Improving Outcome in Patients With Hepatitis C Virus Genotype 4
Improving Outcome in Patients With Hepatitis C Virus Genotype 4
Several factors influence treatment outcomes among patients with chronic hepatitis C. A trend is growing to adapt an individualized treatment approach to optimize treatment outcomes among chronic hepatitis C patients. Hepatitis C virus (HCV) genotype is an important factor that determines treatment outcomes among patients with chronic hepatitis C. HCV has six genotypes, and genotype 4 (G4) accounts for 20% of all global HCV infections. Patients with G4 are underrepresented in clinical trials involving patients with chronic hepatitis C because most patients infected with G4 are in Egypt, Africa, and Middle Eastern countries. Therefore, there is little information about the predictors of response to standard treatment among chronic hepatitis C patients with HCV G4. Initial evidence suggested that patients with G4 HCV are as difficult to treat as patients with G1; however, recent evidence suggests that the response rates to treatment among patients with G4 may be better than those with G1 but not those with G2 or G3. This review discusses the clinical data among patients with G4 and assesses the impact of an individualized approach on improved treatment outcomes in these patients.
Hepatitis C virus (HCV) infection is a major health problem throughout the world. Recent estimates indicate that 175 million people are infected. Advances in the treatment of HCV, such as pegylation of the interferon molecule, have been paralleled by improvements in patient outcomes. Clinical research findings published during the last 5 yr now provide physicians with the knowledge to make evidence-based recommendations on the most effective treatment. However, almost without exception, the major clinical trials of pegylated interferon, or peginterferon (PEG-IFN), plus ribavirin have been conducted in the United States and throughout Europe and have focused exclusively on the HCV genotypes prevalent in these regions. Although knowledge of the most effective approach to treating HCV genotypes 1, 2, and 3 is increasing, these advances are not reflected in our knowledge of genotypes 4, 5, and 6.
Genotype 4 HCV represents approximately 20% of global HCV infection and is the source of a considerable burden to health-care providers across the globe. Despite the high prevalence of genotype 4 HCV, we know relatively little about the most effective way to combat this disease. Although it may be tempting to extrapolate our knowledge of genotypes 1, 2, and 3 to the treatment of genotype 4, we also know that each genotype has a unique response to therapy that demands fundamental differences in treatment. Understanding the host and viral characteristics unique to patients with genotype 4 HCV is, therefore, the first step in realizing effective treatment for these patients.
In this review, I consider the evidence regarding the treatment of patients with genotype 4 HCV. I will review the relevant epidemiologic data, including geographic distribution, risk factors, and mode of transmission. Phylogenetic analysis provides insight into the global movement of the genotype 4 virus and how it matures along its migratory path. Finally, I will consider the clinical studies that specifically evaluated the treatment of genotype 4 HCV.
Prevalence. Genotype 4 is the most common variant of HCV throughout Africa and the Middle East. More than 90% of HCV isolates from Egyptian patients are of the genotype 4 variant, which is significant considering Egypt has the highest worldwide prevalence of HCV (10-20%) and an overall seroprevalence that is 10- to 20-fold higher than in the United States. In rural areas of Egypt, the prevalence of HCV reaches 24%. Other countries where genotype 4 is prevalent include the equatorial and west-central African nations of Gabon, Tanzania, Libya, and Zaire, where seroprevalence can go up to 8%.
Across much of Europe, genotype 1 is the most commonly encountered variant, particularly in northern regions, along with lower incidences of genotypes 2 and 3. However, recent evidence shows emergence of genotype 4 HCV among injection drug users (IDUs) throughout Europe; the estimated incidence of HCV in IDUs ranges from 7% in northern Europe to 24% in southern regions. Incidence is greatest in areas of Southern Europe, including Paris, France, where the genotype 4 variant is responsible for more than 10% of HCV cases.
Subtype 4a is the dominant variant found in Egypt; whereas, in Saudi Arabia, another region of high prevalence, subtype 4d is reported. Both subtypes exist in areas of Europe such as southeast France, although it appears that of the 2 subtypes, the 4d variant is the more frequently found and persists in the majority of European IDU populations. Viral genetic sequences become more heterogeneous over time; however, within the European IDU populations there is a high degree of genotype 4 homogeneity, which may suggest that the virus emerged relatively recently through a small number of introductions (perhaps even a single introduction) and has subsequently been propagated by the movement of IDUs across European borders. In the United States, genotype variants 1a and 1b predominate and the incidence of HCV genotype 4 infection is low. The majority of cases of genotype 4 infections are attributed to injection drug use and are associated with mild or moderate liver disease.
