Influence of HIV on Tenofovir Response in Chronic HBV
Influence of HIV on Tenofovir Response in Chronic HBV
We evaluated retrospectively the virological response to long-term tenofovir therapy in a large group of chronic hepatitis B patients, of whom three-quarters were coinfected with HIV. Compared with HBV-monoinfected individuals, those with coinfection were younger, more often seropositive for hepatitis C or delta virus antibodies, and less frequently infected by HBV genotype D. Around half of patients in both groups were HBeAg positive. More than three-quarters of coinfected patients were homosexual men or former IDUs. Before beginning tenofovir, half of HIV/HBV-coinfected patients and more than two-thirds of HBV-monoinfected individuals had been exposed to other anti-HBV agents, lamivudine being by far the most frequent agent. Finally, most patients in our study received tenofovir along with a second anti-HBV agent, emtricitabine being the most common given its convenient coformulation as a single pill (Truvada).
Despite differences comparing HIV/HBV-coinfected and HBV-monoinfected patients at the time of beginning tenofovir, the proportion of baseline HBV viremic individuals who achieved undetectable serum HBV-DNA at weeks 24, 48 and 96 did not differ significantly comparing HBV-monoinfected and coinfected patients. However, in the subset of HBeAg-positive individuals, HIV coinfection was associated with a slower virological response. Whereas more than 80% of HBeAg+, HBV-monoinfected individuals had undetectable serum HBV-DNA at weeks 24, 48 and 96 of tenofovir therapy, these numbers were lower in HBeAg+ coinfected patients (45, 71 and 81%, respectively).
Multivariate analysis provided a clue on the negative impact of HIV coinfection and positive HBeAg on virological response to tenofovir in the whole chronic hepatitis B population. The amount of serum HBV-DNA was the only significant determinant of treatment response. Patients with positive HBeAg and/or HIV coinfection had the greatest HBV-DNA levels, which most likely explained their longer time to reach undetectability, as recently shown by others.
Despite being present in 30% of viremic HIV/HBV-coinfected patients and in 46% of viremic HBV-monoinfected individuals, there was no recognizable effect of drug resistance mutations on response to tenofovir in our study population. Although lamivudine as the only anti-HBV agent is now considered as suboptimal to treat chronic hepatitis B, this drug as a part of triple antiretroviral regimens has been widely used for many years in HIV/HBV-coinfected patients. As it occurred in our series, a large proportion of these individuals harbour HBV-resistant strains. Apart from lamivudine, other anti-HBV agents, such as adefovir or entecavir, had been used to treat our HBV-monoinfected individuals, which explains the recognition of drug resistance mutations other than those classically associated with lamivudine in our series. Differences in prior pharmacological history and the distinct profile of drug resistance mutations exhibited by HIV/HBV-coinfected and HBV-monoinfected patients did not translate into a different antiviral response to tenofovir in our study. These results are reassuring and support that tenofovir activity against HBV does not seem to be impaired significantly by prior exposure to other anti-HBV agents and/or the presence of drug resistance mutations in HBV. Our findings are in agreement with the results from other studies, some of which further highlighted that adding another anti-HBV agent to tenofovir did not result in greater antiviral responses than prescription of tenofovir alone.
Given that coinfection with hepatitis C or delta viruses is relatively common in chronic hepatitis B patients and complex viral interference phenomena exist between these viruses, we explored whether HBV suppression using tenofovir could be influenced in chronic hepatitis B patients coinfected with other hepatitis viruses. We could not find any evidence for it. However, patients with delta hepatitis had lower median serum HBV-DNA levels than the rest and accordingly should achieve undetectability faster on tenofovir.
All 38 HBV-monoinfected individuals and 85% out of 78 viremic HIV/HBV-coinfected patients achieved undetectable HBV-DNA by week 96 of tenofovir therapy. The trend in HBV-DNA decline in the subset of coinfected individuals still viremic at 4 years of tenofovir therapy suggests that they might eventually also reach complete viral suppression, as shown in a recent study that examined virological responses to tenofovir therapy in a large group of chronic hepatitis B patients with very high baseline viral load.
Prior studies have shown that the yearly rate of spontaneous HBeAg clearance in chronic hepatitis B patients ranges from 8 to 12%. In our series, HBeAg loss occurred in 15% of monoinfected and 7% of coinfected patients under an average of 4 years of tenofovir therapy. Clearance of serum HBsAg is the most ambitious objective of HBV therapy, but rarely occurs either spontaneously or as a result of antiviral therapy with nucleos(t)ide analogues. In our series, HBsAg clearance was seen in nine individuals treated with tenofovir (5.1%). Moreover, it is noteworthy that all were coinfected with HIV, which might partially be explained by the longer exposure to tenofovir in this group than in HBV-monoinfected individuals.
In summary, the antiviral efficacy of tenofovir is high and does not differ significantly comparing HIV/HBV-coinfected and HBV-monoinfected patients. Most patients achieve undetectable serum HBV-DNA at week 96 of tenofovir therapy. Baseline serum HBV-DNA is the major determinant of virological response to tenofovir, with no significant influence of HBeAg, drug resistance mutations nor coinfection with hepatitis C or delta viruses.
