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Professor Geoffrey Dusheiko 2006

Anxiety about doing treatment

Q. I was diagnosed a year ago, I have genotype 1a and a viral load of 12 million; I may have contracted the disease up to 29 years ago. I am considering treatment but have grave doubts and concerns about the side effects whilst on treatment and long term effects following treatment. I've read that treatment can cause neurological problems due to brain toxicity. I have had hyperactive thyroid which is currently stable and have stopped medication. I am also concerned that even after 48 weeks of treatment that I may still not have cleared the virus. I take Chinese herbs and find these help a lot with digestive problems. Please can you give me a picture from your understanding?

A. Most people have some qualms before embarking on treatment. The side effects of interferon and ribavirin are unpleasant, and some individuals find them very difficult. Fortunately for most the side effects are acceptable. The most common side effects are seen in the majority of patients (85%) but patients learn to accept the decrease in the quality of life if virus is being cleared. Brain toxicity is not a feature of interferon. Depression can occur. It is not know how this occurs as it is not clear to what extent interferon actually crosses the blood brain barrier, a barrier we all have to protect the brain from toxins. Eye toxicity has been reported, but it is extremely rare, and I have only seen one patient with eye symptoms, which improved after interferon, was stopped. A hyperactive thyroid can be problematic. You will need very careful monitoring of your thyroid function during treatment, and you may actually develop worsening of your thyroid function which could necessitate stopping treatment. However, some patients actually develop an under active thyroid after a period of over activity. All this will need very careful monitoring on treatment by a professional team who are used to dealing with the side effects. Hope that helps

Terrified of doing treatment any new drugs on the horizon?

Q. I have a friend who is frankly terrified of treatment (Geno 1) and is holding on for something new. I know there are a few in the pipeline but as I understand it will not be available to patients for around 4/5 years. Are you excited by new developments and will they allow patients to have significantly increased success and less side effects?

A. I do think that we have crossed the threshold with several new polymerase and protease inhibitors. They clearly inhibit HCV replication and moreover results in very rapid improvement in the liver enzymes (ALT and AST). This is encouraging. Resistance is likely to be a problem, so that they will still need to be used with interferon for now, until several are licensed. There are questions to be asked about their short and medium term safety, but we will proceed very carefully with phase II trials. However there is the promise that we can abbreviate treatment for many patients, and that treatment responses will be improved.

Questions about Treatment

Hepatitis A & B vaccines whilst on treatment.


Q.
I was advised to get Hepatitis A & B vaccines but was too ill at the time. Should I wait till after treatment to have them or is it o.k. to have them on treatment?

A. It would seem reasonable to have the hepatitis A and B vaccination when treatment is completed, but there are no absolute contraindications to these being given during treatment if the risk of acquiring hepatitis A (e.g. on holiday) is deemed to be high

Pegylated Interferon twice a week?


Q. A recent study seems to suggest that PegIntron would be better administered in smaller doses twice per week to prevent low levels at the end of each week. Does this sound like a good idea to you? Do you have any personal preference for any particular interferon in any specific circumstances?

A. The pharmacokinetics of the different interferons remains a vexing question. On purely pharmacological grounds it could be argued that PEG intron should be twice weekly. I am not at all sure that this translates into differences in sustained virological responders, as the effect of interferon on viral suppression is very complicated, and affected by factors other than blood levels of interferon. My bias, and it is a bias at present, is that there is not yet a rational basis for administering PEG intron twice weekly until a head to head comparison between the PEG interferons shows significant differences in responses rates in a prospective trial with appropriately matched patients

Switch interferons?


Q.
I'm a "slow responder" Geno 1, didn't make the 2 log drop at 12 weeks [had approx a 95% drop in viral load]. I am still on treatment and wonder if you feel a switch to a different type of interferon [from Pegasys to PegIntron] may offer any benefits?

A. This is a difficult question to answer categorically. Studies are in progress to determine whether prolonging treatment beyond 1 year for genotype 1 and beyond 6 months for genotype 2 and 3 is useful for slow responders. Until we have this information you and your treating team may wish to continue prolonging treatment, if you have very low levels of virus. It can be difficult to get funding, and it does depending on how you are tolerating treatment, but I believe that this could be considered for individuals who are motivated to continue for a while. You have to accept success or failure with this, as we do not have adequate data. I personally do not think that a switch will make a difference, unless perhaps you are > 80 kg in weight, and you could consider dosing PegIntron by weight.

Cortisone could it help my hepatitis C?


Q. I would like some advice re the use of cortisone. I already take Prednisolone 5mg daily for several adrenal fatigue. It has been suggested to me that taking this might also help with the liver inflammation and possibly with the suppression of the virus if I increase the dose from physiological (as it is now) to a bit more which might bring it into the pharmacological dose level. There is, I realise, an issue about adrenal suppression if I go much higher in dose and what I am trying to weigh up is the cost/benefit ratio of such an increase in terms of helping my liver.

