EDITORIAL

 

Viral dynamics and prediction of response to treatment with pegylated interferon and ribavirin in patients with chronic hepatitis C

Dinámica viral y predicción de la respuesta al tratamiento con interferón pegilado y ribavirina en pacientes con hepatitis crónica por virus C

 

 

J. Aguilar Reina

Emeritus, Servicio Andaluz de Salud. Hospitales Universitarios Virgen del Rocío. Sevilla, Spain

 

 

Chronic infection with hepatitis C virus (HCV) affects a huge number of people worldwide and may progress to liver cirrhosis and hepatocarcinoma. It is the first cause of liver transplantation in western countries, and results in major healthcare and social costs. Treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) may modify disease progression if successful in eradicating infection, which only occurs in slightly more than half of patients. The rest, around 40%, will only receive a costly medication that usually impairs quality of life and may at times induce serious adverse events with no benefits whatsoever. Such events increase in number in the presence of concomitant medication including erythropoietin or colony-stimulating factors, which allow initiating or maintaining therapy in cytopenic subjects. A significant number of infected patients who would potentially benefit from therapy remain untreated because of such uncertainty and likely general status worsening long-term, and PEG-IFN + RBV is commonly administered only to subjects with advanced disease, where effectiveness is lower. Such circumstances have encouraged a search for response predictors, either negative or positive.

Male gender, age older than 45 years, and overweight are known to be associated with lower response rates. However, none of these factors, or their simultaneous occurrence, will determine therapy failure; nor their absence accurately predicts therapy success. When other parameters are also considered, including genotype, viral load, body mass index, liver fibrosis extent, alcohol use or iron metabolism, predictive capabilities improve, but a relevant group of patients remains where treatment results in unexpected effects. Only when two extreme groups are considered, with hypothetical cohorts (1) where each and every patient has all favorable or unfavorable parameters (body mass index above 30 kg/m² or below 20 kg/m²; age older than 60 years or younger than 20; viral load greater than 9,000,000 IU/ml or smaller than 40,000 IU/ml; advanced or absent liver fibrosis; binge or no drinking, abnormal or normal transaminase index), are significant differences observed. However, such hypothetical cohorts are far removed from the real scenarios where treatment decisions are to be made.

The contribution of other parameters requiring biochemical tests unusual in daily practice has been investigated - increased peripheral insulin resistance is associated with lower chances of response to PEG-INF + RBV, but more than 30% of patients with HOMA > 2 will eventually exhibit virus eradication (2). Quasispecies present before treatment onset influence such response (3).

Evidence that a number of host-related factors, in addition to virus-related factors, condition treatment response has prompted genetic studies initially on the major histocompatibility complex (4) and then on numerous genes in a quest for a genetic signature predictive of response (5). Research is ongoing using powerful technologies to broadly analyze the human genome (6).

An analysis of data obtained for the accreditation of therapy with PEG-IFNa2a + RBV was first to provide a factor with a high negative predictive value: when viral load was not negative or had at least decreased by 2 log₁₀ after 12 weeks on treatment (early virological response), a sustained response could only be expected in 3% of treated individuals. Using PEG-IFNa2b + RBV, the odds for response under those same conditions was 0%. The importance of these results is greater, inasmuch as they refer to carriers of viral genotype 1, which induces a lower response rate and requires treatment for 48 weeks. Failure to respond early has led to therapy discontinuation after 3 months in patients who otherwise would have received medication for longer periods of time without ever reaching viral eradication; however, a sustained response cannot be taken for granted in positive cases, and will only be found in around 70% of subjects (7,8).

The study of viral kinetics during therapy allowed to identify a so-called rapid response (when viral load as assessed with a sensitive method is negative after 4 weeks), and also led to predict response at the end of treatment (9-12); it also allowed to variably shorten length of therapy in patients infected with any genotype (13-15), and to suggest prolonged therapy for those infected with genotype 1 in the absence of rapid response (16).

While the identification of such response types - given their negative predictive value - has allowed to reduce discomfort, adverse effects, and costs by discontinuing treatment when advisable, it also served to encourage physicians and patients to improve adherence when there is a response, and to initiate therapy early in order to rapidly have reliable predictive information available. Several studies suggest that decreases in viral load will be identified in association with potential sustained responses in much less than 4 weeks, maybe during the first few days on therapy (17-19). In the current issue of Revista Española de Enfermedades Digestivas, Hernández et al. (20) deal with this issue by researching the relationship between viral load decrease within one month after treatment onset and the possibility of predicting response at therapy completion; they find a high predictive value for rapid response, and also for reductions by 2 by 2 log₁₀ at 2 and 4 weeks, despite the series' limited size. This amount of viral load reduction leads to consider rapid response at weeks 2 and 4, and if the expected response at 3 months ultimately occurs much earlier this will logically identify those who will eventually have their infection eradicated (provided they will complete therapy), even though the negative predictive value becomes necessarily lower, since patients with smaller viral load decreases may later present with early response and then exhibit sustained response. This paper suggests that a viral dynamics approach may offer still more information regarding the prediction of PEG-IFN + RBV effectiveness in patients with chronic infection with HCV.

Sustained response, or a lack thereof, may be considered the result and expression of a number of forces that, on the one hand, facilitate and, on the other hand, oppose virus eradication. Such forces include all the aforementioned factors and them some unknown ones, and essentially refer to viral sensitivity and capacity to block therapy-induced mechanisms and immune response in each specific patient. This interpretation may account for the predictive ability of both early and rapid responses (as an expression of the balance between forces during early treatment), which is higher than that obtained when considering the limited number of factors involved in sustained response.

 

References

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