Virological Response to Tenofovir Disoproxil Fumarate in HIV-Positive Patients with Lamivudine-Resistant Hepatitis B Virus Coinfection in an Area Hyperendemic for Hepatitis B Virus Infection

Yu-Shan Huang; Sui-Yuan Chang; Wang-Huei Sheng; Hsin-Yun Sun; Kuan-Yeh Lee; Yu-Chung Chuang; Yi-Ching Su; Wen-Chun Liu; Chien-Ching Hung; Shan-Chwen Chang

doi:10.1371/journal.pone.0169228

Abstract

Background

Sequential addition of tenofovir disoproxil fumarate (TDF) is often needed for patients coinfected with HIV and hepatitis B virus (HBV) who develop HBV resistance to lamivudine after combination antiretroviral therapy (cART) containing only lamivudine for HBV. We aimed to assess the virological response of HBV to add-on TDF in patients coinfected with lamivudine-resistant HBV.

Methods

Between November 2010 and December 2014, 33 HIV/HBV-coinfected patients with lamivudine-resistant HBV and 56 with lamivudine-susceptible HBV were prospectively included. TDF plus lamivudine was used to substitute zidovudine or abacavir plus lamivudine contained in cART in patients with lamivudine-resistant HBV infection, while patients with lamivudine-susceptible HBV infection received TDF plus lamivudine as backbone of cART. Serial determinations of plasma HBV DNA load, HBV serologic markers, and liver and renal functions were performed after initiation of TDF-containing cART.

Results

Of 89 patients included, 38.6% tested positive for HBV envelope antigen (HBeAg) at baseline. The plasma HBV DNA level at enrollment of lamivudine-resistant and lamivudine-susceptible group were 6.1 ± 2.2 log₁₀ and 6.0 ± 2.2 log₁₀ copies/mL, respectively (p = 0.895). The cumulative percentage of HBV viral suppression in lamivudine-resistant and lamivudine-susceptible group was 81.8% and 91.1% at 48 weeks, respectively (p = 0.317), which increased to 86.7% and 96.2% at 96 weeks, respectively (p = 0.185). At 48 weeks, 11 patients testing HBeAg-positive at baseline failed to achieve viral suppression. In multivariate analysis, the only factor associated with failure to achieve viral suppression at 48 weeks was higher HBV DNA load at baseline (odds ratio, per 1-log₁₀ copies/mL increase, 1.861; 95% CI, 1.204–2.878). At 48 weeks, HBeAg seroconversion was observed in 5 patients (1 in the lamivudine-resistant group and 4 in the lamivudine-susceptible group; p = 0.166). During the study period, HBsAg levels decreased over time, regardless of lamivudine resistance. Loss of HBsAg was observed in 3 (3.4%) patients in the lamivudine-susceptible group.

Conclusions

Add-on TDF-containing cART in patients coinfected with lamivudine-resistant HBV achieved a similar rate of HBV viral suppression compared to TDF-containing cART as initial regimen in patients coinfected with lamivudine-susceptible HBV. A higher baseline HBV DNA load and HBeAg positivity were associated with failure to achieve HBV viral suppression.

Citation: Huang Y-S, Chang S-Y, Sheng W-H, Sun H-Y, Lee K-Y, Chuang Y-C, et al. (2016) Virological Response to Tenofovir Disoproxil Fumarate in HIV-Positive Patients with Lamivudine-Resistant Hepatitis B Virus Coinfection in an Area Hyperendemic for Hepatitis B Virus Infection. PLoS ONE 11(12): e0169228. https://doi.org/10.1371/journal.pone.0169228

Editor: Ming-Lung Yu, Kaohsiung Medical University Chung Ho Memorial Hospital, TAIWAN

Received: September 13, 2016; Accepted: December 13, 2016; Published: December 29, 2016

Copyright: © 2016 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The authors received no specific funding for this work.

Competing interests: Hung CC has received research support from Janssen, Merck, and ViiV and speaker honoraria from Abbvie, Bristol-Myers Squibb, Gilead Sciences, and ViiV, and served on advisory boards for Gilead Sciences, Janssen, and Abbvie. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction

Hepatitis B virus (HBV) coinfection is common in HIV-positive patients [1]. In Taiwan, 19.8% of HIV-positive patients have concurrent chronic HBV infection [2], though the prevalence of HBsAg positivity has gradually declined after the implementation of nationwide neonatal HBV vaccination program in 1986 [3]. Individuals with both diseases are at greater risks to develop hepatitis and liver decompensation, and their course of chronic HBV infection is more aggressive than those with HBV mono-infection [4–6]. HBV DNA levels have also been shown to predict overall mortality in HIV/HBV-coinfected patients, especially prior to developing acquired immunodeficiency syndrome (AIDS) [7]. To prevent HBV-related liver damage and late complications, it is essential for patients with HBV infection to achieve durable viral suppression before strategies for functional and durable cure of chronic HBV infection are available [8].

Lamivudine that is contained in combination antiretroviral therapy (cART) for HIV used to be the only active antiviral agent against both HIV and HBV. However, the genetic barrier to development of lamivudine resistance is low, as mutations in tyrosine-methionine-aspartate-aspartate (YMDD) motif of HBV emerge frequently. When HIV/HBV-coinfected patients receive lamivudine as the only active drug for HBV, the resistance rates to lamivudine may reach 40% after 2 years and 90% after 4 years in these patients [9–11]. Sequential addition of another anti-HBV agent is often inevitable for HIV/HBV-coinfected patients who started cART in early days before the availability of other anti-HBV agents with greater activity against both HBV and HIV [1].

Among the antiretroviral agents that are active against HIV and HBV, tenofovir disoproxil fumarate (TDF) has potent antiviral effect on both wild-type and lamivudine-resistant HBV [12–14]. TDF-containing cART may lead to high rates of HBV envelope antigen (HBeAg) seroconversion and suppression of HBV replication compared with HBV monotherapy with lamivudine in HIV/HBV-coinfected patients [15]. In HIV/HBV-coinfected patients failing lamivudine, TDF is frequently used as rescue therapy [16, 17]. A previous study reported the association of prior lamivudine exposure with delayed HBV suppression in HIV/HBV-coinfected patients on TDF treatment [18], but this finding was not confirmed in the meta-analysis [19]. To date, data are still limited regarding the impact of prior lamivudine exposure with emergence of lamivudine resistance on the effectiveness of subsequent TDF/lamivudine- or TDF/emtricitabine-containing cART.

In this study, we aimed to assess the virological responses of HBV to TDF-containing cART in HIV/HBV-coinfected patients who had HBV resistance to lamivudine, and to identify factors associated with failure to achieve HBV viral suppression after 48 weeks of treatment with TDF-containing cART.