I am fibrotic, mild inflammation with moderate fibrosis and some portal bridging at biopsy 4 years ago.

Also I believe there is a blood test biopsy now available at a lab somewhere in Scotland and I wonder if you might have any details of this so I can request a second non-invasive biopsy to see what the state of play is with my liver right now.

A. Cortisone has anti-inflammatory properties, and could suppress inflammation in the liver but has the adverse effect of increasing levels of virus in the liver, and reducing the chances of responding to treatment. It is not likely to help your liver in the long run. I note you have moderate fibrosis. You could consider treatment, but would need to consider whether you could reduce cortisone (in consultation with your endocrinology specialist) while on treatment to maximise the chance of a response. There is a blood fibrosis test available via lab21; their tel number is 01489 898600 www.lab-21.com

Palpitations


Q.
What causes palpitations on treatment?

A. Interferon may have cardiac effects even in otherwise healthy people. This may explain the palpitations, but investigations include thyroid functions, and ECG, echocardiogram, and heart rate and rhythm monitoring may be required.

Diabetes

Q. Lots of people seem to develop diabetes on treatment. What are the causes and are they monitored throughout treatment?

A. Diabetes may be associated with hepatitis C particularly in patients with cirrhosis. In my experience, diabetes does not occur that frequently in patients without cirrhosis on treatment. However, interferon does have some effect on glucose metabolism and may aggravate diabetes or effect insulin treatment.

Relapse rates

Q. I am geno 1b on 48 weeks combination therapy, 32 weeks in. I have gone clear. What are my chances of relapsing before the 6 month post treatment test for SVR? What are the statistics for relapse? How does your experience with your patients match up to the stats?

A. The chances of relapsing post treatment in a patient are about 1:3. This in part depends on the rapidity of the response in treatment so that if the individual was PCR negative very early (one - 3 months) then the chance of a relapse would be lower than this. This would seem to be the case in practice.

High platelet count

Q. I have a continually high abnormal platelet count of 450/ 457 etc.
I have asked many times what this means and have never been given a satisfactory response and still don't know. I understand what low platelet count means.

A. I do not have an answer for you either I am afraid. The commonest cause of a high platelet count is essential thromobocytosis, which is related to bone marrow production. Your counts are a little raised, but may not be clinically significant. Have you seen a hematologist, and has bone marrow examination been considered?

A. Thank you, I am currently under a few professors who are trying to get to root of problems.
They have all picked up on high platelet count but I shall have it investigated further.

Hepatitis C vaccine

Q. What advances do you feel have been made towards a hepatitis C vaccine, will there ever be one?

A There has been a little progress. HCV proteins have been expressed and used to vaccinate chimpanzees and a few human subjects. Antibody responses have been observed. The challenge remains for finding HCV proteins that will universally elicit protective or neutralising antibodies to protect against the array of hepatitis C genotypes. There is also some interest in developing therapeutic vaccines which could ameliorate the chronic infection. However, no clinical useful measures are in place at present that compare to interferon and ribavirin.

Questions about Post Treatment

Statistics of patients who remain clear?

Q. Are studies and statistics being gathered as to how long post treatment clears remain clear and does clear really mean clear?

A. A negative PCR six months after stopping treatment (by a sensitive PCR test) indicates clearance. The infection may not be cleared, as trace residual amounts of virus can be detected in lymphocytes after many bursts of amplification. These probably represent defective virus which may actually remain to boost or remind our memory immune system to control virus. Disease does not appear to progress at meaningful rates in patients who have had a sustained virological response i.e. are PCR negative six months after stopping treatment

Worried, cleared virus but never had biopsy

Q. I am 43, female and 23 months post treatment, all blood tests are normal and I have now been discharged and advised to have yearly LFT's at my GP's to monitor. I probably had hep c (geno 3) for 23 years before my treatment in 2002/03 and during that time, as I was unaware I had the virus, I was drinking alcohol regularly.

I never had a biopsy but my ultrasounds were all good, other than showing just a trace of fatty liver. However, I remain concerned as I never knew what level, if any, of liver damage I had sustained. From my understanding, blood tests and ultrasounds can miss significant problems with the liver and the biopsy remains the most accurate way of assessing damage. I am anxious that I may have had a high level of fibrosis despite all the good results. If that was the case what is the likelihood of that reversing now I have cleared the virus and over what period of time do improvements occur. Also is there still an increased risk of HCC (primary liver cancer) or other complications in the years to come?

Lastly what are your views on drinking alcohol post treatment (eg not to excess but an occasional glass of wine with a meal.

