Hope on horizon for patients with Hepatitis C: Sofosbuvir for 99% less comes to india

Wonder Hepatitis C drug almost here.....at 99% reduced price

Hepatitis C is a viral disease that mainly affects the liver and is transmitted parenterally ( through contaminated blood products, syringes etc), vertically (from mother to child in womb) and sexually.

More than 40% of patients infected with the virus develop chronic infection because the body is unable to eliminate the virus from the system.

Progression of chronic hepatitis is usually slow and culminates within 10-20 years of acquiring infection into cirrhosis and chronic liver failure that may be fatal without transplantation. About 4 out of every 100 patients with cirrhosis due to hepatitis C develop cancerous growths (hepatocellular carcinoma) in the liver that significantly reduces their survival. Alcoholism, obesity, diabetes mellitus, immunosuppressive medication and HIV infection are risk factors for early progression of chronic hepatitis to cirrhosis and liver failure.

In the absence of a reliable vaccine, treatment of chronic hepatitis C has so far yielded less than optimal results (40-55% sustained viral response). Silent undetected progression of disease, multiple genotypes of virus and  poor tolerance of patients to medications ( particularly those with cirrhosis) contribute to the poor response.

Inability of cirrhotic patients to tolerate medications and reduced effectiveness results in most patients having detectable virus in blood at time of transplantation. Reinfection of new liver occurs within hours of transplantation and inflammation of graft starts weeks to months after transplantation depending on various factors like viral load, type of liver graft, immunosuppression, age and other factors. Post transplant recurrence of hepatitis C is more difficult to treat due to the presence of immunosuppression and sustained virological response is between 15-50% in various studies. A significant number of patients may need a second graft between 5-25 years after transplantation for recurrence of hepatitis C and cirrhosis.

Treatment of chronic hepatitis C has hinged on mainly two drugs: the antiviral drug Ribavarin (RBV) and the immunobodulator drug Interferon (IFN). Most regimens for treatment of hepatitis B include RBV and IFN (usually in pegylated form). Genotype 1 infection in particular has significantly poor response to PEG-IFN and RBV. Recently it has been identified that those patients that have infection with CC subtype of IL28 gene has double the response when compared to CT or TT genotypes.

Further research into HCV treatment resulted in a new class of molecules called Protease inhibitors that inhibit viral enzymes 
 Bocepravir and Telaprevir were the first generation of protease inhibitors introduced for management of chronic hepatitis in untreated as well as previously treated patients with chronic HCV and compensated cirrhosis. Addition of a protease inhibitor to combination of IFN & RBV significantly increased the sustained viral response rate ( by 15-30%) for difficult to treat genotype 1 patients over IFN&RBV alone except in treatment experienced patients who were null responders. Monotherapy is not recommended because rapid resistance results.

Simepravir (SPV) is a second generation protease inhibitor effective against HCV introduced about a year ago. It is never used a monotherapy. For genotype 1 a patients , SPV in combination with IFN & RBV for both treatment naive and experienced patients with genotype 1 infection. It can also be effective in combination with RBV and Sofosbuvir for patients who cannot tolerate toxic IFN therapy. SPV based triple therapy is a superior alternative to first generation protease inhibitors and is better tolerated. It can also be used as an alternative to Sofosbuvir in combination with a longer course of IFN & RBV. One of the main disadvantages in the high cost .....about 70000 USD ( approximately Rs 43 lakh) for a 12 week course.

Sofosbuvir (SBV) is also a polymerase inhibitor effective against HCV introduced about a year ago. It is effective for all genotypes of HCV but FDA approved only for 1,2,3 &4. It can be used with RBV with or without PEG-IFN and has shown promise in treatment naive, experienced as well as HIV coinfected patients of chronic hepatitis C and compensated cirrhosis. It has high acceptability due to fewer side-effects and interactions, once daily dosing and pan-genotypic activity. For genotypes 2 & 3 an all oral regimen of SBV and RBV is effective. For 1,3,4 & 5 genotypes addition of PEG-IFN is recommended but for those who cannot tolerate IFN, combination of SBV,SMV with or without RBV is showing promise.

Therefore Sofosbuvir is considered a breakthrough wonder drug for HCV currently and is expected to figure in more and more regimens for HCV. The prohibitive cost of 84000 USD ( 55 lakh INR) has been the main deterrent in greater availability and application of the drug even among insured patients in the western world. The greatest benefit of SBV seems to be in genotype 1 patients which accounts for more than 60% patients in the USA. SBV monotherapy was effective in more than 70% patients in achieving SVR while in combination with IFN & RBV the SVAR rate was more than 90% even among null-responders.

In India the prevalence of HCV is between 3-5 % of the population with 20-25% of patients with chronic liver disease being due to HCV infection. Genotype 3 is the commonest in India (66%) while Genotype 1 is less common (13%). 

