HBV Journal Review
May 1, 2013, Vol 10, no 5
by Christine M. Kukka
EASL 2013 Edition
Antiviral Combination Used for HIV Appears
Effective In "Immune Tolerant" Patients
A New Zealand researcher tried an antiviral drug combination used to treat HIV and found it very effective in temporarily reducing high viral loads in hepatitis B "e" antigen (HBeAg)-positive patients. However, the drug was effective only while patients took the tenofovir and emtricitabine (Truvada) combination.
Current medical guidelines do not recommend treating these "immune tolerant" patients, whose immune systems appear to tolerate high levels of the hepatitis B virus (HBV) without attacking the infected liver cells. Eventually, these patients' immune systems attack the HBV infection, but only after years of dangerously high viral loads.
After four years of treatment with the tenofovir-emtricitabine drug combination, 76% of 62 patients achieved nearly undetectable viral load without any signs of drug resistance. Only 55% of a similar immune-tolerant control group treated with just tenofovir (Viread) achieved undetectable viral load after four years, according to the report presented at the European Association for the Study of the Liver (EASL) conference held in Amsterdam in late April.
However, only five patients in the study lost HBeAg and only three of the five developed "e" antibodies, which usually results in a permanent lowering of viral load. None of the patients lost hepatitis B surface antigen (HBsAg) or developed surface antibodies— a sign of clearing the infection.
Half of the patients stopped treatment after the study concluded and all of them experienced a rebound in their viral loads to the same high levels as existed before treatment began.
While it appears an indefinite course of treatment would be needed in this "immune tolerant" population to suppress viral load, researchers suggest that doctors could selectively use the drug in patients with family histories of cirrhosis or liver cancer.
Despite Universal Care, Hepatitis B Care Is Inconsistent Across Canada
Despite accolades for its universal access to medical care, hepatitis B patients in Canada face inconsistent care across provinces, and even hepatitis B vaccination practices vary widely across the country, according to a March 2013 report entitled Liver Disease in Canada: A Crisis in the Making by the Canadian Liver Foundation.
Surprisingly, the country that delivers health care to all residents regardless of their ability to pay has different hepatitis B treatment guidelines and drug reimbursement rates from province to province. According to the report:
Inconsistent treatment: Each province has its own reimbursement policies and standards for when hepatitis B treatment is required, and which drug should be used. For example, several provinces allow the use of the antiviral entecavir (Baraclude) only when hepatitis B patients have developed cirrhosis. En-tecavir is one of two antivirals currently recommended for all first-line hepatitis B treatment by U.S. and European guidelines.
"Only in Quebec is the reimbursement policy in line with clinical practice guidelines," the report's authors wrote. "It is striking that there is no uniformity between provinces with regard to access to hepatitis B treatment," the report noted.
The inconsistent treatment guidelines also means that many people who require treatment won't get treatment simply because of the province they live in. Delaying hepatitis B treatment results in cirrhosis, liver cancer, and death.
Outdated treatment guidelines: Some of the guidelines also allow treatment only if alanine transaminase (ALT) levels are elevated, which often indicates liver damage is occurring. That assessment is outdated—numerous studies have shown that liver damage can be severe, due to long-term infection, even if current ALT levels are normal.
The report revealed that in 2009, 58% of hepatitis B patients covered by free, public health care received the antiviral lamivudine (Epivir-HBV). This outdated antiviral has an extremely high rate of drug resistance and is no longer recommended for use as a first-line treatment.
Meanwhile, the report revealed that 90% of affluent Canadians who were also covered by private health insurance policies were treated with more modern and effective antivirals other than lamivudine. This shows that even in Canada, people with high income and private insurance had access to superior hepatitis B treatment.
Record-keeping ineffective: Canada does not distinguish hepatitis B from hepatitis C in its death records, therefore tracking the infection's true impact cannot be documented. Additionally, deaths from cirrhosis and liver disease—though resulting from hepatitis B or C—are classified separately.
Only one province —Ontario —tracks hepatitis B deaths. Extrapolating from that data, the report estimates that 14,000 people die annually from hepatitis B in Canada, and that figure is expected to rise due to increases in hepatitis B cases through immigration from Asia and Africa.
Inconsistent immunization policies: Immunization schedules also vary between provinces. While British Columbia, New Brunswick, and Prince Edward Island guidelines recommend hepatitis B vaccination during infancy, the remaining provinces require immunizations later in childhood, during adolescence.
As a result, new hepatitis B cases are actually increasing during childhood in Canada because immunizations aren't occurring until adolescence.
