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LATINO Study Comments by Jules Levin
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Below are several important results reported from yesterday's final publication of the results from the LATINO Study, as I am highlighting these results because I think they are important to comment on.
"In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 μ
g per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded."
from Jules: FIRST, an important message-- a number of internet news services have distributed their own interrpretations of the LATINO Study results, and they don't understand HCV treatment and have delivered the wrong interpreation and message to patients. They have unfortunately delivered a unduely discouraging message and the absolute wrong message to Latino and African-American HCV+ patients. The headlines for these newswire services say Latinos respond poorly to peg/RBv and response rates are poor compared to whites. Although they are correct that SVR rates in the study are 34% for Latinos vs 49% for caucasians, this is not new information, we have known what the response rates are by African-Americans and Latinos for many years. The point is that this type of headline discourages patients from being tested for HCV, from seeking care, and from starting therapy because they see low response rates. The truth is that unless a patient gives therapy a chance and starts it there is obviously no opportunity to achieve a cure. AND, there is no way to predict how an individual will respond to therapy. Unless an individual starts therapy they cannot predict how they will respond. After 4 weeks on therapy it is easy to tell if that person has a good chance of achieving an SVR based on the reduction in viral load by week 4 or by week 12. Anyone, regardless of color or race or ethnicity can achieve a good response and the only way to see if you can achieve this is to begin therapy. The 34% SVR rate is the average of 300 patients in the study with a certain percent of patients who achieve SVR and a certain percent who don't, obviously 34% achieve an SVR and 66% don't. There is no way to know if an individual is one of the 34% unless they begin therapy. After 4 or 12 weeks if response is not good the doctor and patient can decide to stop therapy.
Certain key issues are unique to Latinos and African-Americans. Response rates to peg/RBV are much lower for these 2 groups than for caucasians. This fact has tremendous impact on therapy. The lower response rates deter patients in the 2 groups from seeking therapy and also care, and deter these patients from agreeing to start therapy. This requires better education about the disease and it's mortality and better support services and programs for these 2 patient populations. This problem and the personal characteristics of these patients make them much more 'vulnerable' patients in this disease, and therefore they require heightened attention.
This study reports low viral load, below 400,000, is associated with better response rates but the study does not report the exact SVR rate for patients with low viral load. For vulnerable patients, and I include HIV coinfected patients as vulnerable, better education requires teaching them that perhaps starting therapy earlier, when viral load is low, is preferable. The author Discussion mentions that Latinos are more likely to have diabetes, steatosis, excessive weight and insulin resistance and that these characteristics cause lower response rates. Unfortunately this study does not report the SVR rates based on these characteristics. It would be of great interest to see SVR rates for Latinos who do and do not have these conditions. Since the SVR rates would likely be higher for patients who do not have these conditions this information would be informative and educationally useful. This raises another important point. All patients but particularly African-Americans and Latinos because they have lower SVR rates should receive education that these patient conditions affect the cure rates for HCV. Vulnerable patients need special education so they can take all possible precautions to improve their chances to achieve a cure. When new oral HCV drugs are added to therapy where a patient will receive the oral drug plus peg/RBV in a triple regimen, and the 2 HCV protease inhibitors are expected in about 1.5 to 2 years, the SVR rates will increase for genotype 1 but for these vulnerable patients these aforementioned conditions may still have an affect on SVR rates. Phase III for the 2 oral HCV protease inhibitors have just started so we don't have data yet on the outcomes and results for Latinos and African-Americans, but I presume these conditions will be important, I expect SVR rates will be lower for African-Americans and Latinos. Still, SVR rates will be greatly improved for all patients including caucasians and African-Americans and Latinos with a triple regimen that includes an HCV protease plus peg/RBV. So far studies show 50% or more increases in SVR rates for genotype 1 treatment-naive patients with average SVR rates of about 65% in the phase 2 studies of triple therapy compared to rates seen with standard of care peg/RBV but most of the patient results are for caucasians. I expect we will see results for African-Americans and Latinos from phase III studies and I expect to see lower SVR rates compared to caucasians but much improved SVR rates with the triple therapy compared to only peg/RBV. Once we have 2 oral HCV drugs to add to peg/RBV I expect SVR rates will increase to 75-90% for all patients including African-Americans and Latinos. But the 2nd oral drug is several additional years away after the 2 HCV protease inhibitors hit the market. In the meantime we wait for phase 3 study results and I expect it will be important to consider carefully treatment decisions and to factor in the risk for HCV drug resistance to the new HCV protease inhibitors in making treatment decisions. Of particular note response rates to HCV treatment-naive patients are different than for patients who previously were treated with peg/RBV. And of particular note there are different types of previously treated patients: those who relapsed from previous therapy (that is, they achieved undetectable viral load at the end of treatment but viral load rebounded after stopping therapy), patients who were partial responders (that is, they achieved a pretty good initial response to peg/RBV and had a nice reduction in viral load but viral load rebounded while on therapy), and the 3rd group is the non-responders (these are patients who had little response to peg/RBV). It is important to understand that phase 2 results from triple therapy studies show differences in response rates by each of these patient groups with relapsers and partial responders having good responses in the telaprevir (Vertex) HCV protease inhibitor triple therapy studies but prior non-responders showed lower response rates, rates closer to 40% or a little less. We will look for phase 3 results in non-responders to help understand therapy for non-responders. It is important tobear in mind that using today’s standard of care and retreating prior peg/RBV on-responders with peg/RBV only shows about a 1-12% SVR rate so a I expect retreatment with triple therapy that provides say 35% SVR rate for prior non-responders is a significant improvement but we have to wait to see the results from phase 3 for prior non-responders.
