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Latinos and Chronic Hepatitis C: A Singular Population
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Clinical Gastroenterology and Hepatology
May 2008
Maribel Rodriguez-Torres
Conclusion
Latinos are the largest minority in the USA and have high rates of HCV infection as well as other viral infections. The course of CHC in Latinos is more aggressive, with more risk to develop cirrhosis. Emerging evidence suggests that Latinos have decreased efficacy to treatment with Peg IFN and RBV. Factors related to metabolic syndrome, IR, and hepatic steatosis as well as genetic differences not only for metabolic syndrome but for immune responses to IFN are important pathophysiologic mechanisms. In addition, there are substantial barriers for Latinos to access medical care. Language and cultural differences and socioeconomic factors, including lack of medical insurance, higher use of alcohol, and possibly bias, are noteworthy obstacles to diagnosis and treatment. The severity of the liver disease and the association to the constellation of metabolic syndrome medical conditions justify that Latinos be considered a special population with urgent need of intervention strategies. Culturally structured educational programs to achieve earlier diagnosis and treatment in Latinos with HCV infection are badly needed. Aggressive alcohol and substance use intervention, including education and training of IDU to decrease high risk behavior and reduce the number of new HCV infections, is of extreme importance. Research in Latino CHC population is essential to elucidate efficacy rates, predictors of SVR, and to consider strategies to improve SVR. Research is also necessary to scrutinize genetic and immune differences that impact HCV clearance, progression of liver disease, and response to therapy. To circumvent host-related complexity to clear HCV infection with present therapies, Latinos should be considered a priority population for research in STAT-C trials. To continue the current passive approach to the Latino HCV-infected population will have dire consequences during the next decades. It will result in a serious public health problem, with significant increase in medical costs and use of medical resources but, most importantly, loss of lives caused by end-stage liver disease.
Latinos are the largest minority in the USA and have higher rates of HCV infection. The course of chronic hepatitis C in Latinos is more aggressive, with higher risk to develop cirrhosis than any other ethnic group or race. Available information suggests that more rapid progression of liver disease is aggravated by decreased efficacy to treatment with available therapies. The causes for more aggressive progression and decreased efficacy of treatment are complex. Factors related to metabolic syndrome, insulin resistance, and hepatic steatosis are important, as well as genetic differences, not only for metabolic syndrome but for immune responses to interferon. In addition, there are substantial barriers for Latinos to access medical care. Language, cultural differences, and socioeconomic factors, including lack of medical insurance, more frequent use of alcohol, and possible medical care provider bias, are significant obstacles to diagnosis and treatment. The severity of the liver disease and the association to metabolic syndrome medical conditions justify that Latinos be considered a special population with urgent need of intervention strategies. In this article we present all the available evidence on epidemiology, natural history of chronic hepatitis C, and efficacy of anti-HCV therapy in Latinos infected with HCV.
HCV is the most common blood-borne infection in the United States.1 Chronic hepatitis C (CHC) can lead to cirrhosis of the liver, end-stage liver disease, hepatocellular carcinoma (HCC), and is the most frequent cause of liver transplantation. In March 2002 there were 37.4 million Latinos in the United States, representing 13.3% of the total population and the largest and the faster growing minority in the total population.2 Two thirds (66.9%) were of Mexican origin, 14.3% were from Central and South America, 8.6% were Puerto Rican (including both those living in Puerto Rico and the continental U.S.), 3.7% Cuban American, and 6.5% from other Latino country origin. The growth of the Latino population is estimated to reach 18.3% of the total population for the year 2025.2 Reports from Centers of Disease Control and Prevention have shown that although total new cases have declined since 1989, new cases in African Americans and Latinos are increasing.1, 2, 3 There is evidence of higher histologic activity and higher fibrosis progression rates in Latinos than in whites and African Americans.4, 5 Despite these facts, Latinos have been underrepresented in clinical research and undertreated for a variety of medical conditions.6 This underrepresentation is evident in pivotal CHC clinical trials and extends to treatment of CHC in the general community. The congruency of large number of patients, higher prevalence, and more rapid fibrosis progression envisages HCV infection as a severe public health concern in Latinos. It is the purpose of this article to review the available information regarding epidemiology, course of CHC, and efficacy of anti-HCV treatment in Latinos. The information of the epidemiology and natural course of CHC that is reported was obtained from multiple retrospective studies or cross-sectional population analysis.
