January 8, 2013

Reuters Health Information

Jan 02, 2013

By Will Boggs MD and Nancy Lapid

NEW YORK (Reuters Health) Jan 02 - In patients transplanted for hepatitis C cirrhosis, the virus inevitably recurs. Now a new meta-analysis suggests that cyclosporine-based immunosuppression may be associated with a better response to antiviral therapy after transplant than tacrolimus-based protocols.

Recurrent hepatitis C virus (HCV) after transplant leads to cirrhosis in up to 30% of recipients within five years. Treatment with antivirals is less effective after transplant than before.

Dr. Eberhard L. Renner and colleagues from the University of Toronto, Canada pooled data from 18 studies of HCV-positive liver transplant recipients treated with interferon and ribavirin to investigate whether rates of sustained virological response (SVR) are higher with cyclosporine vs tacrolimus.

As reported December 27 online in Liver Transplantation, a random effects model confirmed that cyclosporine was associated with 18% higher efficacy (p=0.05) compared with tacrolimus. There was, however, significant heterogeneity across the studies.

In the four studies that reported genotype-specific SVR rates, SVR rates were consistently higher for G1 patients and for G1/G4 patients on cyclosporine than for G1 patients and G1/G4 patients on tacrolimus. Too few patients with G2/G3 were available for statistical analysis.

End of treatment response rates from six studies did not differ significantly between cyclosporine and tacrolimus patients, but relapse rates were lower with cyclosporine than with tacrolimus (19% vs 26%; p=0.02).

Rates of early discontinuation of antiviral therapy ranged from 11% to 17% for cyclosporine and from 8% to 24% for tacrolimus.

Results from the available studies did not allow definitive conclusions about rejection rates or patient and graft survival rates for the cyclosporine and tacrolimus groups.

"The mechanism or mechanisms by which cyclosporine improves the efficacy of interferon-based antiviral therapy in liver transplant recipients with recurrent HCV are not fully understood," the researchers note. "They may, however, include direct antiviral properties, with cyclosporine (but not tacrolimus) having been shown to inhibit HCV replication and to add to the antiviral efficacy of interferon in vitro."

"Although our results lend further support to a beneficial effect of cyclosporine in patients with recurrent HCV who are undergoing antiviral therapy, they are not conclusive with respect to an overall benefit of using one or another calcineurin inhibitor as the backbone of immunosuppression in HCV-positive liver transplant recipients," the authors continue.

"Confirmation of this marginal benefit in a randomized controlled trial is needed," they add, "although our results suggest that a very large study would be required to achieve the statistical power needed to definitively address this issue."

Dr. Renner did not respond to a request for comments on this report.

Dr. Patricia Sheiner, Director of Transplantation at Hartford Hospital in Hartford, Connecticut, who was not involved in the study, told Reuters Health that although this wasn't a randomized trial, the results are interesting.

Modern antiviral therapy for recurrent hepatitis C after liver transplantation generally consists of interferon, ribavirin, and one of the new protease inhibitors, she said. The problem, she continued, is that the protease inhibitors increase the blood levels of both cyclosporine and tacrolimus (Prograf), but to a far greater extent with tacrolimus.

"Almost no transplant programs are using Prograf when treating recurrent hepatitis C with triple antiviral therapy in these patients," Dr. Sheiner said. "They're putting people on cyclosporine."

"The drug-drug interaction makes Prograf almost unusable with the protease inhibitors," she added. "So in light of the fact that the new protease inhibitors need to be given with cyclosporine, this study is reassuring."

SOURCE: http://bit.ly/VvaQJG

Liver Transpl 2012.

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How does breastfeeding protect against HIV?

By Beth Skwarecki
Posted: January 8, 2013

The amazing thing about babies drinking breastmilk from HIV-positive mothers is that they don’t always contract HIV.

Statistics vary, but about 85% of the time, that baby is still HIV-negative when they wean (assuming they were negative at birth). Why? Research has been building up over the last few years to try to tease out the answer to that question, and currently the spotlight is on a family of molecules that are the third-most-abundant in breastmilk (after fat and protein) but that the baby can’t digest: sugar-based oligosaccharides.

OK, I’ll back up. If you’re reading this from a place where clean water is abundant, and formula is available at the grocery store and you have the money to buy it, you may be wondering why it’s an issue at all – why risk that 15% transmission rate when you could just feed the kid formula and not have to worry? Worldwide, that’s often not the case. The WHO’s current guidelines state that formula should be used only when it is accessible, feasible, affordable, sustainable, and safe; but where that’s not guaranteed, mothers should breastfeed if at all possible.

