New HCV Drugs:Expected Risks-Challenges in Liver Transplant
New Therapies Against Hcv: Expected Risks and Challenges Associated
with their use in the Liver Transplant Setting
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To appear in: Journal of Hepatology
Received Date: 31 May 2012
Revised Date: 20 July 2012
Accepted Date: 20 July 2012
McCaughan, G.W., New Therapies Against Hcv: Expected Risks and Challenges Associated with their use in the Liver Transplant Setting, Journal of Hepatology (2012), doi: http://dx.doi.org/
1. Current approaches to HCV therapy in the Liver Transplant Setting
Current approaches to Anti-Viral Therapy (AVT) in the setting of liver transplantation are based on the use of Pegylated Interferon in combination with Ribavirin (Peg/Riba). Attempts to clear HCV pretransplant have been successful in about 15-20% patients with genotype 1 infection and about 20-35% with genotype 3(1,2) Such patients usually have relatively lower MELD scores (< 18) than many other patients listed for transplant. Despite this AVT is associated with an increase risk of serious bacterial infections (3). Sustained Viral Response (SVR) pre transplant is associated with lack of viral recurrence post transplant (1,2) Early post transplant AVT is not thought to be useful due to lack of efficacy and poor tolerability (4,5).
The commencement of AVT is usually considered at about the 12-month mark based on protocol biopsies. Patients with either F2 or F1 with significant portal inflammation (stage >= to 2) are usually considered for AVT6.-8. SVRs in the range of 20-30 % patients with HCV Genotype 1 (G1) and 40-50% for patients with HCV G3 are obtained (6-8). SVR post transplant has been linked to both donor and recipient IL28 Polymorphisms (9-11). Achievement of SVR in the post transplant setting is associated with improved survival compared to patients who do not achieve an SVR (6-8).
Given the importance of viral clearance in the pre and post transplant setting such results have been thought to be somewhat unsatisfactory and the liver transplant community has been eagerly awaiting new anti- HCV therapies.
2. A brief summary of the new HCV therapies
Perhaps it is best to consider the new AVTs as first, second and third “wave” therapies. (Table 1)
These new AVTs include Direct Antiviral agents (DAAs). The first DAA wave consists of therapy with the NS3/4A Protease Inhibitors (P.Is) Boceprevir or Telaprevir added to Pegylated Interferon and Ribavirin (12-15). National registration bodies have recently approved these new agents.
They are administered 3 times per day and are aimed against HCV G1.Added toxicities are considerable. (12-15) SVRs are increased from 45-50-% to 60-70% for treatment naïve patients.
The second wave consists of replacing Boceprevir and Telaprevir with second generation NS3/4A Protease, HCV polymerase or NS5a inhibitors. (Summarized in reference16) These agents can be give daily, sometimes have additional genotype specificity but may also still have significant side effect profiles (17-33).
The next generation Protease Inhibitors in combination with Peg/Riba generally seem to have similar efficacy to the first wave new AVT (17,18,22,24,26,28) although results with Polymerase and NS5a inhibitors (plus Peg/Riba) have
increased SVRs up to 90% (19,21,23,25,26,29-31) There is preliminary data that combinations of DAAs and Peg/ Ribavirin (so
called quadruple therapy) may have very high SVRs. (>95%)(20,27,28,32).
Despite some enthusiasm for the best of the second wave therapies, the third “wave” is likely to be the most significant and certainly most exciting. This wave aims to replace Interferon altogether. The regimes use DAAs in combination without Interferon but sometimes with Ribavirin eg: a HCV NS5A polymerase Inhibitor combined with second (or third
generation) NS3/4 Protease Inhibitors or an NS5A inhibitor (31,32-36).
