New drugs that directly target the hepatitis C virus usher in a new era of treatment, Liz Highleyman reports.
Combined with interferon injections and ribavirin pills, the latest hepatitis C drugs are dramatically more effective. Two have now been licensed and there are others on the horizon. At present they will have to be taken with the standard hepatitis C treatment of pegylated interferon and ribavirin, but interferon-free, all-oral combinations are likely to follow.
Interferon (given by injection) works by stimulating the body's own immune response, but the new drugs work just like antiretroviral drugs for HIV, attacking the virus at different stages of its lifecycle.
The first of these new drugs – the hepatitis C protease inhibitors boceprevir (Victrelis) and telaprevir (Incivo,or Incivek in the US) – were approved in Europe and the US for mono-infected people (those who don’t also have HIV) last summer. Drugs like these can overcome some of the causes of a poor response to interferon, such as having the difficult-to-treat hepatitis C genotypes 1 and 4, the unfavourable IL28B gene variation, advanced liver fibrosis or prior treatment failure.
Hepatitis C protease inhibitors for co-infection
About one-third of people with HIV also have hepatitis C, including a majority of injecting drug users and a growing number of HIV-positive gay and bisexual men. Hepatitis C-related liver disease is a major cause of death for people with HIV in high-income and resource-limited countries. HIV-positive people generally have higher hepatitis C viral load, experience more rapid liver disease progression and do not respond as well to interferon-based treatment as people with hepatitis C alone.
The new drugs can help overcome the disadvantage of co-infection. "This is a huge leap forward in treatment of hepatitis C in HIV patients," said Douglas Dieterich from Mount Sinai School of Medicine in New York. "The virus is cleared, gone forever, and shouldn’t come back."
Dieterich presented the first co-infection cure findings at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle this March. His study enrolled HIV-positive people with hepatitis C genotype 1 who had not tried interferon before.1 They took telaprevir or a placebo three times daily in combination with pegylated interferon and ribavirin for twelve weeks, then continued on interferon and ribavirin alone for another 36 weeks.
The trial included 60 participants: 13 with CD4 counts of at least 500 cells/mm3 who were not yet taking antiretroviral therapy for HIV, 24 taking an efavirenz-based antiretroviral regimen and 23 taking one based on atazanavir.
Overall, 74% of people who used telaprevir triple therapy achieved ‘sustained virological response’ (SVR, a continued undetectable hepatitis C viral load) twelve weeks after ending treatment (known as SVR 12). This is a good predictor of 24-week SVR, which is considered a cure. Results were similar in the no-ART, efavirenz and atazanavir groups.
Another study, presented by Mark Sulkowski from Johns Hopkins School of Medicine, looked at boceprevir triple therapy in co-infected people.2 They were assigned to receive boceprevir or placebo three times daily, plus pegylated interferon and ribavirin, for 48 weeks. All were on fully suppressive HIV protease inhibitor regimens.
Here, the SVR12 rate was 61% with boceprevir triple therapy versus 27% with pegylated interferon/ribavirin alone, with three other people still undergoing follow-up.
Hepatitis C rebound during treatment was reassuringly rare in both studies, allaying fears that HIV-positive people might be more likely to relapse. "The vast majority who responded on therapy sustained their virological response and achieved a cure," Sulkowski emphasised.
The side-effects of triple therapy generally were not more common or more severe among co-infected people. However, one drawback of the new drugs is that they do add new side-effects to the ones already familiar to people taking pegylated interferon and ribavirin, such as depression and flu-like symptoms. Telaprevir frequently causes a skin rash and itching, which can be severe in some cases, while boceprevir can worsen the anaemia and white blood cell deficiencies already caused by ribavirin. Both can cause gastrointestinal symptoms and odd taste sensations.
It may be worth it, though. "I didn’t expect results for either drug to be so good," Dieterich summarised. Cure rates were "shockingly comparable" in HIV/hepatitis C-co-infected and hepatitis C-mono-infected people, while side-effect rates were "virtually the same" and did not present an obstacle to treatment.