The Latino Population in the United States
The term Latino evokes the commonality of people from Latin America regarding geography, history, and cultural background and heritage. It is preferred to the term Hispanic because it is more representative of the diversity of the many Latin American countries. Latino means ethnicity, not race, and Latinos might be of any race. Latinos might have racial characteristics from Indian, black, Asian, or white European, or a combination of features. Hispanics have been recognized at the U.S. Census Bureau as a different ethnic group since the 1970s and include people from predominantly Spanish-speaking countries in the Western hemisphere such as Mexico, Central and South America (except Brazil), Puerto Rico, Dominican Republic, and their descendants.7 The federal government recognizes the ethnicity of Latinos as described and the racial group as self-informed by the subjects.
It is projected that by the year 2040 there will be 87.5 million Hispanic individuals, comprising 22.3% of the population.8
Although Latinos share many aspects of common heritage and language, cultural and other differences exist among Latinos from different countries, including differences in public health profiles and health outcomes. For all Latinos, there are disparities in access to medical care and poor health outcomes compared with whites.9
With data from National Vital Statistics System and the 1990 and 2000 Censuses, age-specific diabetes-related death rates were calculated. Diabetes-related deaths were 2- fold more numerous among Mexican Americans and Puerto Ricans than for Cuban Americans. Socioeconomic factors such as income and achieved level of education are factors that add to the diversity among Hispanic populations.10
Epidemiology of Hepatitis C Virus Infection in Latinos
Ethnicity impacts all features of HCV infection: epidemiology, natural history, and treatment access and outcomes.11 According to the National Health and Nutrition Examination Survey 111 data, between 1988 and 1994, the prevalence of HCV infection in Latinos was higher than for whites in all age groups.1 For Mexican Americans, the only Latino population examined, prevalence rates increased from 2% in the 20- to 29-year age group to 6% in the 50- to 59-year group, representing 6 times the rates for whites.12
The only reported prevalence study in a 100% Latino population was performed at the city of San Juan, Puerto Rico and reported HCV-antibody-positive in 6.3% of the population.13
It is noteworthy that chronic liver disease and cirrhosis are the 4th most common cause of death among Latinos, which is a strong signal of the future impact of HCV infection in this population.14
Natural History of Hepatitis C Virus Infection in Latinos
Risk Factors for Infection
Established risk factors for HCV infection are injecting drug use (IDU), blood transfusions, and solid organ transplantation before 1992, use of coagulation factors before 1987, vertical transmission, and multiple sexual partners.
