The treatment outcome of chronic HBV infection among HBV/HIV co-infected and HBV mono-infected patients

Abstract

The aim of this study was to analyze the treatment response of hepatitis B virus (HBV) to lamivudine and tenofovir disoproxil fumarate in HBV/HIV co-infected patients in comparison to HBV mono-infected patients. This study was conducted at the University Hospital for Infectious and Tropical Diseases in Belgrade from January 2000 until December 2017 and included all patients with chronic hepatitis B who received antiviral therapy. All patients initially treated with lamivudine were switched to tenofovir if lamivudine failure occurred. A patient was considered to have achieved a full treatment response if the level of HBV DNA was lower than 20 IU/ml or undetectable. HBs and HBe antigen loss and HBs seroconversion were also monitored. After a mean duration of lamivudine-containing antiretroviral therapy (ART) of 4.87 ± 3.48 years and lamivudine mono-therapy of 4 ± 2.52 years, failure was recorded in 82.1% and 79.3% of patients, respectively. HBV viral loads were 20 ± 32 IU/ml and 3 ± 13 IU/ml after 2.49 ± 1.56 years of tenofovir-containing ART and 1.9 ± 1.13 years of tenofovir mono-therapy, respectively. Overall mean treatment duration, taking both lamivudine- and tenofovir-based regimens into account, was 4.18 ± 2.72 and 6.17 ± 3.63 years in the mono- and co-infected patients, respectively (p = 0.02).

Keywords

Human immunodeficiency virus hepatitis B treatment antiviral antiretroviral therapy

Introduction

Moderate prevalence rates (2%–7%) of chronic hepatitis B (CHB) are seen in southern regions of Eastern and Central Europe and are mostly a consequence of percutaneous exposure and risky sexual behaviors. HBV infection is the tenth leading cause of death worldwide with 15%–40% of those chronically infected eventually developing cirrhosis. Moreover, CHB is associated with considerable morbidity and mortality in HIV co-infected patients.^1–5 The prevalence of HBV co-infection among HIV-infected patients in Serbia is estimated at 6%.

A new therapy monitoring tool, quantitative HBV DNA testing became available in Serbia in the early 2000s. Predictably, virologic breakthrough was soon demonstrated in a number of lamivudine-treated patients. European, American and most of the guidelines from other developed regions of the world recommend tenofovir as the first-line nucleotide/nucleoside analogue for the treatment of HBV/HIV co-infected patients since 2008.^6,7 Tenofovir is also recommended as the drug of choice for the treatment of chronic HBV mono-infection.² In Serbia, like in many developing countries, lamivudine-containing antiretroviral therapy (ART) or lamivudine mono-therapy is the only therapy covered by medical insurance for treatment-naïve CHB patients.⁵ Thankfully, since 2010, tenofovir disoproxil fumarate is available in Serbia for patients who failed lamivudine-based therapy. Therefore, lamivudine-containing ART is initiated in all HBV/HIV co-infected patients, with the possibility of switching to a tenofovir-based regimen upon lamivudine failure. Most of the patients who failed lamivudine-containing ART were switched to a regimen with a tenofovir/emtricitabine backbone. CHB among mono-infected patients was treated in much the same manner – tenofovir was initiated only after virologic breakthrough had been proven during lamivudine therapy. In conclusion, all Serbian patients with CHB (irrespective of their CD4 cell count and/or stage of liver fibrosis) have been treated with lamivudine and/or tenofovir mono-therapy or ART regimens containing the aforementioned two drugs. The main goals of antiviral therapy are the normalization of the alanine aminotransferase (ALT) serum activity, achieving suppression of viral replication and HBeAg and HBsAg loss, preferably followed by HBe and HBs seroconversion.

Objectives

The aim of this retrospective cohort study was to analyze HBV treatment (lamivudine and tenofovir-based antiviral regimens) response in HBV/HIV co-infected patients and HBV mono-infected patients.

Materials and methods

This cohort study conducted at the University Hospital for Infectious and Tropical Diseases in Belgrade included HBV mono-infected or HBV/HIV co-infected patients in whom HBV antiviral therapy had been initiated from January 2000 until December 2017. The hospital treats all patients diagnosed with CHB and/or HIV infection in the Belgrade metropolitan area and a part of western Serbia. Patients with HCV co-infection were excluded from the study. HIV was diagnosed using the standard two-tier testing protocol. The WHO staging system for HIV infection was utilized to stratify the co-infected subpopulation.

Diagnosis and treatment of CHB

The diagnosis of CHB was established according to the biochemical and serologic markers of HBV infection, along with the characteristic pathohistological findings on aspiration liver biopsy when available. The aspiration liver biopsy was also performed in order to assess severity of fibrosis and necroinflammatory activity using METAVIR and to exclude other causes of liver injury. In some patients, the liver biopsy was not performed due to the presence of hemangiomas, liver failure accompanied by a dysregulation of the coagulation cascade, or other reasons (e.g. patients’ reluctance to undergo the procedure). All patients were tested for the presence of other causes of liver injury other than HBV infection and only those in who alternative causes of liver injury had been excluded were included in the study. The patients had to remain HBsAg positive and anti-HBs negative at least six months in order to be included in the study. The diagnosis of cirrhosis was established on the basis of histological findings when available or a combination of clinical and laboratory findings.

