CHRONIC HEPATITIS C – THE PROMISE AND THE COST OF A ‘CURE'

Hepatitis C is spreading in Pakistan

• Hepatitis C is very common in the underdeveloped areas of Pakistan.
• The reason for the spread is :
1. Lake od education about this disease in the underdeveloped areas.
2. Quakes in the villages use one syring for number of the patient.
3. Barbers are using the same razor for so many customers.
4. Dentists use one needle for the local injection.
5. Blood transfusion without proper screening.

Chronic Hepatitis C (CHC) is an inflammation of the liver caused by a virus (Hepatitis C virus, HCV). The virus was discovered in 1989 as the causative agent of what was till then known as non-A non-B hepatitis. It is transmitted through contact with infected blood and blood products. Among those who are infected, the infection becomes chronic, i.e. persists for longer than six months, in 75-85% of the people. If left untreated or unresponsive to treatment, CHC may lead to cirrhosis of the liver and liver cancer over a course of a few years to decades. Traditionally considered to be asymptomatic before cirrhosis or liver failure sets in, CHC is nevertheless associated with debilitating symptoms for many patients which reduce the quality of life considerably.

• Approximately 2%–3% (130–170 million) of the world’s population has been infected with HCV. In many developed countries the prevalence of HCV infection is <2%. The prevalence is higher (>2%) in several countries in Latin America, Eastern Europe, and the former Soviet Union, and certain countries in Africa, the Middle East, and South Asia; the prevalence is reported to be highest (>10%) in Egypt. In Pakistan the prevalence of CHC is 4.8%., (http://www.ncbi.nlm.nih.gov/pubmed/21495584) which along with chronic hepatitis B contributes to a high burden of chronic liver disease.

• Last month, the FDA (U S Food and Drug Administration) approved the oral drug Sofosbuvir (Sovaldi, Gilead Sciences) for treatment of chronic hepatitis C. It is being termed as a ‘game changer’ in the treatment of CHC, having shown promising results in ‘difficult to treat’ patients. It comes with a hefty price tag of $1000 a pill, which means a 12-weak course would cost $84,000 and a 24-week course, which is recommended for infection with type 3 virus will cost twice that amount.
• I will return to this new miracle but let me first say a few words about the history of the treatment of CHC.

Chronic hepatitis C was initially treated with intramuscular interferon as a monotherapy and then in combination with Ribavirin as ‘combination therapy’. In the last decade ‘pegylated’ interferon was introduced which could be injected into the skin and needed less frequent dosing. Interferon was advertised as a “miracle cure” for CHC, after it failed to come up to expectations as an anti cancer drug in the 1980s. In effect interferon by itself clears HCV infection in only 15% of the patients. It is only by adding Ribavirin to the regimen that the ‘sustained virological response’ to this treatment increased. However, a meta-analysis of 83 randomized trials totalling 12,707 patients by the Cochrane Collaboration, a non-profit partnership of healthcare professionals from around the world, concluded the following:
in the addition of ribavirin to interferon increases the number of patients who clear the HCV and the number of patients with improved liver histology to about 40%. The combination of ribavirin and interferon is also likely to reduce the risk of liver disease or all-cause mortality. However, the number of patients that must be treated to prevent one patient from developing a disease or dying seems very high. In addition, the combined treatment was associated with an increased risk of anaemia and several other adverse reactions.

• The results raise a dilemma: is it justified to increase the risk of gastrointestinal, infectious and other dermatological adverse reactions and hematologic disorders by adding ribavirin to interferon, while it has not been clearly demonstrated that the antiviral effect of the intervention is directly related to the reduction of all-cause mortality? We therefore suggest that the use of the combined intervention be strictly subordinated to the welfare of the specific patient. In addition, we suggest that all future trials in this area focus more on adverse clinical outcomes and long-term reactions.”
• (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005445.pub2/abstract)

• I have not seen any such ‘subordination to the welfare of the specific patient’ in the excessive enthusiasm for this ‘miracle cure’ as patients were prescribed the ‘combination therapy’ without much discrimination. Long term follow-up practices are already very poor in our healthcare set up, and this has a huge negative impact on the quality of care when a disease requires long term treatment. Thus even after nearly twenty years of experience with interferon therapy and 15 years with ‘combination therapy’, we are not any wiser about the adverse effects of these drugs in our patients that the Cochrane review board has warned us about. Nor do we have any reliable data that would tell us how many patients we cured or whether clearing of the virus from the blood in fact led to reduced mortality in our patient population.