Prevalence studies to assess the real number of HCV-infected patients are especially difficult in urban areas and among active IDUs. A report on prevalence and correlates of HCV infection among active IDUs in Puerto Rico reported high rates of HCV infection of 89%. Those who initiated IDU had a 57% infection rate within a year of IDU. Similar to other studies, predictors for HCV infection were increasing years of injection, injecting in shooting galleries, and self-reported sexually transmitted disease infections.15
This study demonstrated, as has been reported, that history of IDU is the most important risk factor for HCV infection in Latinos as in any other ethnic or racial group.16, 17
This study also confirmed findings from a study conducted in IDU at California that found Latinos to have the highest proportion of HCV coinfection with HAV and HBV.18
Studies performed to better understand the risk behavior among IDU have shown that duration of use and sharing drug use paraphernalia are predictive of HCV infection.19 Other studies have reported on behavior differences among IDU Latino populations. Mexican Americans and Puerto Ricans were found to inject more frequently, share more paraphernalia, and disinfect less often with bleach than African Americans.20
Characteristics of Chronic Hepatitis C in Latinos
Hepatitis C Virus Genotype
Contrary to African Americans, who are reported to have higher rates of genotype 1 infection, Latinos have the same risk of infection with genotype 1 HCV as whites and other ethnic groups.18, 22 A study that examined HCV-infected Latino patients under treatment by community physicians found infection with genotype 1 to be the most common, comprising 82% of cases, with 1a the most common variant present in 39.8% of patients. Patients with non-genotype 1 were detected in 18%, with genotype 2b present in 9.8% of cases.23 Among HCV/human immunodeficiency virus (HIV) coinfected patients, genotype 1, particularly 1a, was the most common, followed by 1b and 3a. Genotype 1a was especially common among women. Mixed infections and undetermined virus were present in a minority of patients.24
Age, Gender, and Concomitant Illnesses
Latinos are infected at younger age than whites and African Americans, are predominantly male, and are more frequently coinfected with HIV.17, 21, 25 A review of HCV/HIV coinfected patients in the Veterans Administration Hospitals found that this population was more likely to be Latino or African American and to have more diagnoses of mental disease including depression, alcohol abuse, and both substance and hard drug use than the HIV monoinfected.26
Severity of Chronic Hepatitis C in Latinos
There is evidence of a more aggressive CHC course in Latinos. Latinos have been reported to have higher serum ALT levels,21, 27 AST levels, total bilirubin, and lower albumin levels than Asians, African Americans, or whites.21 Latinos have higher portal inflammation scores on liver biopsy than whites or African Americans and higher prevalence of cirrhosis than African Americans.27 A study of CHC in ethnic minorities performed in California found Latinos to be overrepresented (51%), as compared with the non-Latino population. African Americans and whites had significantly lower fibrosis progression rate than Latinos; 0.03 F/y and 0.02 F/y, respectively, compared with 0.21 F/y in Latinos.4
In a revision comprising 232 Latino and non-Latino whites from the Los Angeles County Hepatitis Clinic, Latinos were found to have more fibrosis (staging), necroinflamation (grading), faster fibrosis progression rate of 0.14 F/y, and more than 33% had cirrhosis at index biopsy.28 In this study, Latinos were heavier (body mass index >30 kg/m2) and more frequently had diabetes mellitus, hepatic steatosis (79%), and obesity (50%).28 After adjusting for age, diabetes, and alcohol, independent predictors for hepatic steatosis were Latino ethnicity and obesity. Independent predictors of fibrosis staging >4 were grading 1-2; hepatic steatosis; diabetes, AST/ALT ratio >1, grading, age at biopsy, and total serum bilirubin.28
Although IDU is the most important risk factor, history of blood transfusions also appears to be more common among Latinos than in African Americans or whites.17, 21
Rodriguez-Torres et al17 reported a retrospective study that examined time to cirrhosis in 470 Latino patients. A rapid progression to cirrhosis was shown, with 50% of patients documented to be cirrhotic at median time of 42 years after infection but at relatively young median age of 53 years. It was also shown that the overall HCV/HIV coinfected population had a more rapid progression to cirrhosis than the HCV monoinfected patients. However, there was a marked difference in the risk to cirrhosis along gender, with monoinfected men having as severe a risk as the coinfected men, whereas HCV-infected women had lower risk to cirrhosis than the HCV/HIV coinfected. Similar to other reports, independent predictors of cirrhosis were male sex, age at time of biopsy, grading in the HCV monoinfected, and ALT levels in the HCV/HIV coinfected patients.17
These studies suggested that cirrhosis as a result of HCV infection might develop in a significantly higher number of Latino patients, 50%, as compared with whites, with an estimated risk around 30%.17, 29 These findings contrast to reports in another minority, African Americans, where milder biochemical and histologic liver disease is present.30