Mode of Transmission. The mode of transmission of genotype 4 HCV varies according to geographic area. In Egypt, viral transmission occurs mainly via blood transfusion, through nosocomial exposure, and during circumcision with the use of nonsterilized equipment. Intrafamilial exposure is also a primary route of transmission in rural Egypt, and having an anti-HCV positive family member is among the strongest predictors of HCV in Egypt. There is a high probability of HCV infection from an infected spouse. Husband-to-wife transmission is potentially less likely than wife-to-husband. It has been speculated that 8% of married men with HCV were exposed to the virus through their spouses, whereas 2% of married women with HCV acquired the infection from their husbands. IV drug use, a major route of transmission in areas of southern France, Italy, Greece, and Spain, is not thought to be important in the propagation of the virus within Egypt and African nations.
In contrast, IV drug use is the major route of transmission of the genotype 4 virus in western populations. In western populations, coinfection with HIV is common and the movement of infected individuals across European borders is responsible for the spread of the virus from southern Europe into regions that are more northern.
Risk Factors. A history of schistosomiasis and parenteral antischistosomal therapy is significantly associated with HCV in Egypt, whereas, in western nations, patients with a history of injection drug use or blood transfusion and those coinfected with HIV are at greater risk for HCV transmission. Parenteral treatment for schistosomiasis with nondisposable and poorly sterilized needles in the 1960s and 1970s was considered the primary risk factor for genotype 4 HCV infection in Egypt. Although the antischistosomal mass treatment campaign was subsequently discontinued, the incidence of HCV remains high possibly due to intrafamilial and sexual transmission, and occupational transmission among health-care workers. In rural areas, there is an association between HCV and marital status: prevalence rates are much higher in those individuals who are or have been married than in those who have never married (43% vs 13%, respectively). In these same rural areas, traditional scarification and tattooing practices may also contribute to transmission of the virus.
HCV replicates using an RNA polymerase that lacks the general proofreading ability. As a result, this enzyme is prone to error during replication and is thus responsible for the high genetic variability within the HCV family of viruses. It is likely that, within each infected individual, HCV circulates as a series of quasispecies that differ by up to 5% in genetic sequence. However, on a broader scale, all known HCV isolates have been categorized as 6 distinct genotypes, or clades, which are distinguished from one another by 30-50% variation in their respective nucleotide sequences. Subtypes of each genotype (e.g., a, b, c) may have an additional 15-30% heterogeneity in their sequences. For example, the 222-nucleotide NS5 region of the genotype 4a genome displays 64-68% homology with the genotype 1 through 6 subtypes.This high variability is important when considering neutralizing antibodies, which are often specific for a particular serologic type of the virus.
There is also marked genetic variability within the genotype 4 viral strain that is consistent across geographic boundaries. Although subtype 4a is the dominant Egyptian HCV strain, recent studies revealed that other subtypes exist all over Egypt. Genovese et al. performed a similar study using genotype 4 isolates from the Alexandria district of Egypt and assessing heterogeneity within the hypervariable region 1 and the NH2 region of the E2 protein. These researchers found that 78% of isolates were of the 4a variant, whereas the remaining identified variants were 4m (11%), 4o (5.5%), 4n (2.7%), and 4p (2.7%). The results of these studies indicate that HCV genotype 4 in Egypt is extremely variable not only in terms of sequence, but also in terms of functional and immunologic determinants.
