Despite Infrequent "Blips," Tenofovir (Viread) Provides Good Hepatitis B Virus Suppression HIV-HBV Coinfected Individuals

By Liz Highleyman

Hepatitis B Virus

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

Several antiviral agents are approved for treatment of hepatitis B, some of which also exhibit anti-HIV activity. Tenofovir (Viread, also in the Truvada and Atripla coformulation pills) and lamivudine (3TC, Epivir) are approved for both diseases, while emtricitabine (Emtriva) is currently approved only for HIV. As reported at the 2007 Retrovirus conference, entecavir (Baraclude), which is only approved for HBV, also has low-level anti-HIV activity.

Using these dually active drugs -- essentially as monotherapy -- in a regimen that does not pack enough punch against both viruses can lead to the emergence of drug-resistant HBV or HIV. Current treatment guidelines recommend that all HIV-HBV coinfected individuals who need treatment for hepatitis B should use a combination antiretroviral regimen that includes 2 agents that also work against HBV.

As presented at the 16th Conference on Retroviruses and Opportunistic Infections last week in Montreal, Karine Lacombe and colleague analyzed long-term control of HBV, viral breakthrough, and development of resistance in 165 HIV-HBV coinfected patients recruited from the national French HIV-HBV Cohort.

All participants started antiretroviral regimens containing tenofovir and had been taking the drug for at least 6 months (median 31 months) at the time of the analysis. The researchers regularly monitored HBV viral load, tenofovir concentrations in the blood, drug resistance mutations, and liver and kidney function.

With regard to hepatitis B variables, the median baseline HBV viral load was approximately 1800 IU/mL, and 21% had undetectable HBV DNA < 60 IU/mL. Most patients (72%) had HBV genotype A, while 8%-12% had genotypes D, E, or G; a few had multiple or mixed genotypes. A majority (63%) were hepatitis B "e" antigen (HBeAg) positive. Most also received lamivudine before (72%) or during (76%) treatment with tenofovir.

With regard to HIV status, participants had fairly well controlled HIV disease, with a median CD4 count of 370 cells/mm3 and a median HIV viral load of about 70 copies/ml. Just over half (55%) had undetectable HIV RNA < 50 copies/mL.

The investigators defined 4 levels of treatment response:

Controllers: HBV DNA fell and stayed below 2000 IU/mL on treatment;

Non-responders: HBV DNA remained persistently above 2000 IU/mL despite treatment;

Rebounders: HBV DNA was suppressed but then increased during treatment and stayed above 2000 IU/mL;

Blippers: HBV DNA was suppressed below 2000 IU/mL with treatment, but intermittently rose above this level at least once.

Results

HBV viral load fell below 2000 IU/mL after a median 8 months.

At the end of follow-up, 90% of participants were classified as controllers, with HBV DNA < 2000 IU/mL.

17 patients (10%) did not achieve sustained HBV DNA suppression throughout the follow-up period.

3 of these (2%) never achieved HBV DNA suppression and were classified as non-responders.

6 rebounders (4%) had HBV DNA rise and stay above 2000 IU/mL after suppression.

8 blippers (5%) experienced transient HBV DNA increases above 2000 IU/mL after suppression.

Measurement of tenofovir concentrations revealed that most of these patients had inadequate blood levels; after excluding these individuals, only 6 were considered true non-controllers: 2 rebounders (1%) and 4 blippers (3%).

The 2 true rebounders had the following characteristics:

HBV viral load rose 23 months on average after starting tenofovir;

Both had HBV genotype A;

1 was also taking lamivudine and the other had done so in the past.

Both had the L217R polymorphism mutation.

1 had a previously unidentified S219A mutation.

The 4 true blippers had the following characteristics:

Blips occurred 22 months on average after starting tenofovir;

1 had HBV genotype A, 1 had A/G, 1 had G, and 1 had both A/G and D.

2 were also taking lamivudine, 2 had no prior lamivudine experience.

Blips were small, reaching a maximum of 4700 IU/mL.

3 of the 4 had the L217R polymorphism mutation.

1 had a previously unidentified R274W mutation.

The observed S219A and R274W mutations have not previously been associated with drug resistance in previous studies.

After starting regimens including tenofovir, patients experienced significant improvements in liver function:

Mean ALT fell from 79 IU/mL at baseline to 40 IU/mL during therapy;

Mean AST level fell from 62 UL/mL at baseline to 33 IU/mL during therapy.

HBV rebound and blips led to rising ALT levels in some patients, but no clinical symptoms were observed.

Kidney function did not change significantly while taking tenofovir.

Based on these findings, the investigators concluded, "Viral suppression in HIV-HBV coinfected patients treated with [tenofovir] is rapid (median time to virological control = 8.1 months) and sustained (median follow-up = 31 months)."

The added, "More than 98% of the patients had a viral load under 2000 [IU/mL] at end of follow-up," when including both controllers and blippers with adequate tenofovir blood concentrations.

2/17/09

Reference
K Lacombe, J Gozlan, A Boyd, and others. HBV blippers and rebounders under treatment with tenofovir in HIV/HBV co-infection. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 100.