Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Review
Hepatitis C virus genotype 3: a genotype that is not ‘easy-to-treat’ Expert Rev. Gastroenterol. Hepatol. Early online, 1–11 (2014)
Maria Buti* and Rafael Esteban Liver Unit, Hospital Universitario Valle Hebron and Ciberehd del Instituto, Carlos III Paseo Valle Hebron 119, Barcelona 08035, Spain *Author for correspondence: Tel.: +34 9274 6140 [email protected]
The efficacy of antiviral treatment depends on which of the seven genotypes (G1–G7) of hepatitis C virus (HCV) has infected the patient. Conventionally, clinicians regarded G2 and G3 infections as ‘easy-to-treat’: dual therapy with pegylated interferon and ribavirin produces a sustained virologic response in approximately 40–50% of patients with G1 infection, compared with 80% when analyses report combined data for G2 and G3 patients, which is standard practice in many clinical studies. However, sustained virologic response rates appear to be lower in certain subgroups of people infected with G3 compared with those with G2 or the general HCV-infected population. This review examines the growing evidence that factors related to the virus (e.g., baseline viral load and a rapid virologic response) and host characteristics (e.g., steatosis and fibrosis, metabolic syndrome, host polymorphisms and ethnicity) contribute to variations in therapeutic success in G3 HCV. KEYWORDS: cirrhosis • genotype 2 • genotype 3 • hepatitis C virus • rapid virologic response • sustained virologic response
Hepatitis C virus (HCV) chronically infects approximately 185 million people worldwide, equivalent to a global prevalence of about 2.8% [1]. In Europe, approximately 1.1–1.3% of the population is HCV-positive [2]. However, uncertainty surrounds these estimates, partly reflecting issues differentiating acute from chronic HCV as well as incomplete or inconsistent information about the disease burden in many countries [2]. HCV’s natural history is characterized by a long delay between acute infection and the serious complications that are often responsible for the clinical presentation. Between 60 and 80% of acutely infected people develop chronic hepatitis [3]. While an estimated 18.5% of people with chronic HCV develop HCV-related cirrhosis [4], the condition tends to develop between 20 and 30 years after the acute infection [5,6]. Patients with cirrhosis and HCV have a probability of approximately 18– 22% of developing liver decompensation within 5 years [7,8]. HCV is also oncogenic [9] and between 1 and 4% of patients with cirrhosis develops hepatocellular carcinoma (HCC) each year [7,10,11]. Indeed, approximately 15–44% of people with HCC, the
informahealthcare.com
10.1586/17474124.2015.960396
sixth most common cancer worldwide, in Europe have antibodies against HCV [9,12]. HCV is an RNA virus that exhibits rapid, error-prone replication [3]. As a result, HCV is not a single, largely homogenous pathogen. Seven genotypes of HCV [13] have been identified as well as approximately 100 subtypes [3]. The distribution of HCV genotypes differs across the world. Genotype 1 (G1) is the most common genotype in North America, Europe [14], Australia, China, Taiwan and most countries in North Asia [15]. G2 is relatively common in Japan, Korea and Taiwan, although the genotype is less widespread than G1. G1 is also relatively common in the Middle East [15]. G4 tends to predominate in Middle Eastern countries, such as Egypt, Saudi Arabia and Syria. G3 is the second most common genotype in Europe, but is more prevalent in Asia where it predominates in India and Pakistan [15]. Most of G5 infections are located in South Africa [16]. G6 is common in South East Asia, with prevalence particularly high in Vietnam, Myanmar, Hong Kong and Thailand [16,17]. The prevalence and the region of endemicity for HCV-7 are uncertain [13].
2014 Informa UK Ltd
ISSN 1747-4124
1
Review
Buti & Esteban
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
In Europe, G1a and G3 are the genotypes most commonly transmitted among intravenous drug users (IDUs) [18]. Therapeutic blood products predominately transmit G1b [18]. Therefore, G1a and G3 tend to be the most common genotypes in countries with a high rate of transmission among IDUs. In the UK, for example, G1 and G3 account for approximately 45 and 40% of HCV infections [14]. In some other European countries (including Greece, Poland and Sweden), G3 accounts for up to 30% of HCV infections [14].
