Until recently, HCV therapy required lengthy treatment with pegylated interferon and ribavirin, with suboptimal rates of success and high rates of SAEs. Thus, treatment was often reserved for patients with advanced fibrosis and cirrhosis, for whom the risk of adverse events was outweighed by the potential benefits of a cure. When DAAs were introduced in high-income countries, treatment eligibility was also very restricted based on disease severity or other factors in order to minimize the budgetary impact (243). This dynamic is now changing for several reasons. First, the price of DAAs is falling in some countries. Second, there is a better understanding of the benefits of early treatment of HCV infection, prior to the development of fibrosis. Recent studies show that patients who achieve SVR tend to have improvements in liver inflammation and fibrosis (244), and also in work-based productivity (245) and quality of life (246, 247). SVR is also associated with improved extrahepatic manifestations independent of the stage of the underlying liver disease. Finally, the new DAAs are much safer and produce high cure rates. For these reasons, eligibility criteria are becoming more liberal, and some countries are expanding their HCV treatment programmes so that they can treat virtually all people with HCV infection and “eliminate” HCV in their populations.
Despite these developments, in most countries, treatment allocation will initially be very restricted because of the high price of medicines and lack of laboratories and health-care infrastructure. Therefore, a framework to help policy-makers decide whom to prioritize for treatment is important.
TABLE 10.1Factors to be considered in prioritizing who receives treatment
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Increased risk of death: - -
advanced HCV-related liver disease (METAVIR score F3–F4) - -
treatment after liver transplantation
Risk of accelerated fibrosis: - -
coinfection with either HIV or HBV - -
high level of alcohol use
Metabolic syndrome, extrahepatic manifestations and evidence of end-organ damage: - -
debilitating fatigue - -
significant psychosocial morbidity (due to stigma, discrimination, fear of transmission to others)
Maximizing reduction in incidence: - -
PWID - -
MSM with HIV - -
prisoners - -
sex workers - -
women with childbearing potential - -
health-care workers.
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Allocation of costly medicines is a perennial challenge that has complex ethical and economic implications. Various principles have been proposed, including morally relevant values such as treating people equally, giving priority to the worst off and saving the most lives (248). As in most countries, treatment will be rationed based on the availability of resources; this may mean prioritizing treatment for “high-risk” populations. The scope of this section is to aid policy-makers by providing a guidance framework to aid decision-making processes for the initial stages of implementing HCV treatment strategies.
Two broad criteria can be used to prioritize treatment – minimizing mortality and morbidity by prioritizing those people with advanced HCV-related liver disease or who have factors that make them more likely to progress to cirrhosis; and maximizing the prevention benefit by prioritizing people at highest risk of transmitting HCV infection, for example, PWID.
10.1. Factors to be considered in prioritizing who receives treatment
10.1.1. Increased risk of death
Advanced HCV-related liver disease (METAVIR score F3–F4)
Patients with advanced fibrosis and cirrhosis are at increased risk of death, mainly due to complications of cirrhosis and HCC, but also all-cause mortality (249, 250). Successful treatment is associated with reduced complications and liver-related morality (251, 252). A paradigm shift in the treatment of HCV is the emergence of efficacious, tolerable and safe interferon-free DAA regimens suitable for patients with advanced cirrhosis (253).
Analysis of data on effectiveness from three LMIC – Egypt, Thailand and Côte d'Ivoire (HCV prevalence 14.7%, 2.2% and 3%, respectively) – suggested that, given a limited number of treatment slots, treatment with DAA regimens among persons with F3–F4 disease would result in an increase in life-years saved of 16.7% in Egypt, 22% in Thailand and 13.1% in Côte d'Ivoire when compared with treating persons with F2–F4 disease (254, 255).
It should be recognized that a small proportion of patients with decompensated cirrhosis appear to deteriorate during treatment. Clinical management of these patients is challenging, as it is difficult to predict which patients will experience this deterioration. Therefore, treatment of HCV infection should be considered only under close supervision of specialist teams with experience in treating and managing complications.
Treatment after liver transplantation
Treatment of patients following liver transplantation improves the chances of long-term liver graft survival. Following liver transplantation, more than 95% of the grafted livers will become reinfected with HCV and typically fibrosis develops more rapidly (256).
Retransplantation in patients with HCV is complicated by poorer outcomes compared to retransplantation done for other causes, and therefore the goal would be to treat before the development of cirrhosis in the grafted liver (257).