A. More and more we will be treating patients without a prior liver biopsy, and questions like yours will arise. The good news is that you have cleared the virus. I would examine your liver function tests. If you have a normal serum albumin, normal prothrombin time, and normal platelets, and had these prior to commencing treatment, then it is unlikely that you had cirrhosis. If this is the case, then a biopsy seems unnecessary as the risk to you of further complications of liver failure seems very small indeed, and the risk of primary liver cancer must also be very small. Monitoring with liver function tests should suffice. Perhaps a Fibroscan or Fibrotest would be reassuring as these tests can discriminate low levels of fibrosis from advanced fibrosis. It seems a pity to subject you to a biopsy now that you have cleared virus unless there is a good clinical reason for doing so.

PS if you have normal ALT, albumin, pro time with good liver function then small amounts of alcohol as you suggest are very reasonable and may have some beneficial effects on coronary heart disease.

Post treatment recovery times


Q.
It seems that post-treatment recovery times vary considerably. Do you have any advice that would help shorten them?

A. Yes, this is a disconcerting aspect for patients. In my experience it is very variable. If you measure quality of life using quality of life indices, most patients report an improvement after clearing virus (See Bonkovsky H et al) However indeed some do not, and it takes some time (as much as a year) before they report improvement. I do not know the explanation for this or how to expedite recovery unfortunately. A good holiday in the sun perhaps?

Gallbladder Problems

Q. I have had hepatitis C for many years. I had my gallbladder taken out a few years ago and I now have periodic pain in the area where my gallbladder was accompanied by white stools and nausea. Do you think this could be related to scarring in the bile duct which apparently I have. Also I am interested to know your view on the connection between hepatitis C and gall bladder problems as it seems many people with hepatitis C have to have their gallbladder removed.

A. Unfortunately some patients may have persistent pain after gall bladder removal. This could be related to "spasm" of dyskenesia. It may be that you have a stricture but this would need an ERCP to investigate this. Gallbladder disease is very common. I do not think that hepatitis C per se causes gall stones or cholecystitis, but this is more common in patients with cirrhosis.

Relapse after treatment

Genotype 1 relapser

Q. What are the chances of someone with genotype 1a who relapsed at 6 months after treatment achieving SVR with a second go at treatment?

A. Disappointing results. There is probably only a low (10%) chance of responding to re-treatment with current agents, despite the good response initially. This is because the patient has already received the "best available" treatment and there is not much room at present for improvement until new treatments become available.

Genotype 5 relapser

Q. I have just (December 2005) finished a 42 week course of treatment, but have been told that the virus is still detectable. My genotype is 5a I note from your biography that your medical training was in South Africa where this particular genotype is more common than here in the U.K. Do you have any data regarding success rates and treatment regimes in South Africa?

As far as I know I contracted the hep c virus via a blood transfusion received in 1972 whilst undergoing complex, reconstructive facial surgery. My consultant has informed me that he sees little point in re-treating me and has set up a follow-up appointment in December 2006 (12 months after my initial treatment ended). Do you have any thoughts about my case; I will be very interested to read your response.

A. I am sorry that you have not had a response. Unfortunately there are no large controlled trials of treatment for genotype 5 and none have been done in South Africa, where as you correctly state, genotype 5 has been described. It is an omission, I guess.

We came across a very small group of patients treated in Belgium where 4/7 treated patients responded, which seems quite high. There may be other factors that have determined a lack of response in your case. Perhaps it is worth taking a "holiday" from treatment for a period and then retrying as we are not likely to have new treatments for genotype 5 for a while. The new protease inhibitors are likely to be quite specific for genotypes but perhaps polymerase inhibitors like NM283 (Valopicitabine) could be helpful in patients with non 1 genotype. I would not despair. Sometimes retreatment can work (perhaps 10-15% chance depending upon the type of response, but it may be worth waiting for new treatments.

Genotype 3 relapser

Q. I'm asking this on behalf of a friend. As a non responder Geno 3a who was undetectable on treatment but failed the six month post treatment test, have you any suggestions of a way forward with treatment (fibrosis 4).

A. Unfortunately your friend has had a relapse. This is relatively common in genotype 3 with fibrosis. It may be worth either trying again for a longer period of treatment, or waiting for new polymerase and protease inhibitors to come into trials. I would think that it may be possible to achieve a sustained virological response with a second course of treatment for longer. Hope this helps

Genotype 3 relapser

Q. I am female 51 geno 3a, and relapsed after completing 24 wks treatment in December 2005. Which of the new treatments being developed will be available first in the UK and when are they likely to be available? Also I was on HRT - Progesterone from the age of 35 until 46 and am convinced that this kept me reasonably healthy. Would there be any value in asking my GP to try HRT again while I wait for my next go at treatment?