Reduction of SBV costs by nearly 99% to USD 900 ( 55000 Rs)  for 12 weeks by the company, is therefore a hugely welcome step to liver physicians caring for patients with HCV infection, particularly null-responders, relapsers or patients with genotype 1 and those who cannot tolerate IFN therapy. Though still out of reach of many patients in India, it will be an option for insured or reimbursed patients who could have more effective treatment to prevent the development of cirrhosis or liver cancer or requirement of liver transplantation in the future.

Liver Metastasis (Secondary liver cancer): is it the end of the road?

Liver metastasis (Secondary liver cancer) is not the end of the road in the era of modern liver surgery & transplantation

Cancer deposits within the liver from a site outside the liver are called liver metastases or secondary liver cancers. In fact more than 50% cancers in the liver do not originate in the liver cells but are metastasis from other sites.

Liver is the third commonest site for development of secondary deposits from cancer anywhere in the body. For cancers originating in the stomach, intestine, pancreas, gallbladder/bile duct, colon and rectum; it is the second commonest site after local lymph nodes.

Why is the liver a common site for liver metastasis?

The liver receives blood from the arterial system like other organs and tissues. Additionally nutrient rich blood from the gastrointestinal tract also enters the liver through the portal vein. This dual blood supply exposes the liver to greater risk of receiving circulating tumor cells from cancers anywhere in the body.

The microscopic structure of the liver is unique. it has blood spaces called sinusoids that have lining like blood vessels; but with with gaps in between the adjacent cells. This allows cancer cells that arrive via blood to slip outside the wall into the liver substance more easily than in other organs.

The sinusoids described above are also lined by special immune cells called Kupffer cells that specialise in extraction of abnormal cells and proteins from the blood flowing in the sinusoids. Kupffer cells also extract cancer cells arriving via blood which helps them gain access to the liver.

Metastasis is fortunately an inefficient process!

Fortunately, metastasis is not an efficient process. Less than one in a million cells that reach the liver would develop into metastasis.

Once cells arrive in the liver they usually remain dormant in the absence of conducive environment for them to grow by stimulating factors or factors that enable them to received extra blood and nutrients that help them grow rapidly into metastasis. In certain cancers like breast cancer, the cancer releases factors in the blood that creates sites called pre-metastatic niches within the liver where , if the cancer cells reach, they have higher chances of developing into metastasis.

Cancer cells that come out of dormancy become cell clusters called micro-metastasis. Micrometastasis remain dormant within the liver unless they acquire potential to grown budding blood vessels (angiogenesis), which transforms them into metastatic deposits.

How many cancer patients develop liver metastasis?

As a result of improvement in survival for most cancers, cancer patients are surviving significantly longer for the last three decades than earlier.Advances in radiological techniques have increases the sensitivity of detection of liver metastasis than conventional techniques. In particular metabolic imaging like FDG-PET scanning has increased detecttion of metastasis by more than 25% in most cancers.

It is believed that more than 30% cancer patients will have liver metastasis detected during their lifetime and if autopsy is performed for all patients dying of cancer, 65% would have metastasis in the liver. Importantly in 15-30% of these patients, liver is the only site of metastatic deposits.

More than 30% of patients with cancer in colon and rectum have liver metastasis when the cancer is first detected (synchronous) and more than 70% develop liver metastasis after treatment of their colonic or rectal cancer (metachronous).

Liver metastasis is the end of the road....myth or fact?

Traditionally the detection of liver metastasis has been considered the end of the road for many years. Barring liver metastasis from slow growing and indolent neuroendocrine tumours, patients with liver metastasis are likely survive less than 2 years after diagnosis.

In the modern era of multidisciplinary cancer management, systemic chemotherapy has become more effective, safe and molecular targets within cancer cells have been identified in some cancers for specific non-cytotoxic targeted therapy. With these advances, survival even after detection for liver metastasis has progressively improved but yet long term survival (>5yrs) has been unachievable by this modality alone for most cancers. However chemotherapy alone cannot cure liver metastasis unless all cancer cells are conlusively shown to be killed within the metastasis. Sadly more than 50% liver metastasis that show reduction in size or completely disappear on scans (ghost lesions), have viable tumor cells under the microscope.

With improvements in technology, safe anaesthesia practices, better imaging and greater experience in liver surgery, the procedure has become safer and is regularly being performed with near 0% mortality.Liver surgery has been therefore increasingly applied to metastatic liver disease in the hope that removal of liver metastasis would help in prolonging survival. Despite good safety profile, long term survival with surgery alone has also been disappointing. Surgery is unable to treat micrometastasis, circulating tumor cells and dormant cells because they cannot be detected on current imaging modalities...therefore systemic therapy has to be married to surgery when treating liver metastasis for most patients if long term survival is to be achieved.