Genotype 4 is also predominant in Saudi Arabia, constituting 62% of HCV infection, followed by genotypes 1 (24%), 3 (9%), and 5 (0.3%). Unlike the predominance of subtype 4a in Egypt, subtypes 4c/4d are the most prevalent in Saudi Arabia, suggesting that the origin and transmission of genotype 4 in this country might be different from that in Egypt. Nicot et al. also performed a phylogenetic analysis of the NS5B region of HCV genotype 4 strains in the mid-Pyrenees area of southwest France. They found two main subtypes, 4a (44% of HCV genotype 4) and 4d (34% of HCV genotype 4); however, there were also 10 additional less common variants, each of which contributed between 1% and 5% of the HCV genotype 4 population (4k, 4f, 4r, 4t, 4c, 4h, 4i, 4n, 4o, and 4p). IDUs were infected almost exclusively with the 4a and 4d variants. Patients who acquired HCV via transfusion or nosocomial, interfamilial, or undetermined routes were further classified based on geographic origin: French patients were infected with eight subtypes (but still mainly 4a and 4d), whereas patients from central Africa were infected with various subtypes, including 4f (28%), 4k (28%), 4r (12%), and 4u (12%).
Little is known about the natural history of acute HCV genotype 4 infection. Few prospective studies have revealed a higher rate of spontaneous resolution in patients with acute HCV genotype 4 compared to those infected with genotype 1. The rates of fibrosis progression were not significantly different between patients with chronic HCV genotype 1 and HCV genotype 4 monoinfections. Chronic HCV genotype 4 is associated with hepatic steatosis. Preliminary evidence suggests that genotype 4 HCV infection may place patients at greater risk for hepatocellular carcinoma than other HCV variants. Some studies have indicated a link between subtype HCV genotype 4 non-Hodgkin's lymphoma.
Following liver transplantation, patients with genotype 4 have experienced significantly greater fibrosis progression rates and are significantly more likely to have severe fibrosis cirrhosis than are nongenotype 4 patients. In this study of 128 patients, the 5-yr cumulative risk for development of severe fibrosis was 24% in nongenotype 4 patients and 85% in patients with genotype 4. Furthermore, confluent necrosis was observed in more than 50% of the patients with genotype 4 and in less than 25% of nongenotype 4 patients.
Concurrent Schistomsoma mansoni infection may have an important impact on the outcome of liver disease in patients with HCV, with a higher incidence of cirrhosis and elevated risk for hepatocellular carcinoma seen in HCV genotype 4 and schistosomiasis coinfected patients than in those with HCV alone. Hepatocellular carcinoma developed in up to 11% of coinfected individuals, with an eventual mortality rate of 23%. Conversely, no patients with HCV genotype 4 or with schistosomiasis alone experienced hepatocellular carcinoma. In addition, histology scores for grade (total inflammatory score) and stage (fibrosis/cirrhosis score) were significantly higher in coinfected individuals.
Early reports indicated that patients with genotype 4 HCV infection responded as poorly to interferon monotherapy as patients with genotype 1, with sustained virologic response rates (SVRs) of 5-10%. In comparative clinical studies, SVRs improved (range 8-42%) in patients with genotype 4 infection (Fig. 1) with the addition of ribavirin to interferon alfa. However, these studies also showed that responses to combination therapy were poorer in patients with genotype 4 with cirrhosis than in those without advanced liver disease, suggesting that early intervention before the advancement of liver disease may aid efficacy outcomes.
Combination therapy with interferon plus ribavirin is more effective than interferon monotherapy in patients with genotype 4 hepatitis C virus (*P < 0.05 vs monotherapy). EOT = end of treatment; SVR = sustained virologic response.
Figure 1: Combination therapy with interferon plus ribavirin is more effective than interferon monotherapy in patients with genotype 4 hepatitis C virus (*
P < 0.05
vs monotherapy).
The efficacy of PEG-IFN plus ribavirin for treating HCV populations was established in large clinical trials in western countries comprising mainly genotypes 1, 2, and 3. However, because these studies included small numbers of patients with genotype 4 virus (<3%), the outcomes of these studies are not directly applicable to the greater genotype 4 population. Given that the major prevalence of genotype 4 HCV is throughout Egypt and Africa, it is unsurprising that comparatively little clinical research has been conducted regarding the efficacy and safety of combination therapy in this population. However, because up to 20% of the 175 million global cases of HCV are genotype 4, effective, individually tailored treatment approaches are imperative.