That’s because breastfeeding carries so much protection against other nutritional and infectious diseases that the risk is worth it. Even a study that demonstrated the risks of HIV transmission in breastfeeding had a similar mortality rate between the HIV-positive, breastfed group and the formula feeders who were given free formula and instructed in sanitation.

The ideal situation in developing countries is to pair breastfeeding with antiretroviral drug therapy for both mother and child, which can reduce the rate of transmission to just 1%. (But even without drugs, WHO recommends breastfeeding anyway). South Africa adopted this policy in 2012 with some controversy; the rate of exclusive breastfeeding there is abysmally low. Some studies have shown that combining human milk with other foods – even solid foods in the case of an older baby, or even water – increases the likelihood of transmission from milk. The reason isn’t understood.

Last year, a study in PLOS Pathogens confirmed what both epidemiological and in vitro studies had hinted at: human milk prevents oral transmission of HIV. The authors created “humanized” mice, with bone marrow, liver, and thymus tissue from humans, and thus (as they described it) a “fully functioning human immune system.” They showed that the mice could contract HIV orally, but when the virus was delivered in the presence of human milk (obtained from HIV-negative women), transmission was completely stopped.

Obviously, the story isn’t that simple; it doesn’t account for the transmission that does occur. Calculations put the chance of contracting HIV from breastmilk at .00064 per liter, or .00028 per day of breastfeeding. Milk also varies from mother to mother, and it varies over time, which adds extra challenges to studying what’s going on. Meanwhile, the rate of virus particle shedding, and the form of virus (in or out of cells, for example) can also vary.

A magic ingredient?

Without human milk, infants are effectively missing a piece of their immune system; secretory IgA antibodies, for example, are abundant in milk and act in the infant’s gut. Proteins like lactoferrin have antimicrobial activity. The component that has been highlighted recently as preventing HIV transmission is a family of molecules made of strings of sugars. They’re called Human Milk Oligosaccharides.

Although they are made of sugar, HMOs aren’t digested by the infant.We used to think they must be “prebiotics” consumed by the bacteria that live in the baby’s gut, and that’s often true; one bug, Bifidobacterium infantis, consumes the lion’s share of the short-chain HMOs.

By tailoring the exact mix, moms are selecting particular types of bacteria for their child’s gut, in much the same way you can attract certain birds to your yard by the types of seed you put in your bird feeder. This explains, at least in part, why breastfed babies have dramatically different gut flora than babies that drink formula – even one bottle of formula can change their gut microbiome forever.

But, according to recent research, the protection from HIV may come from a different feature of HMOs: their ability to act as decoy binding sites for HIV.

One of the lesser-known jobs of oligosaccharides is that, in combination with proteins, they can stick out from a virus or cell surface, making a sort of flag that other cells can recognize. In the case of HIV, the virus bears an oligosaccharide that looks for a sugar-binding protein called DC-SIGN on the surface of human intestinal cells. But when decoy oligosaccharides from milk flood the gut, DC-SIGN binds to these instead, keeping the baby’s bloodstream HIV-free … for the moment, anyway.

Recent research has found multiple HMOs that protect against HIV, and at least one that increases risk; but overall, the more HMOs in milk, the smaller the risk of transmitting HIV. Lars Bode, the researcher behind many of the studies I’ve cited here, has written that “remarkably little is known about how, when and where [HMOs] are metabolized.” Human milk contains a complex cast of characters that we are just beginning to understand.

Expect to hear more about this family of molecules; hints from patent searches show that companies are interested in them: as prebiotics, and for protection against infant diseases like necrotizing enterocolitis. In the meantime, this research may lead to new ways of preventing HIV transmission, and confirms breastfeeding as a healthy practice for moms in developing countries.