Methods

Patient population and study design

This prospective observational study was conducted at the National Taiwan University Hospital (NTUH), a tertiary care center and the largest designated hospital for HIV care in Taiwan. After TDF and TDF/emtricitabine became available in the clinical care in Taiwan in November 2010 and November 2014, respectively, all adult patients with HBV and HIV coinfection who regularly sought HIV care at NTUH between November 2010 and December 2014 were consecutively included and two groups of HIV/HBV-coinfected patients were defined: add-on TDF to replace one nucleoside reverse-transcriptase inhibitor (NRTI) other than lamivudine in patients who had been taking lamivudine-containing cART with emergence of lamivudine-resistant HBV with (lamivudine-resistant group); and initiation of TDF/lamivudine or TDF/emtricitabine-containing cART in patients who were antiretroviral-naïve or who resumed cART after interruption in the absence of HBV resistance to lamivudine (lamivudine-susceptible group). Patients were excluded if they were aged less than 20 years, their plasma HBV DNA levels were less than 1000 copies/mL within 3 months of enrollment, or they had received or were receiving anti-HBV therapy other than lamivudine such as interferon, telbivudine, entecavir or adefovir. After enrollment, all patients switched to or starting TDF-containing (TDF/lamivudine or TDF/emtricitabine) cART were followed for at least 48 weeks to evaluate the virological response of HBV to TDF-containing cART.

We performed on-treatment analysis to estimate the proportion of patients who achieved undetectable plasma HBV DNA load at each time point. Our primary end-point was the proportion of patients who achieved undetectable plasma HBV DNA load at week 48, and the secondary end-point was the proportion of patients who had undetectable plasma HBV DNA load at week 96. The study was approved by the Research Ethics Committee of NTUH (registration number NTUH-201201028RIB). All patients gave written informed consent before enrollment to provide their blood samples and clinical and laboratory data for research.

Data collection and definitions

We used a standardized case record form to collect the information on the patients’ demographics, comorbidity, treatment history of cART, abdominal ultrasonography, and laboratory data. The baseline values of plasma HBV DNA load, resistance mutations of HBV, serologies of HBV and HCV, aminotransferase levels, serum creatinine, serum alpha-fetoprotein, CD4 lymphocyte count, and plasma HIV RNA load were obtained within 3 months before initiation of TDF-containing cART. After starting TDF-containing cART, serial blood samples were collected from patients at weeks 4, 8, 12, 24, 36, and 48 and then every 48 weeks subsequently. Serial determinations were performed for plasma HBV DNA load, HBV serologic markers, alpha-fetoprotein, and liver and renal functions. The numbers of patients with HBeAg seroconversion, loss of HBV surface antigen (HBsAg), and HBsAg seroconversion were documented. The estimated glomerular filtration rate (eGFR) was calculated by the modification of diet in renal disease (MDRD) equation.

Undetectable plasma HBV DNA load was defined as <128 copies/mL. Chronic HBV coinfection was defined as the persistence of HBsAg for >6 months, and hepatitis C coinfection was defined by positive anti-HCV antibody. Hepatitis flare was defined as >5-fold elevation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (upper limit of normal for AST and ALT, 36 and 41 IU/L, respectively); and hyperbilirubinemia as a total bilirubin >2.0 mg/dL without evidence of hemolysis or taking atazanavir-containing cART. We used AST-to-platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis. The APRI was determined as follows: [(AST/upper limit of normal of AST)/platelet count (10⁹/L)] x 100. Parenchymal liver disease or cirrhosis was documented by the presence of coarse echogenicity and irregular liver surface as demonstrated by abdominal ultrasonography.

Laboratory investigations

Determinations of plasma HBV DNA load and HBV serologic markers.

Plasma HBV DNA load was quantified using the Abbott Real Time HBV assay (Abbott Laboratories, Abbott Park, IL, U.S.A) with a lower detection limits of 15 IU/mL after 2.5-fold dilution of serum samples, and the results were stated as 1 IU/mL = 3.41 copies/mL. HBeAg, anti-HBe antibody, HBsAg, anti-HBs antibody, and antibodies to HCV were determined using enzyme immunoassay (Abbott Laboratories, Abbott Park, IL, U.S.A). Quantification of HBsAg levels was determined by ARCHITECT il000 chemiluminescence microparticle immunoassay (Abbott Laboratories, Abbott Park, IL, U.S.A).

HBV genotyping and detection of lamivudine-resistant mutations.

A nested PCR was performed to amplify part of the polymerase gene containing the tyrosine-methionine-aspartate-aspartate (YMDD) motif from patients with detectable HBV DNA. The expected size of PCR product is 1.2kb. The first and second primer pairs used are 1821F (5'-TTT TTC CCC TCT GCC TAA TCA-3')/1825R (5'-AAA AAG TTG CAT GGT GCT GG-3') and 3106F (5'- ACA CTG CCA GCA GCA CCT CCT CC -3')/1088R (5'-AGC CTG CTT AGA TTG TAT ACA TGC-3'). The amplification condition was 35 cycles of 94°C for 30s, 56°C for 30s, 72°C for 2 min, and a final extension at 72°C for 7 min. A 5-μL aliquot of the first round PCR product was used for the second round PCR, whose condition was the same as the first round. Sequencing analysis was performed with an automatic ABI-DNA sequencer (Model 377 A; Applied Biosystems). The HBV genotype was determined by constructing the phylogenetic trees using the neighbor-joining method and the Kimura 2-parameter distance matrix listed in the MEGA (molecular evolutionary genetics analysis) analytical package [20]. The presence of the YMDD mutant (rt pol gene mutations rtM204V plus rtM204I) and/or rtL180M was confirmed by sequencing readout.

Determinations of plasma HIV RNA load CD4 lymphocyte count.

Plasma HIV RNA load was quantified using the Cobas AmpliPrep/Cobas TaqMan HIV-1 test (version 2.0, Roche Molecular Systems, Inc.). CD4 lymphocyte count was determined using flow cytometry (BD FACS Calibur, Becton Dickinson and Coulter Epics XL, Beckman Coulter, CA, USA).

Statistical analysis

Patients’ demographics and basic characteristics were evaluated by descriptive statistics. Categorical variables were compared using chi-square test or Fisher’s exact test. Continuous variables were compared using the Kruskal-Wallis one-way analysis of variance or Mann-Whitney U test. For data from correlated-samples, variables were compared using Wilcoxon signed rank test. A two-tailed p value <0.05 was considered statistically significant. Univariate and multivariate logistic regression model was used to assess factors associated with failure to achieve viral suppression after 48 weeks of TDF-containing cART treatment. Stepwise model selection with Akaike Information Criterion (AIC) was performed, and variables were entered into the model with p value <0.25 as a requirement for acceptance. All statistical analyses were performed using SPSS software version 20.0 (SPSS Inc., Chicago, IL, USA).

Results

Clinical characteristics of patients

During the 4-year study period, a total of 89 HIV/HBV-coinfected patients were included for analysis. Among them, 33 patients had coinfection with lamivudine-resistant HBV, and 56 patients had lamivudine-susceptible HBV. The baseline characteristics of the patients are shown in Table 1. The majority of patients were middle-aged men who have sex with men. Genotype B was the dominate HBV subtype in both groups, followed by genotype C. Patients with lamivudine-resistant HBV had been exposed to cART containing only lamivudine for HBV for an average of 6.5 years before enrollment, and all patients with lamivudine-susceptible HBV were cART-naïve, except one who had interrupted cART (15 months of abacavir/lamivudine plus atazanavir) for 4 years before enrollment.