Two open-label studies have compared combination therapy with PEG-IFN alfa-2bplus ribavirin with conventional interferon plus ribavirin for treatment of genotype 4 chronic HCV ( Table 1 ). A randomized, parallel group study enrolling Saudi patients who have chronic genotype 4 HCV reported that SVRs were higher in patients receiving combination therapy with PEG-IFN alfa-2b plus ribavirin than in patients receiving conventional interferon plus ribavirin; however, the differences between treatment groups did not reach statistical significance. In another study, patients were allocated to combination therapy with PEG-IFN alfa-2b for 24 or 48 wk or to an induction dose regimen based on conventional interferon, according to the patient's ability to finance treatment. This study reported significantly improved SVRs with PEG-IFN alfa-2b compared with the conventional interferon regimen. Cost is a particularly important factor in allocating treatment in the developing countries of the Middle East where HCV genotype 4 is most prevalent; however, the unique criteria used to assign treatment in this study may also have introduced some bias, and it is unclear to what extent the PEG-IFN treatment groups represent a higher socioeconomic class with access to generally improved standards of health care, diet, and other potentially confounding variables. These two studies show that, in patients with genotype 4 HCV, treatment with PEG-IFN alfa-2b plus ribavirin results in improved sustained outcomes compared with conventional interferon-based therapy. This conclusion is also indirectly supported by the favorable results of an open-label, single-treatment study that reported that SVRs of 68% were achievable in treatment-naive patients with genotype 4 HCV who were receiving PEG-IFN alfa-2b plus ribavirin for 48 wk.
Preliminary observations from retrospective studies also suggest that PEG-IFN plus ribavirin is more effective in HCV monoinfected patients than in those coinfected with HCV genotype 4 and HIV and that, overall, response rates in patients with genotype 4 are similar to those reported for genotype 1 patients. These observations require confirmation.
Defining the optimal treatment duration ensures successful long-term treatment outcomes using the shortest possible treatment duration to reduce expenditure and tolerability concerns. Although patients with genotype 1 HCV generally receive treatment for 48 wk, there is considerable evidence that shorter treatment durations may be effective for genotypes 2 and 3.
A recent double-blind, randomized study was conducted to determine the optimum treatment duration for patients with genotype 4. In this study, patients received PEG-IFN alfa-2b and ribavirin, each delivered according to a weight-based administration schedule for 24, 36, or 48 wk ( Table 1 ). In this study, end-of-treatment responses and SVRs were significantly higher in patients receiving treatment for 36 or 48 wk (66% and 69%, respectively) than in those allocated to the 24-wk regimen (29%) (P = 0.001).
This study also reported important information regarding the influence of relapse rates, early virologic response (EVR), and pretreatment viral load in patients with genotype 4. Relapse rates during follow-up were one of the main factors affecting the final study outcomes. However, relatively high relapse rates were observed in the 24-wk treatment group (20 of 45 patients who achieved end-of-treatment response subsequently experienced relapse). Patients from the 36- or 48-wk treatment arms who achieved an end-of-treatment response invariably also achieved an SVR (Fig. 2). EVR was also an important factor in determining the study outcomes. In total, 25 (38%) of 66, 63 (97%) of 65, and 66 (100%) of 66 patients with an EVR had an SVR in the 24-, 36-, and 48-wk treatment groups, respectively. Importantly, EVR was associated with a 100% negative predictive value—no patient without an EVR had an SVR, regardless of treatment duration. Finally, extended treatment duration was also important in patients with a high pretreatment viral load. Of the patients with HCV RNA levels more than 2 million copies/mL at baseline who had an SVR, 65% received therapy for 48 wk and 35% received treatment for 36 wk. No patients with a high pretreatment viral load had SVR with the 24-wk regimen.
The incidence of dose reductions in this study may also help to define the most appropriate dosage regimen. Although the frequency and type of general adverse events were similar in each group, PEG-IFN dose reductions were significantly more common in patients receiving 48 wk of therapy than in those receiving 24 or 36 wk of therapy (P < 0.05). Therefore, patients with long-term genotype 4 HCV infection may benefit from treatment with PEG-IFN alfa-2b 1.5 µg/kg/week plus ribavirin 1,000-1,200 mg/day for 36 wk. This treatment regimen offers efficacy similar to that of longer treatment durations while reducing tolerability concerns.
