who injects drugs or a member of the prison population, would be less likely to spread the disease if treatment were offered in the early stages of the disease. Additionally, the models fail to account for quality of life and other major contributing factors [17]. According to the AASLD, once a person experiences advanced stage liver disease (F3-F4), the risk of developing complications such heptocarcinoma (HCC) is considerable. Furthermore, individuals who have advanced fibrosis remain at risk for HCC even after SVR is achieved, thereby reducing their lifespan [20]. However, another cost analysis study that took more variables into consideration concluded that DAAs should be given to every eligible person waiting on treatment [21].


Coverage and Access

With the exorbitant cost of DAAs, many insurers, especially government-based programs such as Medicare and Medicaid, require patients to go through an arduous pre-approval process before they can receive access to DAAs. In efforts to curtail costs, insurance companies have created various requirements that patients must satisfy before becoming eligible for DAA treatment. The requirements vary greatly from state to state, which can affect the ability to translate research from the pre-approvals process from one state to another. The four main categories from which each state draws their restrictions the progression of liver fibrosis, patient absence from alcohol and drug use, HIV co-infection status, and prescriber limitations. The restrictions contradict the guidelines outlined by the AASLD and IDSA, which may lead one to draw the conclusion that the restrictions associated with the pre-approvals process are only in place to restrict access to expensive medications and create disparities in health [22]. Ultimately, the pre-approvals process, a by-product of the large cost of DAAs, serves an institutional barrier of care for some of the most vulnerable patients with HCV.

One study found that insurance type was a contributing factor in the ability to access DAA treatment for HCV. After analyzing a large cohort of patients from multiple states, it was found that one in six patients were outright denied access to DAA therapy. Unsurprisingly those with government-based insurances were more com- monly denied treatment, with Medicaid having the greatest number of denials [2]. The Lo Re et al. (2016) study researched disparities by insurance type and concluded that almost half of patients who were on Medicaid, the most vulnerable HCV patients, were outright denied treatment for DAAs [2]. Of the patients with advanced cir- rhosis, one of four individuals with Medicaid were denied treatment compared to almost no denials of comparable patients on other forms of insurance, including the government run Medicare. In addition, patients who were allowed to access DAAs on Medicaid were required to wait longer for treatment.

Another study completed by Do et al. (2015), found that only one in ten patients were denied treatments, and they even drew the conclusion that Medicare and Medicare were significant predictors of approval and decreased wait times on appeal decisions with a higher percentage of appeals approved, in stark contrast to the study published by Lo Re and colleagues [23]. Even Do recognizes that his participants’ abilities to access care might be an overestimate because his subjects were in the care of specialists at major tertiary hospitals with liver clinics. One can conclude that the ability of patients to access DAAs, even when on Medicare and Medicaid, can be greatly improved based on healthcare setting; however, one can also observe that one in ten patients are still not getting care even when accessing the highest level specialty providers.

The conflicting information leads to the need for further research into why patients on Medicaid are disproportionately not able to access DAAs for HCV treatment. Do et al. (2015) clearly showed that patients on Medicaid are able to access treatment when given specialized care, but further research needs to be conducted to determine why a larger cohort of Medicaid patients who are not privy to such advanced care are unable to receive treatment. Another consideration is the relatively relaxed preauthorization requirements in Connecticut (the location of the Do study).


Current and Future Directions

Cost and cost effectiveness is a direct diving force in determining the various payers’ decision to cover DAAs, but it is almost impossible to know the cost at which individual buyers acquire DAAs because pharmaceutical companies consider the exact prices as confidential business information. The cost of DAAs across the globe varies widely showing increased variability among high-income countries without regard to the countries annual gross national income. With such variability among price in high income countries, countries should observe the world stage to determine the best practices for obtaining the most affordable DAAs for their citizens. [21].

The United States also faces another barrier to lowering cost in that it does not have a way to increase its buying power. The states that participated in pooled buying with other agencies within their state were able to procure DAAs at lower costs. The departments that did not practice any cost lowering measures pay, which only confirms that increased purchasing power will only serve to decrease the cost of DAAs [3]. The Massachusetts Department of Health and Human Services further showcased the ability of increased purchasing power to lower the cost of prescription drugs when it announced in June 2016 that it had reached a deal with Gilead “significantly” reduce the price of Harvoni [24].

Unfortunately, increased buying power can only decrease costs to a limited extent. Some suggest that the federal government take a drastic step of non-voluntarily seizing the patent for DAAs based on eminent domain with the claim that cost to manufacture would be reduced to just $3 a pill. Such a tactic is not without precedent. The government seized the patent for the antidote to anthrax follow- ing the events of September 11th. However, that drug manufacture lowered the price of the drug to retain the patent [7].

While some states have been proactive in removing certain sanctions, the removal has no uniformity from state to state. For example, the restriction lifted at Tufts only removed the need for advanced liver disease [25]. The change did nothing to eliminate the requirement for abstaining from alcohol or drugs; failing to realize a growing body of literature that suggests that treatment can in-fact be a means of prevention and cost reduction. New York has made some of the most sweeping changes when the Attorney General announced in April 2016 that nearly all commercial health insurance plans in the state would remove the requirements for liver fibrosis, the use of drugs, or restrict the authorizing physician to be a specialist [26]. Unfortunately, even in states where institutional barriers, such as preauthorization, have been lessened to improve access to DAAs, only 14% of those who are diagnosed with active HCV are in treatment [20].