Marina Nunez, MD, PhD, associate professor of Infectious Diseases at Wake Forest School of Medicine, discusses "Hepatitis C and Other Risks Factors for Hepatocellular Carcinoma."
MARINA NUNEZ: Good morning. I want to thank the organizers for inviting me to participate in this symposium. And as Dr. Clark said, I'm going to talk about hepatitis C and risk factors for liver cancer. So we have seen in the United States, an increase in the incidence of hepatocellular carcinoma over the past 20 years and also accompanied by an increasing mortality related to liver cancer, especially in the age group between 50 and 64 years old off of age. The risk factors for hepatocellular carcinoma are mainly the stage of cirrhosis, which can be caused by different causes of liver disease. Hepatitis C is huge in our country. Liver-- fatty liver disease, alcohol, autoimmune disease, or other causes of cirrhosis. Hepatitis B, it's also oncogenic per se. It's an oncogenic virus and can directly cause liver cancer in the absence of cirrhosis. Aflatoxin is a toxin, which is also carcinogenic. But this is more relevant for Asian countries, not in our country. So this is a case that I saw a few years ago. He was a 45-year-old Asian male with a diagnosis of end stage renal disease. He was being evaluated for kidney transplant. And he had been known to be [INAUDIBLE] since 2001. He was tested because his mother had died from hepatitis B complications. And according to him, he had never been treated because he-- the virus was considered to be silent. And the DNA was relatively low, 1,156 international units. And then the transaminases were also within normal limits. However, platelet count were already a red flag, suggesting cirrhosis, which was confirmed in the ultrasound. And, unfortunately, at age 45, he's facing already two lesions in the liver concerning for hepatocellular carcinoma. This patient was lost from followup, so I don't have the outcome. But I just wanted to highlight what are the groups that are at higher for developing liver cancer and who are the ones who will benefit more from surveillance. So these are the recommendations for the Liver Society. They were updated in 2011. And the groups that are considered to be deemed for hepatitis-- hepatocellular carcinoma surveillance just because it's cost-effective-- and the definition of cost-effective is when the risk of live cancer exceeds 1.5% per year in patients with hepatitis C or 0.2% per year in patients with hepatitis B. So that's the definition of cost-effectiveness in terms of surveillance for liver cancer. So those groups are Asian males with hepatitis B, males older than age or females older than 50. Also, hepatitis B patients with family history of liver cancer, they are then at higher risk. And African and North American black carriers of hepatitis B, they should be checked for liver cancer at an earlier age because they are at higher risk. So then we have all the other patients with cirrhosis. They could have arrived to the cirrhosis stage because of differing etiologies. hepatitis C, hepatitis B, fatty liver, or other causes. And then there are some groups in whom we know that the risk of liver cancer is increased, but in whom the efficacy of surveillance has not been demonstrated. And those include carriers of hepatitis B that are less than 40 males or less than 50 females or patients with hepatitis C with-- who have a stage 3, but they are not already in the stage of cirrhosis, also, fatty liver with no cirrhosis. So those patients are in-- there is a gray area because there is not effectiveness in the surveillance, but we know that they are at higher risk. So the screening for HCC would be individualized in those patients. So the recommendation from the guidelines is to do the surveillance with ultrasonography every six months. And they make the point that you don't need to shorten the interval, even if you think that there is a higher risk for liver cancer. And the reason for that is because this six month period has been calculated based on the fact that that's the time when you could see double in the increase of the size of the tumor. Alpha fetoprotein levels are not considered a good test for surveillance of liver cancer due to low sensitivity and specificity. So it could help-- I mean to accompany by image studies, but it's not a preferred tool for surveillance of liver cancer. So in our country, among the patients with diagnosis of liver cancer, some of them have hepatitis B. And those are mainly Asians. However-- and because they have a higher proportion in prevalence of hepatitis B. But the majority of the patients in our country have hepatitis C, 47%, and then other etiologies. So hepatitis C is huge in the development of liver cancer in our environment. And this takes me to the next part of the talk, which is, how do we manage, these days, hepatitis C? And this is a busy slide, includes the different families of medicines that have been developed over the years. We have witnessed a very impressive surge in new medications for hepatitis C. And even some of them, we are not using anymore, which is very amazing how-- I mean the field is evolving so quickly. So another busy slide. These are recommendations for hepatitis C treatment as it stands right now. And I put there October 2015 because these guidelines are being updated online regularly, and the is changing very rapidly. So this is as it stands today. So the main genotype that we deal with in our country is genotype 1. And in our environment, the main one is subtype 1a. So for these-- for the treatment of these patients, we have Harvoni, which is one pill, once a day. It includes sofosbuvir and ledipaspir, so it's a one pill combination. And then this can be used with ribavirin for more difficult to treat patients. Patients with cirrhosis, they have lower response, so treatments usually need to be maximized in that population. So we are still using ribavirin from the old days. Main side effect of anemia, which is a problem. But we have ways to deal with that. The other combination of medications that we have for genotype 1's is Viekira Pak. And that can be given with or without ribavirin. But the caveat here is this medication is very good for genotypes subtype 1b but not so good for subtypes 1a. And for those subtypes, you need to use necessarily ribavirin. So that's the problem with that. Then, for genotypes 2, we use sofosbuvir and ribavirin. And they respond quite well. I will show some numbers there after. But they respond rates are very high. So other combinations that we can use for genotype 1 are simeprevir and sofosbuvir, but those are combinations