Home Visits Key to Promoting Hepatitis B Screening Among Ethnic Groups
Educating Asian-Americans about their high risk of hepatitis B, and getting them screened, treated and vaccinated can be a cultural and medical challenge. Many immigrants and their children do not speak English, and many health care providers still do not follow medical guidelines and screen Asian-American patients for hepatitis B or offer translation services in their clinics.
A unique outreach program, conducted by lay health care workers in an Hmong community in Sacramento, proved to be highly effective in getting immigrants from mountainous areas in Laos and Vietnam screened for hepatitis B.
According to the report, authored by University of California-Davis Health System researchers and published in the April 23, 2013 issue of the journal Cancer Epidemiology, Biomarkers & Prevention, the Hmong have high rates of hepatitis B and liver cancer rates that are six- to seven-times that of white or Hispanic populations in the United States.
Because the Hmong know little about hepatitis B and rarely interact with local health care providers due to language and cultural barriers, HBV infection and liver cancer can be advanced when first diagnosed and patients often live for less than a year after a cancer diagnosis.
In the study, lay health care workers—many of whom were Hmong and knowledgeable about the culture and language—visited 260 Hmong residents in Sacramento. The residents were randomly assigned to two groups that received two home visits. During the visits residents received either hepatitis B and liver cancer education or nutrition and physical fitness information.
Six months later, 24% of the group that learned about hepatitis B had been screened at their doctors' clinic, compared to only 10% of the group that learned about nutrition and exercise.
By using Hmong lay educators recruited from two respected Hmong cultural organizations, the UC Davis researchers overcame cultural obstacles to HBV screening.
The participants were given a brochure in Hmong and English that they could use to request a hepatitis B screening during their next clinic visit, where translation services were often not available.
However, much of this effort would not be needed if doctors followed current practice recommendations for screening all Asian-Americans for hepatitis B, researchers noted.
Fibroscan Imaging Plus Blood Tests Could
Researchers have been trying to develop new methods to assess patients' liver damage using blood tests or sonograms to avoid performing invasive and costly liver biopsies. One study, published in the April 2013 issue of the journal Alimentary Pharmacology and Therapeutics, found that two noninvasive tests come close to replacing liver biopsies in accurately measuring liver damage over a five year period.
The researchers used a Fibroscan to evaluate the degree of liver stiffness (also known as fibrosis or scarring). The Fibroscan uses a sonogram to measure the speed of sound waves through the liver to identify mild (fibrosis) to severe liver scarring (cirrhosis.) They also used a blood test called a Fibrotest that measures six elements in a blood sample to determine the degree of liver disease.
Researchers used these two diagnostic tools on 600 hepatitis B patients and followed them for nearly five years. Most of the patients were male, average age 42.5. Most had normal or moderately elevated ALT levels.
Doctors found that 94 (15.7%) had liver damage and liver biopsies were performed on 214 patients to test the accuracy of the noninvasive tests.
The researchers reported that the Fibroscan and Fibrotest together were very effective in assessing liver health and indicating when treatment was needed. In some cases, they reported that the two tests combined were more accurate than a liver biopsy.
"This information is of major importance, helping us to sharpen our various tools for the follow-up of our patients," they wrote. Using the two tests together..."could replace liver biopsy for the evaluation of the disease, whatever the stage of the disease."
Useful in patients with "inactive" liver disease: If proven accurate, these two diagnostic tools could prove critical for patients who are HBeAg-negative, have normal ALT levels, and have low viral loads (HBV DNA) under 20,000 IU/mL. Current medical guidelines do not recommend treatment for such patients.
However, in a study presented at EASL, Tunisian researchers performed liver biospsies on 80 HBeAg-negative patients with normal ALTs and low viral load and found that 40% of the patients had fibrosis or liver damage that required treatment. Having noninvasive tests available to evaluate the liver health in these seemingly asymptomatic patients could better identify who needs treatment and save lives.
However, the tests may miss mild fibrosis: A Romanian study presented at EASL confirmed that the two tests were accurate in..."confirming or excluding significant fibrosis, but they are not very accurate in staging (identifying) low grades of fibrosis."
Reports Mixed as to Whether Entecavir Lowers Cancer Risk in Cirrhotic
Korean researchers treated 220 patients with entecavir, 68% with moderate and 32% with severe (decompensated) cirrhosis, and followed them for five years to see if the antiviral reduced liver cancer in these high-risk patients.
They found the cancer rate was 28.5%. Older age (over 50), male gender and presence of diabetes increased the odds of liver cancer in these patients.