One exciting regime just used a plus Ribavirin (33). This resulted in SVRs of 90-100% in treatment naïve G2/3 patients requiring only 3 months of therapy with no recorded toxicity. However the same regime applied to Genotype 1 patients who were previously null responders to Peg/Riba however seems disappointing with significant relapse rates (34). An alternative regime of an NS5A inhibitor plus a Polymerase inhibitor, given for only 3 months lead to an SVR of 90% patients with HCV G1b who had previously been null responders to Interferon (35). It is generally thought that G1b is more sensitive to the DAAs and is associated with an enhanced resistance barrier. It is unclear whether Ribavirin will remain an important agent in these new treatment regimes (20,28,37)
In summary these “third wave” regimes are aimed to be non-genotype specific, taken once per day, have limited toxicities and taken for short duration (as short as 3 months). As mentioned, SVR is expected to be in 90% range. It should be noted however that many of these studies are at the proof of concept stage and have only been reported in small numbers of patients.
Furthermore these agents have not yet been used in patients with advanced liver disease and portal hypertension.
Currently there is no data on any of these first, second or third “wave” AVT regimes in the setting of liver transplantation. Thus the following discussion is largely speculative and deductive. It will be interesting to come back in the years ahead as new data arise. Hopefully the comments below will have some relevance but that can’t be guaranteed!
3. Use of the new therapies Pretransplant (table 3)
3.1. Triple therapy with either Telaprevir or Boceprevir
The first issue is that these agents are only aimed at HCV G1.
The second issue is that many of these patients will already have failed Pegylated Interferon based AVT. Thus it will remain important (as now) to classify patients into those who have previously relapsed versus those who have been non-responders. Patients without cirrhosis who have relapsed may have up to an 85% SVR to these new regimes whilst non-responders may be as low as 30% (13,14). However previously Interferon treated patients with well-compensated cirrhosis and significant portal hypertension are likely to have much lower SVRs. There is evidence that IL28 polymorphism testing still has a role in treating patients with Telaprevir or Boceprevir (38). Perhaps this will be even more important in treating patients with advanced disease in order to maximize SVRs.
The third issue is- what is the expected the SVR in naïve subjects with cirrhosis and portal hypertension being treated with these agents? Although it is tempting to use these agents (given the increased SVR) it is not clear what that SVR will be. If we
assume a 50% improvement on the current 15-20% SVR in patients with Genotype 1 infection then the likely SVR will still only be in the vicinity of 20-30%. That assumes that the treatment withdrawal rate will be the same as current standard of care therapies. However, that is unlikely.
The fourth issue is the likely increased side effect profile when treating such patients. A recent study in abstract form gives some data on the real time use (non clinical trial) of these regimes in patients with cirrhosis who have been had failed previous
Interferon therapies (39). Although there is no SVR data, safety data for both Telaprevir and Boceprevir were given for the first 16 weeks of therapy. In these patients 19-28% had varices, 29-48% were relapsers, the mean serum albumin was about 40 g/dl, and the mean platelet count was 150,000. Thus although some of these may have been transplant candidates the vast majority were not. Despite this 4 deaths occurred in 362 patients (1.3%) in the first 16 weeks and 6-12% had therapy
discontinued due to Serious Adverse Events. Erythropoietin was used in about 50% of patients and blood transfusion was required in between 6-18% of patients.
This data does raise caution about the safety profile in much sicker patients. Concern with the skin rash in patients with portal hypertension is even greater than in non-cirrhotic patients. These patients have significant defects in neutrophil function (40)
and secondary skin infections (particularly Staphylococcus) could prove fatal.
The final issue is the emergence of anti-protease resistance strains of HCV in pre transplant patients (41). This will be a particular issue in previous Interferon non-responders where if these new therapies are continued for any length of time then
resistant strains will be amplified. Thus stopping rules need to be strictly observed in these patients.
The implication here in transplant patients will be the effect of access to future Protease Inhibitor based therapies if significant resistance is detected. If significant resistance emerges patients with mild disease can probably wait until better agents emerge (third wave). However transplant candidates may require more urgent access to newer therapies but will almost certainly not be suitable for anti protease-based therapies that have cross-resistance profiles with Boceprevir and
I would conclude that the significant use of these first wave therapies in pre transplant waiting list patients will be problematic and perhaps not worth the effort or the risk. As now, such therapies will probably be confined to Childs A patients with Hepatocellular Cancer. Already much discussion has been had on whether to “by pass” these agents in this patient group and head straight to second wave or third wave agents.