We used commercial immunoassays, such as HBsAg/Ab, HBeAg/Ab and HBcAb, according to the manufacturers’ protocols. A real-time PCR protocol using pre-designed primers and probes from Applied Biosystems, TaqMan Universal PCR Master Mix (Applied Biosystems) was used to detect and quantify HBV DNA. Plasma HBV DNA levels were determined prior to tenofovir introduction and during the course of lamivudine and tenofovir therapy. Only patients that fulfilled the EASL criteria for treatment valid at the time of CHB diagnosis were started on lamivudine and only they are included in this study. The patient needed to fulfill all of the following criteria (HBV DNA levels were not available):

HBsAg positivity for at least six months.

Elevated ALT levels.

At least A3 or F2 on METAVIR staging.

Exclusion of other causes of liver injury.

All patients with cirrhosis and proven CHB were treated regardless of whether or not they fulfilled the aforementioned criteria. Upon lamivudine failure, tenofovir was started within a month. One patient received tenofovir or tenofovir/emtricitabine from treatment initiation due to underlying immunosuppression.

Therapy response

During treatment, liver function tests were performed every three to four months during the first year and every six months thereafter. The HBsAg and HBeAg status (the latter was evaluated only in patients who were HBeAg positive before therapy initiation) was checked at 6-month intervals and those who cleared HBsAg or HBeAg were tested for the presence of anti-HBs and/or anti-HBe antibodies. Plasma HBV DNA levels were determined at 6–12 months intervals if PCR was available.

We considered a full therapy response to be achieved if the patient had maintained undetectable viremia or a stable plasma HBV DNA level of less than 20 IU HBV DNA/ml. Patients were deemed partial responders if their HBV viral loads were between 20 and 2000 IU HBV DNA/mL at the end of follow-up. Lamivudine failure was defined as a confirmed increase in the HBV DNA level of more than 1 log10 IU/ml compared to the nadir HBV DNA level during therapy or as an elevation in the ALT level with no explanation other than HBV biochemical breakthrough (only when molecular testing was not available in a reasonable timeframe and the elevation was severe enough to merit an immediate switch to tenofovir).

Ethics and statistical analysis

Verbal consent for participation was obtained from all patients, and the study was approved by the Clinical Centre of Serbia Ethics Committee. All humans research procedures followed were in accordance with the standards set forth in the Declaration of Helsinki principles of 1975, as revised in 2008.

All analyses were performed using an electronic database organized in the SPSS (version 11.5) statistical package. Methods of descriptive statistics were utilized to assess the demographic characteristics of the patients. Patients in both subgroups (co-infected and mono-infected) were stratified into those with less than 100,000 IU/mL, and those with a viral load above this value (high viremia). Continuous variables like follow-up times, serum ALT activities, CD4 cell counts, and viral loads were compared using the t-test and the MWU test. Categorical variables were compared using Chi square or Fisher’s exact test, as appropriate. Treatment success over time was compared between the mono-infected and co-infected utilizing the Kaplan–Meier survival method and compared by the log rank test. Predictors of time to full treatment success were analyzed using Cox regression. Logistic regression modeling was used to identify predictors of full treatment success amongst variables such as baseline viral load, HBeAg positivity, HIV infection, gender, age and the presence of cirrhosis. The level of significance was set at 0.05.

Results

Baseline characteristics

The study population included 316 patients, 79 of which were HBV/HIV co-infected. HBV mono-infected subjects were significantly older than the co-infected (49.8 ± 16.5 vs. 40.8 ± 10.7 years, p < 0.01). Both the mono-infected and the co-infected subgroups had a clear male predominance yet this was significantly more pronounced in the co-infected subgroup (96.2% vs. 73.6%, p < 0.01). HBeAg-positive CHB was recorded in 71.4% of the co-infected vs. 32.6% of the mono-infected subjects (p < 0.01). Among the co-infected, 62.2% had AIDS at baseline, 15.1%, had mild symptomatic HIV infection, while the remaining 22.7% had an asymptomatic HIV infection. The median baseline CD4 cell count among the co-infected was 213 CD4 cells/µL (range 3–904 cells/µL). There was no statistically significant difference in the prevalence of cirrhosis between the two groups (13.5% vs. 10.9%, p = 0.56). The mean pre-treatment serum ALT activity was significantly higher among mono-infected than co-infected subjects (192.2 vs. 72.1 IU/L, p < 0.01) (Table 1).

Table 1.

Characteristics of lamivudine- and tenofovir-treated HBV/HIV co-infected and HBV mono-infected patients.