• Interferon was sold at an exorbitant price before it was subsidized by the government (nothing less than a major success for the pharmaceutical industry) and the economic fallout of getting this treatment for families of the patients cannot be ignored. In the rush for this miraculous cure, most patients in Pakistan were treated even without determining the genotype of the hepatitis C virus they are infected with when it has been established that the viral genotype is the most important factor effecting treatment outcomes for interferon therapy.

• What makes this an even greater cause for concern are the reservations expressed by the Cochrane review board about a causative relationship between reduced mortality and the anti viral effect of the combination therapy. So we continue to enthusiastically prescribe expensive drugs while we know little to nothing about their ability to reduce mortality. What little we do know, is no more than ‘received wisdom’, and we are a rather religious lot, aren’t we?

• Racial and ethnic differences between various patient populations that have been shown to influence treatment outcomes are also largely ignored by the multi billion dollar pharmaceutical industry while developing drugs like interferon (and now Sofosbuvir). Since these drugs have been developed in western countries, there is little evidence for efficacy, dosage and side effects of these drugs in our population. Within the US, interferon based therapies have been shown to be less effective for African Americans than white Americans.

• Among the best known examples of drugs that have been responsible for revealing genetic variation in response between races are isoniazid, succinylcholine, primaquine, coumarin anticoagulants, certain anaesthetic agents, the thiopurines, and debrisoquine. European people show a superior anti-hypertensive response to beta blockers, which was one of the anti-hypertension drugs, when compared with their African counterparts.

• Besides response to the anti-hypertensive drugs, different races had different risks of warfarin therapy (used for blood thinning). Clinical trials suggest that when INR, which is the blood clotting indicator, was low, Asians had a better protection from the blood clot obstruction in their blood when compared with their white counterparts and needed lower doses of warfarin to achieve the desired results as compared to white population.

• We in Pakistan, however, have seldom sought to verify the evidence provided for the efficacy of these drugs in our own populations before we start prescribing them to tens of thousands of patients who buy them at the cost of their life’s savings. In this era of ‘evidence based medicine’, we are happy to follow wherever the pied piper might lead us. Corporate interest stumps patient care in the healthcare sector and any dissenting voices are silenced very soon as governments are prevailed upon to subsidize expensive therapies once a disease becomes a big enough public health concern. Hence we get socialized health care that is nevertheless a victory for the corporate sector. We are being played a very clever hand indeed. Unfortunately, many of those who should side with the poor patients have chosen to advocate the cause of the pharmaceutical industry, and have become marketing tools in their hands, selling one “miraculous cure” after another to unsuspecting patients.

• In view of this history, I am sceptical about this new miraculous cure we are being sold at such a huge price tag. I strongly feel that we need to study this drug in our population for adverse effects, dosage and efficacy before we start prescribing it.
• Medecins Sans Frontieres (MSF) has announced its support for the ‘patent opposition’ just filed at India’s Patent Office by the Initiative for Medicines, Access & Knowledge (I-MAK), which aims to prevent Gilead (Pharmasset) from gaining a patent in India on sofosbuvir. If the plaintiffs win this case, it will allow Indian companies to produce the drug locally which would reduce its cost substantially. This is now a major battleground for MSF’s Access Campaign. The patent battle achieved a major victory in India in 2007 when Glaxo was refused a patent for Combivir, a fixed-dose combination of two AIDS drugs (zidovudine/lamivudine, or AZT/3TC) which allowed Indian companies to market affordable generic versions of this drug, revolutionizing the treatment of AIDS worldwide. In April last year, India’s Supreme Court issued a major judgment against Swiss pharmaceutical company Novartis AG, denying a request to issue a patent for its cancer drug, Glivec.

• Perhaps it is high time that we should follow the example of our neighbours and reform patent laws allowing local manufacturers to market affordable generic versions of life-saving drugs after testing them on the local population for efficacy, dosage and side effects.

Prof.Dr.Abbas Hayat Rawalpindi Medical College Pakistan