Low-cost generic hepatitis C drugs match branded products in viral response

Australian buyer's club shows that using generic drugs is safe and effective
Dr James Freeman presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

Generic versions of direct-acting antivirals purchased from China and India by people unable to obtain treatment in their own countries were just as effective and safe as the branded products, a study of 139 patients monitored by Australian doctor James Freeman has shown. The findings were presented in a late-breaking research session at the International Liver Congress in Barcelona on Saturday.

The study presented preliminary data on sustained virological response four weeks after the completion of treatment, labelled SVR4. The gold standard measurement of cure in hepatitis C is the absence of detectable virus 12 weeks after completing treatment (SVR12), but SVR4 results tend to provide a strong indication of SVR12 results, since the majority of cases of viral relapse occur in the four weeks after completion of treatment.

The high cost of branded direct-acting antivirals has led to rationing of treatment, slow drug approvals and refusal of insurance coverage in many countries. People unable to obtain hepatitis C treatment through existing health care have turned in desperation to the FixHepC buyer’s club for help in obtaining generic versions of sofosbuvir, sofosbuvir/ledipasvir and daclatasvir.

Glossary

generic

In relation to medicines, a drug manufactured and sold without a brand name, in situations where the original manufacturer’s patent has expired or is not enforced. Generic drugs contain the same active ingredients as branded drugs, and have comparable strength, safety, efficacy and quality.

antiviral

A drug that acts against a virus or viruses.

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

Importation of medicines for personal use is permitted under customs regulations in Australia and the United Kingdom, and many other countries have regulations permitting the importation of small amounts of medicines for personal use or their carriage through customs in personal luggage. The FixHepC buyer’s club provided advice and information on how to do this safely and legally, starting in Australia, but soon responding to enquiries from people in Europe, North America, New Zealand and South East Asia.

Dr James Freeman, a doctor based in Hobart, Tasmania, started to take an interest in how to treat patients safely with generic direct-acting antivirals after a patient came to him and asked for advice on how to import and use active pharmaceutical ingredients, obtained from Chinese manufacturers, to treat hepatitis C. Dr Freeman arranged to have them tested to ensure that they were indeed active drug, and to have the chemicals compounded into pills in Australia. The FixHepC buyer’s club was born.

Product obtained from China and subsequently formulated into pills was tested by nuclear magnetic resonance spectrometry, a technique used in pharmaceutical manufacturing to measure the quantity of active pharmaceutical ingredient in a pill. All products contained active drug in the expected quantities.

After generic products became available from manufacturers in Bangladesh and India the buyer’s club discouraged imports from China and began arranging for individuals who wanted to obtain direct-acting antivirals to buy products from reputable suppliers in India, in order to reduce risks in the supply chain.

In January 2016, Dr Freeman began enrolling patients who used the buyer’s club to obtain medication in an observational cohort study, the Reviewing DAA Efficacy Managing Patient Treatment In Online Neighbourhoods (REDEMPTION) study.

Treatment used in this study cost between US$1400 and $1600 for a course of medication, compared to a cost of up to $84,000 for sofosbuvir (Sovaldi) and $94,500 for sofosbuvir/ledipasvir (Harvoni) in the United States. Prices of generic products manufactured in India are likely to fall, possibly as low as $200 per course of treatment, as production increases.

The findings presented at the International Liver Congress are virologic response data four weeks after completion of treatment for the first patients without decompensated cirrhosis who obtained generic products with the support of the FixHepC buyer’s club and who were monitored through the Australian gp2u.com.au telemedicine platform. Virological monitoring was carried out by the patients’ own doctors.

Of the 448 patients enrolled to date, 48.4% had undergone previous treatment for hepatitis C, 31% had cirrhosis and the average age was 54 years. Genotypes 1 and 3 predominated (63.9% and 27.5% respectively). The most commonly used combination were sofosbuvir/ledipasvir (45.8%) and sofosbuvir/daclatasvir (42.6%). A small minority used either sofosbuvir/ledipasvir and ribavirin (4.7%) or sofosbuvir/daclatasvir and ribavirin (6%).

Virological monitoring during treatment showed that viral load changes closely resembled those reported in clinical trials of the combinations used by patients. SVR4 data are available for 139 patients who have completed treatment and undergone viral load testing four weeks after completing treatment.

The overall sustained virological response rate four weeks after completion of treatment (SVR4) was 94.4%. In genotype 1 patients treated with sofosbuvir/ledipasvir, 93.2% achieved SVR4 and 97.4% of those who received sofosbuvir/daclatasvir achieved SVR4. Ninety per cent of the 29 patients with genotype 3 achieved SVR4, and 100% of those with genotypes 2 (n = 6), 4 (n = 3) and 5 or 6 (n = 2) achieved SVR4.

One case of viral breakthrough during treatment occurred. Four deaths occurred during the study, all due to hepatocellular carcinoma. The remaining virological failures were virologic relapses after the completion of treatment.

Virological responses four weeks after the completion of treatment did not differ substantially from those observed 12 weeks post-treatment in clinical trials of sofosbuvir/ledipasvir or sofosbuvir/daclatasvir, where rates of sustained virological response ranged from 90% in genotype 3 to 96% in genotype 1.

No previously unreported side-effects were observed. Headache, nausea and fatigue were the most commonly reported adverse events. Three patients with compensated cirrhosis temporarily decompensated after treatment initiation but continued their courses of treatment.

Further studies are underway to generate more information on the use of generic products in the full range of genotypes found worldwide. “It won’t be long before the [size of the] datasets for generics surpass those produced by companies,” said Dr Freeman.

He warned that anyone seeking to obtain medication from generic producers should look for reputable manufacturers and should be monitored by a doctor. The FixHepC website contains details of how to identify reputable suppliers, how to import medicines legally into Australia, the United Kingdom and New Zealand, and details of how to join the REDEMPTION cohort study.

The findings were greeted positively by the European Association for the Study of the Liver (EASL), the organiser of the International Liver Congress.

“There is a clear role for generic treatments such as these for people with hepatitis C across the world. The implications of increased availability of these drugs could be enormous, presenting more people with the possibility of a ‘cure’ for what is often a debilitating condition,” said Professor Laurent Castera, EASL Secretary General.

References

Freeman J et al. High sustained virological response rates using generic Direct Acting Antiviral treatment for Hepatitis C, imported into Australia. International Liver Congress, Barcelona, abstract LB03, 2016.