Treatment with interferon and ribavirin after transplantation is feasible but the chances of SVR are generally low (258). Newer DAA therapies are advantageous, with reduced DDIs, better tolerability and improved SVR rates (259, 260).
10.1.2. Risk of accelerated fibrosis
Coinfection with HIV
According to the existing HIV treatment guidelines (3), all patients coinfected with HIV should be considered for HCV treatment. Approximately 2.3 million people are believed to be coinfected with HIV globally (15). HIV coinfection is associated with more rapid progression of liver fibrosis (80, 261). Patients with HIV coinfection have reduced access to liver transplantation and outcomes are poor. Thus, treatment may be beneficial at earlier stages of liver disease.
Many patients with HIV coinfection are already on treatment for HIV and therefore easy to access. SVR rates with interferon-based therapies against HCV are lower in HIV-coinfected patients compared with HCV-monoinfected patients. However, when treated with DAAs, SVR rates are comparable among patients with mono- and coinfection. DDIs in patients on ART for HIV are important and should be carefully considered prior to DAA dosing.
Coinfection with HBV
Persons with HBV coinfection should also be prioritized for treatment of HCV due to an increased risk of progression of liver fibrosis and HCC, independent of the development of cirrhosis (262). Globally, up to 10% of patients with HCV are coinfected with HBV (263). Treatment of each virus should be undertaken as in patients with monoinfection.
Metabolic syndrome
In patients with HCV, obesity and the metabolic syndrome are associated with progression of liver disease and increased risk of HCC (264). Furthermore, HCV appears to be strongly associated with type 2 diabetes and insulin resistance (265, 266). Treating HCV infection in persons with diabetes results in a lower incidence of renal and cardiovascular complications as compared to untreated controls (267).
Patients with type 2 diabetes and insulin resistance have an impaired response to interferon-based therapy (268).
10.1.3. Extrahepatic manifestations of chronic HCV infection
Fatigue
Most persons with HCV have no symptoms; however, some exhibit serious and sometimes debilitating symptoms related to HCV infection and may benefit strongly from treatment. Fatigue is a common symptom, which in most cases does not preclude activities of daily living but does impact negatively on quality of life (269). Improvement of these symptoms has been demonstrated after SVR (270). Quality-of-life assessments following treatment with DAA regimens in patients within phase 3 clinical studies demonstrated improvement in fatigue and projected an increase in societal economic benefit (245, 247).
Vasculitis and lymphoproliferative disorders
Cryoglobulinaemia and lymphoproliferative disorders are associated with HCV infection (271), and can be improved or resolved following HCV cure (272). Patients with these conditions are therefore considered a priority for treatment. Cryoglobulins are frequently present among HCV-infected patients. However, a proportion develops evidence of end-organ damage such as renal disease, peripheral neuropathy, arthropathy, and peripheral and central nervous system vasculitis. Treatment with interferon is feasible; however, it can mimic the manifestations of cryoglobulinaemia (273, 274). Renal disease, commonly membranoproliferative glomerulonephritis, can be improved with treatment of HCV, with reversal of proteinuria and the nephrotic syndrome (275).
10.1.4. Maximizing reduction in incidence
People who inject drugs and others with an increased risk of transmission
PWID who engage in drug consumption-related risk behaviours and HIV-positive MSM who engage in high-risk sexual practices have a high incidence of HCV infection and, through those behaviours, can transmit the virus to others. While increasing awareness about the disease and measures to reduce risk are important, only HCV treatment can reduce the current prevalence among these populations. Persons who achieve cure are no longer at risk of onward transmission of HCV.
Mathematical models suggest that even a modest increase in treatment coverage can result in reductions in HCV prevalence (186, 187, 191, 192). These models also demonstrate that the prevention effect of HCV treatment is increased if it is combined with harm reduction services such as OST, and needle and syringe programmes. According to systematic reviews of interferon-based regimens, PWID have equivalent treatment efficacy and adherence as non-PWID (185, 276). While fears remain regarding HCV reinfection in PWID populations, studies suggest that reinfection rates in successfully treated patients are low, assuming that treatment is combined with other harm reduction measures (185, 277).
Significant increases in the incidence of HCV have been reported in HIV-positive MSM in Europe, the United States, Australia and Asia, with reinfection rates in this population of between 6% and 33% (278). Treating MSM could lead to a reduction in transmission risk.