With greater experience, combination of systemic therapy and surgery has been introduced for management of liver metastasis with much better outcomes over the last 15 years with survival exceeding 50% at 5 years for liver metastasis from colon, rectum, breast, ovary/testis, neuroendocrine cancer using peri-operative systemic therapy and surgery in selected patients.

All over the world, surgeons haveperformed liver transplantation for patients with large metastasis from slow growing neuroendocrine tumors that are not amenable to excision, with good results (even better than for hepatocellular carcinoma) and this is accepted universally. One of the most famous recipients of a liver transplant for such metastasis was late Steve jobs of Apple.

Recently a group from Norway showed excellent results after liver transplantation for liver metastasis from colorectal cancer and the idea is evoking interest all over Europe. However this is yet to gain acceptability elsewhere.

A perusal of published literature on liver surgery for liver metastasis brings forth the following points

1. Liver resection, if safely performed, to remove all existing liver metastases is useful for all cancers
2. Patients should be selected based on medical fitness, extent of tumor in liver & experience of treating team
3. It must be part of multidisciplinary strategy that includes systemic therapy & interventional radiology
4. Best survival is obtained after complete excision of liver metastasis is obtained if the metastases are few in number, confined to the liver, if the metastasis are sensitive to chemotherapy and appear many years after the primary tumour has been treated.

Therefore in the modern era, in selected patients, liver metastasis is definitely not the end of the road. This statement is particularly true for patients with liver metastasis from cancer of the colon or rectum, neuroendocrine tumors, breast cancer, testicular & ovarian cancer and gastrointestinal stromal tumors (GIST).

All patients with liver metastasis benefit from liver directed therapy, choosing the appropriate therapy and at the right time is important for optimum outcome.

 

World Hepatitis Day 2014: Hepatitis is closer than you think....think again

Hepatitis....know it...confront it

Hepatitis is a term used for inflammation of the liver cells due to any cause

Causes of hepatitis

1. Viruses: hepatitis viruses A-H, non-hepatitis viruses: herpes, cytomegalovirus etc
2. Bacteria
3. Parasites
4. Drugs
5. Chemicals & toxins including alcohol

It can manifest in two forms

Acute hepatitis

Recurrent hepatitis

Chronic hepatitis

Common routes of transmission of hepatitis are through contaminated food and drink (feco-oral route), through blood & blood products (parenteral route) and sexual contact.

Transmission through placental circulation from pregnant infected mother to child in the womb is called vertical transmission.

Acute hepatitis is characterised by abdominal discomfort, low-moderate grade fever, nausea, lethargy and loss of appetite. Most viral infections are associated with feeling of uneasiness, weakness, body pain before development of jaundice (prodrome). Jaundice is the hallmark of acute hepatitis and is usually detected by yellow discolouration of eyes and passage of dark yellow urine. Liver function tests show raised bilirubin level (mainly conjugated) accompanied by elevated liver enzymes (AST, ALT and frequently ALP). Urine shows elevated bile salts. Massive elevation of enzymes >1500 IU is rare. High fever usually indicates concurrent inflammation within the biliary system (cholangitis).

Acute hepatitis is a self-limiting disease and in most cases with supportive care, complete uneventful recovery results over a period of a few weeks. Recovery may be prolonged in elderly patients, pregnant women, those receiving medication to reduce immunity or those who have pre-existing liver damage from alcohol, fatty liver or other causes.

Alcoholic hepatitis is a unique form of hepatitis that occurs after years of large consumption of alcohol. It usually follows a binge of alcohol but can occasionally seen in early phases of abstinence. 

It is a severe form of hepatitis that causes a systemic inflammatory state often associated with infection, kidney dysfunction and progression to liver failure. The underlying liver is usually pre-cirrhotic or frankly cirrhotic in patients with alcoholic hepatitis. Many patients with alcoholic hepatitis have muscle wasting and nutritional defects making them prone to infections and multi organ failure leading to significant mortality despite supportive care.

In less than 5% cases, the liver damage caused by inflammation overwhelms the body immunity and the capacity of the liver to repair and regenerate. In such situations patients may progressively and rapidly develop cardinal features of liver failure : Deep jaundice  Mental changes (Encephalopathy & Clotting dysfunction. This syndrome is called Acute liver failure if patient had normal liver to start with and Acute on chronic liver failure if patient has a recognised or unrecognised chronic liver disease to start with.

Both are very severe conditions and if condition does not respond to medical measures, can be fatal.

Chronic hepatitis is usually the result of persistent or recurrent damage or the failure of immunity to clear the acute infection or insult. Chronic hepatitis is seen in 20-30% most of which is due to hepatitis B or C virus infections. Common hepatitis virus A is never chronic while less common hepatitis can rarely cause chronic infection.