Abstract and Introduction
Abstract
Several factors influence treatment outcomes among patients with chronic hepatitis C. A trend is growing to adapt an individualized treatment approach to optimize treatment outcomes among chronic hepatitis C patients. Hepatitis C virus (HCV) genotype is an important factor that determines treatment outcomes among patients with chronic hepatitis C. HCV has six genotypes, and genotype 4 (G4) accounts for 20% of all global HCV infections. Patients with G4 are underrepresented in clinical trials involving patients with chronic hepatitis C because most patients infected with G4 are in Egypt, Africa, and Middle Eastern countries. Therefore, there is little information about the predictors of response to standard treatment among chronic hepatitis C patients with HCV G4. Initial evidence suggested that patients with G4 HCV are as difficult to treat as patients with G1; however, recent evidence suggests that the response rates to treatment among patients with G4 may be better than those with G1 but not those with G2 or G3. This review discusses the clinical data among patients with G4 and assesses the impact of an individualized approach on improved treatment outcomes in these patients.
Introduction
Hepatitis C virus (HCV) infection is a major health problem throughout the world. Recent estimates indicate that 175 million people are infected. Advances in the treatment of HCV, such as pegylation of the interferon molecule, have been paralleled by improvements in patient outcomes. Clinical research findings published during the last 5 yr now provide physicians with the knowledge to make evidence-based recommendations on the most effective treatment. However, almost without exception, the major clinical trials of pegylated interferon, or peginterferon (PEG-IFN), plus ribavirin have been conducted in the United States and throughout Europe and have focused exclusively on the HCV genotypes prevalent in these regions. Although knowledge of the most effective approach to treating HCV genotypes 1, 2, and 3 is increasing, these advances are not reflected in our knowledge of genotypes 4, 5, and 6.
Genotype 4 HCV represents approximately 20% of global HCV infection and is the source of a considerable burden to health-care providers across the globe. Despite the high prevalence of genotype 4 HCV, we know relatively little about the most effective way to combat this disease. Although it may be tempting to extrapolate our knowledge of genotypes 1, 2, and 3 to the treatment of genotype 4, we also know that each genotype has a unique response to therapy that demands fundamental differences in treatment. Understanding the host and viral characteristics unique to patients with genotype 4 HCV is, therefore, the first step in realizing effective treatment for these patients.
In this review, I consider the evidence regarding the treatment of patients with genotype 4 HCV. I will review the relevant epidemiologic data, including geographic distribution, risk factors, and mode of transmission. Phylogenetic analysis provides insight into the global movement of the genotype 4 virus and how it matures along its migratory path. Finally, I will consider the clinical studies that specifically evaluated the treatment of genotype 4 HCV.
Epidemiology
Prevalence. Genotype 4 is the most common variant of HCV throughout Africa and the Middle East. More than 90% of HCV isolates from Egyptian patients are of the genotype 4 variant, which is significant considering Egypt has the highest worldwide prevalence of HCV (10-20%) and an overall seroprevalence that is 10- to 20-fold higher than in the United States. In rural areas of Egypt, the prevalence of HCV reaches 24%. Other countries where genotype 4 is prevalent include the equatorial and west-central African nations of Gabon, Tanzania, Libya, and Zaire, where seroprevalence can go up to 8%.
Across much of Europe, genotype 1 is the most commonly encountered variant, particularly in northern regions, along with lower incidences of genotypes 2 and 3. However, recent evidence shows emergence of genotype 4 HCV among injection drug users (IDUs) throughout Europe; the estimated incidence of HCV in IDUs ranges from 7% in northern Europe to 24% in southern regions. Incidence is greatest in areas of Southern Europe, including Paris, France, where the genotype 4 variant is responsible for more than 10% of HCV cases.
Subtype 4a is the dominant variant found in Egypt; whereas, in Saudi Arabia, another region of high prevalence, subtype 4d is reported. Both subtypes exist in areas of Europe such as southeast France, although it appears that of the 2 subtypes, the 4d variant is the more frequently found and persists in the majority of European IDU populations. Viral genetic sequences become more heterogeneous over time; however, within the European IDU populations there is a high degree of genotype 4 homogeneity, which may suggest that the virus emerged relatively recently through a small number of introductions (perhaps even a single introduction) and has subsequently been propagated by the movement of IDUs across European borders. In the United States, genotype variants 1a and 1b predominate and the incidence of HCV genotype 4 infection is low. The majority of cases of genotype 4 infections are attributed to injection drug use and are associated with mild or moderate liver disease.