However, as this review indicates, SVR rates are probably not homogenous throughout the G3 cohort and the ‘approximately 80%’ figure may be an oversimplification. Factors relating to the virus
Classically, two factors related to HCV influence natural history and treatment response, at least in G1, the most studied genotype: HCV subtype and viral load. HCV subtype
HCV genotypes & clinical outcome
A growing body of evidence suggests that patients infected with G3 could have a worse clinical outcome compared with other genotypes. In a study from the USA, after adjusting for demographic and clinical characteristics, the risks of cirrhosis and HCC were 31 and 80% higher, respectively in patients with G3 compared with G1 [19]. In another study, G2 patients were consistently at lower risk of liver-related events than those with G1, after controlling for viral load suppression and other potential confounders. In contrast, G3 patients were consistently at higher risk of liver-related events. Mortality was 20% lower (95% CI: 0.76–0.84; p < 0.001) in patients infected with G2 and 17% higher with G3 (95% CI: 1.11–1.24; p < 0.001) compared with G1. In addition, the risk of decompensated cirrhosis was 44% lower (95% CI: 0.52–0.61; p < 0.001) with G2 and 42% higher with G3 (95% CI: 1.32– 1.52; p < 0.05) compared with G1. HCC risk was 48% lower (95% CI: 0.46–0.58; p < 0.01) with G2 and 63% higher with G3 (95% CI: 1.47–1.79; p < 0.001) compared with G1 [20]. Influence of HCV genotype on the treatment response
Genotype influences the efficacy of antiviral treatment, which is assessed based on a sustained virologic response (SVR). The European Association for the Study of the Liver defines SVR as undetectable HCV RNA 24 weeks after completing antiviral treatment [21]. Undetectable HCV RNA 12 weeks after finishing treatment predicts SVR after 24 [22]. Dual therapy with pegylated interferon (peg-IFN) and ribavirin produces SVR in approximately 40–50% of treatment-naı¨ve people with G1 infection. Adding boceprevir or telaprevir to peg-IFN and ribavirin improves the overall SVR rate for G1 by at least 20– 25% [23]. The SVR rate with peg-IFN and ribavirin is approximately 80% for G2 and G3, when results from the two genotypes are combined [21]. Therefore, many clinicians regard G2 and G3 infections as relatively ‘easy-to-treat’. The label of ‘hard-to-treat’ for G1 and G4 infections can equally be considered an oversimplification. For example, in response to pegIFN and ribavirin, SVR rates vary from approximately 43 to 70% in G4, with response-guided therapy achieving SVR in over 80% of patients in some studies [24]. It is likely that differences in SVR rates may not simply be due to viral factors making a genotype ‘hard-to-treat’ or ‘easy-to-treat’, but may be related to the host characteristics of the cohort studied. This review examines the contribution viral and host factors have to the success of treatment in G3-infected patients. doi: 10.1586/17474124.2015.960396
G3 HCV probably consists of at least 10 subtypes [25]. However, the authors know of only one study that stratifies results by G3 subtypes. The open-label randomized study compared 24 and 48 weeks treatment of G3 HCV with peg-IFN and ribavirin. SVR rates were 48 and 42% with 24 and 48 weeks treatment, respectively [26]. Although the study stratified by G3 subtype, the sample size for G3b (n = 4) and G3c (n = 3) was insufficient to allow meaningful comparisons in SVR with G3a (n = 91). Currently, no data stratify responses to regimens containing new direct-acting antivirals (DAAs), such as sofosbuvir, according to G3 subtype. In addition, HCV’s rapid, error-prone replication allows the virus to evolve phenotypes capable of escaping rapidly from the host’s humoral and cellular immune responses [3]. Furthermore, HCV’s ‘multilayered evasion of innate immunity’ impairs the host’s ability to mount effective antigen-specific adaptive immunity. These factors can be expected to be applicable to all genotypes and contribute to HCV’s persistence and resistance to therapy [27]. This may be exemplified by the differences in viral load, rapid virologic response (RVR) and HCV-related steatosis in some patients with G3 compared with the overall G3-patient cohort. Viral load
Baseline viral load can influence the likelihood of attaining an SVR. Several studies have shown that patients infected with a high viral load of G3 achieve lower SVR rates. A meta-analysis encompassing 2275 patients assessed the efficacy of a 24-week course of peg-IFN and ribavirin in subjects infected with G2 or G3. The eight studies included in the meta-analysis used various thresholds for low viral load (£400,000 to £800,000 IU/ml). SVR rates were 75% in people infected with G2 and 69% in those infected with G3 (odds ratio [OR]: 1.49; 95% CI: 1.23–1.80). G3 patients with high viremia showed lower SVR rates (58%) than patients with a high G2 viral load (75%; OR: 2.36; 95% CI: 1.80–3.09). The difference between genotypes in patients with low viremia was less marked: 75 and 79% for G3 and G2, respectively (OR: 1.50; 95% CI: 1.08–2.09) [28]. However, differences in the definitions of viral load between the studies complicate interpretation of these data. The mechanisms underlying the different relationships between viral load and SVR in G2 and G3 also require further investigation. However, high viremia may offer a marker of more rapid disease progression, a hypothesis possibly supported Expert Rev. Gastroenterol. Hepatol.
