Evaldo Stanislau Affonso de Araújo

The year 2011 will be an extraordinary one. Twenty-two years after the discovery of hepatitis C virus (HCV) we finally have a therapy that acts directly on the virus. We have entered the era of therapy with direct-acting antiviral agents (DAAs). During therapy evolution, we have always searched for a term that would characterize the current modality. We relinquished the " one size fits all ", then the " a la carte " therapy, in which dose customization is essential. We have recently started using response-guided therapy (RGT), in which the duration of therapy is defined according to the moment of HCV non-detection. And now, after the first protease inhibitors (PIs) have been approved, will it be possible to define therapy through a new expression? I believe the discussion and therapeutic decisions will gravitate around the binomial safety-compliance, and then, less is more, or more is less , should be the best definition for this new era. The addition of PIs generates a higher rate of sustained viral response (SVR) in treatment-naïve patients, relapsers and nonresponders, in cirrhotic patients, African-Americans and those with an unfavorable IL28-B profile. It also minimizes the relevance of other characteristics, usually unfavorable ones, associated with the patient (e.g., high HOMA), and potentially reduces therapy duration. In contrast, this new addition results in adverse effects, complex drug-drug interactions and potential resistance. Finally, there is greater or lesser complexity and high prices. Thus, these are decisions to be made in the near future: who should be treated with triple therapy and how to choose among the available options? This is not an easy question to answer. First of all, who should be treated? Certainly those infected with genotype 1. It should be clear to all that new PIs act only on HCV genotype 1 (with evidence of action against genotype 2 and, for boceprevir, also against genotype 3). 1 The high cost should guide selection criteria, including economic ones. Prioritizing some patients will be a natural choice. In this sense, cirrhotic patients, those with advanced fibrosis or at increased risk of progression (older patients, those with exuberant inflammatory activity), in addition to those previously treated, would be the main candidates. The dilemma to be faced is that patients with milder disease would be the ones to attain the most benefit (with higher rates of SVR), while the afore mentioned priority patients besides having been less studied have shown lower SVR rates (nonetheless overcoming the control group). 1-6 I do not think the answer will come from a single source, much less from therapeutic, scientific or governmental guidelines. In the context of case-by-case and individual decisions, creating an inflexible policy is a complex task. Moreover, the "price" analysis alone will not suffice. From a financial perspective, a complete pharmacoeconomical analysis seems more reasonable. Therefore, if a "more expensive" therapy brings positive economic impacts in the medium and long term, cost-effectiveness will be proven. Whether we should treat patients with milder disease is an unanswered question. These patients are in better condition to wait for new therapeutic options that will emerge in the coming years. On the other hand, on an individual basis, to treat patients with milder disease is not inadequate and it is an option that has sound scientific evidence. 1-6 On the other end of the spectrum, even patients with advanced fibrosis should be analyzed individually. There has been a grouping of "F3" with "F4" (cirrhotic) patients in the analysis of PI pivotal studies. 2 But do these patients represent the same phenomenon? Is the classification method (liver biopsy or noninvasive methods) appropriate? Are all cirrhotic patients the same, or would cirrhotic patients (by definition) but with good functional reserve be better and more responsive? The set of factors related to the patient (including the socioeconomic ones), to the virus and to therapy leading to a case-by-case discussion will be crucial in this decision-making. If deciding who will be treated is a complex task, the choice between the options available to the clinician and the patient - boceprevir or telaprevir - will be another routine decision. In this case, four attributes will be decisive: results (SVR), compliance, genetic barrier to resistance, and safety. A CLOSER LOOK ON TELAPREVIR AND BOCEPREVIR Telaprevir and boceprevir are two different compounds ( Figure 1 ) that belong to the same therapeutic class and share a common site of action, the HCV protease. 7 Although both are classified among the linear protease inhibitors, when considering the structural differences of these compounds it is natural that their clinical use be distinct in terms of administration, dose, drug-drug interactions and adverse events, despite similar clinical efficacy (SVR equivalent). Table 1 summarizes some of their attributes. 8 Attribute 1: Attained clinical outcomes (SVR) The analysis of phase-3 studies of telaprevir and boceprevir showed a clear superiority of triple therapy (PegIFN + ribavirin + PI) compared to dual therapy (PegIFN + ribavirin). 1-6 It is important to emphasize that these are distinct studies, with different populations and therefore their results are not comparable, as there were not head-to-head comparisons of the two agents. One of the characteristics that emphasizes how different the studied populations were, was the observation that in the control groups the responses were different between the boceprevir and telaprevir studies. 1-6 It was also noteworthy that the administration of boceprevir was preceded by four weeks of dual therapy with PegIFN and ribavirin (the lead-in phase), while this strategy was used in only one of the telaprevir studies. 1,2,4,6 Allowing for those caveats, we could emphasize that pooled analysis of overall results showed a difference of 25-28% higher (63-66% vs. 38%) in terms of SVR for treatment-naïve patients who used triple therapy with boceprevir, 1,4 and 25-31% (69-75% vs. 44%) for those who used telaprevir (group 12 weeks) compared to standard. 1,3.5 Regarding those previously treated, a 45% higher response was obtained in the triple therapy group using boceprevir (66% vs. 21%) 1,2 and 47% (64% vs. 17%) in those who used telaprevir without lead-in, when compared to controls with dual therapy. 1,6 Among the treatment-naïve patients, 44% to 58% were eligible for shorter therapy with boceprevir and telaprevir, respectively. 1 In previously treated individuals, 46% of those who had used boceprevir received abbreviated therapy. 1 This information was not available for telaprevir, as the criteria for defining the null response was distinct for boceprevir (patients who, in the lead-in phase, showed less than 1 log10 reduction of the viral load). 1,2,6 Regarding the lead-in phase, it is used with boceprevir based on the results of phase-3 studies. In phase-2 boceprevir studies, a direct comparison between using and not using the lead-in showed no significant difference in terms of SVR (56% vs. 54% in the 28-week groups, and 75% vs. 67% in the 48-week groups). 1 There was a trend toward lower breakthrough among patients who used lead-in (4% vs. 9%). As in the Realize study, the arm that performed the lead-in with telaprevir showed slight superiority in terms of SVR, particularly among relapsers (88% vs. 83%) and null responders (33% vs. 29%). 1,6 It seems that the question of performing the lead-in will be particularly useful in previously treated patients. This initial phase will be important to assess the response to interferon-alpha, to allow pharmacological stability and full effect of ribavirin and to better characterize the type of response of patients whose previous records, for several reasons, prevented a proper classification. In treatment-naïve patients, it may also be useful as a way to measure compliance, evaluate toxicity associated with dual therapy, and even to decide not to include the PIs in the regimen of patients with rapid virological response (RVR) [around 15% of patients], 9 whose chance of SVR would be just over 90% in these circumstances. Therefore, more than a part of boceprevir-associated therapy, the lead-in seems to be an extremely useful tool to categorize patients. On the other hand, not using it is also acceptable for both PIs and clinical practice will certainly allow a better evaluation of future research on the subject. Attribute 2: Compliance (administration) A major difficulty with this first generation of PIs is the pill burden. In case of telaprevir, dosage will be 2 tablets every 8 hours, whereas boceprevir requires intake of 4 pills every 8 hours. Both require 3 daily doses of pills and a number varying between 6 and 12 pills a day. 1,10,11 The telaprevir therapy lasts for 12 weeks, while boceprevir therapy duration will vary from 24 to 32 weeks, unless early withdrawal interrupts therapy. 2,4,11 Consider that it might be necessary to associate the use of pegylated interferon to both drugs, ribavirin and other drugs to control any adverse symptoms and/or concomitant diseases. The total treatment time may be 24, 28, 36 or 48 weeks, considering the lead-in and the possibility of RGT in treatment-naïve patients (24-28 weeks for telaprevir and boceprevir, respectively) or previously treated individuals (36 weeks, boceprevir) or full therapy (48 weeks for both). 1-6 The number of pills, dose interval and therapy duration are therefore critical. But it is also necessary to consider the matter of toxicity and drug-drug interactions, which will be discussed later, and dietary restrictions. Boceprevir should be taken with a light meal. 10 Telaprevir should be taken 30 minutes after a caloric (520 calories) and high-fat meal (21 g), or there will be significant loss of absorption (up to 237% lower if administered in the fasting state). 11 Therefo

