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Hepatitis C Treatment and Management

March 2009

Hepatitis C treatment: how, why, when

"I've heard about what happens in families during HCV treatment, people get so depressed, in such a mental state -- the husband or wife will say "I hate you" ... because people on interferon are so unbearable ... it's not worth it!

There's no guarantee you'll get rid of HCV, or even get better -- but your life can be ruined!"

This section focuses on conventional hepatitis C treatment with the current standard of care, which is a combination of pegylated interferon and ribavirin.

Lifestyle-related choices that help your liver are covered in the section Living with coinfection.

One approach to managing hepatitis C (HCV) is to decide first what your priority is. Clearing the virus is the most important goal for many people but not for everyone. In some cases, treatment may be more likely to improve the condition of your liver than to clear the virus. In other cases, treatment may not be necessary right away, or ever.

For some people, deciding whether to start HCV treatment is an easy decision. For most, it isn't. There are a lot of factors to be considered.

"I didn't care about the liver disease, but I needed to be not infectious. I had all the side effects during treatment ... the side effects went away as soon as I finished the treatment and I feel pretty much like my old self now."

Who needs treatment?

This section focuses on conventional HCV treatment with the current standard of care, which is a combination of pegylated interferon and ribavirin.

Lifestyle-related choices that help your liver are covered later in the section "Living with coinfection".

Treatment guidelines generally agree about when to treat hepatitis C (HCV), and who to treat.

Regardless of HIV status, for all HIV-positive people this is when the benefits of therapy outweigh the risk. Sometimes treatment is recommended for people with coinfection earlier than HIV-negative people.

  • Treatment is more effective when given during acute infection, and is often recommended for HIV-positive men who have acquired hepatitis C sexually.
  • People with mild liver disease do not require treatment right away.
  • Treatment should be offered to people with moderate liver damage, since they are at risk of progression to cirrhosis.
  • People with compensated cirrhosis can be treated, but treatment is less likely to be effective, and side effects may be worse. Careful monitoring is needed.
  • People with decompensated cirrhosis cannot be safely treated for hepatitis C. This is when a liver transplant is the only option.

How is hepatitis C treated?

Hepatitis C treatment is a combination of two drugs, pegylated interferon (PEG interferon) and ribavirin (RBV).

Interferon is a man-made version of a chemical made by the human body that works against HCV in two ways. It works directly against the virus. It also stimulates the immune system to fight viruses. "Pegylated' means that a small molecule has been attached to interferon to keep it in the body longer. This means you only need to inject once a week, and makes it more effective at treating HCV.

PEG interferon

There are two types of PEG interferon:

  • alpha-2a (manufactured by Roche, trade name Pegasys). Pegasys is a liquid that comes in one vial and is stored in the refrigerator. Everyone uses the same dose of Pegysys, regardless of their weight.
  • alpha-2b (manufactured by Schering Plough, trade name PegIntron or ViraferonPeg). PegIntron is a powder that has to be reconstituted with purified water, both of which come in separate vials. PegIntron is dosed by weight.

Different formulations have been studied differently in patients with different severity of disease. They have not been compared directly, and so it is difficult to know whether one may be better than another in different circumstances.

What is pegylated interferon?

Interferon is a man-made version of a chemical made by the human body that works against HCV in two ways. It works directly against the virus. It also stimulates the immune system to fight viruses.

Pegylated means that a small molecule has been attached to interferon to keep it in the body longer. This means you only need to inject once a week, and makes it more effective at treating HCV.

 

Ribavirin, AZT and ddI

Both AZT and ddI increase the toxicity associated with ribavirin. These HIV drugs should not be used during hepatitis C treatment.

Ribavirin

Ribavirin is a nucleoside analogue, from the same family as many HIV drugs, but it does not work against HIV.

On its own, ribavirin is not effective against hepatitis C. It needs to be used with PEG interferon.

Ribavirin is given as pills or capsules, twice daily. It is usually dosed by body weight and by HCV genotype. Brand names for ribavirin include Copegus, Rebetrol and Ribasphere.

