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Hepatitis C Treatment Today

Fall 2007

The decision to start treatment for hepatitis C must be shared by doctor and patient, and everyone with a chronic hep C infection should be evaluated for treatment. But since the treatment can cause difficult side effects, and is less effective in people who also have HIV, education and support are critical if it is to be worthwhile. This article will highlight the current state of treatment and the issues people coinfected with HIV should know before they begin.

The main goal of hepatitis C treatment is eradication of the virus, which currently is seen as a cure (we'll know for certain when people have been followed for more than five years). This is called a sustained virologic response (SVR -- no detectable virus in the blood six months after completing treatment). Attaining an SVR decreases liver inflammation and fibrosis (scarring), lowering the chance of cirrhosis and liver cancer. As treatment for hepatitis C virus (HCV) has improved, guidelines have been changed, so that everyone with HCV should be evaluated for treatment.

Since HIV and HCV can both be transmitted by blood, testing for HCV antibodies is recommended for everyone with HIV. People at high risk for HCV, particularly those who have shared needles, may need an HCV viral load test even if they test negative for HCV antibodies. Up to 9% of people with a history of high-risk behaviors and elevated liver enzymes have an "occult" (hidden) HCV infection. Everyone with HCV should also be tested for hepatitis A and B, and if negative should be vaccinated against both.

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Current HCV treatment combines weekly injections of pegylated interferon (Pegasys or PegIntron) and twice-daily ribavirin capsules. Both drugs decrease the formation of new viruses, preventing further spread of HCV to healthy liver cells. Interferon also helps to eliminate already infected cells. Although these two interferons are different, there do not appear to be major differences in their ability to treat HCV. However, no head-to-head studies have been done. (In the U.S., only Pegasys is currently approved by the FDA for the treatment of HCV in people with HIV, but PegIntron is also used in these patients.)

A liver biopsy before treatment is useful, to check the degree of inflammation and fibrosis. A biopsy can help to predict the course of HCV disease, since most everyone with early fibrosis of the liver's portal vein is likely to develop cirrhosis after two decades if untreated. People with less severe disease may never develop cirrhosis, so careful monitoring is an alternative to treatment. In addition, a liver biopsy may be repeated in five years to see if the disease has progressed. However, the treatment of even mild HCV before someone is 60 years old may improve survival and reduce the risk of cirrhosis, since people with less fibrosis respond better to current treatment.

Not everyone with HCV is a candidate for treatment. People who have decompensated cirrhosis (meaning the liver cannot keep up with the amount of fibrosis that has occurred) should not begin HCV treatment. Treatment is generally not recommended for people with autoimmune hepatitis, severe anemia, unstable diabetes or cardiovascular disease, or psychiatric problems that have not responded to treatment. Likewise, those who are malnourished, jaundiced, or who have swelling of the abdomen (ascites) or brain (encephalopathy) should not take current HCV treatment. In these cases, a liver transplant is often the only option, and these are now being done in coinfected people. HCV cirrhosis is the most common reason for liver transplants in the U.S. and Europe.


Acute HCV Treatment

About 75% of people newly infected with HCV have few or no symptoms. Treatment is most effective if given early, but it's best to wait one to three months after infection, since about 20% of people will clear the virus without treatment. Peg-interferon with or without ribavirin should be considered in those who do not clear HCV after three months, as more than 80% may respond to this treatment. People with no symptoms should be treated immediately, as they appear to have a higher risk of chronic disease than those who do have symptoms soon after infection. Six months of treatment that was started twelve weeks after acquiring HCV led to an SVR in a majority of people with HIV, regardless of their genotype.


Treatment for HCV Monoinfection

HCV treatment for people without HIV is usually taken for 24 weeks for those with genotype 2 or 3, or for 48 weeks for genotype 1. Studies have shown SVR rates of 80% for genotypes 2 and 3, and 42% for genotype 1. People with genotype 1 who do not show an early viral response (EVR -- an undetectable HCV viral load after twelve weeks of treatment) have little chance of achieving an SVR, and treatment may be stopped. Since people with genotype 2 or 3 usually respond to treatment, checking for an EVR may not be needed.

In Europe, treatment with a shorter course of Pegasys (24 weeks) has been approved for certain monoinfected people who had a rapid viral response (RVR -- an undetectable HCV viral load after one month of treatment). One study found that 16 weeks of treatment for people with genotype 2 or 3 who had an RVR was as effective as 24 weeks. A higher ribavirin dose may be the key to achieving an RVR. But shorter courses of therapy are not universally accepted and more studies are needed.


Treatment for HIV/HCV Coinfection

The decision to start treatment for hepatitis C is based on a combination of blood tests and liver biopsy.

Treatment is strongly recommended for people with elevated liver enzymes (ALT and AST), CD4 counts above 350, HIV viral load below 1,000, and no alcohol intake. The degree of fibrosis should also be taken into account.

HIV treatment should be optimized before starting HCV treatment. Videx should not be taken with ribavirin because of an increased risk of lactic acidosis and pancreatitis, raising the risk of cirrhosis. Retrovir (AZT) increases the risk of anemia when taken with ribavirin, and Zerit is associated with weight loss and lipoatrophy (unwanted fat loss). Viramune and Aptivus (the latter in combination with Fuzeon) have been associated with serious liver damage in people with HIV, and Zerit and Videx have been associated with other liver problems in people who are coinfected. People with HCV genotype 3 are at greater risk for liver toxicity from HIV meds. The amount of fibrosis raised levels of Aptivus, increasing the risk for increased liver enzymes, while Reyataz levels did not increase. Also, better tolerance to HCV treatment was noted with newer NRTIs like Ziagen.

