New hepatitis C infections in the United States

The US Centers for Disease Control and Prevention (CDC) released new data in May showing that the number of new hepatitis C virus (HCV) infections reported to the agency nearly tripled between 2010 and 2015.

Approximately four times as many new infections were reported in 2015 compared to 2010, and the increase in incidence was most rapid in young people aged 20-29 and in the Midwest, New England and Appalachia.

The increase in new hepatitis C infections is being driven by an upsurge in injecting drug use in small towns and rural areas among people who have been abusing prescription opioids. There was a large outbreak of hepatitis C infections due to sharing of injecting equipment in the state of Indiana in 2015. This outbreak was brought under control by the establishment of an emergency needle and syringe programme which provided free needles and syringes in order to reduce sharing of injecting equipment, as well as testing for hepatitis C and HIV.

However, access to basic harm reduction measures that could reduce the risk of hepatitis C transmission is poor across much of the United States. Recently published US research shows that the vast majority (80%) of young people with HCV infection in the United States have to travel at least ten miles to access needle exchange programmes, and half lived over 37 miles from the nearest programme. Political hostility to needle and syringe programmes remains intense in many parts of the United States. The CDC noted that 18 US states have no laws permitting the establishing of needle and syringe programmes.

The CDC study identified a range of policy barriers to hepatitis C treatment and prevention in the United States, illustrating the factors that need to be considered when seeking to reform drug laws in order to improve access to health care:

  • Requirements for a minimum period of drug abstinence in order to receive Medicaid-funded treatment for hepatitis C were in place in 24 states. Delaying access to treatment delays cure of hepatitis C and leaves individuals at risk of transmitting HCV to others.
  • Only three states permitted sale of syringes without prescription to people who inject drugs, had decriminalised possession of needles and syringes and permitted their distribution.
  • The lack of provisions in other states leaves people vulnerable to prosecution if they try to protect themselves by seeking or carrying clean injecting equipment, and leaves people engaged in syringe programmes vulnerable to prosecution too.

Policies on harm reduction in the United States and Canada are being debated as a result of the growth in opioid injecting and the rise in overdose deaths in recent years.

HCV reinfection among people who inject drugs

Jason Grebely at HR17. Photo by Liz Highleyman,

The requirement for abstinence from drug use is an important barrier to hepatitis C treatment. People are required to remain drug-free because of assumptions about their ability to adhere to treatment while using illicit drugs, and also by fears that active drug users will quickly become reinfected with hepatitis C.

At the recent International Harm Reduction Conference (HR17) Dr Jason Grebely reported that people cured of hepatitis C in the C-EDGE CO-STAR study of direct-acting antiviral (DAA) treatment had rarely been reinfected in the three years following treatment.

Participants were required to be on stable opioid substitution therapy using methadone or buprenorphine for at least three months at study entry. Urine drugs screens were done regularly, but people were not excluded from the trial if they continued to use illicit drugs, as over half of them did. Ninety-one per cent of people were cured after 12 weeks of treatment with grazoprevir/elbasvir (Zepatier).

Three years later, eight people had been reinfected, an incidence of 4 infections per 100 person-years of follow-up. Three of the eight spontaneously cleared the hepatitis C virus (HCV) after becoming reinfected.

In this study, no one reported using a needle or syringe after it had already been used by someone else, but 42% had used other drug paraphernalia such as spoons, water or filters after someone else. Hepatitis C can be transmitted by using any of these items after someone with hepatitis C infection, because tiny amounts of blood can be left behind after drugs are prepared using these items.

Advocates at the conference said that reinfection represents a failure of harm reduction services and advice. Dr Grebely said that faster scale-up of DAA treatment for people who inject drugs would reduce the risk of reinfection by reducing the number of people who can pass on hepatitis C to others.

Gilead warning on generics – weeks after more evidence on effectiveness

James Freeman at the International Liver Congress. Photo by Liz Highleyman,

The pharmaceutical company Gilead Sciences has warned people using buyers clubs to import generic versions of its hepatitis C drugs sofosbuvir and sofosbuvir/ledipasvir that these products might be substandard, unapproved drugs or counterfeits.

“To the extent patients take unapproved generic versions of one or more of our medications and are injured or not cured by these products, our brand or the commercial or scientific reputation of our HCV [hepatitis C virus] products could be harmed,” Gilead stated in a quarterly report to the US Securities and Exchange Commission on potential risks faced by the company.

As a US-registered company Gilead is obliged to draw the attention of shareholders and potential investors to known risks. 

Although a small number of counterfeit versions of its products have been identified in Japan, Israel and Switzerland, it is important to note that these were products purporting to be branded Gilead drugs, not generic versions.

