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ICAAC 2008: Another Study Confirms Hepatitis B Virus Suppresses Hepatitis C Virus Replication in HBV-HCV Coinfected Individuals

Due to overlapping transmission routes, many people are dually infected with both hepatitis B virus (HBV) and hepatitis C virus (HCV).

In a poster presentation this week at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington, DC, Italian researchers presented data confirming prior research showing that the presence of HBV interferes with HCV replication.

The investigators performed long-term clinical and virological follow-up of 29 chronic hepatitis C patients with HBV superinfection and 29 HCV negative individuals with acute hepatitis B. Patients in the 2 groups were matched for age (+/- 5 years), sex, and HBV risk factors.

Results

• At the first observation, HBV-HCV coinfected patients and HBV monoinfected individuals had similar HBV DNA viral load (mean 7.1 vs 1.6 x 108) and a similar trend towards becoming HBV negative (HBV clearance).

• Severe acute hepatitis B was more frequent in the HBV-HCV coinfected group than in the HBV monoinfected group (34.5% vs 6.9%; P < 0.05).

• Of the 28 patients in the HBV-HCV superinfection group who were still alive at the end of acute illness (1 died of sub-acute progressive hepatitis), 24 (85.7%) were followed for 2-6 years (median 5 years):

• 21 of these 24 patients became hepatitis B surface antigen (HBsAg) negative (87.5%);

• 2 progressed to HBsAg positive chronic hepatitis (8.3%);

• 1 underwent liver transplantation (4.1%).

• Data on HCV RNA levels before the development of acute hepatitis B and every 12 months thereafter were available for 19 patients:

• All became HCV RNA negative during the acute phase of hepatitis B (100%);

• 16 patients still had undetectable plasma HCV RNA after 1 year (84.2%);

• 9 still had undetectable HCV RNA after 2 years (47.4%);

• 6 still had undetectable HCV viral load after 3-6 years (31.6%).

• The 6 patients who remained persistently HCV RNA negative during follow-up were compared with the 13 who experienced reactivation of HCV replication:

• During the acute phase of hepatitis B, there were no observed differences in HBV viral load (P = 0.4);

• Serum ALT values, however, were higher in the persistently HCV negative subgroup (mean 5291 vs 2208; P < 0.01).

Based on these findings, the researchers concluded, "HBV superinfection in HCV chronic carriers was associated with a strong inhibition [of] HCV replication," especially in 6 patients with marked hepatonecrosis who fully cleared chronic HCV infection.

Second Univ. of Naples, Naples, Italy; A.O. San Sebastiano e Sant'Anna Caserta, Caserta, Italy.

10/31/08

Reference

E Sagnelli, N Coppola, M Pisaturo, and others. HBV Superinfection in Chronic HCV Carriers: Clinical and Virological Long-Term Follow-Up Study. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract V-1628.

 

ICAAC 2008: Drug Interaction Observed between NRTI Tenofovir (Viread) and Experimental Hepatitis C Protease Inhibitor Telaprevir

Due to overlapping risk factors, many people are coinfected with some combination of HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV). Treating patients with more than one virus involves additional complications, including the potential for drug interactions. In a poster presented at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008), taking place this week in Washington, DC, researchers from Tibotec described a study looking at interactions between the company's experimental HCV protease inhibitor telaprevir (VX-950) and the widely prescribed anti-HIV drug tenofovir (Viread, also in the Truvada and Atripla combination pills), which was also recently approved as a treatment for chronic hepatitis B.

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Severe Liver Fibrosis during Acute HCV Infection in HIV Positive Men Who Have Sex with Men

Over the past several years, there have been increasing reports of outbreaks of acute hepatitis C virus (HCV) infection among HIV positive men who have sex with men (MSM). Acute HCV is the initial 6-month period of newly acquired HCV infection.