Beware: drug interactions
Along with the good news, however, there were also some concerns. One of the biggest challenges of co-infection treatment is the risk of drug-drug interactions, which can raise or lower concentrations of other medications, leading to worsened side-effects, or viral breakthrough and treatment failure.
Ideally, interactions between hepatitis C antivirals and HIV antiretrovirals should be assessed in laboratory studies and HIV-negative volunteers before a new drug is tested in co-infected patients, but this does not always happen. The European Medicines Agency and US Food and Drug Administration encourage such studies but do not require them.
Telaprevir's drug-drug interactions with antiretrovirals were well studied in advance, enabling well-informed choices about which HIV drugs to allow in its co-infection trial; those taking efavirenz had to increase their telaprevir dose to compensate for the reduced levels of the drug caused by an interaction with efavirenz.
But in the boceprevir trial, researchers made educated guesses based on drugs' pharmacokinetic profiles and how they are processed in the body.
The hazards of the second approach came to light when belated testing in HIV-negative volunteers showed that adding boceprevir to ritonavir-boosted HIV protease inhibitors could lower blood levels of both drugs to ineffective levels.3 Boceprevir reduced minimum concentrations of boosted atazanavir (Reyataz), darunavir (Prezista) and lopinavir (Kaletra) by as much as 60%, while these HIV drugs reduced boceprevir levels by up to 45%.
As a result, in February Merck issued a ‘Dear health care professional’ letter4 stating that the company "does not recommend" co-administration of boceprevir with boosted HIV protease inhibitors. Given that we already know that efavirenz causes substantial drops in boceprevir levels, HIV regimens based on raltegravir (Isentress) look like the best bet for combining with this drug.
"We should have had this data earlier," stressed Renaud Persiaux of the French treatment activists’ coalition TRT-5. "We ask pharmaceutical companies to do drug/drug interaction studies early on, as this will increase safety for patients."
And yet, given the good result of the trial presented by Sulkowski, this may not have mattered in this case. Given this conflicting data, what should someone with both HIV and hepatitis C do now?
What to do now?
Boceprevir and telaprevir are currently only approved for hepatitis C-mono-infected people by the EU and US licensing agencies. But in the UK, NICE (the body producing clinical standards in health and social care) recently gave a favourable opinion on boceprevir and telaprevir-based triple therapy with interferon and ribavirin.5
“This ‘approval’ includes co-infected patients,” says Dr Sanjay Bhagani of London’s Royal Free Hospital, “though whether commissioners will pay for this or not is a different matter.”
These new drugs are not cheap. The ‘list prices’ (the ones the NHS ends up paying are likely to be lower) are £30,800 for a 44-week course of boceprevir and £22,398 for a 12-week course of telaprevir – and, on top of that, you have to add in £11,000 for the interferon and ribavirin.
At this stage, your best chance of receiving these new drugs is through being part of a clinical trial, as the drug company has to pay for the cost of these. “There is no access to the new hepatitis C treatments for co-infected patients on a routine basis,” says Dr Mark Nelson of London’s Chelsea and Westminster Hospital. “But you can get the drugs from major centres like us and the Royal Free, who will be doing the clinical trials people need to join."
Whether you should try the new drugs depends primarily on whether you have progressive liver disease. Just as HIV treatment has been based on worsening immune deficiency, hepatitis C treatment should be based on worsening liver fibrosis.
Not everyone with hepatitis C will need treatment. Only a quarter of hepatitis C-mono-infected people develop serious liver disease, and this typically takes 10 to 40 years, often with no symptoms until advanced stages. For co-infected people without an urgent need for hepatitis C treatment, there’s probably time to wait.
Even if the approved drugs were more readily available, Mark Nelson comments, they're like the first-generation HIV protease inhibitors.
"Telaprevir and boceprevir are relatively difficult to take and relatively toxic compared to the second generation. If you have minimal liver disease, probably the best option is to wait."
Daniel Fierer from Mount Sinai Hospital in New York adds that boceprevir and telaprevir are "unpleasant, onerous drugs... Think AZT if we're lucky or, if we're unlucky, ddC... If you don't need it, don't take it." He’s even more pessimistic when it comes to re-treatment. "If patients have failed treatment a number of times, their chances of cure with the new drugs are pitiful," he said. "Taking treatment now may prevent you from getting into a clinical trial further down the line, and you may develop resistance."