Patients who achieved low and undetectable viral loads had lower rates of liver cancer, according to the report presented at EASL. Researchers concluded that while antiviral treatment did not completely eradicate liver cancer risk in cirrhotic patients, those who responded had lower rates.
But a different EASL study that followed entecavir patients for five years appears to contradict those findings. Italian researchers followed 418 patients, most were in their 50s, male, HBeAg-negative and had fibrosis or cirrhosis.
By year 5, all patients had achieved undetectable viral load and one-third even lost HBsAg, with 13 stopping treatment due to the success. They reported that 93% achieved normal ALTs which would indicate no liver damage.
Despite clearing the virus, the lengthy HBV infections took their toll—over the study period 17 cirrhotic patients and five non-cirrhotic patients developed liver cancer.
"Entecavir efficiently suppressed HBV in patients with chronic hepatitis B," researchers noted, but it did not prevent liver cancer.
A third EASL study from Singapore also reported similar findings when entecavir or a combination of lamivudine and adefovir (Hepsera) was used to treat cirrhotic patients. While treatment lowered viral load, it rarely prevented progression of liver damage in hepatitis B patients.
Alcoholism and Smoking Increase Liver Cancer Risk in Younger
A Taiwanese study presented at EASL found that HBV-infected people who drink heavily develop liver cancer more rapidly and at a younger age than hepatitis B patients who do not drink, or uninfected alcoholics.
Researchers followed 966 people with cirrhosis in the study: 132 had HBV infection and alcoholism, 632 had only hepatitis B, and 202 were alcoholics free of infection. Those who drank and had hepatitis B developed cirrhosis on average four earlier than HBV-infected people who did not drink.
When researchers looked at who developed liver cancer over the decade-long study period, they found:
- 28.8% of patients with HBV and alcoholism developed liver cancer.
- 15.8% of patients with just HBV infection developed liver cancer.
- And 10.4% of uninfected alcoholics developed cancer.
The annual incidence of liver cancer was 9.9%, 4.1%, and 2.1% respectively in the three groups.
Researchers also found that among all HBV-infected patients, higher viral load also increased liver cancer risk. Also, people with HBV genotype C had higher cancer rates than those with genotype B.
Smoking also increases risk: Another Taiwanese study presented at EASL followed 7,893 HBV-infected men and women age 20 and older between 1988 and 2006 to see what factors increased the risk of liver cancer, especially among younger patients. They reported that male gender, elevated ALT levels (greater than 80 IU/L) and years of smoking, "predispose HBV carriers to an earlier age of onset of liver cancer."
Inactive Infection and Older Age Increase HBsAg Clearance, as Do
Unknown "Host" Factors
What enables some people to lose HBsAg while others continue to be actively infected with HBV for decades? French researchers followed 315 patients over nearly six years—109 of whom had inactive infection. Who lost HBsAg? Older patients with inactive infections were more likely to clear HBsAg.
Surprising, neither gender, race, treatment, body mass index, alcohol consumption, nor HBV DNA and ALT levels had an impact on who lost HBsAg, according to their report to EASL.
Patients with inactive infection had an annual HBsAg clearance rate of 23.4 cases per 1,000 persons-years, while treated HBeAg-positive patients had clearance rates of 20.7 and untreated HBeAg-negative patients had clearance rates of 10.1.
"The results of this study in a 'real-life' population of HBV carriers show that older age and the inactive HBsAg carrier state are independent predictive factors of HBsAg loss," researchers noted. Treatment only slightly increased the rate of HBsAg clearance. Other "host" factors, such as genotype or a patient's genetics or quality of life, appear to have more impact over HBsAg clearance.
These unknown host factors also appear to play a role in protecting HBV-infected Canadian Inuits from liver damage. Another EASL study found this population had low rates of liver damage over a 23-year-study period, despite their moderate viral loads.
The cause for the relatively benign infection among this community could be the HBV strain or genotype found in the Inuit (genotype B, subtype B6) or other host factors that have not yet been identified, researchers noted.
Dairy-Rich Diets Linked to Increase in Liver Cancer
Diets rich in milk and cheese are known to increase cancer rates in general, so a European team decided to see if a dairy-rich diet increased liver cancer risk in patients with viral hepatitis and found that it does.
While dairy foods are rich in calcium and vitamin D, "their increased consumption may also lead to higher circulating levels of IGF-1, a growth factor possibly related to increased risk of liver cancer," researchers reported to the EASL.
They followed 477,206 Europeans over 11 years and found higher liver cancer rates in those with higher dairy intake in both uninfected and HBV-infected individuals. "Higher circulating IGF-I level due to more dairy food intake may be a possible biologic explanation for these observations, but requires further study," they noted.
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