HCV genotype 3
by the more rapid progression of fibrosis in people with G3 HCV compared with G2. In addition, high viral load might reflect an impaired host immune response or an enhanced ability of G3 to evade host defenses.
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Factors related to the host
Several host factors influence HCV’s natural history and response to treatment, including: age, sex, ethnicity, obesity, levels of low-density lipoprotein (LDL)-cholesterol and insulin resistance and the degree of liver damage [29]. Differentiating whether a factor is host or viral related is often problematic. Some large prospective studies show that patients younger than 40–45 years of age achieved significantly higher SVR rates with peg-IFN and ribavirin than older patients [29]. However, the molecular, pathological and viral-morphological mechanisms and their relative contribution to the age-related responses are unclear. In addition, hepatic steatosis and fibrosis might be a pathological consequence of HCV, especially G3 infections [30] or due to comorbidities. The following discussion examples four host factors – liver damage, metabolic syndrome, host polymorphisms and ethnicity – that potentially contribute to compromised outcomes in people infected with G3 HCV. Liver damage: steatosis & fibrosis
Hepatic steatosis, a common histological feature of chronic HCV infection, is associated with more rapid progression of liver fibrosis and impaired responses to antiviral therapy compared with patients without a fatty liver. However, the HCV genotype also influences hepatic damage: steatosis may progress faster in patients infected with G3 than G2 [31–33]. This difference in speed of progression potentially contributes to the different SVR rates between the two genotypes [34]. G3 is associated with the highest rates of steatosis among the HCV genotypes [33,35,36]. Moreover, G3-related steatosis correlates with viral replication and disappears after successful antiviral therapy, supporting suggestions that steatosis is a morphological expression of a viral cytopathological effect of the G3 infection [35,37]. Hepatic steatosis and fibrosis can arise from a plethora of other causes, including non-alcoholic fatty liver disease, alcohol abuse and concomitant infections. However, studies to date fail to differentiate coincident fatty accumulation from steatosis and fibrosis caused by HCV. This lack of discrimination complicates assessments of causality in particular and the clinical relevance of studies more generally. In addition, advanced fibrosis or cirrhosis – as determined by a patient’s METAVIR score or Ishak score – at the start of treatment are also associated with differences in SVR. In a clinical study, 471 treatment-naı¨ve patients with HCV (106 with cirrhosis) received peg-IFN a-2b and ribavirin. SVR rates were lower (31%) in G1 and G4 than in G2 (80%) and G3 (72%). Overall, cirrhosis independently predicted treatment failure (OR: 3.00; 95% CI: 1.80–5.01). SVRs were lower in cirrhotic (17%) than in non-cirrhotic (36%) patients infected with G1 or G4 (p = 0.01). Differences in SVR between cirrhotic informahealthcare.com
Review
and non-cirrhotic patients also emerged for G3 (33 and 79%, respectively; p = 0.001). The difference between SVR rates among G2 patients (69 and 83%, respectively; p = 0.09) did not reach statistical significance, although the study may be inadequately powered to detect a difference. Nevertheless, the study confirms that HCV genotype and cirrhosis ‘strongly influence’ outcomes. Indeed, the effect may be additive [38]. The extent and severity of fibrosis also seems to be associated with the different treatment responses between G2 and G3 infections. A retrospective study assessed treatment-naı¨ve patients with G2 (n = 72) or G3 (n = 108) participating in a large expanded access trial evaluating treatment with pegIFN-a-2a and ribavirin for 24 or 48 weeks. Patients with G3 HCV were 2.29-times (p = 0.03) more likely to not show SVR compared with those with G2 infections. In addition, the likelihood of not showing a SVR rose