with medicines from different companies. And, therefore, the price is much higher. That's one of the problems with those extra combinations. Same thing for daclatasvir and sofosbuvir. That can be used for genotype 1's. It's been genotypic. However, again, price is a problem there. It can be used with ribavirin for people with cirrhosis. Genotypes 3, the main combination is daclatasvir and sofosbuvir. And that can be used for 12 weeks or 24 weeks if they are cirrhotics. And also, there is an alternative therapy with interferon. That will be the only case where the guidelines mention interferon. And I mean we try to stay away from interferon because of the very poor tolerance and important side effects. So I don't think anyone is prescribing this these days. But still, it is an alternative for that type. Genotype 4, 5, and 6 are very infrequent in our environment. They come normally from Far East, Middle East, or some Asian countries. So we don't have many patients to treat with those types. But you can use Harvoni for the three of them. And then you can use Viekira for genotypes 4 or sofosbuvir, interferon, and ribavirin for genotypes 5 and 6. So let's show a few data on the treatment of genotype 1. This is the combination marketed as Harvoni, sofosbuvir and ledipasvir. And this date represents the sustained virological response. The definition of that is checking the viral load three months after they finish in treatment. If the viral load is undetectable, that's considered cured. That's another nice feature about the hepatitis C treatments, that the treatments, once achieved, the sustained biological response is considered a permanent clearance. They can get re-infected again. But the virus is gone once you clear. So with this definition of sustained virological response, these are very amazing results, close to 100% of response compared to the old days when we used interferons where we achieved-- I mean not even 50%. So, as I mentioned, people with cirrhosis, their responses are a little lower. But I mean, even though-- I mean 95%, so that's very good. And then some patients qualify for a short course of 8 weeks if they have low viral load and they have never been treated. So this is Harvoni. Then, the combination of simeprevir and sofosbuvir which was used initially and now not so much just because you have to use two different medicines from two different companies and then the price is much higher. Good performance, especially with genotypes 1b, especially if they are not cirrhotics, but lower performance for subtypes 1a. And then this is the paritaprevir, dasabuvir, ombitasvir, which is the Viekira Pak, which is marketed as that Viekira Pak and with ribavirin. And these are date in people that are genotype 1's, cirrhotic, [INAUDIBLE] experience. Genotypes 1b performed very well. I mean 99%-100%, which is very good with courses of 12 or 24 weeks. Genotype 1a, it's a little lower because that's the weakness of these compounds. For genotypes 2 and 3, we mentioned the sofosbuvir and ribavirin performs very well in genotypes 2 in the darker green, especially if they are not cirrhotics with numbers between 90% and 100%. However, for genotype 3, the performance is not so good, especially for people with cirrhosis. That's why now, the first line treatment for the genotype 3-- oh, that's genotype 2. I'm sorry. it will be daclatasvir and sofosbuvir. So with this very good panorama that we have right now, with these very effective medications, what can we expect. I mean it's going to drop probably the incidence of hepatocellular carcinoma over the years. However, it's going to take some time to see those effects. On the other hand, right now, we are treating people with at least a stage 2. And that's very much driven by the policies of the insurance. I mean they are very reluctant to pay for these medications because, right now, are quite expensive. And we are very much treating people with at least to a stage 2 or, of course, stage 3's and 4's. So over the years, I expect that we will see a decline in the incidence of liver cancer. But I don't know how many years will that take. I wanted to touch a little bit on what to do with the patients when we clear the hepatitis C, but they already have cirrhosis. So there are some data suggesting that the incidence of hepatocellular carcinoma decreases dramatically. However, they still are at risk. And this is one study showing that with at least 8% of incidence rate at a year of follow up even after clearing the hepatitis C. And the risk appears to be increased in those patients with already cirrhosis at the time of hepatitis C clearance if they have-- if they are in the older ages with 12.2% in patients over 60 years of age. And, of course, if they have laboratory markers suggesting more advanced liver disease, that was also a predictive factor for liver / So patients with low platelets and cirrhosis, they are at higher risk, especially if they are over 60. So those patients, even after clearance, we always make the recommendation of continued surveillance for hepatocellular carcinoma even though they are clear from the hepatitis perspective. So in conclusion, the incidence of liver cancer and mortality has continued to increase in the US, especially in the age group over 50. Hepatitis C is the most frequent underlying liver disease among patients diagnosed with liver cancer in the US. Current hepatitis C treatments achieve very high cure rates, over 90%, in most settings. However, there are still some difficult to treat patients, like end stage renal disease or patients with cirrhosis and already prior failure. So there is still room for improvement in some subgroups. There are several treatment options available for most genotypes with differences in the duration, in the effectiveness according to subtype-- if they have genotype 1-- also in the need or no need to use ribavirin then also the emphasis in the drug-to-drug interaction profile. They high cost of these treatments are representing a barrier because there are restrictions imposed by the health insurers. And, right now, we are concentrating very much on patients with some degree of liver fibrosis. The risk for hepatocellular carcinoma decreases dramatically after the cure of hepatitis C. But, still, there is some risk for patients if they have cirrhosis and markers of more advanced disease and older age. And the surveillance for hepatocellular carcinoma is recommended for some groups of patients, especially those with hepatitis B and with cirrhosis and with-- the modality recommended is liver ultrasound every six months.
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