In the current study, published in the July 15, 2008 online edition of the Journal of Infectious Diseases, Daniel Fierer from the Mount Sinai School of Medicine in New York City and colleagues evaluated risk factors and liver histopathology of 11 consecutively enrolled HIV positive men with recently acquired HCV infection.

Fierer first reported at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) in Los Angeles that several HIV positive MSM with acute hepatitis C showed evidence of severe liver fibrosis, which typically develops much later in the course of HCV infection. He followed up with additional similar findings at the 2008 CROI in Boston.

The recently published report extends the data further.

Results

  • 11 MSM with asymptomatic, sexually-acquired HIV infection of 11 months to 16 years duration were found during routine medical visits to have elevated transaminase levels, which led to further testing and the clinical diagnosis of acute HCV infection.
  • In all these patients, acute hepatitis A virus infection was excluded serologically and acute and chronic HBV infection were included both serologically and by HBV DNA testing.
  • 8 patients were completely asymptomatic for liver disease throughout the acute course of infection; patients 3, 8, and 11 experienced transient jaundice.
  • 10 patients had recently engaged in unprotected receptive anal intercourse, some with many partners.
  • None had experienced ulcerative sexually transmitted infections within the prior year.
  • Patients 1, 3, and 6 reported a single recent episode of injecting methamphetamine; 1 remembered sharing injection equipment, but the others had no recollection of doing so.
  • Patients 2, 6, and 11 had shared paraphernalia used for snorting drugs on multiple occasions with other MSM.
  • Patient 4 had a possible percutaneous exposure.
  • 5 men denied any parenteral risk factors or “club drug” use.

Discussion

According to the investigators, immunosuppression increases the progression of fibrosis in HCV-infected patients. “The magnitude of the acceleration is relatively modest if immunosuppression occurs after the chronic phase of HCV infection has been established,” they wrote. 

The authors pointed out that prior study results have indicated that the fibrosis progression rate (FPR) of patients with chronic HCV monoinfection is 0.11 unts per year and that the FPR of patients with chronic HIV-HCV coinfection is <2-fold greater, at 0.15 units per year.

“The majority of HIV-HCV coinfected injection drug users (IDUs) are not expected to develop cirrhosis (stage 4 fibrosis) for 20 years or more,” wrote the researchers. In contrast, they noted, “Patients who acquire HCV infection when they already have defects in cellular immunity are reported to progress to cirrhosis, end-stage liver disease, and death in as few as 3 years.

They continued, “This dire outcome has been observed in transplant recipients, patients with hematological disorders and immunodeficiencies, and patients with preexisting HIV infection.”

Among the 11 consecutive HIV-infected MSM in the study who underwent liver biopsy during the early periods of HCV infection, nine (82%) had stage 2 fibrosis. In contrast, biopsy specimens from immunocompetent patients obtained during the early periods of HCV infection contained no or minimal fibrosis [1].

“[Therefore] the FPR of the HIV-infected MSM with newly acquired HCV infection in our study was far higher than that of immunocompetent patients with acute HCV infection,” wrote the authors.

“Our findings of moderately advanced fibrosis during the initial period of HCV infection are consistent with the rapid clinical progression to end-stage liver disease reported in previous studies of individuals who acquired HCV infection while already infected with HIV or who acquired HIV and HCV infection simultaneously.”

In their conclusion, the researchers stated that their study indicates that high-risk sexual practices and non injection-drug use may play a role in the transmission of HCV to HIV-infected MSM.

In addition, they wrote, “Our findings also demonstrate that HIV-infected men with acute HCV infection have moderately advanced liver disease. The FPR of this population is 5 times greater than that for people who are not immunocompromised at the time when they become HCV infected. Our findings are of particular importance with regard to the recent outbreaks of acute HCV infection in HIV-infected MSM in Europe and the United States” [2].