with increasing METAVIR fibrosis score, reaching statistical significance compared with F0 at F3 (OR: 10.90; 95% CI: 1.23–96.40; p = 0.032) and F4 (OR: 27.90; 95% CI: 2.93–265.73; p = 0.004) [39]. In addition, the interaction between genotype and cirrhosis reached statistical significance (p = 0.027), suggesting that patients with G3 and cirrhosis have a worse prognosis than those with G2 and cirrhosis. SVR rates in patients without fibrosis (F0) were 100% for G2 and approximately 90% for G3. However, in patients with cirrhosis SVR rates were approximately 78% for G2 and 17% for G3 [39]. Reporting outcomes stratified by genotype and ensuring that studies are powered adequately to detect such differences is especially important with the advent of novel treatments. Several new DAAs potentially allow IFN-free regimens. However, these may also show differential SVRs in G2 and G3. For example, in a study of 207 patients who were not eligible for IFN-based therapy, 12 weeks treatment with sofosbuvir and ribavirin produced SVRs in 93 and 61% of people infected with G2 and G3, respectively (OR: 8.66; 95% CI: 3.62–20.73; p < 0.0001) [40]. Moreover, 21% of cirrhotic patients with G3 achieved SVR compared with 68% of G3 patients without cirrhosis [40]. In contrast, 94 and 92% of G2-infected patients with and without cirrhosis, respectively attained SVR [40]. Metabolic syndrome
The metabolic syndrome refers to a constellation of risk factors for cardiovascular disease, stroke, kidney disease and type 2 diabetes mellitus: abdominal obesity, dyslipidemia, hypertension, impaired fasting glucose and insulin resistance. Approximately a fifth of adults in the USA meet the criteria for the metabolic syndrome [41]. Thus, many patients with HCV will also have one or more elements of the metabolic syndrome. In addition, HCV infection may influence some elements in the metabolic syndrome. HCV is physically associated with very low-density lipoprotein (VLDL), LDL and high-density lipoprotein. HCV also binds to the LDL receptor [3]. Dyslipidemia is one element of the metabolic syndrome. Therefore, further doi: 10.1586/17474124.2015.960396
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Review
Buti & Esteban
studies need to assess whether these interactions contribute to the association between the metabolic syndrome and SVR. Despite uncertainty regarding the pathogenic background, compelling evidence suggests that factors encompassed by the metabolic syndrome may undermine therapeutic outcomes. For example, insulin resistance seems to reduce the likelihood of achieving a SVR [42–44]. One analysis combined G2 and G3 patients and used a homeostasis model assessment of insulin resistance (HOMA-IR) score of 2 and above as a threshold for insulin resistance. People whose HOMA-IR score was less than 2 were 6.5-times more likely to attain SVR following peg-IFN-a-2a and ribavirin than those with HOMA-IR ‡2 [42]. A meta-analysis that encompassed 14 studies supported an association between insulin resistance and lower SVR rates. Subjects with normal insulin sensitivity were almost three-times more likely (OR: 2.86; 95% CI: 1.97–4.16) to attain SVR than those with insulin resistance. The strength of the relationship between normal insulin sensitivity and SVR differed depending on the genotype: G1 (OR: 2.16; 95% CI: 1.51– 3.08), G2 and G3 (OR: 3.06; 95% CI: 1.06–8.82) and G4 (OR: 6.65; 95% CI: 2.51–17.61) [45]. On the other hand, an observational prospective cohort study failed to find any association between HOMA-IR and SVR rates in G1, G2 and G3 patients [46]. BMI, represented in the metabolic syndrome as abdominal obesity, also seems to influence outcomes in people with HCV. Patients infected with G2 or G3 and a BMI ‡30 kg/m2 had a lower SVR rate compared with those with a BMI
Review
Hepatitis C virus genotype 3: a genotype that is not ‘easy-to-treat’ Expert Rev. Gastroenterol. Hepatol. Early online, 1–11 (2014)
Maria Buti* and Rafael Esteban Liver Unit, Hospital Universitario Valle Hebron and Ciberehd del Instituto, Carlos III Paseo Valle Hebron 119, Barcelona 08035, Spain *Author for correspondence: Tel.: +34 9274 6140 [email protected]