SVR rates range from up to 29% for people with genotype 1 to 73% for those with 2 or 3. Better outcomes are seen in people below age 40, in leaner patients with less fibrosis, and in those with low or undetectable HIV viral loads. A higher CD4% and HCV viral load below 400,000 IU improved the chance of SVR in people with genotype 1. However, most coinfected people have high HCV viral loads.

People with genotypes 2 and 3 have a higher chance of a viral rebound, so 48 weeks of treatment are needed. But an SVR appears to be equally durable in coinfected people. Long-term follow-up studies of coinfected people with an SVR have not seen more viral load rebounds, advanced cirrhosis, or liver cancer than that found in monoinfected patients.

Up to 17% of patients stop HCV treatment due to side effects and anemia. Drugs to raise red blood cell counts may be needed in up to 60% of people taking Retrovir (AZT) who develop anemia. Starting EPO (Procrit or Epogen) before HCV treatment may increase the chance of SVR and decrease the risk of anemia. Fortunately, HCV treatment usually does not affect HIV disease, despite the temporary decrease in CD4 counts it can cause.

The study that led to the approval of HCV therapy in people coinfected with HIV used a low dose of ribavirin (800mg daily) in an attempt to prevent anemia. Higher doses of ribavirin (1,000 - 1,200 mg) are now accepted, leading to better SVR rates. More recent findings suggest improved SVR rates with twice weekly peg-interferon or even higher doses of ribavirin.


Will It Work?

The most important predictor of an SVR is the HCV genotype. Treatment is less effective for people with genotype 1, which is the type most common in the U.S. Response to treatment also depends on HCV viral load, dosing, and length of treatment. The sooner HCV viral load becomes undetectable while on treatment, the greater the chance of an SVR. New research suggests that the length of HCV treatment should be changed based upon how quickly an individual achieves an undetectable HCV viral load. People with HCV only, who have genotype 1 and who do not clear HCV within three months of treatment may need to extend the length of treatment to 72 weeks. Monoinfected people with genotypes 2 or 3 who do not have an undetectable HCV viral load within a month of starting treatment had higher SVR rates if they continued treatment for 48 weeks instead of 24. But recent studies of people who are coinfected do not support extended treatment at this time.

Adherence to treatment is important for improving the chance of an SVR. Side effects leading to dose reductions or stopping treatment lower the chances. But lowering the ribavirin dose for the first four to five months may not be a problem if the dose of peg-interferon is maximized.

Even without an SVR, treatment may delay or reverse fibrosis, which reduces the risk of liver cancer and increases the liver's ability to process HIV meds.

It's important that people taking HCV treatment get the support they need. One approach has been directly observed therapy, which has proven effective in people enrolled in methadone maintenance programs. People with hepatitis C should avoid alcohol, as it may lead to a higher HCV viral load, increase the risk of advanced liver disease, lower the chance of being a candidate for treatment, and raise the chance of early discontinuation of treatment. Also, smoking cigarettes was found to decrease SVR rates in people with monoinfection who had genotypes 2 and 3.

Supportive treatments like antidepressants, EPO, and GCSF reduce the chance of depression, anemia, and neutropenia respectively and enhance adherence, but do not raise the SVR rate. The best predictors of SVR in people with genotype 1 are: age below 40, normal GGt and ferritin levels, and HCV viral load below 400,000.

HCV, with or without HIV, increases the risk of insulin resistance (IR), and of diabetes. IR raises liver inflammation and can lead to progressive fibrosis and liver cancer. It can also lower the chance of achieving an SVR in people with genotype 1. Similarly, coinfected patients with IR had a lower chance of a rapid viral response. Marijuana use raised the odds of having increased liver fat content, possibly affecting fibrosis progression and the response to treatment.


How to Handle Side Effects

The most common early side effects of interferon include flu-like syndrome, chills, fever, muscle aches, and headaches. These can be lessened with drugs like Tylenol or Advil, drinking more water, and exercise. Headaches, poor appetite, weight loss, increased need for sleep, psychological effects (irritability, anxiety, depression), hair loss, and low platelets and white blood cells are also common side effects. Mild depression is not unusual and can often be treated, so a mental health screening before treatment is important. People at risk for severe depression may need additional support, which could delay or even rule out HCV treatment. Treatment must be stopped immediately if patients report any vision changes -- this could signal retinitis, which occurs rarely but is more likely in people with diabetes.

The major side effects of ribavirin are anemia, muscle pain, and stomach upset. Some people also become irritable. People should have their white blood cell, hemoglobin and platelet counts, as well as AST, ALT, uric acid, albumin, bilirubin, and thyroid function checked every four weeks. In addition, women should have monthly pregnancy tests and use two methods of contraception, since ribavirin can lead to birth defects.


Conclusions

Treatment of HCV/HIV coinfection is complex and difficult for patients to tolerate, but promising results have been attained with peg-interferon and ribavirin combination therapy. This will continue to be the backbone of HCV treatment for some time, but HAART-like triple therapy, with HCV protease and polymerase inhibitors may increase efficacy (see "What's in the Hep C Pipeline" for more info).

Gabriel Ionescu is an attending physician in the Division of Gastroenterology at St. Luke's-Roosevelt Hospital Center in NYC.




  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 
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