Остановка "Гепатит С"
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Part 3: Conventional Medicine

Special thanks to Joan King of HepCBC, to Viola Vatter of Victoria, BC, and to Alp of Vancouver, BC for their help with Parts 3 and 4.

3.1.0 Standard treatment

3.1.1 Pegylated Interferon, Ribavirin and a Protease Inhibitor Combined

For the past few years, standard therapy for hepatitis C has been pegylated interferon plus ribavirin. At first, we had only interferon (IFN) as treatment, and then the “combo treatment”--interferon plus ribavirin-became standard therapy, until pegylated interferon appeared on the scene. Until May 2011, the standard treatment (SOC) for HCV infection was pegylated interferon alpha (either Merck’s Peg-Intron or Roche’s Pegasys) along with ribavirin (Merck’s Rebetrol or Roche’s Copegus). This has changed, and standard treatment in the US now includes a protease inhibitor. The protease inhibitors Boceprevir (Merck) and Telaprevir (Vertex) have now been approved in the US. Boceprevir has also been approved in Canada, as of August 2011, and Telaprevir should be approved shortly.

Interferons are types of naturally-occurring proteins produced by our own immune system. They direct our immune system to attack viruses, bacteria, tumours and other foreign substances that may invade the body. Virtually all interferons used in HCV treatment today are obtained from bacteria that have had slight manmade DNA modifications. In general, genetic material from human leucocytes (white blood cells) is spliced into the genetic material of bacteria, and the bacteria are allowed to reproduce and grow. The inserted genetic material causes the bacteria to produce interferon.

Pegylated interferon (PegIFN) is a type of interferon with a large polyethylene glycol molecule attached to it, so that it stays in the body for a longer time, and we can inject it just once a week, rather than 3 times a week, like we did in the past. Side effects are similar to or slightly less unpleasant than those experienced with non-pegylated interferon.

The two available pegylated interferons, Peg-Intron and Pegasys have been compared. The two substances differ basically in the size of the molecule involved, (about 60 kilodalton for Pegasys, 31 kilodalton for Peg-Intron). Pegasys has a longer half-life. Some studies show that SVR rates (Sustained Viral Response, or loosely, “cure rates”) for Peg-Intron or Pegasys are slightly different, with one being higher than the other, or showing little difference at all.

Ribavirin (RBV) is an antiviral discovered over 30 years ago. No one knows for sure how it works, but when combined with PegIFN, these two drugs have drastically improved the response rates. The dosages of RBV are weight-based, so the more the patient weighs, the higher the dosage of both medications. Generally it seems accepted that SVR rates when combined with either pegylated interferon are about 40-50% for genotype 1 (G1) patients (the most difficult to treat), and about 80% or higher for genotype 2 and 3.

Protease Inhibitors Two PI’s have been added to standard therapy. The protease is a part of the virus that is needed for it to reproduce. Once HCV enters a liver cell, its genes guide the production of proteins that will become the inner core and surface coat of new viral units. First of all, the HCV makes an immature protein— a kind of unfinished sheet of material, which the Hep C protease cuts into the finished proteins, which then become the virus's outer cloak.

Scientists have designed protease inhibitors which stick specifically to HCV protease to stop its scissor-like function.
There is much hope for these protease inhibitors. Where the 40-50% of G1 patients achieved an SVR with PegIFN and RBV, new numbers for protease inhibitors show about 75% of treatment naive patients may achieve SVR with upcoming treatment with the triple combo. Those who responded to previous therapy but relapsed may have a better than 80% chance of SVR. Those who responded but did not clear have about a 60% chance of SVR. Non-responders and null-responders have a 30-40% chance of SVR. (These numbers are based mostly on telaprevir data and may vary depending on the study.)
( www.clinicaloptions.com )

Incivek (Telaprevir or VX-950)

Telaprevir is Vertex’s oral protease inhibitor. The Phase II trials combining telaprevir (T) with peginterferon (P) and ribavirin (R) showed it increased response to treatment in genotype 1 patients from about 45% to 65%, and will cut therapy to 24 rather than 48 weeks, avoiding half of the cost and many side effects. Side effects caused 21% to stop therapy in the telaprevir groups, vs. 11% in the SOC group. Black patients in this study had an encouraging 44% rate of SVR in the telaprevir-based groups.