3.2. Triple/ Quadruple therapy with next generation AVT
If Boceprevir and Telaprevir are likely to have minimal impact then what about the next wave of AVT? As mentioned the major difference between these agents and Boceprevir or Telaprevir is the ease of administration (daily) and less genotype specificity. Side effects still occur (although different) and the SVR seems about the same in next generation P.I.s plus Peg/ Riba. It would seem that the main advantage with these agents would be in patients infected with Genotype 2/3 virus where the P.I had expended genotype specificity. Currently such patient’s pre transplant may have an SVR of up to 35%. Extrapolating that these second wave agents would increase SVR by 50%
then perhaps we could expect SVRs of about 45 % or even 50 % pre transplant. Thus it may be tempting to use them. However the key once again will probably be tolerability. The wide spread use in patients infected with Genotype 1 HCV would seem to have the similar caveats to the use of Boceprevir and Telaprevir.
As mentioned patients infected with Genotype 1 HCV who failed these therapies ‘would not be suitable/ eligible for second wave Protease Inhibitor therapies with cross resistance profiles As previously mentioned Polymerase Inhibitors or NS5A inhibitors plus Peg/Rib however may have a significant impact re SVRs. Tolerability will mainly revolve around the Peg/Rib
combination as now.
3.3. Non interferon based therapy
This seems to be most likely breakthrough and a paradigm shift for patients awaiting liver transplantation. As mentioned the goal of these approaches is fourfold.
(1) To achieve 90% SVR, (2) to have minimal side effects (3) to be pan genotypic and (4) to be of short duration (maximum
6 months). All of these seem potentially achievable. As mentioned 90-100% SVRs have already been reported in treatment naïve patients infected with Genotype 2/3 HCV using just and Polymerase inhibitor and Ribavirin for 3 months (33). Although
initially tested in patients with Genotype 2/3 HCV this regime is thought to be pan genotypic. Use of an NS5A inhibitor + next
generation Protease Inhibitor in patients with Genotype Ib HCV (who were previously null responders to Interferon) also resulted in a 90% SVR (35).
It is expected that an increasing number of combinations will emerge in the next 1-2 years and perhaps be in clinical practice within 5 years. (16-Table 1) If such predictions are true then the whole landscape of human liver transplantation will change
dramatically, perhaps in a similar fashion to the change in outcomes that occurred in patients with chronic Hepatitis B infection
awaiting transplantation in the mid to late1990s with the introduction of Lamivudine and Adefovir. (42)
The first change would be that almost all patients awaiting liver transplantation would be rendered PCR negative and effectively cured of HCV. This would include patients with Hepatocellular Cancer and low MELD scores. These patients based on current paradigms could be treated for 3-6 months with AVT and proceed to transplant within 3-6 months with
the likely hood of no HCV recurrence.
The second group would be those who have end stage decompensated liver disease. Currently it seems very unlikely that such patients will be treated with Boceprevir or Teleprevir or even second wave approaches, as both require Peg and Riba. In the pre-transplant context however I would dispute the automatic conclusion that obtaining an SVR in such decompensated patients will necessarily avoid liver transplantation in a similar fashion to that seen in HBV.
Firstly there are HBV patients who do not recover and die despite successful control of HBV replication (43). MELD scores of > 25 characterize these patients. Secondly decompensation in Chronic HBV infection is often due to flair of HBV replication superimposed on cirrhosis. In other words, HBV patients usually do not just slip slowly into decompensation and
overt liver failure. In contrast that is exactly what patients with end stage HCV cirrhosis do, often precipitated by infection or bleeding.
Although we would all hope that eliminating HCV at this stage would revert such patients to a compensated state this remains to be established. It is worthy to note that data are lacking on significant improvement in MELD scores in patients currently on
waiting lists undergoing SVR with current standard of care with Peg + Riba. At best some of these patients stabilize and even if improvement is seen it happens slowly (Xavier Forns, Barcelona; Greg Everson, Colorado personal communications). It could be argued that non Interferon based regimes will not have the catabolic effects in these patients that is induced by Interferon and hence improvement will be expected and happen over a shorter time frame. This remains an interesting
point of discussion that the future will resolve.