How long is hepatitis C treated for?

In HIV-positive people, treatment for hetatitis C is currently recommended for at least a year, for all genotypes, although recently, researchers have looked at tailoring treatment according to individual response.

Some doctors are treating coinfected people with genotypes 2 and 3 for less time if they have an early response to treatment (see Evaluating response to HCV treatment).

Some doctors treat people with genotype 1 and 4 for longer than a year. In particular, people with HIV/ HCV coinfection may require a longer course of treatment, especially people with genotype 1.

Goals of hepatitis C treatment

Curing hepatitis C

The primary goal is usually to get rid of the hepatitis C infection.

In hepatitis C, a sustained virological response, or SVR, means that a person does not have HCV in his/her blood six months after the end of treatment. Most people who have had an SVR stay free of HCV, although there are less long-term results in HIV-positive people. Although some recent research has found very low levels of hepatitis C in the blood and liver tissue of some people with a sustained virological response, this may not have any significant effect on liver health.

Most people who have had an SVR stay free of HCV, although there are less long-term results in HIV-positive people.

Although some recent research has found very low levels of HCV in the blood and liver tissue of some people with a sustained virological response, this may not have any significant effect on liver health.

Improving liver health

A secondary goal of HCV treatment is to improve liver health by reducing inflammation, and, sometimes, reversing fibrosis.

This even happens in people who do not get an SVR, although only in about half the number of cases.

For some people, the condition of the liver may worsen after HCV treatment, particularly among people who did not clear the virus. It is not clear why this happens.

Maintenance therapy

Use of full or reduced dose pegylated interferon as a maintenance therapy in people who did not clear their hepatitis C with treatment, did not reduce the risk for liver disease progression. Therefore, maintenance therapy is no longer recommended for people with hepatitis C, regardless of their HIV status.

SVR reduces the risk of liver cirrhosis, liver cancer and liver failure for HIV negative and HIV positive people.

For HIV-positive people, there may be an additional benefit from HCV treatment in reducing the risk of liver-related side effects from HIV drugs.

Predicting the response to treatment

Some people think they can't get treated for hepatitis C (HCV) because their CD4 counts are too low. But the things that are important for knowing how well you are doing with your HIV do not always predict how well you will respond to HCV treatment.

In the end, as with HIV, the only way to know how you will respond is to try treatment.

Several factors can help you predict your chance of how well HCV treatment will work, including:

  • HCV genotype (2 and 3 are more sensitive to treatment than 1 or 4).
  • HCV viral load (treatment is more effective with an HCV viral load that starts below 400,000 IU/mL).
  • Race (treatment is less effective for African- Americans -- ongoing research is looking at this question).
  • Amount of liver damage and steatosis (treatment is less effective for people with cirrhosis or steatosis).
  • HIV status (treatment is less effective for HIV-positive people than HIV-negative people).
  • Adherence to treatment, including maintaining the full dose of ribavirin and pegylated interferon at least 80% of the time.
  • Body weight -- treatment is less effective for people who weigh more than 75 kg (165 lbs).
  • Age under 40 years.
  • Effectively manage side effects!

Hepatitis C treatment and HIV coinfection

When should HIV be treated first?

Generally, HIV treatment should be started first if CD4 count is less than 200 cells/mm3, and probably started first if it is between 200-350 cells/mm3.

People with serious liver damage may need HCV treatment even when their CD4 count is lower than this.

HIV treatment may be started at higher CD4 counts if the CD4 count is falling, and HCV treatment will be used soon.

When should hepatitis C be treated first?

If HCV treatment is needed, people on a stable HIV regimen should be treated, even if their CD4 cell count is under 200 cells/mm3.

Older studies, that used standard interferon to treat HCV, reported that it was less effective for people with low CD4 counts. However, in a small group of people studied so far, PEG interferon plus ribavirin works at both high and low CD4 counts.

It is best not to start treatment for both HIV and HCV at the same time. This is because side effects from both treatments make this too difficult.