PROVE2, also a Phase IIb trial, studied telaprevir in 334 treatment-naïve European genotype 1 subjects from 2006 to 2007. SVRs were as high as 69% in some groups with dropout rates of 7% because of rashes.

PROVE3 was a Phase II study of telaprevir in 453 treatment-experienced genotype 1 patients in the US, Canada and Europe.

Previous non-responders had SVR rates as high as 39%. Among prior relapsers, the best SVR rates were 69%. Among those with prior HCV breakthrough the highest the rates were 57%. 48-wks of treatment including PR looks more effective for treatment-experienced patients.

EASL’s Study C209, a Phase IIa trial of telaprevir enrolling 49 treatment-naïve genotype 2 and 3 subjects, reported preliminary results at 2 weeks showing no real benefit for genotype 3 patients, but genotype 2 patients had an encouraging average 4 log viral load drop at about day 6. (EASL Conference 2009)

At the EASL 2009, Vertex presented results of two new, notable HCV protease inhibitor drug candidates. VX-813 is being tested in a Phase I study as of last year Oct. 28, 2008, hcvadvocate.org, and VX-500 is being tested in a recent Phase Ib study, and expects results soon. (www.hcvadvocate.org Feb 10, 2009)

Victrelis (Boceprevir)

Victrelis is Merck’s protease inhibitor. Results from their Phase III studies of the drug combined with PegIFN/RBV in G1 patients, with a 4-week lead-in of SOC alone (high-dose RBV 600-1400 mg/day) were presented. Primary results showed a 59% SVR for the RGT (Response-Guided Therapy) arm and 66% for the 48-week arm, compared to 21% of the control arm subjects. In treatment-naïve patients, adding Victrelis to PegIFN/RBV produced an SVR in 63% in the RGT arm and 66% in the 48-week arm, compared to 38% in the control group.

The patients were tested for IL28B, a genetic marker which identifies patients who are unlikely to respond to treatment. The study showed that the chance of a patient responding can be predicted based on the patient’s response to the 4 week lead-in period and to the presence of IL28B (CC, CT or TT). In patients with the CC gene allele, 89% of the treatment-naïve and 82% of the non-responders (NR) had undetectable virus at 8 weeks, and were scheduled for shorter therapy. Among those with the CT or TT gene allele, 52% of naïve and 48% of NR had an ER (early response) and could take shorter therapy. The response to the 4-week lead-in was the stronger predictor of SVR. The discovery of the importance of the IL28B alleles came from the results of the company’s HCV SPRINT-2 (naïve patients) and HCV REPOND-2 studies (NR patients).

There were some serious side-effects. EPO (Epoetin) was given to some patients to manage anemia. (EASL 2011)
(Note: This FAQ uses “alpha,” although some companies use the term “alfa” with their interferon products, and have them patented this way.)

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3.1.2 Side effects and other considerations

3.1.3 Is treatment worth it?

We often think our goal is an SVR (Sustained Viral Response), but the long-term goal is to prevent Hep-C related death or disability. This study looked at 103 successfully-treated patients treated beginning in 1984. Biopsies and blood tests were compared before and after. Patients seen since 2007 were evaluated by elastography, a type of liver scan. Three of the original patients had relapsed between just over a half a year up to 6 1/2 years after treatment. Of the other 100, 45% had GT1, and 53% had GT2 or 3. 2% had other genotypes. There was no liver failure or liver cancer. ALTs were 27 U/L and ASTs were 24 U/L, average. All other markers remained good, as well. There were no liver-related deaths, and 97% had maintained their SVR. The study concluded that “SVR is associated with both short term and long-term benefits.”
( www.natap.org/2010/AASLD/AASLD25.htm )

The word “cure” is still controversial. A study was done in France, and the results were presented at the EASL conference in Italy in April of 2008. 278 patients who had an SVR (Sustained Viral Response) were followed from 6 months to 17 years. They were tested for HCV-RNA in their blood serum yearly, and all remained undetectable (1050 samples). None of the 71 patients tested showed HCV in PBMCs and none of the 38 patients who provided liver samples showed the presence of virus, either.

