NATAP REPORTS

Current Review & Update on Hepatitis C & HIV/HCV Cection

SUMMER 2001

Improved Histology and Maintenance Therapy; Improved Liver Condition for Nonresponders

In individuals who have not achieved an SVR, interferon (or interferon in combination with ribavirin) may be continued for a prolonged period of time. Defined as "maintenance therapy", a prolonged course of interferon may improve hepatic histology, may delay progression of hepatic fibrosis, and may prevent the development of hepatocellular carcinoma. Interferon has an antifibrotic and antiproliferative benefit that is independent of its antiviral effect. This is the basis for maintenance therapy and data suggesting that interferon may slow or prevent progression to HCC.

From an analysis of multiple studies of Pegasys, the histologic response, as defined by an improvement of least 2 points in the histologic activity index (HAI) overall, was found in 57 % of treated patients compared to 41% of patients receiving standard interferon. The histologic response was most evident in those patients with SVR, in whom 83% also achieved a histologic response. A histologic response was observed in 79% of the patients who received standard IFN. However, it is important to note that even the non-responders derived histologic benefit, with 47% having a histologic response compared to 30% receiving standard IFN. Histologic improvement has been observed in studies involving PEG-Intron. Using PegIntron 0.5 ug/kg dose Knodell HAI inflammation score decreased 5 points after 24 weeks post-treatment, using 1.0 ug/kg inflammation score was reduced 5.4 points, using highest dose of 1.5 ug/kg the HAI score was reduced 4 points, and using standard interferon the HAI score was reduced 4.7 points.

Several studies show improved histology can be achieved with or without virologic response and the studies suggest that this may slow disease progression, stop or slow progression to cirrhosis, and may help prevent liver cancer. These study findings have not been definitive but two four-year studies in HCV-infected patients started in 2000 to try to confirm these preliminary findings (HALT-C, Pegasys; COPILOT, PegIntron). However, for patients with advanced liver disease maintenance therapy may be the only option for slowing progression to cancer or severe complications of hepatitis C. The key may be to find a tolerable dose.

Data was discussed at DDW from several studies regarding the observation of potential benefit by interferon on histologic response.

Mitch Shiffman’s randomized pilot study (Gastroenterology 1999;117: 1164) demonstrated the effect of maintenance therapy. Patients who after 6 months of treatment had significant reductions in serum ALT level (62.6 ± 9.6), HCV-RNA titer (4.79 ± 0.13 copies/mL), and hepatic inflammation (4.0 ± 0.2) had reduced inflammation and a trend toward decreased fibrosis in the group that completed 30 months of maintenance therapy compared to the group that completed 6 months (80% vs 43%). The improvements seen on therapy were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, HCV-RNA, and a return of hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement. Discontinuation of interferon was associated with an increase in the mean fibrosis score and worsening of hepatic histology in 30% of patients.

For patients with advanced HCV, the potential for slowing disease progression is very important. If a patient does not achieve an SVR from therapy, maintaining a lower dose of interferon therapy (maintenance therapy) may prevent or slow disease progression. And maintenance therapy may be the key to sustaining improved histology. Although the Shiffman study showed benefit for maintenance in patients who demonstrated significant improvements during the 6 months on therapy, it was a pilot study and did not look at potential benefit for patients who did not demonstrate such clear benefit from initial therapy. It’s possible that maintenance therapy may sustain much less of a benefit seen during the first 6 months of therapy, that is, small improvements in histology may be sustained.

ALT does not correlate with hepatic inflammation or fibrosis

The effect of a therapeutic response in individuals with normal ALT were presented by Juan Esteban in at AASLD 2000. Several hundred patients were followed for over 8 years and each had two liver biopsies separated by four years. A portion (about 150 patients) were treated with interferon or IFN+ribavirin. Although Esteban did not indicate it, I assume the patients were mono-HCV-infected and not coinfected. He compared those with normal ALT to those with abnormal ALT and found a higher percentage of females in the normal ALT (71%) compared to abnormal ALT (47%). Any alcohol intake was noted in 21% of those with normal ALT and in 40% of those with abnormal ALT. Heavy alcohol intake, defined as greater than 50g/day, occurred in 6% of those with normal ALT and in 17% of those with abnormal ALT. Hepatic histology as determined from liver biopsies differed between those with normal and abnormal ALT (biopsies were scored according to Ishak et al. and fibrosis progression rate per year estimated as the ratio between fibrosis score in the first biopsy and duration of infection [indirect estimate], and difference between fibrosis scores divided by the time interval between biopsies [direct estimate]).