Other patients, however, do not have the luxury of time. The risk of progression to liver damage is higher and it happens faster in co-infected people; successful treatment can slow, halt or even reverse it. Doctors do not want to give treatment to people who never would have progressed to liver damage without it, but are also concerned not to delay too long because once people get to the stage of cirrhosis, treatment becomes more difficult and less effective.
"If people need to be treated, they need to be treated now," said Dieterich. "If they have significant liver disease, I think it's definitely indicated to go ahead. If you need to take pegylated interferon and ribavirin with all their side-effects, you want to optimise your chance of success."
At a CROI symposium on treating HIV/hepatitis C co-infected patients, Jürgen Rockstroh from the University of Bonn proposed an algorithm for deciding when to consider therapy:
- People with no or minimal fibrosis (stage F0-F1) may defer treatment and wait for better therapies.
- People with moderate to advanced liver disease (stages F2-F3) have the biggest risk of progression that could be controlled with treatment now.
- People with cirrhosis (stage F4) have the highest need, but also the lowest response rate and greatest risk of complications, and should only be treated in specialised centres.
It is not as easy to predict who will experience liver disease progression, or even to tell if it is occurring, as it is to measure CD4 cells. Liver biopsy remains the gold standard for staging liver damage, but it is too invasive and expensive to repeat often. Fibroscan (which uses sound waves to measure liver stiffness) and various blood biomarkers are widely used, but they may not be able to distinguish between intermediate stages where decision-making is most critical.
"It's a balancing act," Rockstroh concluded. "How much progression will happen in one, two, or three years, versus the window of development of new therapies?"
On the ground
Despite the long wait and eager reception of the first hepatitis C protease inhibitors, their use does not yet appear to be widespread in practice.
"I've met one person who is taking telaprevir," said Tracy Swan, a long-time community advocate with the Treatment Action Group in New York. "My hunch is that people are waiting for something better if they can."
In the UK, Robert James, patient representative on the BHIVA hepatitis group, says the same. “Only a few people so far are taking telaprevir or boceprevir here and only the BHIVA hepatitis group doctors and their close colleagues are prescribing them,” he says.
Breaking free from interferon
Fears about interferon side-effects remain a major reason people delay or refuse treatment, making interferon-free regimens the holy grail of hepatitis C research. As with HIV therapy, we can expect hepatitis C drugs to become more effective and easier to take over time, with fewer side-effects, more convenient dosing, and shorter treatment durations.
A whole raft of new hepatitis C drugs is on the horizon, with many pharmaceutical companies involved.
- asunaprevir (BMS);
- danoprevir (Roche);
- vaniprevir (Merck);
- BI 201335 (Boehringer);
- TMC435 (Janssen)
Tthese act in a similar way to reverse transcriptase inhibitors (RTIs) in HIV and like them can be nucleoside analogues or non-nucleoside drugs.
- mericitabine (Roche)
- GS 7977 (Gilead)
- setrobuvir (Roche)
- tegobuvir (Gilead)
- BI 207127 (Boehringer)
- VX-222 (Vertex)
These include the promising NS5A inhibitor daclatasvir, the cyclophilin inhibitor alisporivir, and other classes of drugs such as entry inhibitors and TLR agonists.
Roche combined two new drugs, danoprevir and mericitabine, in 2010, proving that oral drugs alone could suppress hepatitis C; viral loads fell 100,000-fold in 13 days in both previously untreated mono-infected patients and prior non-responders.6
More recently, an interferon-free combination of BI 201335, BI 207127 and ribavirin for 16 weeks produced SVR24 rates of about 60% in treatment-naive, hepatitis C-mono-infected, genotype 1 patients.7 A Japanese trial found that 90% of genotype 1 mono-infected patients who had previously not responded to interferon reached SVR after 12 weeks of asunaprevir plus daclatasvir.8
Another trial, though, illustrated the hazards of making things too simple. It found that 100% of previously untreated genotype 2 or 3 hepatitis C-mono-infected patients were cured with 12 weeks of GS7977 plus ribavirin.9 So researchers brought patients with the harder-to-treat genotype 1and who had never responded to interferon into the trial. All of them achieved rapid virological response after four weeks – but after finishing the twelve-week course of treatment, the hepatitis C reappeared in all but one of them.10 People in this situation may need an additional drug or longer treatment duration.