The efficacy of antiviral treatment depends on which of the seven genotypes (G1–G7) of hepatitis C virus (HCV) has infected the patient. Conventionally, clinicians regarded G2 and G3 infections as ‘easy-to-treat’: dual therapy with pegylated interferon and ribavirin produces a sustained virologic response in approximately 40–50% of patients with G1 infection, compared with 80% when analyses report combined data for G2 and G3 patients, which is standard practice in many clinical studies. However, sustained virologic response rates appear to be lower in certain subgroups of people infected with G3 compared with those with G2 or the general HCV-infected population. This review examines the growing evidence that factors related to the virus (e.g., baseline viral load and a rapid virologic response) and host characteristics (e.g., steatosis and fibrosis, metabolic syndrome, host polymorphisms and ethnicity) contribute to variations in therapeutic success in G3 HCV. KEYWORDS: cirrhosis • genotype 2 • genotype 3 • hepatitis C virus • rapid virologic response • sustained virologic response
Hepatitis C virus (HCV) chronically infects approximately 185 million people worldwide, equivalent to a global prevalence of about 2.8% [1]. In Europe, approximately 1.1–1.3% of the population is HCV-positive [2]. However, uncertainty surrounds these estimates, partly reflecting issues differentiating acute from chronic HCV as well as incomplete or inconsistent information about the disease burden in many countries [2]. HCV’s natural history is characterized by a long delay between acute infection and the serious complications that are often responsible for the clinical presentation. Between 60 and 80% of acutely infected people develop chronic hepatitis [3]. While an estimated 18.5% of people with chronic HCV develop HCV-related cirrhosis [4], the condition tends to develop between 20 and 30 years after the acute infection [5,6]. Patients with cirrhosis and HCV have a probability of approximately 18– 22% of developing liver decompensation within 5 years [7,8]. HCV is also oncogenic [9] and between 1 and 4% of patients with cirrhosis develops hepatocellular carcinoma (HCC) each year [7,10,11]. Indeed, approximately 15–44% of people with HCC, the
informahealthcare.com
10.1586/17474124.2015.960396
sixth most common cancer worldwide, in Europe have antibodies against HCV [9,12]. HCV is an RNA virus that exhibits rapid, error-prone replication [3]. As a result, HCV is not a single, largely homogenous pathogen. Seven genotypes of HCV [13] have been identified as well as approximately 100 subtypes [3]. The distribution of HCV genotypes differs across the world. Genotype 1 (G1) is the most common genotype in North America, Europe [14], Australia, China, Taiwan and most countries in North Asia [15]. G2 is relatively common in Japan, Korea and Taiwan, although the genotype is less widespread than G1. G1 is also relatively common in the Middle East [15]. G4 tends to predominate in Middle Eastern countries, such as Egypt, Saudi Arabia and Syria. G3 is the second most common genotype in Europe, but is more prevalent in Asia where it predominates in India and Pakistan [15]. Most of G5 infections are located in South Africa [16]. G6 is common in South East Asia, with prevalence particularly high in Vietnam, Myanmar, Hong Kong and Thailand [16,17]. The prevalence and the region of endemicity for HCV-7 are uncertain [13].
2014 Informa UK Ltd
ISSN 1747-4124
1
Review
Buti & Esteban
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
In Europe, G1a and G3 are the genotypes most commonly transmitted among intravenous drug users (IDUs) [18]. Therapeutic blood products predominately transmit G1b [18]. Therefore, G1a and G3 tend to be the most common genotypes in countries with a high rate of transmission among IDUs. In the UK, for example, G1 and G3 account for approximately 45 and 40% of HCV infections [14]. In some other European countries (including Greece, Poland and Sweden), G3 accounts for up to 30% of HCV infections [14].