References
  1. World Health Organization. 2007. HIV transmission through breastfeeding: a review of available evidence. link
  2. World Health Organization. 2010. Guidelines on HIV and infant feeding 2010. link
  3. Coutsoudis A. Breastfeeding in Women With HIV. JAMA. 2000;284(8):956-957. doi:10.1001/jama.284.8.956. link
  4. Vyankandondera, J., Luchters, S., Hassink, E., Pakker, N., Mmiro, F., Okong, P., … & Lange, J. (2003, July). Reducing risk of HIV-1 transmission from mother to infant through breastfeeding using antiretroviral prophylaxis in infants (SIMBA-study). In 2nd ias conference on hiV pathogenesis and treatment. paris, france (pp. 13-16). news article link

  5. Horvath T, Madi BC, Iuppa IM, Kennedy GE, Rutherford GW, Read JS. Interventions for preventing late postnatal mother-to-child transmission of HIV. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006734. DOI: 10.1002/14651858.CD006734.pub2. link
  6. Wahl A, Swanson MD, Nochi T, Olesen R, Denton PW, et al. (2012) Human Breast Milk and Antiretrovirals Dramatically Reduce Oral HIV-1 Transmission in BLT Humanized Mice. PLoS Pathog 8(6): e1002732. doi:10.1371/journal.ppat.1002732 link
  7. Richardson, B. A., John-Stewart, G. C., Hughes, J. P., Nduati, R., Mbori-Ngacha, D., Overbaugh, J., & Kreiss, J. K. (2003). Breast-milk infectivity in human immunodeficiency virus type 1–infected mothers. Journal of infectious diseases, 187(5), 736-740. link

  8. Hanson, L. A., and T. Söderström. “Human milk: Defense against infection.” Progress in clinical and biological research 61 (1981): 147. link

  9. Harmsen, Martin C., et al. “Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro.” Journal of Infectious Diseases 172.2 (1995): 380-388. link

  10. Asakuma, Sadaki, et al. “Physiology of consumption of human milk oligosaccharides by infant gut-associated bifidobacteria.” Journal of Biological Chemistry 286.40 (2011): 34583-34592. link

  11. Coppa, G. V., et al. “Prebiotics in human milk: a review.” Digestive and Liver Disease 38 (2006): S291-S294. link

  12. Q Zhang, Angela, et al. “Human whey promotes sessile bacterial growth, whereas alternative sources of infant nutrition promote planktonic growth.” Current Nutrition & Food Science 8.3 (2012): 168-176. news article link

  13. Naarding, Marloes A., et al. “Lewis X component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4^+ T lymphocytes.” Journal of Clinical Investigation 115.11 (2005): 3256. link

  14. Bode, Lars, et al. “Human milk oligosaccharide concentration and risk of postnatal transmission of HIV through breastfeeding.” The American Journal of Clinical Nutrition 96.4 (2012): 831-839. news article link

  15. Jantscher-Krenn, E., and L. Bode. “Human milk oligosaccharides and their potential benefits for the breast-fed neonate.” Minerva pediatrica 64.1 (2012): 83. link

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Download the PDF here

Journal of Hepatology
December 2012

Excerpted from the body below of this article, comments by author on future of antiviral therapy in transplant settings:

"5.Non-interferon regimes will be used pretransplantation with subsequent elimination of HCV post-transplant in virtually all patients? (? Yes+++)

....6.Non-interferon regimes will only be required for <6months in the post-transplant setting? (? Maybe)....

.....7.In 10years time, the only HCV patients requiring transplantation will be those with HCC? (? Yes)"

"Triple/quadruple therapies with next generation PIs/polymerase inhibitors: 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 P450 system and thus may be easier to use with current immunosuppressive drugs......Non-interferon-based therapies: As pretransplant, 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 pretransplant, then no AVT at all will be required post-transplant! (see Table 5).......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 3months are 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 better tolerated in ribavirin-free regimes. A challenge here would be the question concerning the duration of therapies post-transplant setting. If 3-month duration emerges as sufficient in the non-transplant setting, the post-transplant situation may require longer duration in the setting of 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 a form of HCV infection could be reversed (although that cannot be totally assured)......Predictions of the (near) future: It seems likely that the new age of AVT will radically improve outcomes for patients with HCV infection 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 worth studying 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, if they do, it will likely be for short periods of time."

body of article.....

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 (PegIFN/RBV). Attempts to clear HCV pretransplant have been successful in about 15-20% of the 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 increased risk of serious bacterial infections [3]. Sustained viral response (SVR) pretransplant 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% for patients with HCV genotype 1 (G1) and 40-50% for patients with HCV G3 are obtained [6], [7], [8]. SVR post-transplant has been linked to both donor and recipient IL28 polymorphisms [9], [10], [11]. Achievement of SVR in the post-transplant setting is associated with improved survival compared to patients who do not achieve an SVR [6], [7], [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.