Mother-to-child transmission
Mother-to-child transmission from monoinfected mothers occurs in 4–8% of infants and from mothers coinfected with HIV in 10.8–25% of infants (30, 32–35). Unlike with HBV and HIV, there are no interventions to reduce this risk of vertical HCV transmission during pregnancy (279). Treatment currently cannot be recommended during pregnancy, especially with ribavirin-based regimens, and also because of the lack of data for the new DAA regimens. Successful treatment of women infected with HCV prior to pregnancy is the only measure that can negate any risk of mother-to-child transmission of HCV.
Incarcerated populations
Among incarcerated populations, HCV incidence is high and HCV prevalence can be as high as 60%, primarily because many prisoners are PWID (280). In the United Kingdom, it is estimated that treatment is cost–effective, and in fact, results in health-care savings (281).
Major barriers related to the management of interferon-based therapies in these institutions preclude adequate treatment, as does the high turnover and movement of incarcerated individuals with poor linkage to care. Shorter, more tolerable treatment regimens with less monitoring needs may help circumvent these issues.
Haemodialysis
Nosocomial transmission events remain an important cause of HCV transmission. Persons on haemodialysis are particularly prone to infection, with length of time on dialysis increasing the risk of HCV acquisition (282). Improved education and strict universal precautions can drastically reduce the risk of nosocomial transmission among dialysis patients but still, particularly in resource-limited settings, this practice is not always optimally adhered to. HCV infection also has a negative impact on graft survival post renal transplantation (283).
Treatment options remain limited for patients with severe renal disease, an eGFR <30 mL/min/1.73 m2 and those on haemodialysis. The dose of ribavirin should be reduced and careful monitoring done for anaemia. DDIs should be carefully considered.
Health-care workers
Health-care workers with evidence of active viral replication (in the United States >104 genome equivalents/mL) are restricted from performing procedures prone to exposure (284). Successful treatment would therefore eliminate any risk of transmission to patients and increase the availability of health-care workers for more wide-ranging clinical activities.
10.2. Service planning
Service planning requires an estimation of the local burden of disease, and an assessment of the availability of resources and infrastructure for rolling out treatment. National programmes are required to plan screening and treatment strategies. At present, many countries have poor documentation of the prevalence of infection; this is particularly the case in low-income countries.
The Global policy report on the prevention and control of viral hepatitis, 2013 provides country-specific information on policies and structures already in place to combat viral hepatitis (126). Building on these policies and structures will be necessary to increase the availability of treatment for those infected. Estimates of how many people are likely to be affected may be made by assessing populations at high risk as well as previously documented prevalence and incidence rates. Regular sentinel screening of targeted populations using serology and NAT is therefore required to facilitate service planning and is the first step in increasing access to care and treatment for hepatitis C. Improvements in molecular tools for rapid screening, including dried blood spot and oral fluid testing, as well as polyvalent platforms for NAT, would increase the number of infected patients identified. They would also allow the expansion of screening services into the field as well as among difficult-to-access populations such as PWID. Integration of HCV screening with HIV, HBV and TB screening services may be suitable in many settings as the routes of transmission are common.
A central barrier to treatment roll-out is cost – this includes the cost of medicines, taxes, import charges, appropriate medical facilities and staff, as well as diagnostic and monitoring facilities. Negotiation on drug costs is required and prioritization of particular groups, for example, patients with advanced liver disease (≥F2 disease or, in more constrained settings, F4) may be required. Integration of services, for example, diagnostic and treatment facilities, may help to minimize costs and is likely to facilitate treatment delivery. Task-shifting is the process of sharing clinical management responsibilities with trained personnel such as nurses, clinical officers and pharmacists. Such personnel should have access to consultations with specialized team members as necessary and are likely to require training in order to facilitate adequate health-care delivery. Sourcing of medication and negotiation on pricing at a central level (using pooled procurement) may also minimize costs. Patent coverage and the availability of prequalified biosimilar agents or generic formulations is another central consideration – this is likely to be of key importance as new DAAs are licensed.
Clinical and laboratory facilities for screening and monitoring patients on treatment are an essential component of health-care provision. The development and implementation of simpler methods to assess HCV viral load and genotype as well as for the tests needed to monitor drug toxicity are important to increase accessibility of treatment in less well-resourced settings. Point-of-care HCV viral load testing may be required in some settings in order to facilitate appropriate treatment. Pharmacy facilities and drug storage space, including refrigeration space for interferon, should be included in the planning of new treatment centres. Sourcing and distribution planning is also required. The registration of new drugs in individual Member States may be time consuming and will require adequate planning.