Summary. The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV-coinfected patients. Twenty-six patients (15 HCV genotype-1 and 11 genotype-3) were treated with a 48-week regimen of peginterferon-alfa-2a (PEG-IFN) (180 μg/week) and weight-based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 ± 0.3 days after initiation of therapy, followed by a 0.3- to 12.9-fold viral rebound until the administration of the second dose of PEG-IFN, which were not associated with SVR or HCV genotype. A viral decline second-phase viral decline slope (i.e., measured from day 2 to 29) <0.3 log/week had a NPV = 100% for SVR. We conclude that first-phase viral decline at day 2 and second-phase viral decline slope (<0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of nonresponse in patients with HCV and HIV.

We examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models. African Americans and whites had a similar distribution of IL28B genotypes (P = 0.5). The IL28B CC genotype was overrepresented (P = 0.015) in patients infected with HCV genotype-3 compared with genotype-1. In both genotype-1 and genotype-3, the first-phase viral decline and the average pegylated interferon-alpha-2a effectiveness during the first week of therapy were larger (trend P ≤ 0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second slower phase of viral decline (days 2-29) and infected cells loss rate, δ, were larger (P = 0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.

Herein, we present a synthesis of two publications that evaluate an abbreviated therapeutic approach to treating chronic hepatitis C virus (HCV) infection. Based on those publications, we discuss the use of the early virologic response (EVR) as a tool for the optimized management of patients under treatment, as well as reviewing concepts of HCV viral kinetics. The fourth-week EVR, characterized by HCV RNA dropping to undetectable levels, allows individuals infected with HCV genotype 1 and presenting low baseline viral loads to be treated with the combination of pegylated interferon and ribavirin for 24 weeks, whereas individuals infected with HCV genotypes 2 or 3 can be treated for only 12 weeks. Therefore, by adopting abbreviated treatment regimens optimized through early prediction of sustained viral response, it is possible to increase the number of patients treated without incurring the excess costs related to high rates of treatment failure and management of adverse outcomes, as well as avoiding the risks of unnecessarily exposing patients to drugs that have the potential to be highly toxic.