Hepatocellular Carcinoma in Latinos
There is limited information on the incidence of HCC in Latinos. A study comparing the cancer incidence among Hispanics and non-Hispanic populations from data of 15 central cancer registries found that cancers with lesser impact in the non-Hispanic population were more commonly diagnosed in Hispanics such as liver, gallbladder, penis, and cervix.31 In a population-based case-control study, diabetes was found to be associated to a 2-fold to 3-fold increase in the risk for HCC, regardless of other risk factors.32 These findings are important because both diabetes and HCV infection are common among Latinos.33 History of diabetes, especially among those who have received insulin therapy, is significantly associated to HCC among non-Asians in Los Angeles County.34 In a study from the Florida Cancer Registry for the years 1985-1995, the annual incidence of HCC among male and female Hispanics and African Americans was consistently and significantly twice the rates of non-Latino whites.35
Factors That Affect Progression to Cirrhosis
Alcohol Ingestion
Chronic alcohol ingestion is well-documented to increase rates of fibrosis progression and risk to cirrhosis.36, 37 The prevalence rates of past heavy drinking among Mexican Americans and Puerto Rican men are 3 times higher than rates reported for non-Hispanic men. With data from the Hispanic Health and Nutrition Examination Survey, it was found that 28%-35% of Mexican Americans and Puerto Ricans reported past heavy drinking, whereas rates for Cuban men was lower, 7%-16%. The average reported years of alcohol use were 2.3-14.9 years and alcohol consumption of 24.4-44.0 drinks per week. The rates of past heavy drinking for Hispanic women were much lower (1%-8%).38
The Puerto Rico Substance Abuse Program conducted a cross-sectional survey of noninstitutionalized, nontransient adolescents and adults living in Puerto Rico between ages 15-64. Around 55.7% of total population admitted to have used alcohol during the previous year. Data from year 2002 showed that 47.3% of the population ingested alcohol (more than 5 drinks at least once), men (49.7%) more than women (35.9%). The percentage of patients who admitted abuse and dependence to alcohol ranged according to sex and age group, from 10.9%-25.7% in men and from 2.5%-9.2% in women.39
Hepatic Steatosis, Metabolic Syndrome, and Insulin Resistance
Hepatic steatosis is a frequent finding in patients infected with HCV and is associated with accelerated progression of fibrosis.40, 41 It has been shown that alcohol and steatosis act additively to increase fibrosis,40 and worsening liver steatosis has been associated to fibrosis progression in paired biopsy studies.42 In patients infected with HCV, steatosis might be caused by metabolic factors, host factors such as alcoholism or age, or by viral factors such as being infected with HCV genotype 3.43, 44
The metabolic syndrome is a group of risk factors for atherosclerotic cardiovascular disease, with clinical diagnosis being based on the presence of abdominal obesity (waist-to-hip ratio and/or body mass index), dyslipidemia, hypertension, and insulin resistance (IR) or glucose intolerance.45 The Latino population has higher rates of type 2 diabetes, obesity, metabolic syndrome, and cardiovascular diseases.46 Studies of progression of CHC have shown that obesity and overweight (>25 kg/m2) are independent factors for liver steatosis. Steatosis grade 2/3 is associated to elevated ALT and stage 3/4 fibrosis.47
The constellation of diseases of metabolic syndrome in Latinos might explain the higher rates of hepatic fibrosis and the rapid progression to cirrhosis because metabolic syndrome is more common among Latinos.48, 49 Recent estimates of prevalence of metabolic syndrome in U.S. adults are 32% for Latinos compared with 22% in African Americans and 24% in whites.48 The metabolic syndrome etiologic factor is IR.50 It has been shown that Latinos have higher prevalence of IR associated to metabolic syndrome.51
Genetic Factors
Genetic host factors and the interplay with environmental factors such as excessive caloric intake and sedentary lifestyle might be the etiologic mechanism for metabolic syndrome and type 2 diabetes. Linkage of diabetes or hyperglycemia to a region of human chromosome 1q21-q25 has been demonstrated. The IRAS Family Study was designed to identify genes predisposing to IR, adiposity, and other characteristics. A link to chromosome 1q has been identified in Latinos with metabolic syndrome.52
Anti-Hepatitis C Virus Therapy in Latinos
Barriers to Treatment
There is no explanation for the absence of Latino participation in major HCV treatment trials. There is no evidence that Latino patients have a negative attitude toward research, or that they are not good study subjects. Although comorbid conditions such as alcohol or drug abuse, psychiatric disease, and other medical conditions might impact eligibility of Latinos, these factors are not different from other ethnic groups. Cultural barriers, especially language, economic and insurance issues, and even bias from the part of medical providers and staff might all play a role in the lack of Latino participation in clinical trials and limited access to therapy.
