HCV: The Best Cure Possible or the Best Possible Cure?

L. Craxí; C. Cammá; A. Craxí


J Viral Hepat. 2015;22(8):627-629. 

Progress in medicine goes along with an exponential growth of the cost of drugs and devices. While any person has the right to obtain the best possible benefit from medical care, a state needs to strike a balance between granting the optimal personal benefit to each individual and the needs of the society as a whole. Health systems in all countries therefore are facing a huge problem of distributive justice, as while they should guarantee individual rights, among which the right to health in its broader sense, including physical, psychological and social well-being (therefore not limited to healing, but extending to compliance and quality of life), they must also grant equal access to the healthcare resources and keep the distribution system sustainable.

The new generation of highly effective direct acting antivirals (DAAs) to treat HCV infection brings major promises to infected patients in terms of exceedingly high rates of sustained virological response (SVR) but also of tolerability, allowing even the sickest patients to be treated.[1] However in most countries throughout the world, the exceedingly high prices of DAAs are hampering their integration into the HCV treatment programmes. A similar situation arose at the outset of the HIV/AIDS epidemics until the availability of generic compounds removed the price obstacle. The current costs of DAA combinations active against HCV mean that on a global level far less patients than needed are being treated and that no population-wide public health benefit can be expected for some of the most heavily affected countries.[2]

Direct acting antivirals in all-oral regimens need to be used in combination to get SVR rates beyond 90%, except for the easiest to treat patients such as those with HCV genotype 2, where sofosbuvir with ribavirin will suffice. A need to prolong therapy to 24 weeks when treatment is given to patients with cirrhosis emerged at least with some regimens. Need for combination and longer treatment duration will cause a further rise of costs, in a context where the prices of DAAs are already deemed to be exceedingly high.[3] Although in an ideal world everybody would like to get rid of interferon and of its complications and inherent limitations, its relatively low price tag still keeps it as an option to partner with one DAA to reduce costs while still obtaining high SVR rates, at least among patients without cirrhosis. Another currently popular option is to allow IFN-free DAA treatment only in patients with advanced fibrosis or cirrhosis, while keeping on hold persons with lesser stages of liver disease (so-called 'informed deferral' policies).[4] The net balance of these attitudes has never been quantified.

In this issue of JVH, Pho et al.[5] perform a cost–utility analysis aimed to quantify the trade-offs of immediate, interferon-containing therapy versus delayed, interferon-free therapy for interferon-eligible patients with HCV genotype 1 chronic infection. The evaluation, addressing a lifelong time horizon, was performed using a decision-analytic approach, and the natural history of progression of chronic hepatitis C was projected by Markov's model. Using grouped data derived from phase III studies, Pho et al. have tested the incremental cost-effectiveness ratio (ICER) of four different antiviral treatment scenarios stratified by the presence or absence of cirrhosis: (i) no treatment, (ii) immediate, one-time treatment with sofosbuvir interferon-containing regimen, (iii) immediate treatment as above with the opportunity for retreatment in patients who fail to achieve sustained virologic response with interferon-free therapy in 1 year and (iv) delayed therapy with interferon-free therapy in 1 year. They found that waiting 1 year for interferon-free therapy resulted in superior health benefits compared with one-time immediate therapy with interferon. This superiority in health benefits was however lost when the wait-time for an interferon-free therapy was >3 years. Time dependency of this choice was consistent across a broad range of disease variables, and more evident in subjects without cirrhosis. As a message, HCV-infected patients facing the decision of whether to accept to be treated immediately, with a less costly IFN-containing (but still sofosbuvir based) regimen, or wait until more relaxed rules and reduced costs will allow them to be eligible for an IFN-free treatment should opt for the IFN-containing regimen if they have severe disease (but not severe enough to prevent the use of IFN) if the projected waiting time for IFN-free DAAs exceeds 1 year.

The issue tackled by Pho et al.[5] is of practical relevance, given that due to costs, many countries are unable to effectively deliver this innovation.[2] One wonders however how large will be the reduction of costs, given that sofosbuvir, a highly priced drug except in Egypt and in some non-Western countries, is still the backbone of the regimen. If new DAA combos are priced in the same fascia of sofosbuvir, the advantage of an IFN-containing combination becomes far less relevant. Moreover, the indirect costs generated by the use of IFN (growth factors, EPO, transfusions, medical care) could offset the sparing obtained.[6] Also, the option of using only PEG IFN and ribavirin in patients with a high likelihood of response[7] as a way to reduce costs has not been explored in the model.