Calling into question the safety and efficacy of generic versions of branded products is a well-established pharmaceutical industry tactic to protect market share. Generic versions of branded products must pass tests to prove that they contain the correct amount of active drug and produce similar drug levels in the human body. Nevertheless, there are numerous examples of generic drug companies failing inspections of their manufacturing facilities or falsifying records of drug testing. In 2014 The New York Times reported cases of fake cancer drugs being supplied by an Indian wholesaler which appeared to be manufactured by a well-regarded Indian generic company. The labels, however, appeared to be forged.

Dr James Freeman, the Australian doctor who has been treating people with hepatitis C who buy drugs from India with the support of the FixHepC Buyers Club, says that the only way to be sure is by testing each batch of drugs to check the level of active ingredient. He tested all drugs purchased by FixHepC buyers and found no problems with any of the drugs supplied.

Ultimately, the only test of whether or not generic drugs work is to ask whether they cure hepatitis C at a similar level to branded products.

Follow-up of 448 people who bought drugs through the FixHepC Buyers Club and submitted verified laboratory reports of their viral load measurements shows a high cure rate. Overall, 90% were cured, but the cure rate was lower in people with genotype 3 (83%) and people with cirrhosis were almost twice as likely to experience viral relapse after treatment. Similar results have been seen in real-world studies of people treated with branded products.

The lesson of this study is that if people fail treatment on generics, they tend to do so for the same reasons as people who experience treatment failure on branded products – because they have genotype 3 infection, because they aren’t treated for long enough, or because they have cirrhosis.

Presenting results of the generic drug study at the International Liver Congress in April, Dr Freeman reminded delegates that the majority of people treated for hepatitis C worldwide received generic versions of direct-acting antivirals, and that the use of generics will accelerate as more countries begin to provide hepatitis C treatment. Egypt alone has treated more than one million people. A recently published cost-effectiveness study of generic drug use to treat hepatitis C in India estimated that the cost of treating people would be recouped within five years in people with cirrhosis and in ten years for all people with hepatitis C.

As generic drugs become more widely available, ensuring the quality of generic versions of direct-acting antivirals will be in the interests of people with hepatitis C. Quality assurance costs money, however. Indian manufacturers have claimed that passing US Food and Drug Administration inspections adds 25% to their manufacturing costs. Companies have to achieve similar standards to receive World Health Organization (WHO) prequalification. So far, only one supplier of hepatitis C drugs has received WHO prequalification, for the active pharmaceutical ingredient that can be used by any generic manufacturer to make sofosbuvir.

Albumin treatment in decompensated cirrhosis

Long-term administration of human albumin was associated with fewer serious complications, less hospitalisation, better quality of life and longer survival for people with decompensated liver cirrhosis, according to a report at the International Liver Congress last month in Amsterdam.

Decompensated liver disease occurs when the liver can no longer carry out its vital functions due to the accumulation of scar tissue and blockage of blood flow. Complications include ascites (fluid build-up in the abdominal cavity), bleeding veins in the oesophagus and hepatic encephalopathy. Ascites is generally treated with diuretics and paracentesis – a procedure that involves draining fluid with a needle – but a liver transplant is the only curative therapy.

The ANSWER study assessed whether long-term administration of human albumin – a protein that helps maintain fluid balance in the body – had advantages over the standard of care. The study found that people who received albumin were more likely to be alive 18 months later and less likely to have required paracentesis.

New drugs for hepatitis B treatment

Tawesak Tanwandee at the International Liver Congress 2017. Photo by Liz Highleyman,

The current standard of care for treatment of hepatitis B is long-term treatment with an antiviral drug that has a high barrier to resistance. At the moment two drugs are available, entecavir or tenofovir. A new formulation of tenofovir, tenofovir alafenamide (TAF) or Vemlidy, has received marketing approval in the United States and European Union. In clinical studies, TAF had similar efficacy as tenofovir disoproxil fumarate (TDF) but caused less kidney and bone toxicity after 48 and 96 weeks.

At last month’s International Liver Congress, results of preliminary studies of a third alternative formulation of tenofovir and another new agent in the same drug class were presented.

The novel tenofovir exalidex is expected to combine less toxicity with more efficacy. The drug seems to cause less kidney and bone toxicity and achieve higher concentrations in liver cells infected by hepatitis B. Early studies show that tenofovir exalidex is safe and produces a greater viral load reduction than TDF at the highest dose.

Besifovir is an antiviral from the same drug class as tenofovir. It is being developed by a South Korean company and has reached phase 3 studies (the last phase before drug approval). Besifovir must be dosed with L-carnitine to prevent deficiency (L-carnitine aids energy production in cells). Virological responses were similar after 48 weeks of treatment in a trial comparing besifovir to tenofovir, but people who received besifovir were more likely to experience an improvement in liver inflammation and fibrosis.

The availability of new agents for hepatitis B treatment will allow doctors to tailor treatment to the needs of individuals and may also encourage price competition, especially in East Asia where the burden of hepatitis B is highest.

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