Download:

Table 1. Clinical characteristics of 89 HIV-positive patients coinfected with lamivudine-resistant or lamivudine-susceptible hepatitis B virus

https://doi.org/10.1371/journal.pone.0169228.t001

While the two groups of patients had similar mean HBV DNA loads (6.1 ± 2.2 vs. 6.0 ± 2.2 log₁₀ copies/mL, p = 0.895) and HBeAg-positive rates (48.5% vs. 32.7% in patients with available data, p = 0.142) at baseline, the two groups differed significantly in many clinical characteristics because the great majority of patients in the lamivudine-susceptible group were antiretroviral-naïve. Compared with patients in the lamivudine-susceptible group, patients in the lamivudine-resistant group had a higher mean age (p = 0.001), HBsAg titer (p<0.001), and CD4 cell count (p<0.001), a lower mean plasma HIV RNA load (p<0.001) and higher proportion of patients with baseline HIV RNA load <200 copies/mL (lamivudine-resistant vs. lamivudine-susceptible, 93.9% vs. 0%). Patients with HBeAg positivity had higher baseline and serial HBV DNA compared with those with HBeAg negativity (S1 Table).

Virological response of HBV to tenofovir-containing antiretroviral therapy

The average follow-up duration of the two groups of patients was 167 weeks. Fig 1 shows the mean changes of plasma HBV DNA load from baseline over time. The mean changes of plasma HBV DNA load from baseline were -2.2, -2.9, -2.8, -3.7, -4.0, -3.8, and -4.0 log₁₀ copies/mL in patients with lamivudine-resistant HBV, and -2.5, -3.4, -3.2, -3.6, -3.9, -3.8, and -3.9 log₁₀ copies/mL in patients with lamivudine-susceptible HBV at weeks 4, 8, 12, 24, 36, 48 and 96, respectively. The mean plasma HBV DNA loads of the two groups were similar at 48 weeks and 96 weeks (p = 0.169 and p = 0.351, respectively) (S2 Table). The cumulative percentage of patients who achieved undetectable plasma HBV viral load (<128 copies/mL) in patients with lamivudine-resistant HBV and those with lamivudine-susceptible HBV was 81.8% (27 of 33 patients) and 91.1% (51 of 56 patients) at 48 weeks, respectively (p = 0.317), which increased to 86.7% (26 of 30 patients) and 96.2% (50 of 52 patients) at 96 weeks, respectively (p = 0.185) (Fig 2). At 48 weeks, 11 patients did not achieve undetectable HBV DNA load. No resistance mutations to TDF were found in these patients, however. The mean CD4 count of all patients was 499 ± 503 cells/μl at week 48 and 521 ± 269 cells/μl at week 96. The mean plasma HIV RNA load of all patients was 1.6 ± 0.3 log₁₀ copies/mL at week 48 and 1.5 ± 0.1 log₁₀ copies/mL at week 96.

Download:

Fig 1. Changes of plasma HBV DNA load in HIV/HBV-coinfected patients with lamivudine-resistant HBV (n = 33) or lamivudine-susceptible HBV (n = 56) who were on tenofovir-containing combination antiretroviral therapy

https://doi.org/10.1371/journal.pone.0169228.g001

Download:

Fig 2. Cumulative percentage of HIV/HBV-coinfected patients with lamivudine-resistant HBV (n = 33) or lamivudine-susceptible HBV (n = 56) who had achieved undetectable HBV DNA (<128 copies/mL) during the follow-up period of tenofovir-containing combination antiretroviral therapy

https://doi.org/10.1371/journal.pone.0169228.g002

The changes of HBsAg levels with time are presented in Fig 3. Declines of mean HBsAg levels were observed in both groups of patients during the first 48 weeks of TDF-containing cART. Compared with patients in the lamivudine-resistant group, patients in the lamivudine-susceptible group had lower HBsAg levels at baseline (p<0.001) and at 48 weeks (p = 0.070), though the difference at week 48 did not reach statistical significance.

Download:

Fig 3. Changes of HBsAg levels in HIV/HBV-coinfected patients with lamivudine-resistant HBV or lamivudine-susceptible HBV on tenofovir-containing combination antiretroviral therapy

https://doi.org/10.1371/journal.pone.0169228.g003

The changes of plasma HBV DNA load and HBsAg levels with treatment with TDF plus emtricitabine or lamivudine in patients with HBeAg positivity and those with HBeAg negativity are shown in S3 Table and S1–S3 Figs.

Loss of HBsAg was observed in 3 (3.4%) patients at 96 weeks (n = 2) and 144 weeks (n = 1), and one of them had HBsAg seroconversion. All of these 3 patients were in the lamivudine-susceptible group. Another one patient in the lamivudine-susceptible group was found to have both positive HBsAg and anti-HBs at 144 weeks. At 48 weeks, HBeAg seroconversion was observed in 1 of 16 (6.3%) patients in the lamivudine-resistant group, and 4 of 16 (25%) patents in the lamivudine-susceptible group (p = 0.166).

Factors associated with failure to achieve viral suppression at 48 weeks

Overall, 78 (87.6%) patients had achieved undetectable HBV DNA load before 48 weeks. All 11 patients who failed to achieve undetectable HBV DNA load at 48 weeks had positive HBeAg at baseline, compared with only 23 (29.9%) in 77 patients that had successful HBV viral suppression (1 patients did not have HBeAg data at baseline). In univariate analysis, the factors associated with failure to achieve viral suppression at 48 weeks were higher HBV DNA and HBsAg levels at baseline (p = 0.004 and p = 0.009, respectively; Table 2). In multivariate analysis, the only independent factor associated with failure to achieve viral suppression at 48 weeks was higher plasma HBV DNA load at baseline (adjusted odds ratio, per 1-log₁₀ copies/mL increase, 1.861; 95% CI, 1.204–2.878; p = 0.005).

Download:

Table 2. Multivariate logistic analysis to identify the factors associated with failure to achieve HBV viral suppression (<128 copies/ mL) after 48 weeks of tenofovir-containing antiretroviral therapy

https://doi.org/10.1371/journal.pone.0169228.t002

Adverse events on TDF-containing treatment and patient outcomes

The mean baseline eGFR of patients with lamivudine-resistant HBV and those with lamivudine-susceptible HBV were 97 ml/min/1.73m² and 110 ml/min/1.73m², respectively, and 98 ml/min/1.73m² and 102 ml/min/1.73m² at week 48, respectively. The serial data of eGFR are shown in S4 Table. During the study period, one patient in the lamivudine-resistant group discontinued TDF because her eGFR decreased from 37 ml/min/1.73m² at baseline to 12 ml/min/1.73m² at week 36. After TDF was discontinued, renal function improved and the patient did not have hepatitis flares until study ended. No other TDF-related severe adverse events were documented. Two patients experienced acute hepatitis resulting from acute HCV infection and trimethoprim/sulfamethoxazole-associated hepatotoxicity, respectively. Seven patients were lost to follow-up after one year, one patient died from lung cancer, and the remaining patients continued their HIV care regularly. With TDF-containing cART, the ALT levels and APRI scores were significantly lower at week 48 (ALT, p<0.001; APRI, p = 0.007) and week 96 (ALT, p = 0.001; APRI, p<0.001) compared with the baseline data (S5 Table).