Significant differences were seen in liver damage between those with normal and abnormal ALT. Perhaps most importantly observed in this study and also seen in several other studies, ALT does not necessarily predict the stage of liver disease. Moderate and more advanced liver disease can be present when ALT is normal. This may be a more crucial consideration in coinfection since liver disease progression can be accelerated by HIV. In those with normal ALT (biopsy performed), 55% were mild, 36% were moderate and 2% severe chronic hepatitis, and 2% cirrhosis. In those with abnormal ALT, 24-29% had mild biopsy results, 32-48% moderate, 19-27% severe chronic hepatitis, and 5-17% cirrhosis. Four years later, a repeat biopsy in individuals with normal ALT showed no cirrhosis, decompensation, hepatocellular carcinoma or death. In 114 patients with abnormal ALT, 8% had progressed to cirrhosis, 2% had decompensated liver disease, 2% had hepatocellular carcinoma and 2% had died.

Interestingly, Esteban's data in the program abstract indicated patients with elevated ALT saw increased fibrosis if untreated or if they were non-responders to HCV treatment, but decreased fibrosis in those with sustained viral response. However, it is not clear how Esteban defines nonresponders. Irregardless, some non-responders to IFN still had an improvement in hepatic histology (18%) or stopped fibrosis progression (49%). The proportion of patients whose fibrosis improved or remained unchanged was higher in non-responders than in untreated patients. Additionally in follow-up, non-responders treated with IFN+RBV saw their fibrosis progression rates decrease (from 0.215± 0 to 0.057± 0.350; p=0.02), while it remained unchanged in untreated patients and non-responders treated with IFN alone. Esteban concluded that combination treatment slows disease progression in virologic non-responders but that the duration of benefit remains unclear. This study supplies more evidence that maintenance therapy may be beneficial and it suggests that maintenance therapy including RBV maybe more beneficial than IFN alone. Esteban also suggests in his conclusions that ALT may help predict disease progression, but ALT is no substitute for a biopsy. More details on this study are available on the NATAP web site where the abstract will be available. NATAP AASLD 2000 Conference Report-

http://www.natap.org/2000/aasld/dal_rp11more_evidence.htm

Also available on the NATAP website:
"Maintenance interferon for chronic hepatitis C: More issues than answers?"
Written by Gregory T. Everson, M.D., presents an interesting overview.

http://www.natap.org/2001/apr/maintenance043001.htm

Liver transplants in coinfection & HCV recurrence following liver transplantation

Histologic recurrence develops in at least 50% of patients within the first year after transplant, with progression to cirrhosis in about 20%. High lipids and diabetes are negative risk factors. One of the challenges of transplantation is to prevent reinfection and particularly progressive liver disease following liver transplantation. Encouraging but preliminary data was presented on treating established recurrence with Pegasys 180 mg given weekly for 48 weeks. Preliminary week 24 data demonstrated that about 44% had a 2 log10 drop in HCV-RNA and 25% were HCV-RNA negative. In a separate study, Firpi reported at DDW that 20% receiving standard interferon with 1000-1200 mg daily ribavirin for 12-18 months had a sustained viral response (6 months after stopping therapy). Of the 50 patients who qualified for this study, 4 died, 3 required discontinuation, and 38% dose reduced.

HIV-infected patients are not generally prioritized for liver transplants. Reimbursement is an issue because insurers consider transplants in coinfected individuals to be experimental. In spite of the many advances in organ transplantation, the presence of HIV in a patient has been considered a contraindication to transplantation. The following summarizes the current concerns: (1) a stable HIV-positive candidate will immunologically decompensate with immunosuppression (from immunosuppressive drug therapy used following transplant); (2) the viral load will increase and/or immunosuppression may enhance HIV mutations (patients go off HIV therapy briefly after the transplant); (3) the pharmacokinetics and pharmacointeractions of current antiretroviral agents and immunosuppression may lead to subtherapeutic effects or toxicity; and (4) the public perception of offering transplantation to HIV-positive patients will lead to diminished support for donation. With the use of HAART and the therapeutic successes that have resulted from its use, liver transplants in HIV have become more viable.

Several transplant sites throughout Western Europe and the US are performing liver transplants in HBV or HCV infected patients who are also infected with HIV. The University of Pittsburgh appears to have the best success rate and has been the most willing to transplant coinfected patients. They also appear to have a helpful reimbursement program. Their survival rates appear to be comparable to those of transplant patients without HIV.

Pittsburgh has done a total of 7 liver transplants and 4 kidney transplants in the HAART era. Previous information was that 1 patient had died relatively early (2 weeks after liver transplantation) due to poor graft function and requirement of life support prior to surgery. Since then, there has been 1 additional death at 20 months due to chronic rejection in a patient who became "noncompliant" when the protease inhibitor was discontinued without appropriate adjustment of tacrolimus levels (unbeknownst to the transplant team), with resultant rejection. The remaining 9 patients are all alive with stable HIV disease. Fung is publishing the results of the 7 liver patients with the 5 from Miami, Florida. None of their patients has died.

Effect of Diet on HCV

In general, good nutritional principles should be followed by all individuals, and even more so if they are infected with HCV. For the vast majority of HCV-infected individuals, no dietary modification is necessary. Individuals who have decompensated liver disease may need to restrict protein intake. Iron supplementation should only be undertaken after consultation with a physician. Iron absorption is very tightly controlled by the body and intake in most individuals is much more than is needed. The question remains whether we should be proactive about early dietary changes for persons infected with Hepatitis C but who have not manifested symptoms of liver failure? While an ounce of prevention is worth a pound of cure, changing eating habits is very difficult to make and harder to adhere to.