10.3. Service delivery
The key programmatic components of service delivery are adequate clinic infrastructure, laboratory and diagnostic services, reliable drug supply, human resources (doctors, nurses, trained persons to provide psychological support), a referral system, monitoring and evaluation, and civil society participation. Improving access to treatment requires the identification of infected patients. Implementation of screening for HCV therefore needs to be prioritized and targeted screening of high-risk populations carried out. Subsequently, persons with HCV infection require access to medical facilities for treatment, with ongoing follow up and monitoring for toxicity and efficacy. Integration with pre-existing services such as those already established for HIV would be of added value.
Service delivery may be achieved more readily by providing standardized, simplified treatment regimens at a population level. Decentralized service delivery has already enabled the treatment of large numbers of people infected with HIV. Service delivery should make use of simplified operational guidelines, training materials and approaches to clinical decision-making, as well as limited formularies. An initial clinical assessment is essential prior to commencing therapy in order to assess the presence of pre-morbid conditions that may rule out or delay treatment such as severe intercurrent illnesses, for example, TB, decompensated cirrhosis or pregnancy. A psychological assessment at this time and evaluation for potential DDIs are also essential. Disease education, patient preparation for side-effects while on treatment, support and appropriate informed pre- and post-test counselling are required. Access to appropriate diagnostic facilities for toxicity and efficacy monitoring is of critical importance and could be facilitated by utilizing the same or similar platforms currently being rolled out for HIV (285).
For treatment, standardized regimens should be used in combination with simplified clinical decision-making tools and standardized monitoring. Minimum packages for care and treatment require to be formulated locally, and treatment and monitoring algorithms developed. Such algorithms should include information on when to start therapy, when to stop, follow up, side-effects and management flow sheets. Management of DDIs is important, particularly in those coinfected with HIV. Monitoring and evaluation of centres treating persons for HCV is an essential component of appropriate management. Implementation of standard registers for tracking progress, such as those developed for use in TB treatment programmes, will allow monitoring and evaluation of progress after roll-out of treatment for HCV. Increased supervision of sites is likely to be important during the early stages of treatment roll-out. Other guidance on the delivery of treatment for HCV to people in LMIC has been developed by Médecins Sans Frontières (189).
10.4. Concerns of infringement of patient rights due to implementation of anti-diversion measures
In response to calls to make expensive, life-saving medicines more readily available in LMIC, pharmaceutical companies have applied measures such as voluntary licensing, tiered pricing and direct negotiations with national governments. These measures result in significantly lower prices in some countries, primarily LMIC, than those charged for the same medicines in other, primarily high-income countries. Such large price discrepancies and lack of access to affordable medicines increase the risk of product diversion from countries where treatment is less expensive to countries where it is more expensive. Pharmaceutical companies, national treatment programmes and private distributors thus implement what are called anti-diversion measures. These practices were first introduced to control the resale of ARVs for HIV (286). Possible specific measures include product packaging that is specific to the treatment programme, different trade names, different colour of tablets and electronic tracking tools. Concerns have been raised about some additionally stringent anti-diversion measures that have been implemented in relation to the new HCV treatments. Current reported practices to control the individual diversion of medicines include the following:
distribution of medicines with bar codes that include some patient information;
access to medicines provided on a named patient basis with proof of identification;
requiring proof of residence and citizenship before providing access to medication;
photographing the patient when he/she picks up the first bottle of medicine;
distribution of a limited (e.g. 2 weeks or 1 month) supply of medicine at a time with the requirement that empty medicine bottles be brought or sent back in exchange for new bottle(s);
requiring documentation of a negative viral load result if a patient fails to return an empty bottle of medicine (to prove that the patient has been taking the medicine rather than having sold it).
Preventing diversion of medicines is a legitimate concern of pharmaceutical companies and treatment programme managers, as well as hospital staff. However, it is important that anti-diversion measures operate within the bounds of medical ethics. These include the following:
Confidentiality of patient information – access to patient-identifying information should be restricted to health-care providers caring for the patient;
Autonomy – patients have a right to make decisions about their health care, including stopping treatment if they so choose;
Privileged physician–patient interaction: treatment decisions should be made by health-care workers providing care to a patient;
Proportionality – anti-diversion measures should not put an undue burden on patients, health-care workers and treatment programmes;
Non-discrimination – anti-diversion measures should not directly or indirectly restrict access to care for vulnerable and marginalized communities such as refugees, PWID, migrants, homeless persons or those with unstable living arrangements.