Discussion

This study demonstrates that virological response of HBV to subsequent add-on TDF to replace one NRTI of current cART in HIV/HBV-coinfected patients with emergence of lamivudine-resistant HBV was similar to that of initiation of TDF-containing cART as the first regimen in patients without lamivudine-resistant HBV. Among HIV/HBV-coinfected patients, the factors associated with failure to achieve HBV viral suppression at 48 weeks were a higher plasma HBV DNA load and HBeAg positivity prior to TDF-containing cART. During study period, HBsAg levels decreased over time, regardless of the presence or absence of lamivudine resistance.

To prevent complications of chronic HBV infection, the current goal of HBV therapy is to achieve sustained suppression of viral replication to the lowest detectable level. In antiretroviral-naïve HIV/HBV-coinfected patients, TDF/lamivudine- or TDF/emtricitabine-based regimens are recommended as first-line cART [21]. Dual therapy with TDF/lamivudine or TDF/emtricitabine against HBV not only prevents the emergence of lamivudine resistance [22], but also suppresses HBV replication more effectively than lamivudine monotherapy [15, 23, 24]. However, studies are limited that explore the activity of add-on TDF on HBV replication in HIV/HBV-coinfected patients who fail previous lamivudine monotherapy for HBV [16, 17, 25, 26], including those with advanced liver disease [27]. In 2006, Schmutz et al. published a 1:2 matched pair analysis comparing the antiviral efficacy of first-line treatment with TDF and lamivudine to sequential TDF after the development of HBV-DNA relapse (>10⁵ copies/mL) while on lamivudine monotherapy [16]. They concluded that the proportions of patients with undetectable plasma HBV DNA load at 12, 48 or 96 weeks and loss of HBeAg and HBsAg were similar between the two study arms. However, not every patient in the study was assessed for lamivudine resistance before switching to add-on TDF. A later study investigating the long-term efficacy of TDF showed no difference of virological response (HBV DNA <20 IU/mL) up to 60 months between HIV/HBV-coinfected patients with or without lamivudine resistance at baseline [28].

In line with those previous reports, we found that similar proportions of patients who achieved undetectable HBV DNA load at 48 weeks and 96 weeks of treatment between the patients with and those without lamivudine-resistant HBV. While more studies of long-term clinical and virological outcomes of the two groups of patients are warranted, the findings support the use of TDF/lamivudine- or TDF/emtricitabine-based therapy in HIV/HBV-coinfected patients who develop lamivudine resistance of HBV. For HIV/HBV-coinfected patients currently on lamivudine monotherapy for HBV with good suppression of HBV replication, whether it is more beneficial to initiate TDF-based cART immediately or to continue lamivudine monotherapy for HBV with careful HBV load monitoring remains uncertain.

In our study, a higher HBV DNA load and HBeAg positivity at baseline were associated with failure to achieve HBV suppression at 48 weeks. These two factors have also been shown to influence time to accomplish virological response in TDF-experienced, HBV mono-infected patients with lamivudine failure [29]. As in the meta-analysis [19], we did not find the association between lamivudine exposure and delayed HBV suppression. Another study from Kosi et al [15] that compared the effect of different anti-HBV regimens contained in cART (lamivudine monotherapy, simultaneous TDF/lamivudine, and lamivudine followed by TDF/lamivudine) revealed no correlation between anti-HBV treatment options and HBV viral suppression. Kosi et al described that HBV genotype non-A, detectable HIV viremia at 1 year, lower CD4 count, and reporting <95% adherence were significant risk factors for HBV virological non-response [15]. Our patients in this study were only infected with HBV genotypes B and C, which were the dominant genotypes among Taiwanese patients [30], and no difference in HBV suppression was found between patients with either genotype. In contrast, plasma HIV RNA load and CD4 count prior to TDF therapy had no impact on HBV viral suppression in our study.

Along with HBV virological suppression, HBeAg seroconversion and HBsAg loss are also important therapeutic goals in HBV treatment. In therapeutic trials of lamivudine- or TDF-containing cART, HBeAg seroconversion rates among HIV/HBV-coinfected patients ranged from 17 to 46% after 2 to 5 years of cART [28, 31–33]. In our study, 5 of 32 (15.6%) patients with available data had HBeAg seroconversion at week 48. Although no statistical significance was demonstrated due the small sample size, a higher HBeAg seroconversion rate was observed in the lamivudine-susceptible group than the lamivudine-resistant group (25% vs. 6.3%, p = 0.166).

HBsAg loss was generally uncommon in HIV/HBV-coinfected patients. An annual HBsAg seroconversion rate of 2.6% in HIV/HBV-coinfected patients has been reported [34]. In our cohort, we found that 3.4% of patients experienced HBsAg loss. The study by Matthews et al demonstrated a higher rate (13%) of HBsAg loss over a median follow-up of 108 weeks [35]. The author suggested that the higher rate of HBsAg loss might result from immune restoration, represented by marked CD4 count elevation and sustained HIV suppression in their study. In HIV/HBV-coinfected populations, studies exploring quantitative HBsAg kinetics were still limited. Declines in quantitative HBsAg had been shown to predict HBsAg seroclearance [32, 36]. Our study demonstrated decreasing trends of quantitative HBsAg up to 96 weeks in response to TDF-containing cART. However, the number of patients with HBsAg loss is too small in our cohort for further investigation into the correlation between HBsAg titer and HBsAg seroclearance.

Our study has several limitations. First, the sample size is small and, therefore, we were not able to demonstrate a statistically significant difference of virological response rates of lamivudine-resistant and lamivudine-susceptible HBV to TDF-containing cART between the two groups. With introduction of TDF for HBV or HIV infection, HIV/HBV-coinfected patients start cART containing TDF/lamivudine or TDF/emtricitabine according to the HIV treatment guidelines [21]; it is therefore that resistance of HBV to lamivudine have become rare for such comparisons to conduct. Second, the study was not a randomized clinical trial and the two groups of patients with significant differences in several baseline characteristics were included in routine clinical care in different time periods when cART has evolved significantly. Third, we did not evaluate the adherence of patients. The failure of HBV viral suppression may result from non-adherence to cART. However, all 11 patients who failed to achieve HBV suppression at 48 weeks in our study had plasma HIV RNA loads ranging from undetectable to 90 copies/mL, suggesting good adherence to cART.

In conclusion, add-on TDF-containing cART in HIV/HBV-coinfected patients with lamivudine-resistant HBV achieved a similar rate of HBV viral suppression compared to initiation of TDF-containing cART in HIV/HBV-coinfected patients with lamivudine-susceptible HBV as the frontline regimen for both HIV and HBV. A higher plasma HBV DNA load and HBeAg positivity at baseline were associated with failure to achieve HBV viral suppression at week 48 of TDF-containing cART. For HIV/HBV-coinfected patients failing lamivudine, TDF combined with lamivudine or emtricitabine could serve as an effective and well-tolerated therapy against HBV.