Hepatitis C treatment and CD4 cell count

Even if you are on HIV treatment, interferon can cause your CD4 count to drop. However, your CD4 'percentage' usually remains the same, or may even increase. This shows that the drop in the count is unlikely to reflect a real change in your immune system.

To support this, the three major HCV treatment trials in HIV-positive people did not find more opportunistic infections among people with low CD4 counts (under 200 cells/mm3).

There have been some reports of oesophageal candida and TB in HIV-positive people using HCV therapy. In some cases, prophylaxis for certain opportunistic infections may be recommended.

After HCV treatment is ended, the CD4 cell count usually returns to the pre-treatment level within a few months.

In someone whose CD4 count is already strong (above 500 cells/mm3) there is no need to use HIV treatment before HCV treatment.

HIV treatment concerns in people with coinfection

The most important aspects of HIV treatment are just as relevant for people who also have hepatitis C (HCV), including choice of treatment, adherence, side effects and resistance.

The main differences in HIV treatment for someone who also has HCV relate to:

  • Timing of HIV treatment
  • Concern for liver toxicity/damage as a side effect of HIV drugs
  • Choice of HIV drugs

Some drugs are less "liver-friendly" than others. It is not clear though whether small increases in liver enzymes increase the risk of clinical disease. Caution is clearly important. HIV drugs should be selected carefully, and liver enzyme levels monitored regularly.

Some side effects occur more frequently in people with HCV coinfection, including lipodystrophy (fat accumulation or fat loss) and abnormal blood fat and insulin levels.

HCV increases the risk of developing diabetes and this risk is higher in HIV-positive people. Use of HIV protease inhibitors and nucleoside analogues, especially d4T (stavudine, Zerit), has been linked with an increased risk for high blood sugar and diabetes.

However, this risk should never be used as a factor to withhold HIV treatment.

Drug interactions between HCV treatment and HIV meds

ddI (didanosine, Videx) should not be used during HCV treatment, because of a serious interaction with ribavirin that can cause lactic acidosis, pancreatitis, and the risk of liver failure in people with advanced cirrhosis.

AZT (zidovudine, Retrovir, also Combivir) is not recommended because of the increased risk of anaemia.

d4T (stavudine, Zerit) in some studies was linked with an increased risk for significant weight loss and lipoatrophy (fat loss) in people using ribavirin.

How well does treatment work?

Clearly, many factors are involved with response to treatment.

The information in the table below is a snapshot of response rates from trials of PEG interferon plus ribavirin.

Table 4: Response rates to treatment

Sustained Virological Response (SVR) rates

HCV monoinfection
(24 weeks for genotypes 2 and 3
48 weeks for genotype 1)

HIV/HCV coinfection
(48 weeks for all genotypes)

Overall

56-61%

27-40%

Genotype 1

42-44%

14-38%

Genotype 2 and 3

70-82%

Up to 73%

Evaluating response to hepatitis C treatment

How response to HCV treatment is measured

The response to hepatitis C (HCV) treatment is measured by HCV viral load tests at different times.

SVR (sustained virological response)

An SVR means that HCV is not detectable in blood six months after completing treatment. Many experts think of SVR as a cure.

SVR rates are usually the most important results to look for from a clinical trial.

SVR-12 is used in research, meaning that a person is still undetectable 12 weeks after finishing treatment. Relapes almost always occur during the first 12 weeks after finishing treatment.

EVR (early virological response)

An EVR means that the hepatitis C viral load has dropped by 99% (2 logs), or is undetectable after 12 weeks of treatment.

Someone who does not have an EVR only has a 1-4% chance of getting an SVR. Usually, people choose to stop hepatitis C treatment if they do not have an EVR.

ETR (end of treatment response)

An end-of-treatment response means that hepatitis C virus can not be found using an HCV viral load test at completion of therapy. Some people with an ETR will see HCV viral load return, so ETR is not a reliable predictor of long-term response.

