How to optimize HCV therapy in genotype 4 patients

Abstract

HCV is a worldwide disease with an estimated prevalence by WHO of 3%. Hepatitis C virus 4 is prevalent in Africa and the Middle East, especially Egypt. The treatment of HCV4 is affected by many factors, related to the virus itself (genotype, pretreatment viral load and prevalent quasispecies), to the host (genetic factors, age, ethnicity and liver histology), to the presence of comorbidities (obesity, insulin resistance and co-infections) and to the therapeutic drugs (type, dose and duration). Optimizing treatment is the goal of daily practice to obtain the best results for the patient.

Abbreviations

DAAD

direct acting anti-viral drugs

DM

diabetes mellitus

EVR

early virological response

HCV

hepatitis C virus

HCV1

HCV genotype 1

HCV-4

HCV genotype 4

HOMA-IR

homeostasis model assessment-IR

IL28B

interleukin 28-b

IR

insulin resistance

IRRDR

IFN/RBV resistance-determining region

OBI

occult hepatitis B virus infection

PEG-IFN

pegylated interferon

RVR

rapid virological response

RBV

ribavirin

SVR

sustained virological response

QALY

quality-adjusted life years

HCV is a global disease whose morbidity and mortality are increasing. The World Health Organization estimated that 3% of the world's population or approximately 130–170 million people were chronically infected with HCV at the end of the 20th century, and 2.3–4.7 million new infections per year. Hepatitis C virus is also responsible for 300 000 deaths annually [1]. Six major genotypes have been identified worldwide and HCV-4 is the predominant HCV genotype in the Middle East and Africa, especially Egypt [2]. Treatment of HCV with pegylated interferon (PEG-IFN) and ribavirin (RBV) represents the cornerstone and the standard of care (SOC) for the management of all HCV genotypes [3]. Response to treatment varies, and the incremental cost-effectiveness of combination therapy with PEG-IFN for men ranged from 26 000–64 000 dollars per quality-adjusted life years (QALY) for genotype 1 and from 10 000–28 000 dollars per QALY for other genotypes, respectively, and, for women, 32 000–90 000 dollars for genotype 1 and 12 000–42 000 dollars for other genotypes respectively [4]. The relatively high cost of treatment with PEG-IFN/RBV regimens, the frequent side effects during and after therapy and the psychological impact on non-responders make it essential to optimize results by optimizing patient selection. Optimization HCV treatment is an ongoing issue in daily clinical practice based on determining how, who and when to treat.

Predictors of treatment response

Treatment decisions should be based on criteria and factors that affect the likelihood of treatment outcome. The treatment of HCV4 is affected by many Host/Virus factors that must be precisely evaluated and optimized before treatment initiation.

HCV-related factors

HCV genotype

Like HCV1, HCV4 was previously considered to be one of the most difficult-to-treat genotypes. However, the new protease inhibitors (telaprevir and boceprevir) have significantly improved treatment outcome in patients with HCV1, so that today HCV4 lags behind all other genotypes [3].

Baseline viral load

Available data on the assessment of viral load as a predictor of treatment response suggest that high baseline viral load (most studies use a cut-off value of 400 000 IU/ml) is a negative predictive factor for treatment outcome [5-8].

HCV quasispecies

The presence of multiple HCV species in the pretreatment serum of HCV4 patients could be a major cause of HCV4 resistance to treatment. Greater sequence heterogeneity generates diverse quasispecies, providing a reservoir of mutations that enable virus-escape from antiviral therapy [9, 10].

Host-related factors

Genetic factors (IL28B - IP-10- NS5A sequence heterogeneity)

Polymorphisms in the region of the IL28B gene have been associated with PEG-IFN and RBV treatment response in genotype 1 HCV infections. In a unique well-characterized cohort of HCV4 patients, a recent study evaluated the association of the IL28B polymorphism and the response to treatment or the severity of liver disease [11]. This study included 164 HCV4 patients from different ethnic groups (Egyptian, European and Sub-Saharan African). Among these patients, 82 were studied for response and 160 for disease severity. These data showed that the IL28B rs12979860 CC genotype was associated with a better treatment response. The response rates were 81.8, 46.5 and 29.4% for genotype CC, CT and TT respectively. No significant relationship was found between rs12979860 and the severity of disease. Analysis of IL28B genotype could be used as a guide to treatment in these patients. Another genetic factor, IP-10 (CXCL10 – a chemokine active on lymphocytes) in plasma and intrahepatic IP-10 mRNA are elevated in patients with chronic HCV genotype 1/4 who do not achieve a sustained viral response (SVR) [12]. More recent data on viral genetic polymorphisms, especially within core and NS5A regions, have been shown to influence the response to PEG-IFN/RBV. In a study by El Shamy et al. on 43 Egyptian patients with HCV4 treated with PEG-IFN/RBV, sliding window analysis over the carboxy-terminus of the NS5A protein identified the PEG-IFN/RBV resistance-determining region (IRRDR) as the most prominent region associated with a SVR. Twenty-one/25 patients (84%) with SVR and only 5/18 patients (28%) without a SVR were infected with HCV with IRRDR containing 4 or more mutations (IRRDR≥4) (P = 0.0004). Multivariate analysis identified IRRDR≥4 as an independent predictor of SVR. The positive predictive value of IRRDR≥4 for SVR was 81% (21/26; P = 0.002), whereas the negative predictive value for non-SVR was 76% (13/17; P = 0.02). These results suggest that IRRDR≥4 could be a useful predictive marker for a SVR in patients with HCV4 infection treated with PEG-IFN/RBV [13].