In addition to these issues is the recent provocative finding that patients with HCV infection still have increased liver related morbidity and mortality compared to the general population despite obtaining an SVR (44). If this is true then
liver transplantation for patients with decompensated HCV and an SVR may still be required.
To conclude, third wave therapies are likely to dramatically change the landscape. It is predicted that these therapies delivered pre transplant will prevent HCV recurrence post transplant. Treatment duration may differ depending on genotype and previous responses to interferon. Patients with HCC and HCV will still require transplantation. It remains unclear however what percentage of patients with decompensated advanced liver failure and high MELD scores will be “rescued” thus avoiding transplant altogether. Watch this space…
4. Could new therapies prevent HCV infection of the allograft at
time of transplant?
4.1. New anti HCV monoclonal antibodies
Current approaches using such interventions have not been successful. However a more recent study using a human monoclonal antibody against HCV E2 suppressed viral replication during the 7 days of therapy immediately post transplant (44). Thus this approach may still have some merit.
4.2. What about blocking uptake at receptor level?
The identification of Claudin1, CD81, Occludin and Scavenger receptor class B1 (SR-B1) as a network of receptors involved in HCV uptake does raise the possibility that blocking Mabs aimed at HCV binding sites could prevent HCV up take into the liver at the time of transplantation (46,47).
Currently however no such in vivo data exist although a recent study in humanized mice showed that novel monoclonal antibodies against SRB1 were effective not only in preventing uptake but also cell – cell spread of HCV (48)
4.3. What about blocking uptake at the Tyrosine kinase level ?
Recent data indicate that the tyrosine kinase system feeding off the Epidermal Growth Factor Receptor is crucial in the complete uptake of HCV into hepatocytes (49).
Such inhibitors currently exist in oncological practice and could theoretically be applied intraoperatively and immediately post surgery to block uptake of HCV at the time of allograft implantation. The toxicity of such molecules administered for short periods of time may be minimal. Perhaps such agents could be used in combination with neutralizing Mabs and blocking Mabs
aimed at HCV receptors. It is unclear what duration of therapy post liver transplantation would be required but it seems likely it would be > one week.
In conclusion such approaches outlined in this section are intellectually appealing but currently it is not clear how practical they would be. They may be unnecessary if third wave DAAs are very successful.
5. Use of new therapies post liver transplant (table 4)
5.1. Triple therapies with either Telaprevir/ Boceprevir
As mentioned, current treatments with Peg + Riba yield about a 20-30 % SVR (G1) in the stable post transplant setting. The use of Telaprevir or Boceprevir in these patients may increase the SVR to about 40 %. (G1) Thus there is currently great interest in introducing such therapies as soon as possible in this setting. Several confounding issues however
Firstly drug – drug interactions (50-52). Boceprevir and Telaprevir are metabolized via the Cytochrome P450 3a system and compete with Cyclosporine, Tacrolimus, evolimus and Rapamycin for metabolism. Emerging data suggest that the area
under the curve for these immunosuppressive agents is dramatically increased when given with Telaprevir or
Boceprevir. Increases of up to 70 fold have been observed with Tacrolimus and 5 fold with Cyclosporine. This will make Boceprevir or Telaprevir difficult to use but not impossible. Dose adjustments of these immunosuppressive drugs in a similar fashion to those required with some HART regimes in HIV infected transplant patients will be required.
Secondly the side effect profile in immunosuppressed patients may be exaggerated and thirdly the issue of previous non-responsiveness to Interferon and potential protease Inhibitor resistance may significantly decrease efficacy. Lastly optimal durations of therapy will need to be established.