Discussion
We evaluated retrospectively the virological response to long-term tenofovir therapy in a large group of chronic hepatitis B patients, of whom three-quarters were coinfected with HIV. Compared with HBV-monoinfected individuals, those with coinfection were younger, more often seropositive for hepatitis C or delta virus antibodies, and less frequently infected by HBV genotype D. Around half of patients in both groups were HBeAg positive. More than three-quarters of coinfected patients were homosexual men or former IDUs. Before beginning tenofovir, half of HIV/HBV-coinfected patients and more than two-thirds of HBV-monoinfected individuals had been exposed to other anti-HBV agents, lamivudine being by far the most frequent agent. Finally, most patients in our study received tenofovir along with a second anti-HBV agent, emtricitabine being the most common given its convenient coformulation as a single pill (Truvada).
Despite differences comparing HIV/HBV-coinfected and HBV-monoinfected patients at the time of beginning tenofovir, the proportion of baseline HBV viremic individuals who achieved undetectable serum HBV-DNA at weeks 24, 48 and 96 did not differ significantly comparing HBV-monoinfected and coinfected patients. However, in the subset of HBeAg-positive individuals, HIV coinfection was associated with a slower virological response. Whereas more than 80% of HBeAg+, HBV-monoinfected individuals had undetectable serum HBV-DNA at weeks 24, 48 and 96 of tenofovir therapy, these numbers were lower in HBeAg+ coinfected patients (45, 71 and 81%, respectively).
Multivariate analysis provided a clue on the negative impact of HIV coinfection and positive HBeAg on virological response to tenofovir in the whole chronic hepatitis B population. The amount of serum HBV-DNA was the only significant determinant of treatment response. Patients with positive HBeAg and/or HIV coinfection had the greatest HBV-DNA levels, which most likely explained their longer time to reach undetectability, as recently shown by others.
Despite being present in 30% of viremic HIV/HBV-coinfected patients and in 46% of viremic HBV-monoinfected individuals, there was no recognizable effect of drug resistance mutations on response to tenofovir in our study population. Although lamivudine as the only anti-HBV agent is now considered as suboptimal to treat chronic hepatitis B, this drug as a part of triple antiretroviral regimens has been widely used for many years in HIV/HBV-coinfected patients. As it occurred in our series, a large proportion of these individuals harbour HBV-resistant strains. Apart from lamivudine, other anti-HBV agents, such as adefovir or entecavir, had been used to treat our HBV-monoinfected individuals, which explains the recognition of drug resistance mutations other than those classically associated with lamivudine in our series. Differences in prior pharmacological history and the distinct profile of drug resistance mutations exhibited by HIV/HBV-coinfected and HBV-monoinfected patients did not translate into a different antiviral response to tenofovir in our study. These results are reassuring and support that tenofovir activity against HBV does not seem to be impaired significantly by prior exposure to other anti-HBV agents and/or the presence of drug resistance mutations in HBV. Our findings are in agreement with the results from other studies, some of which further highlighted that adding another anti-HBV agent to tenofovir did not result in greater antiviral responses than prescription of tenofovir alone.
Given that coinfection with hepatitis C or delta viruses is relatively common in chronic hepatitis B patients and complex viral interference phenomena exist between these viruses, we explored whether HBV suppression using tenofovir could be influenced in chronic hepatitis B patients coinfected with other hepatitis viruses. We could not find any evidence for it. However, patients with delta hepatitis had lower median serum HBV-DNA levels than the rest and accordingly should achieve undetectability faster on tenofovir.
All 38 HBV-monoinfected individuals and 85% out of 78 viremic HIV/HBV-coinfected patients achieved undetectable HBV-DNA by week 96 of tenofovir therapy. The trend in HBV-DNA decline in the subset of coinfected individuals still viremic at 4 years of tenofovir therapy suggests that they might eventually also reach complete viral suppression, as shown in a recent study that examined virological responses to tenofovir therapy in a large group of chronic hepatitis B patients with very high baseline viral load.
Prior studies have shown that the yearly rate of spontaneous HBeAg clearance in chronic hepatitis B patients ranges from 8 to 12%. In our series, HBeAg loss occurred in 15% of monoinfected and 7% of coinfected patients under an average of 4 years of tenofovir therapy. Clearance of serum HBsAg is the most ambitious objective of HBV therapy, but rarely occurs either spontaneously or as a result of antiviral therapy with nucleos(t)ide analogues. In our series, HBsAg clearance was seen in nine individuals treated with tenofovir (5.1%). Moreover, it is noteworthy that all were coinfected with HIV, which might partially be explained by the longer exposure to tenofovir in this group than in HBV-monoinfected individuals.
In summary, the antiviral efficacy of tenofovir is high and does not differ significantly comparing HIV/HBV-coinfected and HBV-monoinfected patients. Most patients achieve undetectable serum HBV-DNA at week 96 of tenofovir therapy. Baseline serum HBV-DNA is the major determinant of virological response to tenofovir, with no significant influence of HBeAg, drug resistance mutations nor coinfection with hepatitis C or delta viruses.