Dr Omar el Sherif and Dr Orla M Crosbie examine the rates of hepatitis C in Ireland and report on the latest available treatments from the 2011 AASLD Annual Meeting in San Francisco.
Hepatitis C virus (HCV) infection remains a major global health issue and a leading cause of chronic liver disease and cirrhosis. In Ireland, the prevalence of chronic HCV infection is estimated to be between 0.5-1.2 per cent of the population (20,000 to 50,000 people), with the majority of cases remaining undiagnosed.
Given the latency period between acquiring the virus and the development of complications, the healthcare burden of HCV-related cirrhosis in this cohort is expected to rise significantly over the next two decades. Putting this into a global context, in the US population from 1999-2007, deaths from hepatitis B virus have remained fairly constant, death rates from HIV have decreased and HCV death rates have increased significantly and have now overtaken HIV as a cause of mortality.
Genotypes 1 (55 per cent) and 3 (39 per cent) are the predominant genotypes in Ireland. The main risk factors for acquiring HCV in an Irish population are intravenous drug use (80 per cent) and the receipt of infected blood or blood products (16 per cent), with only a minority of patients acquiring the virus through sexual exposure (1.2 per cent). Overall, the median age of diagnosis in Ireland is 28 years, whilst those who acquired the infection through blood products tend to be slightly older at the time of diagnosis (median age of 34 years).
The sex distribution of patients varies significantly and is related to the mode of virus acquisition — some 70 per cent of infected intravenous drug users are male, whereas 71 per cent of those infected from contaminated blood products are female, reflecting the anti-D contamination from 1977 to 1979.
HCV and treatment
Although the HCV virus was only identified in 1988, there have been remarkable advancements in the characterisation of the virus and our understanding of the complex interplay between it and the host immune system. The hallmark of HCV, an RNA virus, is its significant genetic variability, resulting in the existence of six major genotypes and over 100 subtypes.
This variability arises from the virus’s high mutation rate, and in part explains the difficulty in mounting an effective humoral immune response in the host, and the development of resistance to anti-viral therapy. The virus itself is not cytopathic to hepatocytes, and liver injury results from the cell-mediated immune response to the virus.
The rationale for treatment of chronic HCV infection is well established. The goal of treatment is eradication of HCV RNA and cure is defined as the achievement of a sustained virological response (SVR). This is associated with decreases in all-cause mortality, liver-related complications, hepatocellular carcinoma rates and the need for liver transplantation.
Antiviral therapy is recommended for patients who: 1) are over 18 years of age; 2) have a positive HCV antibody and detectable serum HCV RNA; 3) have liver biopsy findings consistent with a chronic hepatitis (though not essential); and 4) have no contraindications to treatment. Current standard of care (SOC) therapy consists of pegylated interferon and ribavirin (P/R).
With SOC therapy, SVR is achieved in 40-50 per cent of patients infected with HCV genotype 1 after 48 weeks, compared to 60-80 per cent with genotype 2 and 3 after 24 weeks. Current therapy success is limited (particularly for genotype 1) by the high rate of partial and non-responders, and notable relapse rates after completion of treatment.
Role of IL-28B polymorphisms
Genetic variations on chromosome 19, near the interleukin 28b gene (also known as IFN-lambda-3), have been shown to influence response to therapy with interferon. Single-nucleotide polymorphisms or SNPs can be examined at different locations, The ones studied most to date are in position rs12979860. The CC genotype is associated with a twofold increase in response to interferon (82 per cent chance of response with genotype 1) compared to the CT (42 per cent) and TT (33 per cent) types.
SNPs at rs8099917 are also predictive of response, GG being the favourable SNP here. It is now known that the CC genotype is the single most powerful pre-treatment predictor of response to IFN; however, once therapy is commenced, the rapid virological response (RVR) becomes the most helpful tool in predicting which patients achieve an SVR. These SNPs, however, do not appear to be as useful in patients with genotype non1. They also predict which patients are likely to spontaneously clear HCV in the acute phase.
The genotype frequency in a small population of our patients tested to date in Cork has shown that 33 per cent have the CC genotype, 58 per cent the CT and 9 per cent the TT genotype, consistent with international figures to date.
At the recent American Association for the Study of Liver Diseases (AASLD) Annual Meeting held earlier this month in San Francisco, some 26 per cent of abstracts presented at the meeting were on the topic of hepatitis C, indicating how important this virus is currently in the field of hepatology. The rapidly-growing research field of HCV therapeutics was also reflected by the fact that most of the late-breaking abstracts were about new and emerging treatments for HCV.
At the same meeting, AASLD launched its recently-updated guidelines for the management of patients with HCV. It is therefore an exciting and challenging time for clinicians and patients working with HCV, as an enormous amount of information has suddenly become available to us, with potentially several new therapeutic algorithms and options. While trying to plan the best treatment options for individuals with HCV, we will simultaneously have to absorb and gain experience with several new drug combinations and adapt therapeutic options accordingly.