The authors observed that regular screening of MSM for HCV antibodies “is not currently recommended by U.S. or international HIV care guidelines, and ALT elevations during acute HCV infection are relatively transient and therefore could be easily missed during routine clinical care.” They maintained that many (if not most) cases of acute HCV infection “are not diagnosed, even in areas in which the outbreaks have been recognized.”

In closing, the study authors urge caregivers to initiate more intensive screening of HIV-infected MSM, “given the grave implications of missing the diagnosis of acute HCV infection in these patients.”

Divisions of Infectious Diseases and Liver Diseases, Department of Medicine, and Department of Pathology, Mount Sinai School of Medicine, New York, NY.

8/05/08

Reference

DS Fierer, AJ Uriel, DC Carriero, and others. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study (brief report). Journal of Infectious Diseases. July 15, 2008 [Epub ahead of print].

Other Citations

1. SM Kamal, Turner B, Q He, and others.. Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum markers of fibrosis. Hepatology 43: 771–779. 2006. 

2. M Danta, D Brown, S Bhagani, and others.. Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. AIDS 21: 983–991. 2007.

ICAAC 2008: Efficacy of Tenofovir (Viread) plus Emtricitabine (Emtriva) in HIV-HBV Coinfected Patients

The nucleotide reverse transcriptase inhibitor tenofovir (Viread, also in the Truvada and Atripla combination pills) is widely prescribed for the treatment of HIV, and was also recently approved for chronic hepatitis B virus (HBV) infectionAs described in a poster presented at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008), taking place this week in Washington, DC, researchers assessed the efficacy of combination therapy with tenofovir plus emtricitabine by means of a retrospective chart review.

Current guidelines recommend that HIV-HBV coinfected patients who require hepatitis B treatment should receive a combination HAART regimen that contains drugs active against both viruses. In addition to tenofovir, such agents include lamivudine (3TC, Epivir), emtricitabine (Emtriva, also in the Truvada and Atripla pills), and -- to a lesser extent -- entecavir (Baraclude).

The analysis included 31 HIV-HBV coinfected patients. 12 lamivudine-naive patients were prescribed tenofovir plus emtricitabine as part of their antiretroviral regimen; at baseline, these patients had a median HBV DNA level of 5.8 x 10(7) copies/mL. 19 treatment-experience patients who had previously failed lamivudine therapy were prescribed tenofovir plus emtricitabine after lamivudine failure; this group had a median HBV viral load of 7.6 x 10(7) copies/mL.

Results

• The median time to complete HBV suppression in the lamivudine-naive group was 466 days, compared with 877 days in the lamivudine-experienced group (P = 0.001).

• After 12 months, 60% of the lamivudine-naive patients achieved undetectable HBV DNA (< 200 copies/mL) compared with 21% in the lamivudine-experienced group (P = 0.092).

• After 24 months, 100% of the remaining lamivudine-naive patients, but only 31% of the lamivudine-experienced group, had undetectable HBV DNA (P=0.015).

• Among initially hepatitis B "e" antigen (HBeAg) positive patients, 14% in the lamivudine-naive group and 9% in the lamivudine-experienced group experienced HBeAg loss.

"HBV DNA suppression to under 200 copies/mL was achieved significantly more rapidly among treatment-naive patients," the investigators stated.

"There was a trend towards a greater proportion of naive patients with HBV suppression at 12 months, and a significantly greater proportion of naive patients were suppressed at 24 months," they added. "Loss of HBe antigen was uncommon and not significantly different between the two groups."

Based on these findings, they concluded, "Our results support the practice of initial dual therapy" in HIV-HBV coinfected patients.

New York Univ., New York, NY

10/28/08

Reference

CA Engell, RS Holzman, and JA Aberg. Efficacy of Tenofovir Plus Emtricitabine in Treatment of HIV/HBV Coinfected Patients. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract V-1626.

Can Rapid Virological Response Predict Sustained Response to Pegylated interferon plus Ribavirin in HIV-HCV Coinfected Patients?