Supporting Information

S1 Fig. Changes of plasma HBV DNA load in HIV/HBV-coinfected patients with baseline positive HBeAg (n = 34) or negative HBeAg (n = 54) who were on tenofovir-containing antiretroviral therapy.

https://doi.org/10.1371/journal.pone.0169228.s001

(TIF)

S2 Fig. Cumulative percentages of HIV/HBV-coinfected patients with baseline positive HBeAg (n = 34) or negative HBeAg (n = 54) who had achieved undetectable HBV DNA (<128 copies/mL) during the follow-up period of tenofovir-containing antiretroviral therapy.

https://doi.org/10.1371/journal.pone.0169228.s002

(TIF)

S3 Fig. Changes of HBsAg level in HIV/HBV-coinfected patients with baseline positive HBeAg (n = 34) or negative HBeAg (n = 54) who were on tenofovir-containing antiretroviral therapy.

https://doi.org/10.1371/journal.pone.0169228.s003

(TIF)

S1 Table. Clinical characteristics of 88 HIV/HBV-coinfected patients with HBeAg-positive or -negative at baseline.

https://doi.org/10.1371/journal.pone.0169228.s004

(DOC)

S2 Table. Response of HBV to tenofovir-containing combination antiretroviral therapy based on presence of lamivudine-resistance to HBV.

https://doi.org/10.1371/journal.pone.0169228.s005

(DOC)

S3 Table. Response of HBV to tenofovir-containing antiretroviral therapy based on presence of baseline HBeAg positivity.

https://doi.org/10.1371/journal.pone.0169228.s006

(DOC)

S4 Table. Change of estimated glomerular filtration rate (eGFR) under tenofovir-containing combination antiretroviral therapy based on presence of lamivudine-resistance to HBV.

https://doi.org/10.1371/journal.pone.0169228.s007

(DOC)

S5 Table. Changes of alanine aminotransferase, alpha-fetoprotein, and APRI score in response to tenofovir-containing combination antiretroviral therapy based on presence of lamivudine-resistance to HBV.

https://doi.org/10.1371/journal.pone.0169228.s008

(DOC)

Acknowledgments

We would like to thank the patients for participation in this study and Taiwan Centers for Disease Control for the research grant support.

Author Contributions

Conceptualization: YSH KYH CCH.
Data curation: YSH YCS WCL.
Formal analysis: YSH KYH YCC.
Funding acquisition: YSH CCH.
Investigation: SYC YCS WCL.
Methodology: SYC YCC.
Project administration: CCH.
Resources: CCH SCC.
Software: YCC YCS WCL.
Supervision: CCH SCC.
Validation: WHS HYS.
Visualization: YSH.
Writing – original draft: YSH CCH.
Writing – review & editing: YSH CCH.