Despite these concerns there are now several reports in abstract form on the use of either of these two agents in the post transplant period. (53-61) These reports usually only include a small number of patients although when presented at various meetings the numbers have been greater. In essence several themes have emerged. (Table 4). Firstly there is little
or no SVR data, Secondly drug interactions seemed to have been well managed although very high levels of Tacrolimus have
occasionally been seen,
Thirdly many users have converted their patients to Cyclosporine based immunosuppression before commencing AVT, Fourthly side effects and dose reduction of Ribavirin is common. In some studies treating Cholestatic hepatitis has not always been successful due to introduction of triple therapy based AVT at very late stages of disease. Mortality has been reported in such patients. A recent report however does show a SVR can be achieved in cholestatic hepatitis (62)
5.2. Triple/Quadruple therapies with next generation
The issues here are similar to those raised with Boceprevir and Telaprevir although the ease of use and increased genotype susceptibility and increase SVR in non-protease based therapies may encourage early introduction. Furthermore some P.Is have been developed that are not metabolized via the Cytochrome P 450 system and thus may be easier to use
with current immunosuppressive drugs (63).
5.3. Non interferon based therapies
As pre-transplant, there is great hope for the future here. Apart for the potential for marked increased efficacy, the lack of toxicity and absence of significant drug -drug interactions may enable the best of these therapies to be introduced very early post transplant in patients who remain viremic at transplant (in a similar fashion to HBV antivirals). This would result in
viral control from the time of transplant. It should however be pointed out that if these third wave agents cure HCV pre transplant then no AVT at all will be required post transplant!!!
It is known that HCV replication occurs at the time of allograft implantation but for the first month post transplant this rarely results in allograft pathology (64,65). Thus if viral control during this time and elimination within 3 months is achieved it is likely
that these type of agents could very well eliminate HCV related allograft pathology. This would be the holy grail of using such
therapies if required early post transplant. It would be presumed that very early use post transplant would be best tolerated in Ribavirin free regimes. A challenge here would be the question re duration of therapies post transplant setting. If 3 months
duration emerges as sufficient in the non transplant setting the post transplant situation may require longer duration in the setting on immunosuppression. This will need to be studied. Even if early viral control and or elimination does not become the optimal strategy it is likely that the use of these regimes will achieve a 90% SVR at later stages of infection, once again duration of therapy in the post later post transplant will need to be clarified. Using such approaches should completely
eliminate Cholestatic HCV and even if such cases do occur it would be hoped that the severe allograft dysfunction associated with form of HCV infection could be reversed (although that can not be totally assured).
6. Predictions of the (near) future
It seems likely that the new age of AVT will radically improve outcomes for patients with HCVinfection in the setting of liver transplantation. Currently this is a hope as there is no data to support this claim. It is a strong intellectual prediction based on non-transplant data. It may be only the introduction of the third wave of non-Interferon based therapies that will achieve this routinely in the pre and post transplant setting. Whether immediate uptake of the first and second wave therapies is warranted remains debatable and whether neutralization of the virus at the time of transplant is worthy of study may depend on how successful the third wave of HCV therapeutics is in the transplant setting. In the long-run successful use of the third wave will abolish HCV infection even in advanced disease well before transplant is required.
This will leave only HCC patients and patients with advanced liver failure that slip through the net and present late requiring
transplantation. Furthermore such patients will not require post transplant AVT or of they do it will likely be for short periods of time Whatever the exact outcomes exciting and challenging times lie ahead.
As examples of questions that will be answered quite soon the reader is invited to answer yes or no to the following and revisit your answers in 3-5 years from now
1. The introduction of Boceprevir or Telaprevir will significantly alter outcomes for patients on the transplant waiting list. (? No)
2. New second generation protease inhibitors will significantly alter outcomes for patients on the waiting list? ( ? Maybe)
3. Blocking HCV uptake at the time of transplant will become part of future anti HCV strategies? (? No)
4. Non interferon based therapies will lead to reversal of hepatic decomensation in the pretransplant setting? (? Maybe)
5. Non Interferon regimes will be used pre transplantation with subsequent elimination of HCV post transplant in virtually all patients? (? Yes+++)
6. Non Interferon regimes will only be required for < 6 months in the post transplant setting? (? Maybe)
7. In 10 years time the only HCV patients requiring transplantation will be those with HCC? (? Yes)