RVR (rapid virological response)

An undetectable HCV RNA after four weeks is called a rapid virological response (RVR). If HCV viral load is undetectable, it is a good indication of continuing to have an SVR later. However, RVR is not good at predicting who is unlikely to respond, so treatment should not be stopped if there is no RVR. RVR is currently only used in research

Relapser

The term relapser refers to someone who has an EVR or ETR, but whose virus rebounded and who didn't achieve an SVR.

Non-responder

Non-responder is a general term for someone who does not have an EVR, or, if they stay on treatment for 24 weeks, does not ever have a 99% drop or an undetectable HCV RNA while on treatment

Hepatitis C treatment timeline for people with HIV

HCV treatment timeline for HIV-positive people

Week 4
After 4 weeks treatment check hepatitis C viral load (HCV RNA) for a rapid virological response (RVR: undetectable HCV viral load). This is mainly still a research test.

  • RVR is a good predictor of SVR. Continue treatment.
  • No RVR: continue treatment, because it is too soon to predict how you are likely to respond.

Week 12
After 12 week check HCV viral load for Early Virological Response (EVR: either a 99% drop in HCV viral load or an undetectable result).

  • EVR: Continue treatment
  • No EVR: Stop treatment because SVR is VERY unlikely (94%-100% of people in trials with no EVR had no SVR). If you have serious liver damage, you and your doctor may decide to try interferon maintenance therapy. This is where you treat to delay or stop HCV progression, rather than to clear HCV. Some doctors may suggest using daily consensus interferon, but there has only been one based on one small study of this in HIV-positive people.

Week 24
Check HCV RNA at week 24. If undetectable, continue treatment according to genotype

Week 24, 48 or 72
Check HCV viral load when you stop treatment, for End-of-Treatment Response (ETR: undetectable HCV viral load).

  • If HCV is detectable, consider repeating test. Stop treatment if the second result is also detectable. If you have serious liver damage, you and your doctor may decide to try maintenance therapy (see above).

Week 48, 72 or 96
Check HCV RNA six months after finishing treatment for sustained virological response (SVR: undetectable HCV viral load).

  • If you are undetectable, you have cleared your HCV.
  • If HCV viral load is detectable, treatment has not cleared your HCV. It still may have improved the condition of your liver.

Hepatitis C treatment and injecting drug users

Hepatitis C (HCV) treatment has traditionally been withheld from injecting drug users, even though current treatment guidelines recommend that treatment decisions be made on a case-by-case basis.

Fortunately, this has begun to change. Experience in HIV treatment confirms that it is possible for drug users to adhere to anti-retroviral therapy, and response rates from clinical trials of HCV treatment in IDUs are similar to those reported in non-users.

  • Try not to miss medical appointments. Some doctors will use this as part of the criteria for not treating your HCV.
  • Don't avoid medical care because you are using. This is especially important while you are on HCV treatment, because your doctor won't be able to monitor and treat your side effects.
  • If you are on methadone, wait to taper or stop after treating HCV. Sometimes people find that methadone helps them through treatment, and may choose to increase the dose to help with side effects.
  • It is important to find a doctor who is willing and able to work with drug users and who will treat your HCV. Asking other drug users to recommend a doctor -- or to steer you away from one -- may be a good place. to start.
  • Discuss side effects of HCV treatment with your doctor, and ask how they will be managed. If you need pain medication or other medications with abuse potential, discuss this with your doctor. Make an agreement on how the two of you will handle this.

Depression and other mental health diagnoses are much more common among people with HCV, people with HIV, and drug users than the general population. Many of these conditions are treatable.

People with a history of depression are more likely to develop depression during HCV treatment. Depression can also happen to people who have not been depressed in the past. If you are concerned about the psychiatric side effects of HCV treatment, but want to treat your hepatitis C, consider support from mental health care services.

Some people can manage HCV treatment while they are using drugs; others have found that stopping or cutting down on drug use has helped them to prepare for, and stay on HCV treatment. This could be from a self-help programme, counselling, drug treatment, or heroin substitution, methadone maintenance, naltrexone implants, or using buprenorphine. Increasing the dose of methadone has helped people manage side effects of HCV treatment.