Research has shown that HIV positive people with hepatitis C virus (HCV) coinfection tend to respond less well to interferon-based therapy, but the factors that predict favorable response are generally similar. The objective of the current study, published in the August 2008 issue of the Journal of Viral Hepatitis, was to evaluate the role of rapid virological response in predicting sustained virological response to anti-HCV therapy.

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Antiviral Therapy May Promote Hepatitis B Virus Genotype Changes

Hepatitis B virus (HBV) is known for its ability to mutate rapidly as it replicates, which enables it to develop resistance to antiviral treatment. As reported in the November 2008 Journal of Hepatology, a team of Spanish researchers assessed the frequency of mixed HBV genotypes in people with chronic hepatitis B, as well as genotype changes during natural disease evolution and as a result of antiviral therapy.

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EASL 2008: Some HIV-HBV Coinfected Individuals Experience Delayed Response to Tenofovir (Viread)

Tenofovir (Viread), a nucleotide analog approved for HIV treatment, has also demonstrated antiviral activity in patients with chronic hepatitis B virus (HBV) infection. The aim of the present study, presented at the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan, was to evaluate the rate of primary non-response to tenofovir in treatment-experienced HIV-HBV coinfected patients.

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Detectable HCV in Peripheral Blood Cells after Interferon-based Therapy Predicts Relapse in HIV-HCV Coinfected Patients

Traditionally, individuals treated for chronic hepatitis C virus (HCV) infection who maintain undetectable HCV RNA (genetic material) in their blood 6 months after completing therapy are defined as achieving sustained virological response (SVR). It is not clear how the presence of HCV in the liver and elsewhere in the body affects the likelihood of sustained treatment response versus relapse, especially in HIV positive people.

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AZT (Retrovir) Ups Anemia Risk in HIV-HCV Coinfected Patients, But Rate Remains Low

Since the advent of effective antiretroviral therapy has reduced the rate of death due to opportunistic illnesses and other AIDS-related causes, liver disease has emerged as a major cause of death among HIV positive people. HIV, in turn, has also influenced rates of death among patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, according to a study published in the February 2008 Journal of Hepatology.

In this analysis, Patrick Marcellin and colleagues estimated mortality related to HCV and HBV infection in France. A random sample of 999 death certificates was obtained from among all 65,000 French death certificates in 2001 that listed HBV, HCV, hepatitis, liver disease, possible complication of cirrhosis, bacterial infection, HIV, or transplantation as causes of death. Physicians who reported these deaths were sent a questionnaire to identify how many deaths were related to HBV or HCV infection. Death rates were then estimated according to national population census data.


Results

• The estimated annual number of deaths associated with HCV was 3618 (6.1 deaths per 100,000 inhabitants).

• The estimated annual number of deaths associated with HBV was 1507 (2.5 per 100,000 inhabitants).

• The estimated number of deaths attributable to HCV was 2646 (4.5 per 100,000 inhabitants).

• The estimated number of deaths attributable to HBV was 1327 (2.2 per 100,000 inhabitants).

• In the HCV infected group, 95% had cirrhosis and 33% had hepatocellular carcinoma (HCC).

• In the HBV infected group, the rates were similar: 93% and 35%, respectively.

• 11% percent of these deaths occurred in patients with HIV coinfection.

• Deaths related to hepatitis B or C occurred at an earlier age in patients with a history of excessive alcohol consumption. 

"In France, 4000-5000 deaths related to HCV and HBV infection occurred in 2001," the researchers concluded. "Alcohol consumption and HIV infection were important co-factors."

They added that, "These data emphasize the need for ongoing, efficient public health programs that include screening, management, and counseling for HCV- and HBV-infected individuals."

02/29/08

Reference

P Marcellin, F Pequignot, E Delarocque-Astagneau, and others. Mortality related to chronic hepatitis B and chronic hepatitis C in France: Evidence for the role of HIV coinfection and alcohol consumption. Journal of Hepatology 48(2): 200-207. February 2008.