Recommending vitamin and herbal supplements can get expensive and may not significantly increase quality of life. This by no means implies that people with Hepatitis C should not pay attention to their dietary habits and nutritional requirements. Each individual will need to be evaluated by a dietitian with experience in liver disease to determine his or her own requirements. The reason for this is because people do not select their diets based on physical and/or medical requirements alone, but also from their cultural upbringing, access to food/meals, and certain habits set by choice and convenience.

A nutritional foundation of dietary practices should be the guide for persons with Hepatitis C, especially at times when there are no gastrointestinal symptoms and liver function tests are normal or mildly elevated with no other clinical abnormalities. Perspectives on diet and nutrition are offered below, including from Jocelyn Rodrigues, MPH, RD, CDN. A healthy balanced diet including reasonable amounts of red meat is desirable, unless otherwise indicated by a patient’s condition:

1. Get half of your daily calories in carbohydrates. Whole grain starches, vegetables and fruits should be the mainstay of carbohydrates. Sugar and sugary foods, like donuts and candy bars, should be minimized. If you have diabetes, speak to your doctor.

2. Keep protein intake up. Have some protein at every meal. Portion matters more than kind of protein. Make sure to include beans and tofu products, nuts, and dairy products.

3. Moderate fat consumption. Cutting back sugary foods tends to reduce fat intake. Nuts and tofu, which are protein sources, have a healthy amount of unsaturated fat. Use vegetable oil and butter sparingly. The goal in reducing fat intake is mainly for weight purposes.

4. Maintain or achieve desirable body weight. Those who are obese, more than twenty pounds over their ideal weight for height, should lose weight. Those who are mildly overweight should watch out for insidious weight gain.

Marion Peters, MD, Hepatologist and GI specialist at UCSF says: if a patient has encepholopathy, which can occur as part of decompensated cirrhosis, they should limit their protein intake, but not necessarily eliminate red meat. Iron accumulation can be a problem only if you eat excessive amounts of red meat. Otherwise, eating red meat is fine and in fact could be part of your diet. Just don’t eat red meat three times per day. If you are taking HCV therapy, you should indulge yourself a little to increase caloric intake and particularly it’s ok to eat red meat. Dr Peters says that studies suggesting iron accumulation in the liver can be a problem is when iron intake is very high and excessive.

On the topic of iron storage in the liver and it’s potential harm, Ms. Rodrigues says: from a nutrition perspective, the following is known--

1. Iron is poorly absorbed through the GI tract. Heme-iron (ie. meats) have a better absorption rate but absorption is not 100%. Non heme-iron (ie. fortified flour, cereals, spinach, etc) is better absorbed than meat, yet absorption still is not 100%. Therefore, at any given high iron meal a maximum of 40-50% of the iron is absorbed. Iron supplementation helps increase the likelihood for absorption.

2. During inflammation (ie. fever) iron storage in the liver is increased. Diabetics and certain substance abusers may have conditional hemochromatosis. (a hereditary disorder of iron metabolism characterized by excessive accumulation of iron in tissues, diabetes, liver dysfunction, and a bronze skin pigmentation).

3. As for HCV, earlier studies suggested that increased liver iron levels elicit liver oxidative stress, with consequent steatosis (fatty liver) and glutathione depletion. (Iron storage, lipid peroxidation and gluthathione turnover in chronic anti-HCV positive hepatitis. J. Hepatol 1995 Apr;22(4):44-56 , Therapy of hepatitis C: other options. Hepatology 1997 Sep;26 (Suppl 1): 143S - 151S.) Therefore, Rodrigues feels that this information suggests high iron levels may be harmful to the liver.

However, Ms Rodrigues says the question of whether to restrict or supplement iron intake needs to be considered individually, taking into consideration person's dietary habits, results of laboratory tests including testing of iron levels, medications, physical health, and medical history. It is safe to say, that for men with elevated iron levels (serum ferritin especially), taking a multivitamin without iron is recommended. Women who are premenopausal should consider iron supplementation, unless otherwise indicated, if serum ferritin is high and there is grade 2 or 3 fibrosis. But in post-menopause iron supplementation may not be suggested. Women who are experiencing heavy bleeding during menstruation may need iron supplementation. But these sitautions vary by individual and consultation with your doctor is recommended. Men and women who start interferon/ribavirin treatment will need to be reassessed. As liver inflammation subsides with IFN/Riba, serum ferritin will normalize, and depending on the person's dietary intake and total iron, iron supplementation may be indicated. Decreased serum ferritin is a sensitive indicator of iron deficiency, however it may not be reliable if there is co-existing inflammatory infection or co-existing liver disease such as Hep B or Hep C.