New drugs for HCV
The main new therapeutic options for HCV, the directly-acting antiviral (DDA) drugs, consist of the protease inhibitors, the polymerase inhibitors, NS5A agonists and cyclophilin inhibitors. The two agents soon to be available (early 2012, already available on a named-patient basis) in Ireland and elsewhere are the NS3/4A protease inhibitors boceprevir (BOC or VICTRELIS) and telaprevir (TEL or INCIVO). These agents have potent anti-viral activity, but when used alone result in the development of resistance and viral breakthrough and therefore need to be used with peginterferon and ribavirin (P/R).
Triple therapy with TEL or BOC and P/R has several advantages over standard dual therapy, in particular the significantly higher SVR rates seen in all patient groups, both patients naïve to therapy and previous treatment failures with HCV genotype 1. While TEL and BOC have in vitro activity against G 2 and 4 (not 3), they have only been studied extensively in genotype 1 in humans and are currently only recommended for use in patients with G1.
Several landmark studies have been published this year, looking at the performance of triple therapy in both naïve and treatment-failure patient groups.
The SPRINT 2 study looked at treatment-naïve G1 patients using a four-week lead-in with just P/R and then adding in boceprevir after four weeks and continuing with triple therapy. A lead-in phase was used to reduce the chances of drug resistance, but also it helps to predict the ultimate SVR in individual patients. Significantly higher SVR rates were seen after 28 and 48 weeks of therapy; 67 per cent and 68 per cent respectively vs 40 per cent in the P/R group.
Similar SVR rates were seen in the 28- and 48-week group and very good SVR rates of 74 per cent were seen even in those patients with a positive viral load still at week eight.
RESPOND-2 went on to look at previous treatment failures. Again, a lead-in of four weeks with P/R was used and then BOC for 32 in response-guided therapy (RGT) or for 44 weeks; RGT was used in patients who were HCV negative by week eight, and given 32 weeks of BOC in total, compared to the other group that received 44 weeks of BOC. SVR rates of 59 per cent and 66 per cent were seen in these two groups, significantly higher than with P/R alone (21 per cent).
For those who had cleared the virus by week eight, SVR rates of 86 per cent and 88 per cent were seen with BOC/P/R. The rates of response in patients with prior relapse were 69 per cent and 75 per cent and the rate in previous non-responders was 40 per cent and 52 per cent, a very impressive figure for prior treatment failures. SVR rates of 77 per cent were seen when cirrhotics were treated for 48 weeks, compared to no SVRs for those given P/R alone.
The viral load at week four was the strongest predictive factor for an SVR. Treatment was stopped at week 12 if still HCV positive and this occurred in 61 per cent of controls and only 18-22 per cent of patients in the BOC groups. This information has now been used to draw up a treatment algorithm for patients intending to use BOC, and is shown in Figure 2. It should be noted that PEG interferon α1a was used in these studies, but BOC has been licensed for use with both PEGα 1a and 1b.
Other studies
Similar-type studies were performed with telaprevir, but without a lead-in phase. ADVANCE looked at treatment- naïve G1 patients and found significantly higher SVRs with TEL used for just 12 weeks with P/R, followed by a further 12 or 36 weeks of PR, the duration depending on the extended RVR (eRVR).
Following a total of 24 or 48 weeks of therapy, SVR rates of 69 per cent and 75 per cent respectively were seen in both groups, again superior to SOC.
According to eRVR, an impressive 58 per cent of patients were suitable for 24 weeks of therapy. REALISE treated previous non-responders with TEL, all for 48 weeks in slightly different regimes, and found again that the SVR was significantly higher with TEL than SOC: SVR was 83-88 per cent for previous relapsers vs 24 per cent SOC, 54-59 per cent vs 15 per cent for previous partial responders and 29-33 per cent vs 5 per cent for previous null responders.
ILLUMINATE looked at response-guided therapy (RGT); ie, it looked at length of treatment required depending on RVR and found a shorter course of therapy (total 24 weeks) was as effective as 48 weeks if the patient had an eRVR (92 per cent vs 88 per cent). Those that did not achieve an eRVR still had an SVR of 64 per cent. Half of the 61 cirrhotics in the trial achieved an eRVR; of these, 92 per cent had an SVR after 48 weeks’ therapy, compared to only 61 per cent after 24 weeks, hence the current recommendation that all cirrhotics receive 48 weeks of therapy. Figure 3 shows the algorithm devised for therapy with TEL.
Not unexpectedly, more side effects were seen with triple therapy: anaemia in particular with BOC and rash is a common problem with TEL, as well as the expected side effects from P/R. Both drugs inhibit the cytochrome P450 isoenzyme CYP3a and the half life of drugs metabolised by this enzyme may be increased with more adverse effects. This is a potential concern for co-infected patients, as the trials to date have excluded patients with HIV.
However, a late-breaking abstract at AASLD showed impressive results and safety in co-infected HIV patients with and without antiretroviral therapy, treated with TEL and P/R. Both need to be given thrice-daily at present, although further studies have shown that bd dosing may be as effective. This further complicates the therapeutic regime, especially as ribavirin is taken bd. TEL also has to be taken with a high-fat meal, with 20gms of fat at least to maximise absorption.