Mode of Transmission. The mode of transmission of genotype 4 HCV varies according to geographic area. In Egypt, viral transmission occurs mainly via blood transfusion, through nosocomial exposure, and during circumcision with the use of nonsterilized equipment. Intrafamilial exposure is also a primary route of transmission in rural Egypt, and having an anti-HCV positive family member is among the strongest predictors of HCV in Egypt. There is a high probability of HCV infection from an infected spouse. Husband-to-wife transmission is potentially less likely than wife-to-husband. It has been speculated that 8% of married men with HCV were exposed to the virus through their spouses, whereas 2% of married women with HCV acquired the infection from their husbands. IV drug use, a major route of transmission in areas of southern France, Italy, Greece, and Spain, is not thought to be important in the propagation of the virus within Egypt and African nations.
In contrast, IV drug use is the major route of transmission of the genotype 4 virus in western populations. In western populations, coinfection with HIV is common and the movement of infected individuals across European borders is responsible for the spread of the virus from southern Europe into regions that are more northern.
Risk Factors. A history of schistosomiasis and parenteral antischistosomal therapy is significantly associated with HCV in Egypt, whereas, in western nations, patients with a history of injection drug use or blood transfusion and those coinfected with HIV are at greater risk for HCV transmission. Parenteral treatment for schistosomiasis with nondisposable and poorly sterilized needles in the 1960s and 1970s was considered the primary risk factor for genotype 4 HCV infection in Egypt. Although the antischistosomal mass treatment campaign was subsequently discontinued, the incidence of HCV remains high possibly due to intrafamilial and sexual transmission, and occupational transmission among health-care workers. In rural areas, there is an association between HCV and marital status: prevalence rates are much higher in those individuals who are or have been married than in those who have never married (43% vs 13%, respectively). In these same rural areas, traditional scarification and tattooing practices may also contribute to transmission of the virus.
HCV replicates using an RNA polymerase that lacks the general proofreading ability. As a result, this enzyme is prone to error during replication and is thus responsible for the high genetic variability within the HCV family of viruses. It is likely that, within each infected individual, HCV circulates as a series of quasispecies that differ by up to 5% in genetic sequence. However, on a broader scale, all known HCV isolates have been categorized as 6 distinct genotypes, or clades, which are distinguished from one another by 30-50% variation in their respective nucleotide sequences. Subtypes of each genotype (e.g., a, b, c) may have an additional 15-30% heterogeneity in their sequences. For example, the 222-nucleotide NS5 region of the genotype 4a genome displays 64-68% homology with the genotype 1 through 6 subtypes.This high variability is important when considering neutralizing antibodies, which are often specific for a particular serologic type of the virus.
There is also marked genetic variability within the genotype 4 viral strain that is consistent across geographic boundaries. Although subtype 4a is the dominant Egyptian HCV strain, recent studies revealed that other subtypes exist all over Egypt. Genovese et al. performed a similar study using genotype 4 isolates from the Alexandria district of Egypt and assessing heterogeneity within the hypervariable region 1 and the NH2 region of the E2 protein. These researchers found that 78% of isolates were of the 4a variant, whereas the remaining identified variants were 4m (11%), 4o (5.5%), 4n (2.7%), and 4p (2.7%). The results of these studies indicate that HCV genotype 4 in Egypt is extremely variable not only in terms of sequence, but also in terms of functional and immunologic determinants.