If you are still injecting drugs, ask your doctor or local syringe exchange programme for information on safer injection to lower your risk of HCV reinfection (and other infections).

Concerns for people in recovery

Many people fear that they will relapse to active drug use, because the symptoms of interferon are very similar to opiod withdrawal.

The risk of relapse is lower when side effects are promptly and effectively treated and when counselling and support from peers and medical and mental health providers is available.

Some people are concerned about self-injecting PEG interferon. If possible, injections can be given once weekly by a nurse to avoid triggering a relapse to injection drug use.

Retreating hepatitis C

With greater access to treatment, the number of people who did not clear the virus during treatment is also increasing.

Strategies for retreating hepatitis C (HCV), including treatment with a different formulation of interferon, called consensus interferon, or a higher dose of PEG interferon and/or ribavirin and a longer course of treatment have yielded disappointing results.

If you did not respond to treatment with the older non-peglated formulations of interferon, which was much less effective, you should consider retreating with pegylated interferon.

Some of the new oral hepatitis C drugs are being studied in people who were unsuccessfully treated for hepatitis C. Based on the experience with HIV, it may be better to wait until there is more than one new HCV drug to add to a regimen that didn't work before.

Management of cirrhosis

A damaged liver can still function, but people who have developed cirrhosis are at risk for liver failure and other serious, life-threatening complications.

People with compensated cirrhosis should be screened for liver cancer, and monitored regularly for decreasing liver function and varices. These are stretched and bursting veins resulting from liver scarring that obstructs the flow of blood through the portal vein and increases blood pressure. Drugs called beta-blockers can help to prevent varices. Variceal bleeding is managed with medication and surgery.

Changing your diet can help to manage some of the complications of cirrhosis. Cutting down on salt, eating many small light meals per day with protein from vegetables and dairy products rather than meat can help address nutritional imbalances. A nutritionist and your doctor can help you plan a healthy diet.

Hepatic decompensation (decompensated cirrhosis) occurs when the liver cannot compensate for damage, and liver function has deteriorated. After hepatic decompensation, a liver transplant is necessary.

Liver transplant in people with HIV/HCV coinfection

British Liver Trust has a list of UK specialist liver clinics and transplant units.

In people with decompensated liver disease, a liver transplant is the final option.

This is a major operation, and success rates vary. It is also complicated by a scarcity of donor organs that are available for transplant.

For many years, transplant services actively avoided liver transplants in HIV-positive people. This was due to several factors including discrimination from some surgeons, who did not want to operate on HIV-positive people.

The poor long-term life expectancy for HIV-positive people before combination therapy meant that a donor organ would provide fewer years of additional life than it might to a person without HIV or other medical conditions. There were also concerns about using drugs to suppress the immune system that are an essential part of a transplant, in HIV-positive people.

The effectiveness of HIV drugs has changed this. HIV is no longer an exclusion criteria for a liver transplant.

Centres in the UK, Spain, France and the United States have transplanted livers into HIV-positive people. Some centres have reported no significant difference in survival according to HIV status.

However, medical management remains complex, due to drug interactions between drugs used to suppress the immune system after the transplant and protease inhibitors, the risk of graft rejection, HCV reinfecting the new liver, and difficulty in tolerating HIV and HCV treatment after the transplant.

Only a few transplant centres in the UK have reported liver transplants in people with coinfection, and referral to one of these centres is essential. The success is largely limited by recurrent HCV infection in the new liver.

HCV infection progresses more rapidly in people with HIV coinfection, and their survival after hepatic decompensation is shorter that that of people with HCV alone. Some specialists suggest that people with coinfection should be referred to a transplant list at an earlier stage of disease than people with HCV monoinfection.

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This article was provided by HIV i-Base. It is a part of the publication Hepatitis C for People Living With HIV. Visit HIV i-Base's website to find out more about their activities, publications and services.
 

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