Age

Although it is an important factor for treatment outcome, it should be evaluated on a case-by-case basis in relation to the patient's level of activity and life style. Papastergiou et al. [14] evaluated 177 HCV4 patients in a retrospective study and the results of treatment were poor in patients ≥45 years old. Wirth et al. [15] evaluated PEG-IFN α2b/RBV in children and adolescents (3–17 years) with chronic hepatitis C and showed that it was effective (SVR in G1 53%; G2/3 93%; G4 80%) and safe.

Ethnicity

New data are available on the effect of ethnicity on treatment outcome. Dimitroulopoulos et al.. [16] studied sixty patients with chronic HCV genotype 4a (30 Europeans – Group A; and 30 Egyptians – Group B) treated with PEG-IFNα2a/RBV for a fixed duration of 48 weeks. The RVR was 26.7% vs. 30.0% and the EVR 23.3% vs. 16.7%, respectively, while the SVR was 36.7% vs. 26.7% respectively (P = 0.59). This study did not show any significant difference in SVR between the two groups. This Greek group confirmed the results in a retrospective study [14] in 177 chronic HCV genotype 4 patients, 42.9% of whom were Egyptian and the rest Greek. Once again, no difference was found between the two groups. Two comparative French studies evaluated Egyptian vs. European or African ethnicity, and showed that Egyptian ethnicity was a favourable predictor for treatment outcome [17, 18].

Liver histopathology

Patients with advanced fibrosis have lower SVR rates. One of the first studies to determine the predictors of response in HCV genotype 4 was performed by Gad et al. [19] using multivariate logistic regression analysis to select independent predictive factors of SVR. This study concluded that fibrosis (> F2 Metavir), severe steatosis, treatment with standard interferon and high serum AFP levels were all negatively associated with SVR.

Comorbidities

Obesity

Obesity reduces treatment efficacy. Hepatic steatosis increases the necroinflammatory process of HCV and accelerates the development of fibrosis, and obesity probably affects the immune response through the development of leptin resistance [20]. Steatosis is common in patients with genotype 4 HCV and significantly improves after HCV eradication. Steatosis appears to be related to high BMI, rather than viral load or the degree of liver injury [21].

Insulin resistance (IR)

IR is probably one of the most important negative predictive factors of HCV treatment outcome. Controlling diabetes mellitus (DM) and improving IR help in improving treatment response. In a cohort of 40 treatment naive patients with chronic hepatitis C genotype 4 infection (20 patients with well-controlled type 2 DM and 20 patients without), no difference was found in SVR between patients with and without diabetes suggesting that well-controlled DM does not seem to reduce the SVR [22]. Another trial was performed in 131 non-diabetic, genotype 4 HCV patients treated with PEG-IFNα2b/RBV to evaluate IR (using HOMA-IR) as a predictor of response to treatment, this study showed that IR strongly predicts the achievement of RVR and SVR, thus further confirming the value of IR as a factor to determine treatment outcome [23]. This hypothesis was also established in another trial in which an insulin-sensitizing agent (Pioglitazone) was added to IFN/RBV to improve IR [24], there was a significant increase in RVR and SVR in this study compared with patients who received SOC (IFN/RBV).

Co-infections

HIV & HBV are the most common blood-borne diseases in combination with HCV. In Egypt, Transmission and prevalence of HIV is still very low (<0.1% in the population between 15 and 49 years old) [25], HBV prevalence in Egypt ranges between 2–8% of the population [26]. Interestingly, HCV infection may suppress and/or reduce HBV DNA replication [27]. Although it is generally agreed that the presence of HBV markers in chronic HCV patients may be a negative predictor for response to treatment [28], trials to confirm this hypothesis in HCV genotype 4 are lacking. Occult hepatitis B virus infection (OBI) is defined as the presence of HBV DNA in serum and/or liver tissue without detectable HBsAg, with or without anti-HBc or anti-HBs outside the preseroconversion window period [29]. An Egyptian study of 155 chronic HCV genotype 4 patients, 3.9% with OBI and treated with PEG-IFN/RBV, showed that the presence of occult hepatitis B infection had no significant influence on non-response to PEG-IFN/RBV. There is a high proportion of schistosomiasis and HCV co-infection in Egypt. A retrospective study was performed including 3596 chronic HCV4 patients treated with (PEG-IFN/RBV) with positive anti-Schistosomal antibodies in 27.3%. An early virological response (EVR) was achieved in 79% of patients with positive schistosomal serology vs. 83% of those with negative schistosomal serology (P = 0.013). The rate of virological breakthrough at week 24 was higher in patients with a positive schistosomal serology (48% vs. 37.5%) (P < 0.01) and end of treatment response was achieved in 47% of patients with positive schistosomal serology vs. 57% in those with negative Schistosomal serology (P < 0.01). Multivariate logistic regression analysis showed that positive schistosomiasis was significantly associated with treatment failure [30]. Another associated pathogen that should be studied is H. Pylori infection. A recent study in the liver specimens of 85 patients tested for the presence of the H. pylori DNA Cag A gene showed that there was a direct correlation between the presence of the H. pylori DNA Cag A gene and the severity of liver fibrosis and necro-inflammation, especially in chronic HCV patients [31]. Further trials are needed to test the relationship between H. Pylori infection and response to HCV treatment.