References

1. Sun HY, Sheng WH, Tsai MS, Lee KY, Chang SY, Hung CC. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: a review. World journal of gastroenterology. 2014;20(40):14598–614. pmid:25356024
- View Article
- PubMed/NCBI
- Google Scholar
2. Sun HY, Ko WC, Tsai JJ, Lee HC, Liu CE, Wong WW, et al. Seroprevalence of chronic hepatitis B virus infection among taiwanese human immunodeficiency virus type 1-positive persons in the era of nationwide hepatitis B vaccination. The American journal of gastroenterology. 2009;104(4):877–84. pmid:19259078
- View Article
- PubMed/NCBI
- Google Scholar
3. Sun HY, Cheng CY, Lee NY, Yang CJ, Liang SH, Tsai MS, et al. Seroprevalence of hepatitis B virus among adults at high risk for HIV transmission two decades after implementation of nationwide hepatitis B virus vaccination program in Taiwan. PloS one. 2014;9(2):e90194. pmid:24587275
- View Article
- PubMed/NCBI
- Google Scholar
4. Thio CL, Seaberg EC, Skolasky R Jr., Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360(9349):1921–6. pmid:12493258
- View Article
- PubMed/NCBI
- Google Scholar
5. Sheng WH, Chen MY, Hsieh SM, Hsiao CF, Wang JT, Hung CC, et al. Impact of chronic hepatitis B virus (HBV) infection on outcomes of patients infected with HIV in an area where HBV infection is hyperendemic. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2004;38(10):1471–7.
- View Article
- Google Scholar
6. van Griensven J, Phirum L, Choun K, Thai S, De Weggheleire A, Lynen L. Hepatitis B and C co-infection among HIV-infected adults while on antiretroviral treatment: long-term survival, CD4 cell count recovery and antiretroviral toxicity in Cambodia. PloS one. 2014;9(2):e88552. pmid:24533106
- View Article
- PubMed/NCBI
- Google Scholar
7. Nikolopoulos GK, Paraskevis D, Psichogiou M, Hatzakis A. HBV-DNA levels predict overall mortality in HIV/HBV coinfected individuals. Journal of medical virology. 2015.
- View Article
- Google Scholar
8. Brahmania M, Feld J, Arif A, Janssen HL. New therapeutic agents for chronic hepatitis B. The Lancet Infectious diseases. 2016;16(2):e10–21. pmid:26795693
- View Article
- PubMed/NCBI
- Google Scholar
9. Wolters LM, Niesters HG, Hansen BE, van der Ende ME, Kroon FP, Richter C, et al. Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with the human immunodeficiency virus in a Dutch cohort. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2002;24(3):173–81.
- View Article
- Google Scholar
10. Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM, et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. Journal of gastroenterology and hepatology. 2004;19(11):1276–82. pmid:15482535
- View Article
- PubMed/NCBI
- Google Scholar
11. Gu L, Han Y, Li Y, Zhu T, Song X, Huang Y, et al. Emergence of Lamivudine-Resistant HBV during Antiretroviral Therapy Including Lamivudine for Patients Coinfected with HIV and HBV in China. PloS one. 2015;10(8):e0134539. pmid:26288093
- View Article
- PubMed/NCBI
- Google Scholar
12. Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2014;146(4):980–8. pmid:24368224
- View Article
- PubMed/NCBI
- Google Scholar
13. Liu Y, Fung S, Gane EJ, Dinh P, Flaherty JF, Svarovskaia ES, et al. Evaluation of HBV DNA decay kinetics in patients containing both rtM204V/I mutant and wild-type HBV subpopulations during tenofovir DF (TDF) monotherapy or combination therapy with emtricitabine (FTC)/TDF. Journal of medical virology. 2014;86(9):1473–81. pmid:24861361
- View Article
- PubMed/NCBI
- Google Scholar
14. Wang HL, Lu X, Yang X, Ning Q. Efficacy of tenofovir-based rescue therapy in patients with lamivudine-resistant hepatitis B virus: A systematic review and meta-analysis. Clinics and research in hepatology and gastroenterology. 2015.
- View Article
- Google Scholar
15. Kosi L, Reiberger T, Payer BA, Grabmeier-Pfistershammer K, Strassl R, Rieger A, et al. Five-year on-treatment efficacy of lamivudine-, tenofovir- and tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients. Journal of viral hepatitis. 2012;19(11):801–10. pmid:23043387
- View Article
- PubMed/NCBI
- Google Scholar
16. Schmutz G, Nelson M, Lutz T, Sheldon J, Bruno R, von Boemmel F, et al. Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection. Aids. 2006;20(15):1951–4. pmid:16988516
- View Article
- PubMed/NCBI
- Google Scholar
17. Plaza Z, Aguilera A, Mena A, Vispo E, Sierra-Enguita R, Tome S, et al. Influence of HIV infection on response to tenofovir in patients with chronic hepatitis B. Aids. 2013;27(14):2219–24. pmid:23669158
- View Article
- PubMed/NCBI
- Google Scholar
18. Kim HN, Rodriguez CV, Van Rompaey S, Eron JJ, Thio CL, Crane HM, et al. Factors associated with delayed hepatitis B viral suppression on tenofovir among patients coinfected with HBV-HIV in the CNICS cohort. Journal of acquired immune deficiency syndromes. 2014;66(1):96–101. pmid:24500175
- View Article
- PubMed/NCBI
- Google Scholar
19. Price H, Dunn D, Pillay D, Bani-Sadr F, de Vries-Sluijs T, Jain MK, et al. Suppression of HBV by tenofovir in HBV/HIV coinfected patients: a systematic review and meta-analysis. PloS one. 2013;8(7):e68152. pmid:23874527
- View Article
- PubMed/NCBI
- Google Scholar
20. Kumar S, Tamura K, Jakobsen IB, Nei M. MEGA2: molecular evolutionary genetics analysis software. Bioinformatics. 2001;17(12):1244–5. pmid:11751241
- View Article
- PubMed/NCBI
- Google Scholar
21. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed September 14, 2016.
22. Hamers RL, Zaaijer HL, Wallis CL, Siwale M, Ive P, Botes ME, et al. HIV-HBV coinfection in Southern Africa and the effect of lamivudine- versus tenofovir-containing cART on HBV outcomes. Journal of acquired immune deficiency syndromes. 2013;64(2):174–82. pmid:23892239
- View Article
- PubMed/NCBI
- Google Scholar
23. Khamduang W, Gaudy-Graffin C, Ngo-Giang-Huong N, Jourdain G, Moreau A, Luekamlung N, et al. Long-term hepatitis B virus (HBV) response to lamivudine-containing highly active antiretroviral therapy in HIV-HBV co-infected patients in Thailand. PloS one. 2012;7(7):e42184. pmid:22860080
- View Article
- PubMed/NCBI
- Google Scholar
24. Matthews GV, Seaberg EC, Avihingsanon A, Bowden S, Dore GJ, Lewin SR, et al. Patterns and causes of suboptimal response to tenofovir-based therapy in individuals coinfected with HIV and hepatitis B virus. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2013;56(9):e87–94.
- View Article
- Google Scholar
25. Nunez M, Perez-Olmeda M, Diaz B, Rios P, Gonzalez-Lahoz J, Soriano V. Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine. Aids. 2002;16(17):2352–4. pmid:12441815
- View Article
- PubMed/NCBI
- Google Scholar
26. Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker-Melman M, Kessels L, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. The Journal of infectious diseases. 2002;186(12):1844–7. pmid:12447773
- View Article
- PubMed/NCBI
- Google Scholar
27. Gutierrez S, Guillemi S, Jahnke N, Montessori V, Harrigan PR, Montaner JS. Tenofovir-based rescue therapy for advanced liver disease in 6 patients coinfected with HIV and hepatitis B virus and receiving lamivudine. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2008;46(3):e28–30.
- View Article
- Google Scholar
28. de Vries-Sluijs TE, Reijnders JG, Hansen BE, Zaaijer HL, Prins JM, Pas SD, et al. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus. Gastroenterology. 2010;139(6):1934–41. pmid:20801123
- View Article
- PubMed/NCBI
- Google Scholar
29. Baran B, Soyer OM, Ormeci AC, Gokturk S, Evirgen S, Bozbey HU, et al. Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-naive patients with chronic hepatitis B. Antimicrobial agents and chemotherapy. 2013;57(4):1790–6. pmid:23380725
- View Article
- PubMed/NCBI
- Google Scholar
30. Sheng WH, Hung CC, Chang SY, Liu CJ, Chen MY, Hsieh SM, et al. Differential clinical and virologic impact of hepatitis B virus genotypes B and C on HIV-coinfected patients receiving lamivudine-containing highly active antiretroviral therapy. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2012;54(4):548–55.
- View Article
- Google Scholar
31. Miailhes P, Trabaud MA, Pradat P, Lebouche B, Chevallier M, Chevallier P, et al. Impact of highly active antiretroviral therapy (HAART) on the natural history of hepatitis B virus (HBV) and HIV coinfection: relationship between prolonged efficacy of HAART and HBV surface and early antigen seroconversion. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2007;45(5):624–32.
- View Article
- Google Scholar
32. Boyd A, Maylin S, Gozlan J, Delaugerre C, Simon F, Girard PM, et al. Use of hepatitis B surface and "e" antigen quantification during extensive treatment with tenofovir in patients co-infected with HIV-HBV. Liver international: official journal of the International Association for the Study of the Liver. 2015;35(3):795–804.
- View Article
- Google Scholar
33. Boyd A, Maylin S, Moh R, Mahjoub N, Gabillard D, Eholie SP, et al. Hepatitis B surface antigen quantification as a predictor of seroclearance during treatment in HIV-hepatitis B virus co-infected patients from Sub-Saharan Africa. Journal of gastroenterology and hepatology. 2015.
- View Article
- Google Scholar
34. Martin-Carbonero L, Teixeira T, Poveda E, Plaza Z, Vispo E, Gonzalez-Lahoz J, et al. Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues. Aids. 2011;25(1):73–9. pmid:21076274
- View Article
- PubMed/NCBI
- Google Scholar
35. Matthews GV, Ali RJ, Avihingsanon A, Amin J, Hammond R, Bowden S, et al. Quantitative HBsAg and HBeAg predict hepatitis B seroconversion after initiation of HAART in HIV-HBV coinfected individuals. PloS one. 2013;8(4):e61297. pmid:23593455
- View Article
- PubMed/NCBI
- Google Scholar
36. Zoutendijk R, Zaaijer HL, de Vries-Sluijs TE, Reijnders JG, Mulder JW, Kroon FP, et al. Hepatitis B surface antigen declines and clearance during long-term tenofovir therapy in patients coinfected with HBV and HIV. The Journal of infectious diseases. 2012;206(6):974–80. pmid:22782950
- View Article
- PubMed/NCBI
- Google Scholar

[ref1] 1. Sun HY, Sheng WH, Tsai MS, Lee KY, Chang SY, Hung CC. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: a review. World journal of gastroenterology. 2014;20(40):14598–614. pmid:25356024
View Article
PubMed/NCBI
Google Scholar

[2] View Article

[3] PubMed/NCBI

[4] Google Scholar

[ref2] 2. Sun HY, Ko WC, Tsai JJ, Lee HC, Liu CE, Wong WW, et al. Seroprevalence of chronic hepatitis B virus infection among taiwanese human immunodeficiency virus type 1-positive persons in the era of nationwide hepatitis B vaccination. The American journal of gastroenterology. 2009;104(4):877–84. pmid:19259078
View Article
PubMed/NCBI
Google Scholar

[6] View Article

[7] PubMed/NCBI

[8] Google Scholar

[ref3] 3. Sun HY, Cheng CY, Lee NY, Yang CJ, Liang SH, Tsai MS, et al. Seroprevalence of hepatitis B virus among adults at high risk for HIV transmission two decades after implementation of nationwide hepatitis B virus vaccination program in Taiwan. PloS one. 2014;9(2):e90194. pmid:24587275
View Article
PubMed/NCBI
Google Scholar

