Chronic hepatitis B virus (HBV) is a major cause of chronic liver disease and hepatocellular cancer (HCC) worldwide. HBV causes 53% of the worlds' hepatocellular carcinoma, resulting in nearly 330 000 deaths per year . It is widely known that co-infection with HIV and HBV is accompanied by an increased rate of progression to liver cirrhosis, liver cancer and death [2–4]. Liver-related mortality remains the most frequent cause of non-AIDS-related deaths, with low CD4 cell count and active HBV as independent common predictors . When HBV and HIV are treated, HBV co-infection has no impact on response to HAART regarding viral suppression or immune recovery [2,3,6]; however, both immunological surrogate markers and histological improvement are seen with HBV viral suppression. This postpones and/or prevents liver transplant, and also reduces liver-related morbidities and death [7–9]. Patients with HBV/HIV co-infection require both optimum HIV management and HBV viral load suppression. Current European (EASL and EACS) and British (BHIVA) guidelines recommend starting antiretroviral therapy (ART) including tenofovir disoproxil (TDF) with emtricitabine (FTC) or lamivudine (LAM) at CD4 cell count between 350 and 500 cells/μl [10–13].
In HBV mono-infection, accepted regimes include both monotherapy and dual therapy. Currently, despite being widely used, few data exist for combination therapy. However, there are data to support therapy with adefovir and LAM in mono-infected patients following LAM failure, but not as a de-novo combination . In co-infection with HIV, there are conflicting data showing that the addition of LAM (or FTC) to TDF does not appear to improve outcomes in some studies [15,16], but it does in others in which combination HBV therapy is linked to greater HBV DNA suppression in a cohort of LAM-experienced HIV/HBV co-infected individuals .
Entecavir has shown good outcomes regarding HBV viral suppression, resistance and safety profile [18–20] in naive HBV mono-infected patients. Furthermore, entecavir (ETV) has been shown to decrease HIV viral load and cause the appearance of M184V mutations in HIV-positive patients, in case reports [21,22]. Adding ETV to LAM-based ART, which is failing to suppress HBV replication, can be beneficial but associated with a risk of developing ETV resistance , which can occur within 2 months . The combination of TDF and entecavir is included in mono-infected and co-infected guidance [10,12,13]; however, so far, there has been only a small number of studies showing success with ETV and TDF therapy in experienced HBV mono-infected patients [25,26]. This study is the first to assess the efficacy in a series of HIV/HBV co-infected patients.
Aims and methods
The aim of the study is to describe the overall demographics, HBV and HIV viral outcomes and safety in HBV/HIV co-infected patients failing to fully suppress their HBV viral load while on TDF with FTC or LAM, treated with the addition of ETV.
The study was conducted in the Department of Infectious Diseases and Tropical Medicine at North Manchester General Hospital and the Tropical and Infectious Diseases Unit at the Royal Liverpool University Hospital. The units provide care to nearly 3000 HIV-positive patients, 4% of whom are co-infected with HBV.
Patients co-infected with HIV and HBV failing to fully or further suppress their HBV viral load despite a HAART regime with a TDF and LAM/FTC backbone were included in the study. These patients were then commenced on ETV. The timing of this remained with the individual clinician, as no current guidelines exist.
Retrospective and prospective demographic (age, sex, origin), HIV [previous and current antiretroviral, HIV viral load] data and HBV serum marker data were collected using the laboratory database, case notes and other dataset devices. Data collection was carried out between November 2008 and 2009. HIV and HBV quantification were measured using commercially available real-time PCR assays.
Thirteen co-infected patients who had failed to suppress HBV viral load with TDF-based HIV regimes after minimum of 6 months (with exception of one cirrhotic patient) were identified (all were men and eAg positive with 85% white and 15% black African origin). Median age was 45 years (range 28–49), median time from HIV diagnosis 12 years (range 4–18) and median time on antiretroviral drugs for HIV 6.5 years (range 1–17). All of the patients had previous exposure of anti-HBV therapy with LAM (median 72 months, range 9–111, n = 7), TDF (median 15 months, range 9–21, n = 2) or TDF + LAM or FTC combination (median 18 months, range 1–63, n = 13) prior to ETV. Only one patient had preceding treatment with pegylated interferon (Peg IFN) and none received any other drug with anti-HBV activity. (The baseline characteristics are described in Table 1.)
HBV DNA level had not fully suppressed and had stabilized with a less than 1 log fluctuation in seven of 13 (54%) patients while on TDF treatment in the 6 months prior to adding ETV (see Fig. 1).
All patients were receiving a protease inhibitor-anchored HAART regime with TDF and FTC as a part of the nucleoside reverse transcriptase inhibitor (NRTI) backbone. During the study, one patient had the antiretroviral regime changed due to the development of LAM resistance to HIV (zidovudine and abacavir were added to TDF and FTC), ETV and kaletra. One patient was switched from a protease inhibitor to an integrase inhibitor due to intolerance.
Baseline HBV resistance test was performed on 62% of the patients, with one of eight patients having mutations associated with previous LAM monotherapy (rtM240I, rtL180M, rtV173L). The HBV resistance developed, whereas HIV was fully suppressed on a protease inhibitor-based regime with TDF/FTC-containing backbone.
Seven (54%) had undergone previous liver biopsy, three had cirrhosis (Modified Ishak stage score 5–6/6) and the remaining three had minimal fibrosis (Modified Ishak stage score 0–1/6, HAI score 1–5/18).