The study and an extract below reports that patients with cirrhosis have lower response rates, which we have known, and that Latinos were more likely in this study to have cirrhosis, and this is also not new information. We know Latinos tend to be more likely to have HCV disease that progresses more quickly because they are more likely to have conditions that cause HCV to accelerate more quickly including diabetes, using alcohol, having insulin resistance, higher weight is also associated with lower SVR rates and Latinos tend to have higher weights, steatosis (fatty liver) is associated with lower SVR rates and faster disease progression and Latinos are more likely to have fatty liver (fatty liver is associated with a poor diet, more fat in diet, less exercise) and education is important for patients on this subject.
The extract I pulled out below also mention 'genetic and immune differences' between caucasians and Blacks and Latinos that appear to cause the reduced response to interferon. This appears to be an important reason why African-Americans and Latinos have reduced response rates to interferon. Again, this effect will continue to be a factor when we start using triple regimens that include an HCV protease inhibitor plus peg/RBV but SVR rates will improve greatly for African-American and Latino patients as well as for caucasians. But, it is very important to educate African-Americans and Latinos about this. It is important to educate patients, particularly vulnerable patients, about the factors involved in their care and treatment because they often feel mistrustful and because lower response rates deter patients from testing, therapy and care. In general vulnerable patients are more tentative for a numer of additional reasons about seeking care and treatment for many reasons and need targeted support services and programs.
EXTRACTS FROM THE LATINO STUDY
"The predicted expansion of the number of Latinos in the United States suggests that the prevalence of HCV infection will increase. These factors are likely to contribute to the already increasing rates of illness and death due to liver disease among Latinos.....
......The results of this study add to a growing body of evidence of differences in treatment responses among ethnic groups and underscore the need to optimize treatment strategies in order to improve the rate of sustained virologic response among Latino patients infected with HCV genotype 1. Latinos should be considered for clinical trials involving specifically targeted antiviral therapies for hepatitis C to determine whether the addition of investigational agents to standard therapy improves the rate of response in this difficult-to-treat population......
......The Latino Study was a multicenter, prospective study designed to examine the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a plus ribavirin in patients who were infected with HCV genotype 1 and who had not previously been treated....
.....The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001).....
.....The baseline viral load was predictive of the rate of sustained virologic response in the total study population as well as in both study groups
.....the absence of cirrhosis predicted a sustained virologic response among Latinos....
......Latinos are the fastest-growing minority group in the United States and will represent 15% of the total U.S. population by 2010.1 The prevalence of infection with the hepatitis C virus (HCV) has been reported to be 2.1% among Mexican Americans, as compared with 1.5% among non-Hispanic whites.2 However, the overall prevalence among Latinos may be higher than that in the Mexican-American subgroup. Another analysis has shown that the HCV-related mortality rate among Latinos is nearly twice the rate among non-Latino whites.3 HCV infection in Latinos is characterized by more aggressive inflammatory activity and fibrosis,3,4,5,6 greater disease progression,7,8 and greater risk of cirrhosis6,9 than in non-Latino whites and blacks......
.......Excessive weight, steatosis, and insulin resistance have all been shown to reduce the probability of a sustained virologic response to treatment.18,21,22 Latinos have a higher prevalence of insulin resistance and diabetes mellitus than do non-Latino whites and blacks.23 In our study, greater proportions of Latino patients were obese, had diabetes as a concomitant disease, and had more than 33% fatty cells on liver biopsy, results that are consistent with previous findings.6 Although the metabolic profiles of patients were not assessed in this trial, it would be of interest to explore the interplay between metabolic status and treatment response among Latinos......
......Because Latinos of Caribbean descent are more likely than other Latinos to have relatives of African origin in their ancestry, in a post hoc analysis we compared the rates of sustained virologic response among Latinos of various countries of origin and found no significant differences.......
.......by controlling for multiple variables in the design of the study, we demonstrated that there are underlying factors related to Latino or non-Latino background, possibly due to genetic and immune differences, in the response to HCV infection - and particularly in the proportion of patients without a response. An analogy can be drawn with black patients in whom a diminished sustained virologic response probably reflects reduced sensitivity to interferon25 or diminished HCV-specific immunity.26 Toll-like receptors, which normally contribute to innate immunity27,28 and are associated with protection from the development of fibrosis,29 may contribute to reduced response rates. Studies have suggested that a poor response to therapy with peginterferon and ribavirin may be due to genetic variation, but little is known about whether specific haplotypes are more common in certain racial or ethnic groups, and we did not conduct any genetic analyses.30,31 The multiple exclusions that were needed in our study to ensure that the two groups were comparable is also a limitation of the study."
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