Drug developers are looking to produce co-formulations and, ultimately, single-tablet regimens, sometimes buying up other companies to gain access to promising compounds. But this could potentially limit the mix of drugs being tested together.
"We don't want companies to develop in-house combinations only," says Tracy Swan. "They should be using best-in-class drugs to create regimens."
Trials for HIV/hepatitis C-co-infected people are still not moving as quickly as we’d like, but they are happening. Boceprevir and telaprevir are in Phase 3 trials and daclatasvir, BI 201335 and TMC435 are each being tested with pegylated interferon and ribavirin in co-infected people. Interferon-free direct-acting antiviral combinations are not yet being studied in co-infected people. Before they are, researchers are trying to get a handle on to what extent interferon contributes to HIV suppression in the face of drug-drug interactions and what might happen if it's left out. In addition, some hepatitis C drugs, especially the NRTIs, may have a degree of activity against HIV too.
"Hepatitis C drug development is like HIV drug development at warp speed, but that doesn’t mean we're going to have that magic bullet without interferon soon," says Douglas Dieterich.
Sanjay Bhagani also worries about the public health consequences of giving the impression that hepatitis C is ‘easy to treat’. “We need to be acutely aware of rising hepatitis C rates amongst gay men, especially in Europe,” he says. “If we don’t address risk-taking, we may find ourselves trying to treat multiple re-infections, which could be disastrous.”
Most experts predict several more drugs will be approved for hepatitis C-mono-infected people to use with pegylated interferon and ribavirin over the next few years. The first interferon-free combinations for hepatitis C mono-infection may hit the market in three to five years. Treatment for HIV/hepatitis C-co-infection is running a generation behind and, under existing procedures, interferon-free combinations for co-infected people are not expected for seven or so years. But knowledge gained from mono-infection trials and pressure from advocates could hasten that process.
"We are at that transition period where patients that need treatment based on disease stage should get it today and others will be able to wait," concludes Mark Sulkowski. “That will be the art of hepatitis C treatment in HIV-infected patients for the next several years".
- Dieterich D et al. Telaprevir in combination with peginterferon alfa-2a/ribavirin in hepatitis C/HIV co-infected patients: SVR12 interim analysis. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 46, 2012.
- Sulkowski M et al. Boceprevir plus peginterferon/ribavirin for the treatment of hepatitis C/HIV co-infected patients. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 47, 2012.
- Hulskotte E et al. Pharmacokinetic interaction between the hepatitis C protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 771LB, 2012.
- See www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf
- See www.nice.org.uk/nicemedia/live/13482/58368/58368.pdf (boceprevir) and www.nice.org.uk/nicemedia/live/13486/58478/58478.pdf (telaprevir).
- Gane E et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1: a randomized, double-blind, placebo-controlled, dose-escalation trial. The Lancet 376:1467-1475, 2010.
- Zeuzem S et al. Virologic response to an interferon-free regimen of BI201335 and BI207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 hepatitis C infection: Week 12 interim results of the SOUND-C2 study. American Association for the Study of Liver Diseases Liver Meeting, San Francisco, abstract LB-11, 2011.
- Chayama K et al. Dual oral combination therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 achieved 90% sustained virologic response (SVR12) in hepatitis C genotype 1b-infected null responders. American Association for the Study of Liver Diseases Liver Meeting, San Francisco, abstract LB-4, 2011.
- Gane E et al. Once daily PSI-7977 plus RBV: pegylated interferon-alfa not required for complete rapid viral response in treatment-naive patients with hepatitis C GT2 or GT3. American Association for the Study of Liver Diseases Liver Meeting, San Francisco, abstract 34, 2011.
- Gane E et al. 100% rapid virologic response for PSI-7977 + ribavirin in genotype 1 null responders (electron): early viral decline similar to that observed in genotype 1 and genotype 2/3 treatment-naive patients. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 54LB, 2012.