Antibodies were tested in 142 of the patients, and they decreased from an average of 93+21 IU per ml before treatment to 45+21 IU per ml in the last sample given. The stage of fibrosis noticed in the 92 patients with before-and-after-treatment biopsies showed 57% improving, 32% remaining stable, and 11% getting worse. Cirrhosis regression was seen in 70% of the patients. The study indicates that “SVR is associated with HCV eradication and progressive decrease of anti-HCV.” ( www.natap.org/2008/EASL/EASL77.htm )

Some researchers at Memorial University, Newfoundland, in a study published in the May 2009 issue of Hepatology, reported that even though patients have an SVR (Sustained Viral Response) to treatment—no detectable virus in their blood--more sensitive tests are finding that some of them still have tiny amounts of virus. No one knows if they are still contagious. The researchers studied 9 patients with SVR and detected HCV only with the most sensitive tests.

 Then they took T cells from 12 healthy volunteers and exposed the cells to the HCV samples taken from the patients declared to have SVR. 11 of the samples became HCV+. Replication of the virus was caused by samples from 3 of the 9 patients with SVR. The researchers concluded, "These findings provide in vitro evidence that trace quantities of HCV persisting in the circulation for a long time after therapeutically induced resolution of CHC can remain infectious," and concluded, “This can be interpreted as a strong indication of potential virus infectivity in vivo." The good news is that the replication of HCV in the T cells was neutralized with IFN treatment.
( www.physorg.com/news160656818.html May 4th, 2009)

Studies have also shown that the sooner one is treated after infection (with pegylated IFN and ribavirin) the higher the chance of SVR, even with genotype 1. This is especially true if treatment starts within a few months of infection.
Patients over 50 have treatment results similar to those of younger patients, if they don’t have advanced fibrosis or high viral loads, and if they can stick to the treatment. Ribavirin dose reductions are more common in this age group, but these patients can still be effectively treated.
 ( www.hcvadvocate.org/news/reports/AASLD2007/Abstracts/Saturday%20Posters.htm Topic 321)

HCV is usually not a life-threatening infection. It can take several years or even a decade or more before any signs of the disease become apparent. People infected may not even know they are ill. Of course different people will react differently. Some do not fare so well as others, therefore HCV infection should ALWAYS be monitored regardless of when it was contracted.

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3.1.4 When is interferon treatment not indicated?

Patients with chronic hepatitis B or C, with fluid in the abdomen (ascites), bleeding from dilated veins in the esophagus (variceal bleeding), mental confusion (encephalopathy), human immunodeficiency virus (HIV) infection or organ transplant recipients on prednisone, cyclosporine and FK-506 are usually treated only in a clinical trial. Others not suitable for treatment are those with symptomatic heart, lung or kidney disease, and patients on antidepressants or with a history of attempted suicide. Interferon should not be given to women considering pregnancy within six months after treatment, nor to the intended father.

It was feared that patients with active substance abuse (alcohol or illegal drugs) may not comply with treatment, but recent studies have shown differently.

IVDUs on a detox program can be treated with standard therapy with no unexpected side effects and without disturbing the opoid maintenance regimen. Discontinuation occurs mostly within the first four weeks of treatment. Buprenorphine may be more effective than methadone to help patients stick to the schedule.
( www.hcvadvocate.org  Topic 346)

“Treatment of HCV in current and former IDU within a multidisciplinary DOT program can be successfully undertaken, resulting in SVR similar to those in randomized controlled trials.”
(www.blackwell-synergy.com Dr. Jason Greebly, Vancouver, BC)

In cirrhotic, genotype 2 and 3 patients who show a viral response to standard therapy at week 4, 24wks’ treatment resulted in SVR rates of more than 87%, the same as in non-cirrhotic pts. However, the response rates at week 4 are much lower in cirrhotic patients, indicating the necessity of earlier treatment.
( www.hcvadvocate.org/news/reports/DDW2007/Abstracts/MondayAbstracts.htm )

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3.1.5 Interferon breakthrough, Non-response and Relapse

Although treatment initially shows viral clearance in patients with chronic hepatitis C virus (HCV), many
patients experience a relapse after treatment, or breakthrough (relapse during treatment).

