Most HIV/hepatitis B co-infected people who include tenofovir (Viread, also in the Truvada and Atripla coformulation pills) in their antiretroviral regimen achieve sustained suppression of hepatitis B virus (HBV), according to a presentation last week at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal.
Tenofovir – along with 3TC (lamivudine, Epivir) emtricitabine (Emtriva) and, to a lesser extent, entecavir (Baraclude) – has dual activity against both HIV and HBV. Using one of these drugs alone can select for drug-resistant virus. Although tenofovir has a relatively high barrier to resistance, current treatment guidelines recommend that HIV/HBV co-infected individuals should include two dually active agents in their antiretroviral regimen.
Karine Lacombe from INSERM, Paris, and her colleagues looked at long-term control of hepatitis B, viral breakthrough and development of resistance in HIV/HBV co-infected patients taking tenofovir.
The study included 165 coinfected patients recruited from the national French HIV-HBV Cohort at seven centres between May 2002 and May 2003. All participants started antiretroviral therapy containing tenofovir and had been on the drug for at least six months at the time of the analysis, with a median duration of 31 months.
The researchers conducted tests to quantify HBV viral load, determine HBV genotype, measure concentrations of tenofovir in the blood, check for resistance mutations and monitor liver and kidney function.
Study participants had relatively well-controlled HIV disease, with a median CD4 cell count of 370 cells/mm3 and a median HIV viral load of approximately 70 copies/ml (55% below 50 copies/ml).
The median baseline HBV viral load was approximately 1800 IU/ml (21% below 60 IU/ml). Most patients (72%) had HBV genotype A, with genotypes D, E and G ranging from 8% to 12%. A majority of participants (63%) were hepatitis B "e" antigen-positive. About three-quarters also received 3TC, either before (72%) or during (76%) treatment with tenofovir.
Study participants were defined as non-responders if they had HBV viral load persistently above 2000 IU/ml despite treatment. Rebounders were defined as patients whose HBV viral load increased and stayed above 2000 IU/ml after suppression. ‘Blippers’ were defined as individuals who achieved HBV viral suppression below 2000 IU/ml but whose viral load intermittently rose above this level.
Treatment with tenofovir yielded a significant improvement in liver function. The mean ALT level fell from 79 IU/ml at baseline to 40 IU/ml, whilst the mean AST level fell from 62 UL/ml to 33 IU/ml. Kidney function did not change significantly (a potential concern because tenofovir can cause kidney toxicity).
HBV viral load fell below 2000 IU/ml after a median of eight months. At the end of follow-up, a large majority (90%) of participants were classified as controllers, with HBV viral load below this level. Dr Lacombe explained that most of these patients actually had undetectable HBV viral load below 12 IU/ml using a more sensitive test.
A total of 17 patients (10%) did not achieve sustained HBV suppression, including three individuals (2%) who never achieved suppression and were classified as non-responders.
Six participants – the rebounders – saw their HBV viral load rise and stay above 2000 IU/ml after previous suppression. The remaining eight patients (5%) – the blippers – experienced transient HBV viral load increases above this level.
After measuring blood concentrations of tenofovir, however, the researchers found that most of these individuals had inadequate levels. Amongst the participants judged to have adequate drug levels, only six – two rebounders (1%) and four blippers (3%) – failed to achieve sustained HBV viral load suppression.
Looking at just the two true rebounders, HBV viral load rose a median 23 months after starting tenofovir, with a range of 20 to 25 months. Both patients had HBV genotype A. One was also taking 3TC and the other had done so in the past.
Amongst the four true blippers, blips occurred a median 22 months after starting tenofovir, with a range of 20 to 35 months. HBV genotypes were diverse: one with genotype A, one with A/G, one with G and one with both A/G and D. Two were also taking 3TC whilst two had no 3TC experience. Blips were small, reaching a maximum HBV viral load of about 4700 IU/ml.
Both of the true rebounders and three of the four true blippers had the L217R polymorphism mutation. In addition, two individuals were found to have HBV mutations not previously associated with resistance: S219A in one rebounder and R274W in one blipper.
HBV rebound and blips led to rising ALT levels in some patients, but no clinical symptoms were reported.
The investigators concluded that viral suppression in HIV/HBV co-infected patients treated with tenofovir is rapid and sustained, with more than 98% (complete responders plus blippers) controlling hepatitis B if they receive adequate drug levels.
Lacombe, K et al. HBV blippers and rebounders under treatment with tenofovir in HIV/HBV co-infection. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 100, 2009.