Genotype 4 is also predominant in Saudi Arabia, constituting 62% of HCV infection, followed by genotypes 1 (24%), 3 (9%), and 5 (0.3%). Unlike the predominance of subtype 4a in Egypt, subtypes 4c/4d are the most prevalent in Saudi Arabia, suggesting that the origin and transmission of genotype 4 in this country might be different from that in Egypt. Nicot et al. also performed a phylogenetic analysis of the NS5B region of HCV genotype 4 strains in the mid-Pyrenees area of southwest France. They found two main subtypes, 4a (44% of HCV genotype 4) and 4d (34% of HCV genotype 4); however, there were also 10 additional less common variants, each of which contributed between 1% and 5% of the HCV genotype 4 population (4k, 4f, 4r, 4t, 4c, 4h, 4i, 4n, 4o, and 4p). IDUs were infected almost exclusively with the 4a and 4d variants. Patients who acquired HCV via transfusion or nosocomial, interfamilial, or undetermined routes were further classified based on geographic origin: French patients were infected with eight subtypes (but still mainly 4a and 4d), whereas patients from central Africa were infected with various subtypes, including 4f (28%), 4k (28%), 4r (12%), and 4u (12%).
Little is known about the natural history of acute HCV genotype 4 infection. Few prospective studies have revealed a higher rate of spontaneous resolution in patients with acute HCV genotype 4 compared to those infected with genotype 1. The rates of fibrosis progression were not significantly different between patients with chronic HCV genotype 1 and HCV genotype 4 monoinfections. Chronic HCV genotype 4 is associated with hepatic steatosis. Preliminary evidence suggests that genotype 4 HCV infection may place patients at greater risk for hepatocellular carcinoma than other HCV variants. Some studies have indicated a link between subtype HCV genotype 4 non-Hodgkin's lymphoma.
Following liver transplantation, patients with genotype 4 have experienced significantly greater fibrosis progression rates and are significantly more likely to have severe fibrosis cirrhosis than are nongenotype 4 patients. In this study of 128 patients, the 5-yr cumulative risk for development of severe fibrosis was 24% in nongenotype 4 patients and 85% in patients with genotype 4. Furthermore, confluent necrosis was observed in more than 50% of the patients with genotype 4 and in less than 25% of nongenotype 4 patients.
Concurrent Schistomsoma mansoni infection may have an important impact on the outcome of liver disease in patients with HCV, with a higher incidence of cirrhosis and elevated risk for hepatocellular carcinoma seen in HCV genotype 4 and schistosomiasis coinfected patients than in those with HCV alone. Hepatocellular carcinoma developed in up to 11% of coinfected individuals, with an eventual mortality rate of 23%. Conversely, no patients with HCV genotype 4 or with schistosomiasis alone experienced hepatocellular carcinoma. In addition, histology scores for grade (total inflammatory score) and stage (fibrosis/cirrhosis score) were significantly higher in coinfected individuals.
Treatment of HCV Genotype 4 Infection
Early reports indicated that patients with genotype 4 HCV infection responded as poorly to interferon monotherapy as patients with genotype 1, with sustained virologic response rates (SVRs) of 5-10%. In comparative clinical studies, SVRs improved (range 8-42%) in patients with genotype 4 infection (Fig. 1) with the addition of ribavirin to interferon alfa. However, these studies also showed that responses to combination therapy were poorer in patients with genotype 4 with cirrhosis than in those without advanced liver disease, suggesting that early intervention before the advancement of liver disease may aid efficacy outcomes.
Combination therapy with interferon plus ribavirin is more effective than interferon monotherapy in patients with genotype 4 hepatitis C virus (*P < 0.05 vs monotherapy). EOT = end of treatment; SVR = sustained virologic response.
The efficacy of PEG-IFN plus ribavirin for treating HCV populations was established in large clinical trials in western countries comprising mainly genotypes 1, 2, and 3. However, because these studies included small numbers of patients with genotype 4 virus (<3%), the outcomes of these studies are not directly applicable to the greater genotype 4 population. Given that the major prevalence of genotype 4 HCV is throughout Egypt and Africa, it is unsurprising that comparatively little clinical research has been conducted regarding the efficacy and safety of combination therapy in this population. However, because up to 20% of the 175 million global cases of HCV are genotype 4, effective, individually tailored treatment approaches are imperative.