Breakthrough: Breakthrough can refer to the sudden emergence of a treatment-resistant strain or strains of the virus in a patient that has previously been responding well (viral load drop) to treatment, or to a sudden large increase in virus after a promising decline.
( www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=9759607&cmd=showdetailview&indexed=google )

Although Recombinant interferon alpha (rIFN alpha 2) has initially been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV), a few patients experience a relapse during the treatment, in spite of a complete initial response (breakthrough). Continued treatment with rIFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients. - “Breakthrough during recombinant interferon alpha therapy in patients with chronic hepatitis C virus infection: prevalence, etiology, and management.” (Hepatology Vol. 21 no. 3 pp. 645-9, 1995 Mar.)

It may be that patients previously declared as having had a complete initial response followed by breakthrough may actually be non-responders, since the tests years ago were not sensitive enough to detect small amounts of virus that might not have been eradicated.

“The development of neutralizing antibodies to interferon is associated with Breakthrough in about half of the patients; other etiologic factors such as down-regulation of interferon receptors or development of virus resistance to interferon may be implicated in the remaining cases.” Genotype does not seem to make a difference (Ital J Gastroenterol Hepatol. 1998 Jun;30[3]:333-7).

Researchers (abstract #781) tried various combinations of therapies to treat relapse and breakthrough to IFN + ribavirin. 124 patients received Peg-IFN alpha-2a once a week for 48 weeks, combined with either ribavirin, Cellcept, amantadine, or a combination of ribavirin plus amantadine. The best response was 45.2% for the last group. – “What Did We Learn About Hepatitis C From AASLD 2002?” (Alan Franciscus, HCVAdvocate)

Non-Response: When a patient goes on standard treatment and does not achieve at least a 2 log drop in viral load by week 12 they are said to be non-responders. Non-responders have a much lower rate of successful treatment (SVR) than responders although some trial show longer treatment of treatment with higher doses can improve their odds.

Relapse: This is said to occur when a patient who tested virus free during treatment becomes virus
detectable some time after treatment ends.

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3.1.6 Re-treatment

Re-Treatment of Relapsers and Non-Responders: People who didn’t have sustained viral response to interferon alpha/ribavirin may expect a response rate of around 20% for "non-responders" and 50-60% for relapsers if they take a course of pegylated interferon alpha/ribavirin. ( www.natap.org/2001/aasld2/day17.htm  Nov 2001)

Out of 499 patients, 37 % of patients in the study tested undetectable at week 12. Of those, 57 % achieved SVR with 48-weeks of Pegintron + ribavirin. Overall, 23 percent of patients in the study achieved SVR. The researchers recommend 48 weeks of re-treatment for all genotypes who show undetectable virus at week 12 (EVR). EVR is a very good predictor for successful treatment.

The REPEAT study showed that, in very difficult-to-treat patients who didn’t respond to pegylated IFN + ribavirin treatment, SVR rates can double if they are treated for 72 weeks.
 ( www.rocheusa.com/newsroom/current/2007/pr2007110201.html )

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3.1.7 Transplant and Post-transplant

When does a liver transplant need to be done? This is a very complex issue and must be answered on a case-by-case basis. Anyone with hepatitis C should be followed by a physician regularly. If signs of progressive disease appear, the person needs to be referred to a gastroenterologist (specialist in digestive diseases and liver diseases). Since hepatitis C is known to progress very slowly, it is not necessary to have a liver transplant until the disease has reached “end stage.” Factors to be assessed include the rate of progression of the disease, whether or not complications of liver failure have occurred and laboratory values including albumin, bilirubin, and prothrombin time.

What are my chances with a liver transplant?

The 3-year survival rates after liver transplantation between 1991 and 2001 in the US were 81.4% for non-HCV patients, and 78.5% in HCV patients. The rates are improving for non-HCV patients, but not for HCV patients.
( www3.interscience.wiley.com )

How long will a new liver last? No one knows how long a transplanted liver can last. The longest reported transplant survival is 36 years ( www.medscape.com/viewarticle/519810  2005). Ten-year survival is commonplace. Hopefully improvements in techniques and medications that are continually occurring will allow most patients receiving liver transplants today to have long productive lives.

Will the hepatitis C be cured by a liver transplant? No. Hepatitis C can live in cells other than in the liver. Once the old liver is removed and the new one is connected the hepatitis spreads back into the liver within the first weeks to months after the transplant.

This is the bad news: at present we have no way to make the hepatitis C go away completely.

The good news is that overall results with hepatitis C after liver transplantation are good.