[10] View Article

[11] PubMed/NCBI

[12] Google Scholar

[ref4] 4. Thio CL, Seaberg EC, Skolasky R Jr., Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360(9349):1921–6. pmid:12493258
View Article
PubMed/NCBI
Google Scholar

[14] View Article

[15] PubMed/NCBI

[16] Google Scholar

[ref5] 5. Sheng WH, Chen MY, Hsieh SM, Hsiao CF, Wang JT, Hung CC, et al. Impact of chronic hepatitis B virus (HBV) infection on outcomes of patients infected with HIV in an area where HBV infection is hyperendemic. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2004;38(10):1471–7.
View Article
Google Scholar

[18] View Article

[19] Google Scholar

[ref6] 6. van Griensven J, Phirum L, Choun K, Thai S, De Weggheleire A, Lynen L. Hepatitis B and C co-infection among HIV-infected adults while on antiretroviral treatment: long-term survival, CD4 cell count recovery and antiretroviral toxicity in Cambodia. PloS one. 2014;9(2):e88552. pmid:24533106
View Article
PubMed/NCBI
Google Scholar

[21] View Article

[22] PubMed/NCBI

[23] Google Scholar

[ref7] 7. Nikolopoulos GK, Paraskevis D, Psichogiou M, Hatzakis A. HBV-DNA levels predict overall mortality in HIV/HBV coinfected individuals. Journal of medical virology. 2015.
View Article
Google Scholar

[25] View Article

[26] Google Scholar

[ref8] 8. Brahmania M, Feld J, Arif A, Janssen HL. New therapeutic agents for chronic hepatitis B. The Lancet Infectious diseases. 2016;16(2):e10–21. pmid:26795693
View Article
PubMed/NCBI
Google Scholar

[28] View Article

[29] PubMed/NCBI

[30] Google Scholar

[ref9] 9. Wolters LM, Niesters HG, Hansen BE, van der Ende ME, Kroon FP, Richter C, et al. Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with the human immunodeficiency virus in a Dutch cohort. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2002;24(3):173–81.
View Article
Google Scholar

[32] View Article

[33] Google Scholar

[ref10] 10. Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM, et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. Journal of gastroenterology and hepatology. 2004;19(11):1276–82. pmid:15482535
View Article
PubMed/NCBI
Google Scholar

[35] View Article

[36] PubMed/NCBI

[37] Google Scholar

[ref11] 11. Gu L, Han Y, Li Y, Zhu T, Song X, Huang Y, et al. Emergence of Lamivudine-Resistant HBV during Antiretroviral Therapy Including Lamivudine for Patients Coinfected with HIV and HBV in China. PloS one. 2015;10(8):e0134539. pmid:26288093
View Article
PubMed/NCBI
Google Scholar

[39] View Article

[40] PubMed/NCBI

[41] Google Scholar

[ref12] 12. Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2014;146(4):980–8. pmid:24368224
View Article
PubMed/NCBI
Google Scholar

[43] View Article

[44] PubMed/NCBI

[45] Google Scholar

[ref13] 13. Liu Y, Fung S, Gane EJ, Dinh P, Flaherty JF, Svarovskaia ES, et al. Evaluation of HBV DNA decay kinetics in patients containing both rtM204V/I mutant and wild-type HBV subpopulations during tenofovir DF (TDF) monotherapy or combination therapy with emtricitabine (FTC)/TDF. Journal of medical virology. 2014;86(9):1473–81. pmid:24861361
View Article
PubMed/NCBI
Google Scholar

[47] View Article

[48] PubMed/NCBI

[49] Google Scholar

[ref14] 14. Wang HL, Lu X, Yang X, Ning Q. Efficacy of tenofovir-based rescue therapy in patients with lamivudine-resistant hepatitis B virus: A systematic review and meta-analysis. Clinics and research in hepatology and gastroenterology. 2015.
View Article
Google Scholar

[51] View Article

[52] Google Scholar

[ref15] 15. Kosi L, Reiberger T, Payer BA, Grabmeier-Pfistershammer K, Strassl R, Rieger A, et al. Five-year on-treatment efficacy of lamivudine-, tenofovir- and tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients. Journal of viral hepatitis. 2012;19(11):801–10. pmid:23043387
View Article
PubMed/NCBI
Google Scholar

[54] View Article

[55] PubMed/NCBI

[56] Google Scholar

[ref16] 16. Schmutz G, Nelson M, Lutz T, Sheldon J, Bruno R, von Boemmel F, et al. Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection. Aids. 2006;20(15):1951–4. pmid:16988516
View Article
PubMed/NCBI
Google Scholar

[58] View Article

[59] PubMed/NCBI

[60] Google Scholar

[ref17] 17. Plaza Z, Aguilera A, Mena A, Vispo E, Sierra-Enguita R, Tome S, et al. Influence of HIV infection on response to tenofovir in patients with chronic hepatitis B. Aids. 2013;27(14):2219–24. pmid:23669158
View Article
PubMed/NCBI
Google Scholar

[62] View Article

[63] PubMed/NCBI

[64] Google Scholar

[ref18] 18. Kim HN, Rodriguez CV, Van Rompaey S, Eron JJ, Thio CL, Crane HM, et al. Factors associated with delayed hepatitis B viral suppression on tenofovir among patients coinfected with HBV-HIV in the CNICS cohort. Journal of acquired immune deficiency syndromes. 2014;66(1):96–101. pmid:24500175
View Article
PubMed/NCBI
Google Scholar

[66] View Article

[67] PubMed/NCBI

[68] Google Scholar

[ref19] 19. Price H, Dunn D, Pillay D, Bani-Sadr F, de Vries-Sluijs T, Jain MK, et al. Suppression of HBV by tenofovir in HBV/HIV coinfected patients: a systematic review and meta-analysis. PloS one. 2013;8(7):e68152. pmid:23874527
View Article
PubMed/NCBI
Google Scholar

[70] View Article

[71] PubMed/NCBI

[72] Google Scholar

[ref20] 20. Kumar S, Tamura K, Jakobsen IB, Nei M. MEGA2: molecular evolutionary genetics analysis software. Bioinformatics. 2001;17(12):1244–5. pmid:11751241
View Article
PubMed/NCBI
Google Scholar

[74] View Article

[75] PubMed/NCBI

[76] Google Scholar

[ref21] 21. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed September 14, 2016.