Albeit Pho's analysis is conducted rigorously, its conclusions cannot be fully transferred to clinical practice without considering some methodological issues. Decision models are often designed using summary data hampering more detailed treatment comparisons that could be achieved with a prognostic model using individual patient data. These summary results describe only between-population, not between-patient, variation because they reflect group averages rather than individual data. Therefore, conventional quality-adjusted life years (QALYs) are population-level tools and fail to take into account important interindividual differences that might affect the value of a particular intervention.[8] The choice that maximizes the population's health or has the best cost/effectiveness overall is not always the same as the best choice for a specific individual. Moreover, the best choices may differ for different individuals. There is thus interest in how to modify the ICER concept for applications in individual decision-making.[9] While for any person it would be more desirable to receive immediately a highly effective IFN-free regimen, at a societal level, it is important to know that an informed deferral strategy, to be carefully agreed with the patient, allows waiting 1 year for interferon-free therapy with superior health benefits as compared to one-time immediate therapy with interferon. According to Aronsohn,[4] deferring treatment is justifiable and appropriate for many patients, and an informed deferral is needed considering risks related to inaccurate staging of liver disease, inability to predict progression of fibrosis and comorbidity changes over time. Obviously, the clinical value and ethical impact of treatment or deferral should not be compromised by any economic analysis.

Moreover, in a prognostic setting, predictions are used to plan therapeutic choices based on the risk of a specific outcome, and estimates of probabilities are seldom based on a single predictor. In fact, physicians naturally integrate several patient's characteristics and symptoms to make a prediction. Prediction is therefore inherently multivariable.[9] Although deterministic and probabilistic analyses try to take these aspects into consideration, these analyses often fail to capture the full complexity of the clinical decision on the individual patient. In this setting, more detailed treatment comparisons could be achieved by combining the different variables affecting the achievement of SVR using multivariate risk modeling.[10] Pho's model adopts the same expected SVR rate regardless of the type of patient to be treated (naïve or P/R experienced, a relevant issue when dealing with IFN-based regimens).

In the end, a major question mark remains: Is a regimen combining IFN with a highly effective DAA still an acceptable choice in 2015? The ultimate goal for society as a whole is to obtain what is best for each individual, but in doing so, it should aim not towards the best possible cure, but the best cure possible. This basic assumption is essential, even though it often leads to a conflict with the desires and aspirations of individuals, especially because immediate access to information about new and potentially effective treatments is available to anyone. In some instances, the high price tag on treatments and devices is unquestionably related to industrial costs (research, development, licensing, production and distribution), while in others finding any kind of justification is extremely hard. In the instance of HCV treatment, Are we really sure that IFN-free therapies cannot be both the best possible cure and the best cure possible for everyone?[2] These therapies are unquestionably more effective than the others, and the only obstacle towards a sustainable generalized distribution is their extremely high cost, which looks artificially inflated even considering the high R&D costs. The cost of fabricating all the new DAAs does not exceed 300 $ for a 12 weeks course of treatment, a more than 200-fold difference from their retail price.[11] Even allowing for other industrial costs, this rate of amplification is totally unheard in any field of medical care. The basics of modern free market economics dictate that pharmaceutical industries have the right to set the price they like and seek the profit they deem appropriate, while facing supply and demand dynamics. But, Are we sure that both the parties in the negotiation game are playing by the same rules? Are pharmaceutical industries (private, profit-driven enterprises) and public healthcare services really peers? Can we really consider drugs market a free market when it has the dynamics of a monopoly or a cartel? The focal point therefore is increasing the state's negotiating power, which originates from the state's economic force and from the raw number of potential users. It is utterly absurd that despite the focus on European community, and on international trade treaties at large, each individual state negotiates the price of drugs and treatments individually based on its numerical needs. States could and most surely should join forces to apply more pressure on the industry. Possible means of pressure are generic drugs, treatment scale up and chiefly drugs patenting, which has often seen the granting of patents for drugs whose originality and potential benefits wee questionable to say the least. Last, but not the least, health technology assessment should give a strict guidance on the margins of negotiation available to provide the therapy to everyone.

In conclusion, an assessment of the possible timing of deferral of IFN-free treatments without prejudice for a patient's health is a useful tool, but cannot be used to justify the status quo and the adoption of a double track for treatment.