The median length on treatment with ETV and TDF/FTC was 74 weeks (range 16–159). Thirty-eight percent of patients achieved undetectable HBV DNA level by the end of the study. The ALT levels were within normal range (<35 U/l) in 62% of the patients and reduced from their initial level (median decline −28 U/l, range −152 to 37) in 92%. Median decline in HBV DNA was 2758 IU/ml (range 146–2.8 × 108) and 2.53 log10 IU/ml (range 1.28–7.36) (Table 2).
Figure 1 illustrates HBV DNA levels (log10) from 24 weeks prior to commencement of ETV up to the end of the study period.
No adverse reactions related to ETV were described in any of the patients. No significant change in renal function was observed throughout the study [median estimated glomerular filtration rate (eGFR) (calculated using modification of diet in renal disease [MDRD] formula) prior to and at the end of study was 81 ml/min per 1.73 m2 (range 57–107) and 82 ml/min per 1.73 m2 (55–130), respectively]. However, TDF was stopped in one patient due to TDF-related tubular toxicity (hypophosphataemia, glycose and proteinuria) and decline in eGFR below 60 ml/min per 1.73 m2.
We describe the first series of co-infected HBV patients receiving a combination of TDF and ETV. In-vitro pharmacological studies have suggested that a combination of TDF along with nucleoside analogues including ETV could have an additive anti-HBV effect . Furthermore, no significant pharmacological interaction of TDF and ETV co-administration has yet been reported . Therefore, combination of ETV and TDF could be considered as a potentially important treatment option. Currently, there are only a few reports of ETV in combination with TDF successfully treating mono-infected HBV patients [25,26]. Our study shows that this combination in co-infected patients appears well tolerated and has efficacy, with reductions in HBV DNA and nearly 40% achieving undetectable HBV DNA in just over 1 year. Although it is only a modest reduction, this is a study involving an experienced cohort of patients outside of clinical trials. Larger prospective studies are required to confirm the findings seen in this relatively small cohort.
Current EASL guidelines recommend modifying therapy in partial responders (decreased HBV DNA more than 1 log10 IU/ml but detectable HBV DNA) at 24 weeks in LAM monotherapy or 48 weeks in TDF or ETV therapy in HBV mono-infected patients . This approach has been recently challenged by the 144-week data for TDF in mono-infected patients showing persistent reductions in viral load after 2 years ; however, in this cohort, the viral load appeared to have plateaued with a less than 1 log fluctuation in the previous 6 months in seven of 13 (54%) patients. This, however, does not mean that a further drop would not have occurred without ETV.
HIV/HBV co-infected patients are described as having higher HBV viral loads as well as increased liver damage and mortality [2,4], which could explain the slow and lack of full viral suppression. It also suggests the need for more aggressive treatment aiming to achieve maximal HBV suppression. Data from HBV mono-infected patients show that even low virus levels were linked with liver disease progression and HCC . To date, there have been several studies suggesting early virological response (weeks 4, 12 and 24) to HBV therapy being predictors of treatment success or development of resistance [31–33]. Those studies are mostly from the LAM monotherapy era and little is known about similar predictors with TDF-based therapy in the HIV population. One could postulate that a longer time on nonsuppressive therapy may increase the risk of developing resistance, but clearly drugs such as TDF or entecavir have a much more robust barrier to resistance than LAM. Certainly, the 144-week data for TDF in mono-infected patients have not yet demonstrated any resistance .
Our cohort patients were not able to fully suppress their HBV despite prolonged TDF-based therapy (median 18 months), with a median HBV DNA of 2814 IU/ml in one patient with severe decompensated cirrhosis. All patients had either undetectable HIV viremia at baseline or very low level (all <400 copies/ml) suggesting that compliance was good in the cohort; however, no formal adherence assessments were undertaken. Why TDF was not fully suppressed is not apparent. We did not demonstrate the development of resistance to TDF and further work is clearly required. However, it appears that the addition of ETV to TDF and LAM or FTC improves the degree of HBV suppression in this cohort.
Although ETV resistance in previously treatment-naive patients is robust even after 5 years , when ETV is used in LAM experienced, resistance rates can increase due to overlap in their resistance pathways [34,35]. In our experienced cohort, there has been minimal success in HBV suppression when ETV was used without TDF (data not shown) in keeping with other studies , despite positive results in other study, which might be due to relatively short follow-up . This suggests that it may be the combination and not ETV per se that produces the benefit.
Our study is a novel description of combination therapy outcomes in HIV co-infected patients. However, it is a small number of patients who have received TDF and LAM or FTC combinations for varying periods before commencing ETV. Also, the criteria for introducing ETV were not well defined. Clearly, further larger studies with longer follow-up are urgently required to assess this combination as well as other approaches, including ‘wait and see’, particularly in view of the 144-week data.
More data are also urgently required related to frequency of virological HBV failure in co-infected patients receiving TDF and LAM or FTC combinations and the possible reasons including adherence issues, resistance and others.
Despite these limitations, these data provide encouragement for patients who fail to suppress fully over periods, particularly in relation to tolerance and side-effects as well as viral suppression itself.
It does, however, seem reasonable to suggest that in patients failing to fully suppress their HBV viral load on a TDF and LAM or FTC-based backbone after 12 months or so, the addition of ETV is not unreasonable particularly in those with progressing liver disease who will be at high risk of cirrhosis, hepatocellular cancer, hepatic decompensation and death.
The authors wish to acknowledge Dr E.G.L. Wilkins, Dr A. Bonington, Dr A. Ustianowski, Dr A. Miller, Dr N.J. Beeching and Dr S. Khoo who provided consultant supervision and patient care during the study period.
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