However, as this review indicates, SVR rates are probably not homogenous throughout the G3 cohort and the ‘approximately 80%’ figure may be an oversimplification. Factors relating to the virus
Classically, two factors related to HCV influence natural history and treatment response, at least in G1, the most studied genotype: HCV subtype and viral load. HCV subtype
HCV genotypes & clinical outcome
A growing body of evidence suggests that patients infected with G3 could have a worse clinical outcome compared with other genotypes. In a study from the USA, after adjusting for demographic and clinical characteristics, the risks of cirrhosis and HCC were 31 and 80% higher, respectively in patients with G3 compared with G1 [19]. In another study, G2 patients were consistently at lower risk of liver-related events than those with G1, after controlling for viral load suppression and other potential confounders. In contrast, G3 patients were consistently at higher risk of liver-related events. Mortality was 20% lower (95% CI: 0.76–0.84; p < 0.001) in patients infected with G2 and 17% higher with G3 (95% CI: 1.11–1.24; p < 0.001) compared with G1. In addition, the risk of decompensated cirrhosis was 44% lower (95% CI: 0.52–0.61; p < 0.001) with G2 and 42% higher with G3 (95% CI: 1.32– 1.52; p < 0.05) compared with G1. HCC risk was 48% lower (95% CI: 0.46–0.58; p < 0.01) with G2 and 63% higher with G3 (95% CI: 1.47–1.79; p < 0.001) compared with G1 [20]. Influence of HCV genotype on the treatment response
Genotype influences the efficacy of antiviral treatment, which is assessed based on a sustained virologic response (SVR). The European Association for the Study of the Liver defines SVR as undetectable HCV RNA 24 weeks after completing antiviral treatment [21]. Undetectable HCV RNA 12 weeks after finishing treatment predicts SVR after 24 [22]. Dual therapy with pegylated interferon (peg-IFN) and ribavirin produces SVR in approximately 40–50% of treatment-naı¨ve people with G1 infection. Adding boceprevir or telaprevir to peg-IFN and ribavirin improves the overall SVR rate for G1 by at least 20– 25% [23]. The SVR rate with peg-IFN and ribavirin is approximately 80% for G2 and G3, when results from the two genotypes are combined [21]. Therefore, many clinicians regard G2 and G3 infections as relatively ‘easy-to-treat’. The label of ‘hard-to-treat’ for G1 and G4 infections can equally be considered an oversimplification. For example, in response to pegIFN and ribavirin, SVR rates vary from approximately 43 to 70% in G4, with response-guided therapy achieving SVR in over 80% of patients in some studies [24]. It is likely that differences in SVR rates may not simply be due to viral factors making a genotype ‘hard-to-treat’ or ‘easy-to-treat’, but may be related to the host characteristics of the cohort studied. This review examines the contribution viral and host factors have to the success of treatment in G3-infected patients. doi: 10.1586/17474124.2015.960396
G3 HCV probably consists of at least 10 subtypes [25]. However, the authors know of only one study that stratifies results by G3 subtypes. The open-label randomized study compared 24 and 48 weeks treatment of G3 HCV with peg-IFN and ribavirin. SVR rates were 48 and 42% with 24 and 48 weeks treatment, respectively [26]. Although the study stratified by G3 subtype, the sample size for G3b (n = 4) and G3c (n = 3) was insufficient to allow meaningful comparisons in SVR with G3a (n = 91). Currently, no data stratify responses to regimens containing new direct-acting antivirals (DAAs), such as sofosbuvir, according to G3 subtype. In addition, HCV’s rapid, error-prone replication allows the virus to evolve phenotypes capable of escaping rapidly from the host’s humoral and cellular immune responses [3]. Furthermore, HCV’s ‘multilayered evasion of innate immunity’ impairs the host’s ability to mount effective antigen-specific adaptive immunity. These factors can be expected to be applicable to all genotypes and contribute to HCV’s persistence and resistance to therapy [27]. This may be exemplified by the differences in viral load, rapid virologic response (RVR) and HCV-related steatosis in some patients with G3 compared with the overall G3-patient cohort. Viral load
Baseline viral load can influence the likelihood of attaining an SVR. Several studies have shown that patients infected with a high viral load of G3 achieve lower SVR rates. A meta-analysis encompassing 2275 patients assessed the efficacy of a 24-week course of peg-IFN and ribavirin in subjects infected with G2 or G3. The eight studies included in the meta-analysis used various thresholds for low viral load (£400,000 to £800,000 IU/ml). SVR rates were 75% in people infected with G2 and 69% in those infected with G3 (odds ratio [OR]: 1.49; 95% CI: 1.23–1.80). G3 patients with high viremia showed lower SVR rates (58%) than patients with a high G2 viral load (75%; OR: 2.36; 95% CI: 1.80–3.09). The difference between genotypes in patients with low viremia was less marked: 75 and 79% for G3 and G2, respectively (OR: 1.50; 95% CI: 1.08–2.09) [28]. However, differences in the definitions of viral load between the studies complicate interpretation of these data. The mechanisms underlying the different relationships between viral load and SVR in G2 and G3 also require further investigation. However, high viremia may offer a marker of more rapid disease progression, a hypothesis possibly supported Expert Rev. Gastroenterol. Hepatol.