In 1993, 33.8% of all non-elderly adult Hispanics in the USA lacked medical insurance, compared with 8.1% of the entire non-elderly population. Among Latinos, Cuban Americans have higher rates of private health insurance than Mexican Americans or Puerto Ricans.53 When Latinos without medical insurance are compared with Latinos with insurance, the uninsured have no regular source of medical care and are less likely to have routine medical examinations.54
But even in well-documented populations with available medical insurance, Latinos are not receiving anti-HCV therapy. It has been reported that Latinos were more likely to meet all requirements for HCV infection therapy in the Veterans Administration Hospitals system than whites, 48.9% compared with 39.6%, but still the same percentage of patients received treatment, 20% and 19.2%, respectively.25 A recent study that examined 113,927 veterans with diagnosis of HCV infection reported the prescription rate of anti-HCV therapy to be only 11.8%, and that Hispanic ethnicity was a predictor of nontreatment.55
Efficacy of Anti-Hepatitis C Virus Treatment in Latinos
The standard of care for CHC is pegylated interferon (Peg IFN) and ribavirin (RBV) combination. The duration of therapy is 48 weeks for genotype 1 with weight-dosed RBV and 24 weeks for genotype 2/3 with fixed dose RBV.56, 57, 58 Because Latinos have been underrepresented in all pivotal CHC treatment clinical trials, these trials do not support any conclusion on the efficacy of Peg IFN and RBV therapy in this population.
There is evidence that Latinos have lower efficacy of anti-HCV therapy. Table 1 shows reported studies on efficacy of anti-HCV therapy in Latinos. All these studies have limitations because all were retrospective analyses, and none was designed to compare efficacy among ethnic groups or races. A multi-center study with induction dosing of consensus IFN for naive patients resulted in overall sustained virologic response (SVR) rates of 24% for whites, 12% for Hispanics, and 4% for African Americans.59 Another study analyzed 2 multi-center trials to determine predictors of treatment success for naive patients treated with combination therapy of IFN and RBV. SVR was achieved in 61% of Asians, 39% of whites, 23% of Latinos, and 14% of African Americans. After adjusting for known factors that impact response such as genotype, ethnicity was predictive of SVR, with Asians most likely to respond and Latinos and African Americans less likely to respond than whites.60 Results from a cross-sectional secondary analysis from a prospective study conducted at 24 Veterans Administration Hospitals also showed differences in outcome according to ethnicity. The results showed lower end of treatment and SVR responses for Latinos as compared with whites, although the differences were not significant.25 The recent large randomized WIN-R trial comparing treatment with Peg IFN alfa-2b and weight-dosed versus fixed doses of RBV resulted in lower SVR in Latinos infected with genotype 2/3 infection of 54%, compared with SVR of 62% in whites and 72% for Asians. These differences were not significant (P = .14) with whites or Asians (P = .1038). However, differences were significant for genotype 1-infected patients, 24% for Latinos, compared with 35% for whites (P = .005) and 41% for Asians (P = .045.) In the overall study population the differences in SVR were also significant, 34% for Latinos, 46% for whites (P = .002), and 52% for Asians (P = .0057).61 The only prospective study to date that examines impact of ethnicity in efficacy of standard of care in naive genotype 1 patients is underway (Table 2). The Latino trial is a multi-site prospective study designed to compare white Latinos with white non-Latinos, assuming a noninferiority difference in efficacy of 15%. Early interim results from this study showed lower rapid viral response (RVR) and early viral response for Latinos of 10% less than whites and non-Latino ethnicity to be predictive of RVR and early viral response.62 This study is fully enrolled, and the final results are expected with much interest.