[ref22] 22. Hamers RL, Zaaijer HL, Wallis CL, Siwale M, Ive P, Botes ME, et al. HIV-HBV coinfection in Southern Africa and the effect of lamivudine- versus tenofovir-containing cART on HBV outcomes. Journal of acquired immune deficiency syndromes. 2013;64(2):174–82. pmid:23892239
View Article
PubMed/NCBI
Google Scholar

[79] View Article

[80] PubMed/NCBI

[81] Google Scholar

[ref23] 23. Khamduang W, Gaudy-Graffin C, Ngo-Giang-Huong N, Jourdain G, Moreau A, Luekamlung N, et al. Long-term hepatitis B virus (HBV) response to lamivudine-containing highly active antiretroviral therapy in HIV-HBV co-infected patients in Thailand. PloS one. 2012;7(7):e42184. pmid:22860080
View Article
PubMed/NCBI
Google Scholar

[83] View Article

[84] PubMed/NCBI

[85] Google Scholar

[ref24] 24. Matthews GV, Seaberg EC, Avihingsanon A, Bowden S, Dore GJ, Lewin SR, et al. Patterns and causes of suboptimal response to tenofovir-based therapy in individuals coinfected with HIV and hepatitis B virus. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2013;56(9):e87–94.
View Article
Google Scholar

[87] View Article

[88] Google Scholar

[ref25] 25. Nunez M, Perez-Olmeda M, Diaz B, Rios P, Gonzalez-Lahoz J, Soriano V. Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine. Aids. 2002;16(17):2352–4. pmid:12441815
View Article
PubMed/NCBI
Google Scholar

[90] View Article

[91] PubMed/NCBI

[92] Google Scholar

[ref26] 26. Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker-Melman M, Kessels L, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. The Journal of infectious diseases. 2002;186(12):1844–7. pmid:12447773
View Article
PubMed/NCBI
Google Scholar

[94] View Article

[95] PubMed/NCBI

[96] Google Scholar

[ref27] 27. Gutierrez S, Guillemi S, Jahnke N, Montessori V, Harrigan PR, Montaner JS. Tenofovir-based rescue therapy for advanced liver disease in 6 patients coinfected with HIV and hepatitis B virus and receiving lamivudine. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2008;46(3):e28–30.
View Article
Google Scholar

[98] View Article

[99] Google Scholar

[ref28] 28. de Vries-Sluijs TE, Reijnders JG, Hansen BE, Zaaijer HL, Prins JM, Pas SD, et al. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus. Gastroenterology. 2010;139(6):1934–41. pmid:20801123
View Article
PubMed/NCBI
Google Scholar

[101] View Article

[102] PubMed/NCBI

[103] Google Scholar

[ref29] 29. Baran B, Soyer OM, Ormeci AC, Gokturk S, Evirgen S, Bozbey HU, et al. Efficacy of tenofovir in patients with Lamivudine failure is not different from that in nucleoside/nucleotide analogue-naive patients with chronic hepatitis B. Antimicrobial agents and chemotherapy. 2013;57(4):1790–6. pmid:23380725
View Article
PubMed/NCBI
Google Scholar

[105] View Article

[106] PubMed/NCBI

[107] Google Scholar

[ref30] 30. Sheng WH, Hung CC, Chang SY, Liu CJ, Chen MY, Hsieh SM, et al. Differential clinical and virologic impact of hepatitis B virus genotypes B and C on HIV-coinfected patients receiving lamivudine-containing highly active antiretroviral therapy. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2012;54(4):548–55.
View Article
Google Scholar

[109] View Article

[110] Google Scholar

[ref31] 31. Miailhes P, Trabaud MA, Pradat P, Lebouche B, Chevallier M, Chevallier P, et al. Impact of highly active antiretroviral therapy (HAART) on the natural history of hepatitis B virus (HBV) and HIV coinfection: relationship between prolonged efficacy of HAART and HBV surface and early antigen seroconversion. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2007;45(5):624–32.
View Article
Google Scholar

[112] View Article

[113] Google Scholar

[ref32] 32. Boyd A, Maylin S, Gozlan J, Delaugerre C, Simon F, Girard PM, et al. Use of hepatitis B surface and "e" antigen quantification during extensive treatment with tenofovir in patients co-infected with HIV-HBV. Liver international: official journal of the International Association for the Study of the Liver. 2015;35(3):795–804.
View Article
Google Scholar

[115] View Article

[116] Google Scholar

[ref33] 33. Boyd A, Maylin S, Moh R, Mahjoub N, Gabillard D, Eholie SP, et al. Hepatitis B surface antigen quantification as a predictor of seroclearance during treatment in HIV-hepatitis B virus co-infected patients from Sub-Saharan Africa. Journal of gastroenterology and hepatology. 2015.
View Article
Google Scholar

[118] View Article

[119] Google Scholar

[ref34] 34. Martin-Carbonero L, Teixeira T, Poveda E, Plaza Z, Vispo E, Gonzalez-Lahoz J, et al. Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues. Aids. 2011;25(1):73–9. pmid:21076274
View Article
PubMed/NCBI
Google Scholar

[121] View Article

[122] PubMed/NCBI

[123] Google Scholar

[ref35] 35. Matthews GV, Ali RJ, Avihingsanon A, Amin J, Hammond R, Bowden S, et al. Quantitative HBsAg and HBeAg predict hepatitis B seroconversion after initiation of HAART in HIV-HBV coinfected individuals. PloS one. 2013;8(4):e61297. pmid:23593455
View Article
PubMed/NCBI
Google Scholar

[125] View Article

[126] PubMed/NCBI

[127] Google Scholar

[ref36] 36. Zoutendijk R, Zaaijer HL, de Vries-Sluijs TE, Reijnders JG, Mulder JW, Kroon FP, et al. Hepatitis B surface antigen declines and clearance during long-term tenofovir therapy in patients coinfected with HBV and HIV. The Journal of infectious diseases. 2012;206(6):974–80. pmid:22782950
View Article
PubMed/NCBI
Google Scholar

[129] View Article

[130] PubMed/NCBI

[131] Google Scholar

Figures

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Patient population and study design

Data collection and definitions

Laboratory investigations

Determinations of plasma HBV DNA load and HBV serologic markers.

HBV genotyping and detection of lamivudine-resistant mutations.

Determinations of plasma HIV RNA load CD4 lymphocyte count.

Statistical analysis

Results

Clinical characteristics of patients

Virological response of HBV to tenofovir-containing antiretroviral therapy

Factors associated with failure to achieve viral suppression at 48 weeks

Adverse events on TDF-containing treatment and patient outcomes

Discussion

Supporting Information

S1 Fig. Changes of plasma HBV DNA load in HIV/HBV-coinfected patients with baseline positive HBeAg (n = 34) or negative HBeAg (n = 54) who were on tenofovir-containing antiretroviral therapy.

S2 Fig. Cumulative percentages of HIV/HBV-coinfected patients with baseline positive HBeAg (n = 34) or negative HBeAg (n = 54) who had achieved undetectable HBV DNA (<128 copies/mL) during the follow-up period of tenofovir-containing antiretroviral therapy.

S3 Fig. Changes of HBsAg level in HIV/HBV-coinfected patients with baseline positive HBeAg (n = 34) or negative HBeAg (n = 54) who were on tenofovir-containing antiretroviral therapy.

S1 Table. Clinical characteristics of 88 HIV/HBV-coinfected patients with HBeAg-positive or -negative at baseline.

S2 Table. Response of HBV to tenofovir-containing combination antiretroviral therapy based on presence of lamivudine-resistance to HBV.

S3 Table. Response of HBV to tenofovir-containing antiretroviral therapy based on presence of baseline HBeAg positivity.

S4 Table. Change of estimated glomerular filtration rate (eGFR) under tenofovir-containing combination antiretroviral therapy based on presence of lamivudine-resistance to HBV.

S5 Table. Changes of alanine aminotransferase, alpha-fetoprotein, and APRI score in response to tenofovir-containing combination antiretroviral therapy based on presence of lamivudine-resistance to HBV.

Acknowledgments

Author Contributions

References