Two open-label studies have compared combination therapy with PEG-IFN alfa-2bplus ribavirin with conventional interferon plus ribavirin for treatment of genotype 4 chronic HCV ( Table 1 ). A randomized, parallel group study enrolling Saudi patients who have chronic genotype 4 HCV reported that SVRs were higher in patients receiving combination therapy with PEG-IFN alfa-2b plus ribavirin than in patients receiving conventional interferon plus ribavirin; however, the differences between treatment groups did not reach statistical significance. In another study, patients were allocated to combination therapy with PEG-IFN alfa-2b for 24 or 48 wk or to an induction dose regimen based on conventional interferon, according to the patient's ability to finance treatment. This study reported significantly improved SVRs with PEG-IFN alfa-2b compared with the conventional interferon regimen. Cost is a particularly important factor in allocating treatment in the developing countries of the Middle East where HCV genotype 4 is most prevalent; however, the unique criteria used to assign treatment in this study may also have introduced some bias, and it is unclear to what extent the PEG-IFN treatment groups represent a higher socioeconomic class with access to generally improved standards of health care, diet, and other potentially confounding variables. These two studies show that, in patients with genotype 4 HCV, treatment with PEG-IFN alfa-2b plus ribavirin results in improved sustained outcomes compared with conventional interferon-based therapy. This conclusion is also indirectly supported by the favorable results of an open-label, single-treatment study that reported that SVRs of 68% were achievable in treatment-naive patients with genotype 4 HCV who were receiving PEG-IFN alfa-2b plus ribavirin for 48 wk.
Preliminary observations from retrospective studies also suggest that PEG-IFN plus ribavirin is more effective in HCV monoinfected patients than in those coinfected with HCV genotype 4 and HIV and that, overall, response rates in patients with genotype 4 are similar to those reported for genotype 1 patients. These observations require confirmation.
Optimizing the Use of PEG-IFN Alfa-2b Plus Ribavirin in Patients With Genotype 4
Defining the optimal treatment duration ensures successful long-term treatment outcomes using the shortest possible treatment duration to reduce expenditure and tolerability concerns. Although patients with genotype 1 HCV generally receive treatment for 48 wk, there is considerable evidence that shorter treatment durations may be effective for genotypes 2 and 3.
A recent double-blind, randomized study was conducted to determine the optimum treatment duration for patients with genotype 4. In this study, patients received PEG-IFN alfa-2b and ribavirin, each delivered according to a weight-based administration schedule for 24, 36, or 48 wk ( Table 1 ). In this study, end-of-treatment responses and SVRs were significantly higher in patients receiving treatment for 36 or 48 wk (66% and 69%, respectively) than in those allocated to the 24-wk regimen (29%) (P = 0.001).
This study also reported important information regarding the influence of relapse rates, early virologic response (EVR), and pretreatment viral load in patients with genotype 4. Relapse rates during follow-up were one of the main factors affecting the final study outcomes. However, relatively high relapse rates were observed in the 24-wk treatment group (20 of 45 patients who achieved end-of-treatment response subsequently experienced relapse). Patients from the 36- or 48-wk treatment arms who achieved an end-of-treatment response invariably also achieved an SVR (Fig. 2). EVR was also an important factor in determining the study outcomes. In total, 25 (38%) of 66, 63 (97%) of 65, and 66 (100%) of 66 patients with an EVR had an SVR in the 24-, 36-, and 48-wk treatment groups, respectively. Importantly, EVR was associated with a 100% negative predictive value—no patient without an EVR had an SVR, regardless of treatment duration. Finally, extended treatment duration was also important in patients with a high pretreatment viral load. Of the patients with HCV RNA levels more than 2 million copies/mL at baseline who had an SVR, 65% received therapy for 48 wk and 35% received treatment for 36 wk. No patients with a high pretreatment viral load had SVR with the 24-wk regimen.
|
|
Figure 2. (click image to zoom) Relapse rates during 24-wk follow-up among patients who achieved end-of-treatment response when receiving PEG-IFN alfa-2b plus ribavirin for 24, 36, or 48 wk. |
The incidence of dose reductions in this study may also help to define the most appropriate dosage regimen. Although the frequency and type of general adverse events were similar in each group, PEG-IFN dose reductions were significantly more common in patients receiving 48 wk of therapy than in those receiving 24 or 36 wk of therapy (P < 0.05). Therefore, patients with long-term genotype 4 HCV infection may benefit from treatment with PEG-IFN alfa-2b 1.5 µg/kg/week plus ribavirin 1,000-1,200 mg/day for 36 wk. This treatment regimen offers efficacy similar to that of longer treatment durations while reducing tolerability concerns.
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