Published: 20 July 2015
The development of effective new interferon-free treatment makes it possible to cure more than 90% of people with chronic hepatitis C, including most people with HIV and hepatitis C virus (HCV) co-infection, researchers said at the Second International HIV/Viral Hepatitis Co-infection Meeting, preceding the Eighth International AIDS Society Conference (IAS 2015) taking place this week in Vancouver, Canada. Looking at hepatitis B, antiviral therapy can effectively suppress the virus long-term, but most people are still not cured.
Expanding access to expensive hepatitis C treatments has become a key issue in the field as the challenge of developing highly effective and well-tolerated therapy has been largely solved. But taking a step back, a large proportion of people with hepatitis B or C around the world have not been diagnosed, and countries often do not have a good understanding of the extent of their viral hepatitis public health problems.
HIV/HCV co-infection treatment
Prior to the development of hepatitis C virus (HCV) direct-acting antivirals, people with HIV and HCV co-infection did not respond as well to interferon-based therapy as people with HCV alone. However, as interferon-free regimens have come through clinical trials over the past few years, sustained virological response (SVR) rates using drugs like sofosbuvir (Sovaldi), sofosbuvir/ledipasvir (Harvoni) or the Viekirax/Exviera combination have been similar for people with and without HIV.
“Treatment is rarely an emergency. Where there’s uncertainty, it’s a good idea to wait for the data.” Jordan Feld, University of Toronto
A growing number of experts have come to believe that when using interferon-free therapy, HIV-positive and HIV-negative people can be treated the same, except for taking into account potential drug-drug interactions with antiretrovirals. Current European and US hepatitis C treatment guidelines recommend the same regimens regardless of HIV status.
But there is not yet complete consensus that the two groups are just the same, especially when it comes to the most difficult-to-treat patients with multiple predictors of poorer response.
Jordan Feld from the University of Toronto set the stage for this discussion, proposing that while people with HIV and HCV co-infection no longer need to be considered a ‘special population’, there are still some subtle differences that may affect their treatment.
HIV infection may have a greater effect in people with liver cirrhosis and those who did not respond to prior treatment. Other traditional predictors of poor response – which seemed to make little difference in studies of interferon-free therapy for people with HCV mono-infection – may continue be a factor when added to HIV. For example, in the ION-4 study of sofosbuvir/ledipasvir, black patients with co-infection and those with unfavourable IL28B gene variants were more likely to relapse, a difference not observed in people with HCV alone.
The effect of HIV infection may be a concern especially when ‘stressing’ a regimen or pushing it to its limits – for example, treating for only 8 weeks or less rather than 12 or 24 weeks. Also, most industry-sponsored hepatitis C trials looking at co-infection have enrolled participants on stable antiretroviral therapy with undetectable HIV or those with high CD4 counts who did not yet need antiretroviral therapy (according to old guidelines). People with HIV co-infection with less well-controlled HIV may not fare as well.
In addition, as noted in the EASL European treatment guidelines, people with co-infection still experience faster liver disease progression, on average, than those with hepatitis C alone, supporting prioritisation of treatment.
Given what we know now, “I’d rather slightly over-treat until we know otherwise,” Feld cautioned. Waiting for more data – and perhaps for more potent next-generation drugs – is also an option. “Treatment is rarely an emergency,” he added. “Where there’s uncertainty, it’s a good idea to wait for the data.”
He concluded that it’s important to get hepatitis C treatment right the first time, in part because access to treatment is limited and it could be hard to get another shot at it.
Benefits of treatment
Several researchers at the satellite meeting presented interesting findings on the benefits of hepatitis B and C treatment.
There is now considerable evidence that timely hepatitis B treatment using antivirals such as entecavir (Baraclude) or tenofovir (Viread) – even if it does not lead to a cure – can reduce the risk of developing liver cancer, according to Henry Chan from the Chinese University of Hong Kong.
There are few data yet on the long-term benefits of direct-acting antivirals for hepatitis C, though there is considerable evidence that successful treatment with interferon is associated with reduced disease progression and liver-related death.
But “hepatitis C is not a single organ disease,” according to Gail Matthews of the Kirby Institute, who described various extra-hepatic, or beyond the liver, manifestations of HCV infection.
These include excess risk of kidney disease, predisposition to lymphoma and neurocognitive symptoms that can have a significant effect on quality of life. Like HIV, she suggested that chronic HCV infection may cause immune dysregulation that could contribute to cardiovascular disease and other conditions. In addition, many people with hepatitis C experience “more nebulous manifestations” that can contribute to work absenteeism and lost productivity.