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], [13], [14], [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], [13], [14], [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 [16]). These agents can be given daily, sometimes have additional genotype specificity but may also still have significant side effect profiles [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]. The next generation protease inhibitors in combination with PegIFN/RBV 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 PegIFN/RBV) have increased SVRs up to 90% [19], [21], [23], [25], [26], [29], [30], [31]. There is preliminary data that combinations of DAAs and PegIFN/RBV (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 the most exciting. This wave aims to replace interferon altogether. The regimes use DAAs in combination without interferon but sometimes with ribavirin e.g., a HCV NS5A polymerase inhibitor combined with second (or third generation) NS3/4 protease inhibitors or an NS5A inhibitor [31], [32], [33], [34], [35], [36]. One exciting regime just used a nucleoside polymerase inhibitor plus ribavirin [33]. This resulted in SVRs of 90-100% in treatment naïve G2/3 patients requiring only 3months of therapy with no recorded toxicity. However, the same regime applied to genotype 1 patients who were previously null responders to PegIFN/RBV, however, it seems disappointing with significant relapse rates [34]. An alternative regime of an NS5A inhibitor plus a polymerase inhibitor, given for only 3months led to an SVR of 90% in 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 regimens [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 a short duration (as short as 3months). 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 (see Table 2).

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 cannot be guaranteed!

Use of the new therapies pretransplant (Table 3)

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 PegIFN-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 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 the 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 had failed previous interferon therapies [39]. Although there is no SVR data, safety data for both telaprevir and boceprevir were given for the first 16weeks of therapy. In these patients, 19-28% had varices, 29-48% were relapsers, the mean serum albumin was about 40g/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 16weeks, 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 pretransplant 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 antiprotease-based therapies that have cross-resistance profiles with boceprevir and telaprevir.

I would conclude that the significant use of these first wave therapies in pretransplant waiting list patients will be problematic and perhaps not worth the effort or the risk. As now, such therapies will probably be confined to Child 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.

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.Is plus PegIFN/RBV. 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 pretransplant 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% pretransplant. Thus it may be tempting to use them. However, the key once again will probably be tolerability. The widespread use in patients infected with genotype 1 HCV would seem to have 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 PegIFN/RBV, however, may have a significant impact re SVRs. Tolerability will mainly revolve around the PegIFN/RBV combination as now.

Non-interferon-based therapy

This seems to be most likely a breakthrough and a paradigm shift for patients awaiting liver transplantation. 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 6months). All of these seem potentially achievable. 90-100% SVRs have already been reported in treatment naïve patients infected with genotype 2/3 HCV using just polymerase inhibitor and ribavirin for 3months [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 1-2years and perhaps be in clinical practice within 5years ([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 late 1990s, 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 3-6months with AVT and proceed to transplant within 3-6months with the likelihood 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 PegIFN/RBV. In the pretransplant 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 PegIFN/RBV. 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 pretransplant 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...

Could new therapies prevent HCV infection of the allograft at time of transplant?

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 7days of therapy immediately post-transplant [44]. Thus, this approach may still have some merit.

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 uptake into the liver at the time of transplantation [45], [46], [47]. Currently, however, no such in vivo data exist although a recent study in humanized mice has shown that novel monoclonal antibodies against SR-B1 are effective not only in preventing uptake but also cell - cell spread of HCV [48].

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 >1week.

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.

Use of new therapies post-liver transplant (Table 4)

Triple therapies with either telaprevir/boceprevir

As mentioned, current treatments with PegIFN/RBV yield about a 20-30% SVR (G1) in the stable post-transplant setting. The use of telaprevir or boceprevir in these patients may increase 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, exist.

Firstly, drug-drug interactions [50], [51], [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], [54], [55], [56], [57], [58], [59], [60], [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 are common. In some studies, treating cholestatic hepatitis has not always been successful due to the 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 an SVR can be achieved in cholestatic hepatitis [62].

Table 4. Observations in initial assessment of triple therapy for HCV post-liver transplant [53], [54], [55], [56], [57], [58], [59], [60], [61], [62].

sideEffects

Triple/quadruple therapies with next generation PIs/polymerase inhibitors

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 P450 system and thus may be easier to use with current immunosuppressive drugs [63].

Non-interferon-based therapies

As pretransplant, 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 pretransplant, then no AVT at all will be required post-transplant! (see Table 5).