Although the disease comes back it does not seem to greatly damage the liver in the majority of cases. It is possible for the hepatitis to return so severely that the new liver fails, but this is uncommon. Long-term results (ten years) are difficult to interpret since we have only been able to diagnose hepatitis C since 1990.

Many people that were transplanted in the 1980’s may have gotten hepatitis C at the time of transplant, since the blood supply was contaminated then. These people may have different chances compared to those who had transplants because of hepatitis C. Realistically it is likely that hepatitis C will be a long term problem in liver transplant recipients that harbor the virus. We do not yet know how bad a problem this will be.

What can be done for hepatitis C that comes back in a transplanted liver? Standard treatment is being used, sometimes successfully, in post-transplant patients. Regular biopsies are essential. Doctors at the Consensus Conference in Lyon, France, in January 2005, said post-transplant patients with recurring HCV are best treated after 1 year “when lesions with a score ≥ A1F1 appear.” Treatment results in SVR in about one third of their patients. These doctors suggest treatment be continued for 6 months after a negative PCR. If the patient doesn’t respond, they discontinue treatment.
( www.anaes.fr/ )

I have hepatitis B and hepatitis C. Can a transplant still be done? Yes, some transplant centers are currently doing liver transplants for this indication.

Where do donated livers come from? Livers are donated, with the consent of the next of kin, from individuals who have brain death, usually as the result of a head injury or brain hemorrhage. There have also been real successes with living liver donors, where a part of the liver of the donor (still alive) is given to another family member.

How can I donate my organs? If you wish to be an organ donor, carry an organ donor card and place an organ donor sticker on your medical identification card. In Canada, it is permissible for HCV positive persons to donate their organs to other HCV positive persons.

Some Statistics: United States: There are more than 17,000 on the waiting list for livers; there were 25,952 transplants of all types done in 2005 in the US.
( http://www.unos.org/data/default.asp?displayType=usData )

Canada: 723 were on the waiting list in 2006. 460 liver transplants were performed. 120 people died while waiting for a liver transplant in 2006...
( http://secure.cihi.ca/cihiweb/dispPage.jsp?cwpage=reportscorrstats2006ce )

The average waiting time for a liver transplant was 245 days for non-urgent cases, and 6 days for urgent
cases in 2001.
( http://secure.cihi.ca/cihiweb/dispPage.jsp?cwpage=media19sept2001e )

Canadian liver transplant 5-year survival rates are 87%.
( www.commonwealthfund.org/newsroom/newsroomshow.htm?docid=227234 May 4, 2004)

Survival rates in general are improving, probably due to more experience and better pre- and post-transplant treatment. Livers from live donors are now being used in many areas, and provide better results than cadaveric livers.

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3.1.8 Spontaneous clearance

Past studies have shown that about 10% to 50% of those infected with HCV clear the virus with no treatment (average 25%). Unfortunately, determining the numbers is difficult since most people have no symptoms when they are infected. More women clear the virus than men. Spontaneous clearance is also higher in those who have symptoms of acute liver disease which are thought to indicate a strong immune system. Spontaneous clearance usually occurs within 4 months of infection, may take as many as 18 months, and in some cases may occur even later.

Two recent studies have provided more data. In the first, 67 HCV+ adults, 67% IVDU, were studied. 19% knew the source of their infection and 18% of that group reported high-risk sexual practices (sex before age 15, more than 6 partners, prostitution or sex with a prostitute, homosexual partners or partners who were IVDUs or HCV+).

It was decided that those with acute infection were those who became HCV+ within a year of a previous negative test, or tested positive for antibodies with symptoms, or those infected through medical error (iatrogenic risk).

Of these patients, 18% had cleared the virus with no treatment by the time they were re-tested at 6 months. 34% of the women cleared the virus compared to 3% of the men. The results were similar to those found among transfusion recipients.

In another study, 157 children found to be HCV+ between 1990 and 2001 (most infected through transfusions), were studied. Clearance was defined as having 2 or more positive HCV antibody tests but no HCV. In this study, 28% of the children cleared the virus with no treatment. The younger children had a higher clearance rate. The children infected at birth had a 25% clearance rate. Normal ALTs were related to clearance.
( www.hivandhepatitis.com/hepc/news/2007/121107b.html )

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Table of Contents


2.11.0 Long-Term Prognosis (Am I Going to Die?)

Hepatitis C FAQ

3.2.0 Interferons