HCV genotype 3
by the more rapid progression of fibrosis in people with G3 HCV compared with G2. In addition, high viral load might reflect an impaired host immune response or an enhanced ability of G3 to evade host defenses.
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 10/06/14 For personal use only.
Factors related to the host
Several host factors influence HCV’s natural history and response to treatment, including: age, sex, ethnicity, obesity, levels of low-density lipoprotein (LDL)-cholesterol and insulin resistance and the degree of liver damage [29]. Differentiating whether a factor is host or viral related is often problematic. Some large prospective studies show that patients younger than 40–45 years of age achieved significantly higher SVR rates with peg-IFN and ribavirin than older patients [29]. However, the molecular, pathological and viral-morphological mechanisms and their relative contribution to the age-related responses are unclear. In addition, hepatic steatosis and fibrosis might be a pathological consequence of HCV, especially G3 infections [30] or due to comorbidities. The following discussion examples four host factors – liver damage, metabolic syndrome, host polymorphisms and ethnicity – that potentially contribute to compromised outcomes in people infected with G3 HCV. Liver damage: steatosis & fibrosis
Hepatic steatosis, a common histological feature of chronic HCV infection, is associated with more rapid progression of liver fibrosis and impaired responses to antiviral therapy compared with patients without a fatty liver. However, the HCV genotype also influences hepatic damage: steatosis may progress faster in patients infected with G3 than G2 [31–33]. This difference in speed of progression potentially contributes to the different SVR rates between the two genotypes [34]. G3 is associated with the highest rates of steatosis among the HCV genotypes [33,35,36]. Moreover, G3-related steatosis correlates with viral replication and disappears after successful antiviral therapy, supporting suggestions that steatosis is a morphological expression of a viral cytopathological effect of the G3 infection [35,37]. Hepatic steatosis and fibrosis can arise from a plethora of other causes, including non-alcoholic fatty liver disease, alcohol abuse and concomitant infections. However, studies to date fail to differentiate coincident fatty accumulation from steatosis and fibrosis caused by HCV. This lack of discrimination complicates assessments of causality in particular and the clinical relevance of studies more generally. In addition, advanced fibrosis or cirrhosis – as determined by a patient’s METAVIR score or Ishak score – at the start of treatment are also associated with differences in SVR. In a clinical study, 471 treatment-naı¨ve patients with HCV (106 with cirrhosis) received peg-IFN a-2b and ribavirin. SVR rates were lower (31%) in G1 and G4 than in G2 (80%) and G3 (72%). Overall, cirrhosis independently predicted treatment failure (OR: 3.00; 95% CI: 1.80–5.01). SVRs were lower in cirrhotic (17%) than in non-cirrhotic (36%) patients infected with G1 or G4 (p = 0.01). Differences in SVR between cirrhotic informahealthcare.com
Review
and non-cirrhotic patients also emerged for G3 (33 and 79%, respectively; p = 0.001). The difference between SVR rates among G2 patients (69 and 83%, respectively; p = 0.09) did not reach statistical significance, although the study may be inadequately powered to detect a difference. Nevertheless, the study confirms that HCV genotype and cirrhosis ‘strongly influence’ outcomes. Indeed, the effect may be additive [38]. The extent and severity of fibrosis also seems to be associated with the different treatment responses between G2 and G3 infections. A retrospective study assessed treatment-naı¨ve patients with G2 (n = 72) or G3 (n = 108) participating in a large expanded access trial evaluating treatment with pegIFN-a-2a and ribavirin for 24 or 48 