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 3months are 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 better tolerated in ribavirin-free regimes. A challenge here would be the question concerning the duration of therapies post-transplant setting. If 3-month duration emerges as sufficient in the non-transplant setting, the post-transplant situation may require longer duration in the setting of 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 a form of HCV infection could be reversed (although that cannot be totally assured).

Predictions of the (near) future

It seems likely that the new age of AVT will radically improve outcomes for patients with HCV infection 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 worth studying 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, if 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 3-5years 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 decompensation in the pre transplant setting? (? Maybe)

5.Non-interferon regimes will be used pretransplantation with subsequent elimination of HCV post-transplant in virtually all patients? (? Yes+++)

6.Non-interferon regimes will only be required for <6months in the post-transplant setting? (? Maybe)

7.In 10years time, the only HCV patients requiring transplantation will be those with HCC? (? Yes)

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HCV Screening Cost Effective vs Direct HCV Patient Care Costs

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patients with HCV infection have higher direct healthcare costs compared with patients who do not have HCV infection......"the costs associated with the care of patients with CHC are substantial and are driven largely by disease severity......the costs of screening and treatment must be offset by the costs of ignoring these options and allowing chronic HCV disease to progress from NCD to CC and ESLD.........the direct costs associated with chronic HCV are considerable, averaging over $24,000 annually for all patients and $60,000 for those with advanced liver disease........birth-cohort screening of all patients born between 1945 and 1965 is cost-effective, averaging $2,874 per new case identified.......There is a large cohort of aging patients who were infected between 1960 and 1980,3 with a resultant increase in the current number of patients with compensated cirrhosis (CC) and, subsequently, endstage liver disease (ESLD). Between 1996 and 2006 the proportion of patients with HCV-related cirrhosis increased from 9% to 19%, and the prevalence of decompensated cirrhosis increased from 5% to 11%.4 The prevalence of hepatocellular carcinoma (HCC) and HCV-related mortality has also increased considerably......treatment of HCC and liver transplantation are undoubtedly associated with very high healthcare costs......Our estimates of the annual cost of care for patients with ESLD and either HCC ($112,537) or OLT ($145,045)......The subgroup analysis of patients with ESLD demonstrates that the cost of caring for patients with OLT is ~3 times greater than in patients without OLT and the cost of caring for patients with HCC is approximately twice that of caring for patients without HCC......The stepwise increase in direct healthcare costs with increasing liver disease severity highlights the imminent crisis that CHC infection poses in an aging population for the U.S. healthcare system. The proportion of patients with cirrhosis and ESLD, the incidence of HCC, and the rate of liver-related deaths are all increasing.4, 9, 17, 18 Moreover, the greatest increase in the incidence of HCC is occurring in those aged 45 to 60 years, and approximately three-quarters of HCC deaths attributable to HCV infection is occurring between the ages of 45 and 64 years.8, 18 The mean age of patients with NCD, CC, and ESLD in our analysis falls within these ranges."

Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection - "Mean PPPM [per-month-per patient] all-cause healthcare costs were 32% and 247% higher for patients with CC and ESLD" - (12/03/12) Hepatology Nov 2012

"The proportion of patients with cirrhosis and ESLD, the incidence of HCC, and the rate of liver-related deaths are all increasing.4, 9, 17, 18 Moreover, the greatest increase in the incidence of HCC is occurring in those aged 45 to 60 years, and approximately three-quarters of HCC deaths attributable to HCV infection is occurring between the ages of 45 and 64 years"

"our data intuitively demonstrate that, in the future, the costs of screening and treatment must be offset by the costs of ignoring these options and allowing chronic HCV disease to progress from NCD to CC and ESLD. We have clearly shown that the direct costs associated with chronic HCV are considerable, averaging over $24,000 annually for all patients and $60,000 for those with advanced liver disease. A recent study showed that birth-cohort screening of all patients born between 1945 and 1965 is cost-effective, averaging $2,874 per new case identified. If the costs of treatment are included, this adds $15,700 per quality-adjusted life-year (QALY) assuming peginterferon plus ribavirin is used, or $35,700 per QALY saved assuming that a protease inhibitor is used in combination with peginterferon plus ribavirin.29 We have shown that the current cost of HCV disease management would likely offset these expenses."

"In conclusion, this retrospective analysis of a medical and pharmacy claims database demonstrates that the direct healthcare costs associated with CHC infection are high, increase in association with the progression of liver disease, and are highest in those with ESLD. Given the increasing age and disease severity, and the low rate of awareness of infection status in patients with CHC, priority should be given to identifying and treating patients with this disease. Early intervention has the potential to avoid healthcare costs associated with progressive liver disease."