Chronic hepatitis can follow an indolent course being asymptomatic for years before detection. Until liver damage has exceeded the reserve of the liver, liver function tests may be normal apart from subtle alterations.

The chronic inflammation in the liver can lead to development of primary liver cancer ( hepatocellular carcinoma) in unto 4% patients with chronic hepatitis every year.

Chronic inflammation can also lead to progressive scarring and changes in the micro architecture  of the liver leading to fibrosis and eventually cirrhosis. Once cirrhosis develops, the average survival is less than 10 years in most cases. Progressive damage can lead to features of chronic liver failure like jaundice, accumulation of fluid in abdomen (ascites), clotting deficiency and mental changes (hepatic encephalopathy). Reduction in liver function reduces immunity leading to increased propensity for infections and strain on other organ systems. In such a state average survival is less than one year.

Once cirrhosis develops the risk for developing hepatocellular carcinoma doubles to 8% per year.

As in most diseases, prevention is better than cure

Prevention of hepatitis

1. Consumption of safe food and drink
2. Vaccination: hepatitis B, hepatitis A
3. Avoid alcohol & IV drug abuse
4. Avoid unprotected high-risk sexual activity
5. Avoid contaminated syringes, needles, blood and blood products
6. Manage body weight & keep diabetes in check

Early detection of hepatitis

1. Periodic health checks
2. Screening of high risk patients
• children of parents with liver cancer or hepatitis
• siblings & spouses of patients with liver cancer or hepatitis
• patients receiving blood products (haemophiliacs, thalassemics) or dialysis
• iv drug abuse history
• high risk unprotected sexual activity & commercial sex workers
• healthcare workers
• patients with suppressed immunity or those on immunity reducing drugs

Treatment of hepatitis

1. Most cases of acute hepatitis need only supportive care
2. No specific treatment available for most viral hepatitis except hepatitis B and C
3. Inciting cause should be detected, avoided and treated accordingly
4. If acute or acute on chronic liver failure results patients should receive ICU management including ventilator support: some patients who don't respond can be salvaged by urgent liver transplantation
5. Measures to prevent developing chronic hepatitis & cirrhosis should be taken
6. Patients with chronic hepatitis should be aggressively followed for detection of cirrhosis or development of cancer
7. Early cases of liver cancer can be cured by liver surgery if there is no cirrhosis. If thesre is cirrhosis, liver transplant is the best option
8. Patients with complications of liver cirrhosis can be salvaged with liver transplant
9. Measures to prevent recurrence of hepatitis should be instituted even after transplant

Life-saving drug for liver cancer.....gimmicks or reality

Woke up on New Year morning to read an article in the Hindu about a hospital in Coimbatore distributing a 'life saving' drug for kidney and liver cancer in conjunction with a pharmaceutical company.

The Hindu : Cities / Coimbatore : A life-saving New Year gift for cancer patients

The drug in question 'Sorafenib' has been much in the news in India mainly due to controversy regarding its high costs that has prompted the government of India to allow compulsory licensing to manufacture the drug at lower costs to generic manufacturers in India.

While I may be accused of being a cynic staring a hobby horse in the mouth, I would like to know why such largesse is not extended to other molecules that are effective in much more prevalent cancers in this country. Much larger numbers of patients in this country fall prey to oral, cervical, breast, hematologic and gastrointestinal cancers than kidney or liver cancers. However no such largesse or benevolence seems to be in view with regard to those drugs.

 I hold no brief for the original manufacturers of sorafenib, but it does seem a witch-hunt to single out this molecule for compulsory licensing in order to control costs. One cannot but suspect vested interests behind the move. If such efforts are applied across the board to all cancer drugs, I will be one of the first to welcome and applaud it.

Sorafenib is a drug that inhibits an enzyme that controls intracellular signalling pathways in liver and kidney cells and has been shown to have some effect on patients with primary liver cancer. In the only large trial (SHARP) testing the efficacy of sorafenib in primary liver cancers, patients on sorafenib had their life prolonged by a few months over those that did not receive sorafenib. So to indeed call the drug 'life-saving' is a bit exaggerated based on current evidence. Of course prolongation of life by a few months can be a great deal of comfort for the patient with advanced liver cancer but it must be clearly understood that current evidence does not support the use of drug as a curative measure....hence as the best available evidence stands today the drug is a 'life-prolonging' and not 'life-saving' drug.

The drug once started has to be continued life-long. It is not clear whether this free dole promised to patients will be continued for their life or whether after sometime patients will have to purchase the drug. The article seems silent on this.

The drug no doubt could have potential in combination with other potentially curative treatments like resection or transplantation but this potential has not yet been proven in published literature. The use in these circumstances is investigational and success based on anecdotal reports or single centre studies.

Therefore gimmickry and misplaced populism seems to be the order of the day in such events. 

I wish better sense will prevail among those planning such doles and those clamouring for them.