weeks. Patients with G3 HCV were 2.29-times (p = 0.03) more likely to not show SVR compared with those with G2 infections. In addition, the likelihood of not showing a SVR rose with increasing METAVIR fibrosis score, reaching statistical significance compared with F0 at F3 (OR: 10.90; 95% CI: 1.23–96.40; p = 0.032) and F4 (OR: 27.90; 95% CI: 2.93–265.73; p = 0.004) [39]. In addition, the interaction between genotype and cirrhosis reached statistical significance (p = 0.027), suggesting that patients with G3 and cirrhosis have a worse prognosis than those with G2 and cirrhosis. SVR rates in patients without fibrosis (F0) were 100% for G2 and approximately 90% for G3. However, in patients with cirrhosis SVR rates were approximately 78% for G2 and 17% for G3 [39]. Reporting outcomes stratified by genotype and ensuring that studies are powered adequately to detect such differences is especially important with the advent of novel treatments. Several new DAAs potentially allow IFN-free regimens. However, these may also show differential SVRs in G2 and G3. For example, in a study of 207 patients who were not eligible for IFN-based therapy, 12 weeks treatment with sofosbuvir and ribavirin produced SVRs in 93 and 61% of people infected with G2 and G3, respectively (OR: 8.66; 95% CI: 3.62–20.73; p < 0.0001) [40]. Moreover, 21% of cirrhotic patients with G3 achieved SVR compared with 68% of G3 patients without cirrhosis [40]. In contrast, 94 and 92% of G2-infected patients with and without cirrhosis, respectively attained SVR [40]. Metabolic syndrome
The metabolic syndrome refers to a constellation of risk factors for cardiovascular disease, stroke, kidney disease and type 2 diabetes mellitus: abdominal obesity, dyslipidemia, hypertension, impaired fasting glucose and insulin resistance. Approximately a fifth of adults in the USA meet the criteria for the metabolic syndrome [41]. Thus, many patients with HCV will also have one or more elements of the metabolic syndrome. In addition, HCV infection may influence some elements in the metabolic syndrome. HCV is physically associated with very low-density lipoprotein (VLDL), LDL and high-density lipoprotein. HCV also binds to the LDL receptor [3]. Dyslipidemia is one element of the metabolic syndrome. Therefore, further doi: 10.1586/17474124.2015.960396
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Review
Buti & Esteban
studies need to assess whether these interactions contribute to the association between the metabolic syndrome and SVR. Despite uncertainty regarding the pathogenic background, compelling evidence suggests that factors encompassed by the metabolic syndrome may undermine therapeutic outcomes. For example, insulin resistance seems to reduce the likelihood of achieving a SVR [42–44]. One analysis combined G2 and G3 patients and used a homeostasis model assessment of insulin resistance (HOMA-IR) score of 2 and above as a threshold for insulin resistance. People whose HOMA-IR score was less than 2 were 6.5-times more likely to attain SVR following peg-IFN-a-2a and ribavirin than those with HOMA-IR ‡2 [42]. A meta-analysis that encompassed 14 studies supported an association between insulin resistance and lower SVR rates. Subjects with normal insulin sensitivity were almost three-times more likely (OR: 2.86; 95% CI: 1.97–4.16) to attain SVR than those with insulin resistance. The strength of the relationship between normal insulin sensitivity and SVR differed depending on the genotype: G1 (OR: 2.16; 95% CI: 1.51– 3.08), G2 and G3 (OR: 3.06; 95% CI: 1.06–8.82) and G4 (OR: 6.65; 95% CI: 2.51–17.61) [45]. On the other hand, an observational prospective cohort study failed to find any association between HOMA-IR and SVR rates in G1, G2 and G3 patients [46]. BMI, represented in the metabolic syndrome as abdominal obesity, also seems to influence outcomes in people with HCV. Patients infected with G2 or G3 and a BMI ‡30 kg/m2 had a lower SVR rate compared with those with a BMI