Source

Bitetto D. Hepatology. 2012;doi:10.1002/hep.26186.

December 21, 2012

A large number of patients with chronic hepatitis C are vitamin A deficient, and this deficiency is associated with nonresponse to treatment, according to recent results.

In a multicenter study, researchers compared the serum vitamin A and vitamin D levels in 199 treatment-naive patients with chronic hepatitis C, before receiving interferon (IFN)-based antiviral therapy, with those of 119 healthy controls.

Median vitamin A levels were significantly lower among patients with HCV than controls (256 ng/mL compared with 742 ng/mL, P<.0001 for difference). Vitamin A deficiency (200 ng/mL or lower) was observed in 42.2% of patients, compared with none of the controls, with severe deficiency (100 ng/mL or lower) present in 19.6% of cases. Vitamin D deficiency was present in 45.8% of 190 evaluable patients; severe deficiencies in vitamin A and vitamin D (20 ng/mL or lower) existed in 9% of cases.

Patients with severe vitamin A deficiency were more likely to be nonresponsive to treatment (36.1% of cases overall vs. 18.2% of those without severe deficiency, P=.019). HCV genotype 2-3 (P<.001), cirrhosis at baseline (P=.003), IL-28B polymorphism with at least one T allele (P<.001), gGT levels greater than 60 IU/mL (P<.001) and taking 80% or less of the assigned ribavirin dose (P=.002) were predictive of nonresponse.

Among patients with more difficult-to-treat genotypes, multivariate analysis indicated associations between nonresponse to antivirals and HCV RNA levels greater than 600,000 IU/mL (OR=4.39, 1.39-13.8), severe vitamin A deficiency (OR=3.68, 1.03-13.2), IL-28B T/* genotypes (OR=26.3, 4.34-159) and elevated baseline gGT levels (OR=5.24, 1.69-16.2) (95% CI for all).

A second model indicated that patients with low levels of vitamins A and D were at particularly increased risk for nonresponse (OR=12.9, 1.73-96.7). Patients with severe vitamin A deficiency and IL-28BB CT-TT were calculated at the highest risk for nonresponse in a third model evaluating the interaction between IL-28B genotypes and vitamin deficiency(OR=26.5, 2.91-242) (95% CI for all).

“A high percentage of patients with chronic HCV infection presented serum vitamin A deficiency,” the researchers wrote. “This condition is strongly associated [with] nonresponse to antiviral therapy, suggesting that vitamin A serum levels could modulate the responsiveness to IFN-based antiviral therapy. It will be of great importance to verify if vitamin A supplementation could restore the IFN sensitivity in nonresponders, because the success of new [direct antiviral agents] is still conditioned by IFN responsiveness.”

Source

Published on: 2013-01-08

Injection drug users (IDUs) represent a significant proportion of patients with chronic hepatitis C (CHC). The low treatment uptake among these patients results in a low treatment effectiveness and a limited public health impact.

We hypothesised that a general practitioner (GP) providing an opioid maintenance treatment (OMT) for addicted patients can achieve CHC treatment and sustained virological response rates (SVR) comparable to patients without drug dependency.

Methods: Retrospective patient record analysis of 85 CHC patients who received OMT for more than 3 months in a single-handed general practice in Zurich from January 1, 2002 through May 31, 2008. CHC treatment was based on a combination with pegylated interferon and ribavirin.

Treatment uptake and SVR (undetectable HCV RNA 6 months after end of treatment) were assessed. The association between treatment uptake and patient characteristics was investigated by multiple logistic regression.

Results: In 35 out of 85 CHC patients (52 males) with a median (IQR) age of 38.8 (35.0-44.4) years, antiviral therapy was started (41.2%).

Median duration (IQR) of OMT in the treatment group was 55.0 (35.0-110.1) months compared to the group without therapy 24.0 (9.8-46.3) months) (p<0.001). OMT duration remained a significant determinant for treatment uptake when controlled for potential confounding.
SVR was achieved in 25 out of 35 patients (71%).

Conclusion: In addicted patients a high CHC treatment and viral eradication rate in a primary care setting in Switzerland is feasible. Opioid substitution seems a beneficial framework for CHC care in this "difficult to treat"population.

Author: André SeidenbergThomas RosemannOliver Senn

Credits/Source: BMC Infectious Diseases 2013, 13:9

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