Tolerability of Hepatitis C Virus Therapy
There is limited information about adverse events and tolerability of Latinos during treatment with Peg IFN and RBV. There is no evidence that Latinos have more adverse events, or that they are incompliant or have higher attrition rates during therapy.
Reasons for Decreased Efficacy
Viral Kinetics
To our knowledge, viral kinetic studies have not been reported in Latino patients.
Pharmacokinetics of Interferon and Ribavirin
There are no reported differences in the pharmacokinetics of RBV or peg-IFN among Latinos and whites. However, significant decrease in Peg IFN alfa-2a exposure has been documented when standard doses are used in patients who weigh more than 85 kg.63 Lower exposure to Peg IFN alfa-2a with increased body weight is associated to decreased antiviral response and might help explain decreased efficacy of anti-HCV therapy in obese Latino patients.
Higher Rates of Fibrosis and Cirrhosis
It is known that cirrhotic patients have decreased efficacy with Peg IFN and RBV therapy.56, 57, 58 Higher rates of fibrosis in Latinos would contribute to decreased efficacy. Earlier intervention, with programs to screen and diagnose Latino patients before progression to severe fibrosis, could improve the efficacy of therapy.
Steatosis, Metabolic Syndrome, and Insulin Resistance
Obesity, high body weight, and hepatic steatosis have been demonstrated to be associated to decreased antiviral response.56, 57, 64
Obesity is associated to hepatic steatosis, and steatosis is associated to IR.65, 66 Lately, IR rather than steatosis is emerging as the mechanism for decreased efficacy.64 IR has been shown to impair antiviral and immune-stimulating properties of peg-IFN.65, 66
IR has been documented to be associated to lower SVR in HCV and HCV/HIV coinfected patients67 and clearance of HCV infection to improvement in IR.68
Genetics and Immune Responses
The host ethnicity or race affects the antiviral CD4 T-cell responses during the course of CHC. CD8 T cells are the main mediators of hepatic cell injury because they recognize and destroy infected cells. HCV clearance correlates to a vigorous HCV-specific CD4 cell and IFN-gamma production.69 In African Americans, who are known to have decreased efficacy of Peg IFN and RBV therapy, there is evidence of a more robust antiviral CD4 T-cell response than in whites, but this response is not associated to IFN-gamma production, suggesting a dysregulation of the virus-specific CD4 T-cell effector function.70 To our knowledge, no similar studies have been reported in Latino patients with CHC. Rahman and Rehermann71 speculated that differences in the HLA haplotype and HLA diversity might affect the strength and multiplicity of T-cell responses among ethnic groups. They also postulated a possible effect of mode of transmission, because higher numbers of virions might cause T-cell memory disruption that might affect the responses to new infections.
Latinos and Specifically Targeted Antiviral Therapies for Hepatitis C Virus (STAT-C)
The impact of evolving new STAT-C therapies on the efficacy of anti-HCV therapy in Latinos is unknown. However, early results of the first clinical study in which VX-950 (Telaprevir) was added to Peg IFN and RBV are encouraging that adding STAT-C drugs might improve efficacy of treatment in this population. Twelve treatment-naive patients infected with genotype 1 HCV were treated for 28 days with Telaprevir, Peg IFN alfa -2a, and RBV and then continued treatment with Peg IFN alfa-2a and RBV. The triple therapy combination substantially and rapidly decreased HCV RNA levels in the 12 patients in this study, and all patients were HCV RNA non detectable at week 4 RVR.72 Several analyses have shown that extent of viral decline at week 4 of treatment with Peg IFN and RBV is predictive of SVR, and more specifically, that achievement of RVR is predictive of achievement of SVR.73 In this study 10 of 12 patients were Latino, and all achieved RVR.
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