A. We have had a number of correspondents with genotype 3 who indicated that they relapsed. We are giving consideration to a trial of longer treatment. Do you have advanced fibrosis or mild disease? There are three new agents which look interesting: Vertex VX 950 / Schering 504304 (protease inhibitors) and Idenix MN283 a polymerase inhibitor. Hopefully we will be invited to participate in the phase II trials so that patients in the UK will have an opportunity to be included if they wish, in such trials. All the new agents look interesting. All will have to be used with interferon initially, and we will need to examine the safety of these new agents carefully within controlled clinical trials.

It is difficult for me to comment on HRT; you should discuss this with your gynecologist; what was the indication for treatment at an early age: I am not aware of any role for HRT in the management of hepatitis C

Genotype 3 relapser


Q. My situation is as follows
Diagnosed antibody positive October 2002 at Ealing Hospital after persistently raised LFTs
RNA pos. and Genotype 3a
Biopsy October 2003 fibrosis 3/6 inflammation 8/18
Received standard treatment - Peg Interferon + Ribavirin 24 weeks from April to October 2004 at St Marys
Baseline viral load 8,000,000 copies / ml approx.
12 Week PCR showed 2 log drop but not eradication of the virus.
PCR at 6 months post treatment virus undetectable so had achieved SVR.
PCR at 13 months post treatment hepatitis C RNA detected' 900 copies/ml
LFTs now normal.
I am waiting for a repeat of the PCR test.

What do you think are the chances of a repeat treatment of Peg Interferon + Ribavirin succeeding? If you think it would be worthwhile to re-treat, what sort of length of treatment and dosage would you recommend? (I have been told a repeat of 12 months with higher doses on IFN and Rib might be an option). I have had some doctors say re-treatment is probably not worthwhile, and others who say that it is.

I am not sure what to think as my circumstances are unusual, (the length of time before relapse, the very small number of people with Gen3 who relapse after SVR, and the low viral load I now have).

A. I guess we are starting to see a few more patients with genotype 3 and relapse. I note that you were PCR negative at six months post treatment. It would be interesting to know the sensitivity of the test used, as for example the TMA test (10 iu/ml) predicts relapse better than other less sensitive tests in use. My guess is that you did not actually clear virus, but that the virus was still present at levels below the sensitivity ("cut off") of the assay in use. I have a sense (unproven) that you are indeed sensitive to interferon treatment and that you may respond to a longer course of treatment, given the stage of fibrosis and genotype 3. Thus you could either try repeating treatment or wait for improved treatments to come along in the not too distant future. You need to monitor your status with a very sensitive PCR.

Question about waiting times for 1st consultant appointment


Q. In your experience do you think that there are sufficient resources (human and financial) devoted to hepatitis C treatment for you to be able to deliver a high standard of care to all those who need it without long waits.
I have heard of people having to wait over 4 months for a referral to the Royal Free.

A. I agree that 4 months is a long time. We would dearly like to at least halve the time before patients are seen, but will need extra nurses and doctors. We are working on this. We need to divert some resources to a first referral clinic, but in fairness to patients, first referrals need some time, and we are just not able to meet the demand with our current capacity and the pressures on us. We would welcome ideas as it would be helpful to all to reduce referral waiting times, and all the other barriers that exist. I think that awareness has grown, but this has not yet translated into resources. Perhaps we need to take a look at how we organise the clinics at present, but it has been difficult to get extra doctors, extra rooms and extra days.

Q. There has been one suggestion that I have seen recently which might help. The idea is to run hepatitis C classes for patients. Most of the early clinic time seems to be spent answering the same questions, and the idea of the classes is to educate patients so that they have all the basic information before they meet their consultant. It could save a lot of time and resources.

A. I would be happy to try this, but have some reservations. How do you think that patients from many different walks of life will react to a referral to a class before they have had a chance to discuss their own unique situation? What about patient anonymity? Anxieties, fears, and other concerns that patients may have before a chance to discuss their hepatitis C in private with a one on one consultation? It could work, and we could gauge this in a pilot?

Q. I suspect that you might be pleasantly surprised about the attitude of patients. You could overcome a lot of the anonymity problems by stressing that the classes are not just for patients, and are open to anyone with any interest in the virus. That way, nobody attending knows who has the virus and who doesn't. A pilot certainly sounds like a good idea.

A. I am prepared to try this. We could write to patients with appointments that are pending indicating that we will have a class for new patients. We would give them an option to attend well before their clinic appointment, and discuss matters in general terms. We would give them an option to attend or not, i.e. they could, if not comfortable with this idea, bypass the opportunity. We would have to restrict it in the first instance to Royal Free referrals. We could also invite the Hepatitis C Trust and others to others to attend /observe. I will discuss with colleagues/nurses to gauge opinion. Should we discuss futher?