We are now starting to see the first data that treatment with direct-acting antivirals can lead to improvement in these areas. Improvement in physical symptoms can begin within the first few weeks after starting treatment, suggesting that viral suppression is having an effect, Matthews explained.
Meeting co-chair Jürgen Rockstroh noted that these extra-hepatic manifestations occur at all stages of liver disease, adding further support to treatment for all.
Finally, several presentations discussed the idea of hepatitis C treatment as prevention, a concept that has now been widely embraced in the HIV field.
Mathematical modelling studies indicate that expanding HCV testing and treatment can reduce the rate of new infections, or incidence, among people who inject drugs, although the effect varies widely depending on factors like existing prevalence and who gets treated.
Greg Dore, also from the Kirby Institute, described studies looking at expanded hepatitis C treatment and its effect on epidemics among prisoners and men who have sex with men.
“It’s not a crazy idea that you could eliminate HCV – or get it down to very low levels – in the Australian context,” he said.
Treatment as prevention provides a further argument for expanding access to treatment. According to Homie Razavi from the Center for Disease Analysis in the US, treating people with advanced fibrosis or cirrhosis (stage F3-F4) leads to a rapid decline in liver-related death, but models show that in order to significantly reduce the number of new infections, we would have to expand treatment to people who do not yet have evidence of fibrosis (stage F0).
Treatment access and advocacy
While there is a growing consensus that everyone with hepatitis C can benefit from treatment regardless of stage of liver disease, some daunting barriers remain, including the high cost of treatment and the fact that many people with viral hepatitis have not been tested and diagnosed.
Looking at treatment cost, Andrew Hill from the University of Liverpool presented an update to his analysis of the cost to produce direct-acting antivirals for hepatitis C.
Generic sofosbuvir is now being produced by several manufacturers and the cost is coming down more quickly than expected. Originally the cost of the active pharmaceutical ingredient was US$9000/kg, but in July the first order came in at $4000/kg. He predicted a cost of $211 for a 12-week course by the end of 2015 – compared with the list price of $84,000 in the US (though many payers receive substantial discounts).
Daclatasvir (Daklinza) is easier to make and requires a smaller amount for treatment, yet in the UK it cost more than diamonds – $53,000 vs $48,000 for the 5g needed for a 12-week course of treatment, Hill said. He projected that the cost of daclatasvir could come down to $107 by the end of the year.
Widespread access to HIV treatment – which has now reached 15 million people – is one of the greatest success stories in medicine. “This should not stand alone, but be repeated for mass treatment of hepatitis B and C – and this time more quickly,” Hill urged. These reduced costs “could make universal HBV and HCV treatment in lower resource settings a realistic goal.”
The co-infection meeting concluded with a panel of experts discussing public health advocacy and access to hepatitis C treatment.
“It is not a question of whether it’s feasible, it’s a question of how can we make it feasible.” Andrew Ball, World Health Organization
Andrew Ball from the World Health Organization (WHO) noted that hepatitis B and C have a health burden comparable to other communicable diseases like HIV and tuberculosis (TB), but they don’t receive as much attention or funding. “Countries mostly address hepatitis B and C as an individual clinical issue, not a public health issue,” he said.
WHO’s goal is a 90% reduction in hepatitis B and C incidence by 2030, but the technologies we have today are not going to get us there. “It is not a question of whether it’s feasible, it’s a question of how can we make it feasible,” he stressed.
“I don’t think we’ll see dedicated international disease-specific funding” for hepatitis B and C as we did for HIV, he cautioned. “The future is going to be looking at domestic solutions – but even in a country like Egypt this is feasible.”
Debate around intellectual property and its role in high drug prices is already happening, according to Leena Menghaney from Médecins Sans Frontières Access Campaign. “If treatments are not cost-effective, prices have to come down to make them cost-effective,” she said. “Patent monopolies should not only be rejected on technical grounds, but on the grounds that companies are not acting ethically.”
Tracy Swan of the Treatment Action Group argued for the need for a simple standardised first-line regimen that does not require HCV genotyping or resistance testing.
“The regimen we need right now is sofosbuvir plus daclatasvir,” she said. “It may not work for every patient, but given the number of people who die each year, it seems cruel not to step forward. Whatever patent barriers we need to knock down, let’s knock them down!”
Visit the Second International HIV/Viral Hepatitis Co-infection Meeting website: http://coinfectionmeeting.com