Viral resistance is a concern with these drugs and if resistance develops, it may affect the efficacy of other PIs for that patient, although how this will change over time is not certain.
Resistance-associated amino acid variants (RAVs) in the NS3/4A protease region of HCV were detected in the serum of 50-53 per cent of non-SVR patients following failed therapy with PR/BOC, but declined after therapy cessation. Interestingly, 6-9 per cent can have baseline RAVs which do not appear to influence SVR.
Similarly, amongst non-SVR patients treated with TEL, TEL resistance measured at NS3 was no longer detected in 83 per cent at 21 months’ follow-up.
This was noted to occur more commonly in genotype 1a than 1b. Therefore, it is recommended that if viral breakthrough occurs on treatment that the PI should be discontinued immediately and should not be reintroduced. Likewise, interruption in the PI therapy should not occur because of side effects which may develop while on therapy.
Interestingly, the AASLD guidelines now recommend triple therapy for anyone with G1. We think this issue is debatable, as the expense of triple therapy can be avoided in those with favourable Il28B genotyping (and a 70 per cent plus chance of responding to dual therapy). We are of the opinion that dual therapy should be initially offered to those with G1 and favourable Il28B genetics, to avoid the extra cost and side effects of triple therapy. Indeed, Abstract 118 at AASLD demonstrated that dual therapy was more cost effective than triple therapy (given current prises) in G1 patients with favourable Il28B CC genotyping.
Data on other protease inhibitors was presented at AASLD. Just to mention a few:
B1201335 gave a SVR rate of 63 per cent and 72 per cent in naïve patients with genotype 1 who were treated with this PI and P/R for 12 and 24 weeks only respectively in a Phase II trial. Overall, SVRs of 83 per cent (100 per cent in Il28 CC) were seen with the same drug after 24-48 weeks’ therapy. Danoprevir gave SVR rates as high as 83 per cent in naïve G1 patients following 24 weeks of therapy with PR. TMC 435 used with PR gave SVR rates of 100 per cent in CC genotypes, similar to SOC, but higher SVR rates were seen in the CT (80 per cent) and TT (67 per cent) groups.
Other DDAs
The NS 5B polymerase inhibitors include the nucleotide analogue inhibitors (NAIs) and non-nucleotide inhibitors (NNIs). These have two particular advantages compared to PIs, in that they are effective against all genotypes and resistance is less likely to develop, so it seems possible to use them successfully without interferon.
One very promising-looking agent was the nucleotide analog PSI-7977, which when given with ribavirin only (no PEG) resulted in SVRs of 100 per cent in naïve non-cirrhotic genotype 2 and 3 patients after only 12 weeks of therapy. The same agent used with PEG/R in non-cirrhotic genotype 1 patients has shown end-of-treatment response rates in 90 per cent; SVRs are awaited.
BMS-790052, a NS5A replication complex inhibitor, has shown very favourable treatment results when used with PEG/R in G1 and 4 patients (A227).
The same agent used with BMS-650032, a NS3 protease inhibitor, without PR has shown SVRs at 12 weeks (24 weeks awaited) of 90 per cent in G1 previous null responders. Alisporivir, a cyclophilin inhibitor, has shown promising results when used alone in genotype 2 and 3 patients, with half of the patients becoming virus negative by week six with this therapy taken alone.
SVR rates at week 12 and interim results of several other non-IFN regimes were presented at the AASLD meeting, many as late-breaking abstracts, showing again that interferon-free therapy is a realistic option for the future.
Conclusion
In conclusion, the medications available to us for use in the short-term include peginterferon, ribavirin, boceprevir and telaprevir. The latter PIs can be used effectively in patients that have failed previous interferon therapy, including null responders, partial responders and relapsers. In effect, they can be tried on anyone who has had treatment before and who has failed but is willing to give it another try.
The advantage of this is that patients are already very familiar with the side effects of PEG and RBV and have experienced therapy before and can be better prepared mentally, physically and socially for this.
All of the above information has to be amalgamated and used in a safe and effective way for ongoing patient care, with consideration also of the costs involved in the current challenging economic climate.
Interestingly, models again presented at AASLD suggest that the use of DAAs will have only a modest effect on liver morbidity and mortality compared to SOC therapy, unless more patients are treated. We have to try and achieve this by encouraging suitable patients to consider therapy.
International studies show that fear of side effects, duration of therapy and cost are the things that prevent more patients being treated. In reality, these issues take time and consideration to cover in a busy clinic and we cannot overstate the importance of the essential input from specialist nurses in helping to educate patients, provide them with suitable information and continue to support them and keep them safe throughout treatment.
We will also need to carefully audit our results as approaches to therapy are changing rapidly to ensure that we continue to improve outcomes. A multi-disciplinary approach too is vital with our colleagues in molecular virology, as it is likely that molecular information will shape very individual therapeutic regimes for most patients going forward.
- Dr Omar el Sherif, SpR in Gastroenterology and Dr Orla M Crosbie, Consultant Hepatologist, Cork University Hospital.
The authors would like to acknowledge the ongoing support of Dr Liam Fanning, MVL CUH for molecular virology testing and expertise.
About admin
Loading ...