Drug-related factors

Drug type

Pegylated interferon and the addition of Ribavirin significantly improve the results of HCV4 treatment. Recent progress in the management of HCV with the introduction of new direct inhibitors of HCV replication has also improved the management of HCV4 [4]. There are many compounds in phase II and III trials, mainly HCV NS3/4A protease inhibitors [32, 33]. Most of these new antiviral drugs have been developed and investigated for genotype-1 HCV. Although both Telaprevir and Boceprevir are not approved for Genotype 4, Telaprevir was shown to be active against HCV4 after 15 days of monotherapy or in combination with PEG-IFN/RBV compared with PEG-IFN, RBV and placebo [34]. A total of 24 patients were studied (8 patients in each arm), ethnicity varied (38% Egyptians, 25% Caucasian) and none of the patients had cirrhosis. Although the population was small, the results of this proof of concept study suggest that larger trials should be performed with telaprevir in HCV4. Preliminary data have suggested that results in HCV4 may not be comparable with the present regimen of boceprevir [the other approved direct acting antiviral drugs (DAAD)] [35]. TMC435, another new oral NS3/4A protease inhibitor is in phase III clinical trials for the treatment of HCV infection. The phase IIa study (TMC435-C202) investigated the antiviral activity, safety, tolerance and pharmacokinetics of TMC435 monotherapy in treatment-naïve patients infected with HCV genotypes 2–6. For the primary end point at day 8, the mean (±SD) change in plasma HCV RNA (log₁₀IU/ml) from baseline was the greatest in genotypes 6 (−4.35 ± 0.29) and 4 (−3.52 ± 0.43), then genotypes 2 (−2.73 ± 0.71) and 5 (−2.19 ± 0.39) with no antiviral activity for genotype 3 [36].

Drug dose

Adherence to treatment has been shown to be one of the most positive predictors of outcome to treatment. Numerous worldwide studies agree with the 80/80/80 rule (>80% of IFN, >80% of RBV, >80% of treatment duration) [20, 37].

Treatment duration

Most of the recent guidelines depend on HCV genotyping to determine treatment duration [38, 39]. The SOC for the treatment of genotype 4 is similar to that of genotype 1 (48 weeks of therapy). This is the recommended duration based on the results of most large published randomized, international, phase III trials of combined PEG-IFN α2/RBV in the management of chronic HCV patients [6, 7, 40]. However, only a few HCV genotype 4 patients were included in these studies. Assessment of the virological response at weeks 4 and 12 of therapy is an easy and reliable tool to individually tailor treatment. Patients who become HCV-RNA negative (<50 IU/ml by qualitative PCR assay) or have more than a 2 log decrease in serum HCV-RNA level by quantitative PCR assay after 12 weeks of therapy (partial EVR) are defined as having an early virological response (EVR). Failure to achieve an EVR is predictive of patients who are unlikely to achieve a successful outcome with combination therapy. Patients who are HCV-RNA negative after 4 weeks of treatment have a RVR. A RVR is predictive of a successful outcome with combination therapy [41]. The probability of achieving a SVR is mostly dependent upon when the patient becomes HCV-RNA negative. For example, patients who become HCV-RNA negative after 4 weeks of treatment will achieve a SVR more frequently than those who become HCV-RNA negative after 12 weeks. SVR rates are much lower in patients who do not clear HCV RNA during the first 12 weeks of treatment. Completely negative HCV RNA at week 12 (complete EVR) is a better predictor of achieving a SVR 6 months after treatment than a partial EVR. The SVR rate in patients with a RVR was 91, 75%, in those with a complete EVR and only 27% in patients with a partial EVR and negative virus at week 24 [42].

Response-guided therapy

Very few randomized controlled trials results are available in patients with HCV-4 that report a viral response at week 4. As long as no other predictors of poor response exist, patients with HCV-4 who achieve a RVR are potential candidates for shortened 24-week regimens [43, 44]. The advantages of shorter treatment in these patients are an increase in tolerance and decrease in cost. Slow responders who are not HCV-RNA negative at week 4 or 12 are potential candidates for extending treatment up to 72 weeks, although there are no reliable data to support this option.

Conclusion

Many factors help to identify a good response to HCV4 treatment. These may be virus related, host related, drug related or because of the presence of comorbidities. A better knowledge of predictors of treatment response (virus and host related) is mandatory [45]. Factors that can be modified (e.g. body weight, drug adherence, control of DM, patient counselling, etc.) before treatment should improve treatment optimization.

Disclosure

The authors have no disclosure.