Long-term Tenofovir (Viread) Leads to Improvement of Liver Fibrosis in HIV-HBV Coinfected Patients

By Liz Highleyman

Due to overlapping risk factors, a significant proportion of HIV positive individuals have also been exposed to hepatitis B virus (HBV), which over time can progress to liver cirrhosis or liver cancer.

Tenofovir (Viread, also in the Truvada and Atripla coformulation pills) -- one of the most widely used antiretroviral drugs for HIV -- was granted FDA approval in August 2008 as a treatment for chronic hepatitis B.

As previously reported, Karine Lacombe presented data at the 16th Conference on Retroviruses and Opportunistic Infections last week in Montreal showing that despite transient "blips" in HBV DNA, tenofovir produced sustained HBV viral load suppression in HIV-HBV coinfected individuals.

At the same meeting, Lacombe and colleague also presented a poster describing findings from a non-randomized open-label study looking at the long-term effects of tenofovir on liver fibrosis progression.

This analysis included 130 HIV-HBV coinfected participants in the French HIV-HBV Cohort who were treated with tenofovir between 2002 and 2006. Most patients (approximately 85%) were men and the mean age was 41 years. Mean CD4 counts ranged from 366 cells/mm3 in patients with advanced fibrosis to 457 cells/mm3 in those with absent or mild fibrosis. The mean HBV DNA level was 4.0-4.7 log10 copies/mL.

A majority of study participants had previously been exposed to lamivudine (3TC or Epivir HBV, approved as a treatment for both hepatitis B and HIV) before study enrollment (mean duration 28 months); 76% took lamivudine/emtricitabine along with tenofovir during follow-up (often using the 3-in-1 Atripla pill).

Fibrosis was estimated using Fibrometer, a technique combining a variety of non-invasive markers including platelet count, prothrombin time, AST, a2-macroglobulin, urea, and hyaluronic acid. At baseline, 45 patients (35%) had stage F0-F1 or absent-to-mild fibrosis according to Fibrometer, 29 (22%) had stage F2 or moderate fibrosis, and 56 (43%) had stage F3-F4, representing severe fibrosis or cirrhosis.

Participants were followed for a median of about 30 months. Time-weighted change from baseline was calculated every 12 months after treatment initiation, adjusting for age, body mass index, serum HBV DNA, CD4 cell count, alcohol consumption, and hepatitis C or D coinfection. Changes in Metavir fibrosis stage were also assessed for patients who had available paired liver biopsies.

Results

During treatment, transaminase (ALT and AST) levels decreased significantly over time:

ALT: 76 IU/mL at baseline, 47 IU/mL at 24 months, 39 IU/mL at 36 months;

AST: 57 IU/mL, 41 IU/mL, and 33 IU/mL, respectively.

Patients with F3-F4 fibrosis at baseline experienced a steep decline in fibrosis score after 12 months of treatment.

This was followed by a slow and stable decline at 24 and 36 months.

Patients with F0-F1or F2 fibrosis at baseline remained consistently stable over the follow-up period.

In an analysis of 38 pairs of liver biopsies:

9 patients experienced at least a 1 point decrease in fibrosis stage;

4 progressed from stage F2 to F3-F4;

25 remained stable (8 at F0-F1, 6 at F2, 11 at F3-F4).

Looking at histological activity scores, reflecting necro-inflammation:

10 patients experienced a decrease from A2-A3 to A0-A1;

2 increased from A0-A1 to A2-A3;

26 remained stable (20 at A0-A1 and 6 at A2-A3).

"[Tenofovir] induced a significant decrease in fibrosis level after mean treatment duration of 29.6 months," the investigators noted. "This decrease is particularly strong in patients with extensive fibrosis and cirrhosis."

"Activity also markedly decreased while a normalization of transaminases was noted over time," they added.

"Our findings suggest that a long and extensive use of [tenofovir] in HIV-HBV [co]infected patients might help to prevent end-stage liver disease in this population, by slowing or reversing the liver fibrosis process," they concluded.

Because resistance can develop if drugs with dual activity against HBV and HIV are used alone, current treatment guidelines recommend that all HIV-HBV coinfected individuals who need treatment for hepatitis B should receive a complete combination antiretroviral regimen that includes 2 agents that also work against HBV.

3/03/09

Reference
K Lacombe, A Boyd, J Guechot, and others. The Long-term Use of Tenofovir in HIV/HBV Co-infection Induces a Marked Decrease in Liver Fibrosis. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 815.