Patients	HBV/HIV (n = 79)	HBV (n = 237)	p
Age, years	40.8 ± 10.7	49.8 ± 16.5	<0.001
>40 years, % (proportion)	41.8% (33/79)	70% (166/237)	<0.001
Male, % (proportion)	96.2% (76/79)	73.6% (175/237)	<0.001
Precore mutants, % (proportion)	28.6% (20/70)	67.1% (155/231)	<0.001
Cirrhosis, % (proportion)	10.9% (7/64)	13.5% (32/237)	0.558
Pre-treatment ALT, IU/L	72.1	192.2	<0.01
Median baseline CD4 cell count, cells/µL (range)	213 (3–904)
Lamivudine treated, % (proportion)	98.7% (78/79)	100% (237/237)	0.4
Duration of lamivudine-based treatment in years, mean ± SD	4.87 ± 3.48	4 ± 2.52	<0.001
Lamivudine failure, % (proportion)	82.1% (64/78)	79.3% (184/232)	0.6
Tenofovir pre-treatment HBV median viral load, IU/mL	199,526	63,096	0.1
Duration of tenofovir treatment in years, mean ± SD	2.49 ± 1.56	1.9 ± 1.13	0.019
End of follow-up HBV viral load, IU/mL	20 ± 32	3 ± 13	<0.001
Undetectable viremia or viral load <20 IU HBV DNA/ml after tenofovir treatment, % (proportion)	52.9% (27/51)	88.6% (39/44)	<0.001
Partial treatment response to tenofovir, % (proportion)	39.4% (13/33)	9.3% (4/43)	0.002
Post-treatment ALT, IU/L	47	42	0.5
End of follow-up HBeAg loss, % (proportion)	43.9% (18/41)	61.7% (42/686)	0.069
End of follow-up HBsAg loss, % (proportion)	27.8% (22/79)	10.8% (25/232)	0.001
End of follow-up HBs seroconversion, % (proportion)	19% (15/79)	5.8% (13/224)	0.001
Overall HBV treatment duration in years, mean ± SD	6.17 ± 3.63	4.18 ± 2.72	<0.001

HIV: human immunodeficiency virus; HBV: hepatitis B virus.

Lamivudine therapy

The mean duration of lamivudine-containing ART was 4.87 ± 3.48 years, while the mono-infected subgroup was on lamivudine for 4 ± 2.52 years which represented a statistically significant difference (p < 0.01). Lamivudine failure was observed in 82.1% and 79.3% among the co-infected and the mono-infected, respectively (p = 0.6). All but 1 of the 14 co-infected and 22 mono-infected subjects with a proven full treatment response to lamivudine achieved HBsAg loss, while 8 co-infected and 8 mono-infected patients developed anti-HBs antibodies. Sixty-six percent of the co-infected patients with a full and sustained therapy response to lamivudine achieved HBeAg loss. Conversely, HBeAg loss was observed in all the mono-infected with a full treatment response to lamivudine.

Patients in whom lamivudine full treatment success was achieved were followed up for a median of 2.5 years (range 0.6–11.5). Mono-infected patients were followed up for a median of 2.08 years (range 0.6–6), while the co-infected were followed up for a median of 6.35 years (range 1–11.5) which was a significant difference (p < 0.01). Lamivudine failure occurred after a median of 4 years (range 0.3–9) in the mono-infected and after a median of 4.5 years (range 0.4–14) in the co-infected (p = 0.47).

Tenofovir treatment

A single patient was treated with tenofovir-containing ART without previously receiving lamivudine therapy. All other patients, mono-infected and co-infected alike, received tenofovir only after lamivudine therapy had failed. The median HBV viral load prior to tenofovir initiation, was similar in the mono-infected and co-infected subgroups (199,526 and 63,096 IU/mL, p = 0.1). Аlso, the prevalence of high viremia was not significantly different between the mono-infected and co-infected. Patients received tenofovir-containing ART a mean of 2.49 ± 1.56 years and tenofovir mono-therapy a mean of 1.9 ± 1.13 years (p = 0.019).

Full therapeutic success after tenofovir therapy was achieved in 88.6% of mono-infected patients and 52.9% of the co-infected. The time to this outcome was a median of 1.5 years (range 0.5–4.4) in the mono-infected and a median of 1.5 years (range 0.5–3) in the co-infected (p = 0.78).

A partial therapeutic response to tenofovir was achieved in an additional 4 mono-infected and 13 co-infected patients meaning that 97.7% of the mono-infected and 76.5% of the co-infected had less than 2000 IU HBV DNA/ml at the end of follow-up. A partial therapeutic response occurred after a median 3.9 years of tenofovir treatment (range 1–7). The virologic response to ART was satisfactory in tenofovir partial responders meaning that treatment adherence was probably good (8 out of the 11 for which data was available were HIV undetectable at end of follow-up amongst HBV partial responders). The HBV viral load was higher among the co-infected compared to the mono-infected at the end of follow-up – 20 ± 32 and 3 ± 13 IU/mL, respectively (<0.001). Three mono-infected and five co-infected patients lost HBsAg, and two of the mono-infected and five co-infected produced anti-HBs antibodies. Ninety percent of the fully successfully-treated mono-infected lost their HBeAg during tenofovir therapy, while 52.4% of the co-infected achieved the same feat.

Overall therapy response

When overall treatment efficacy was analyzed, including those with a full response to lamivudine therapy, the estimated median time to full treatment response was 4 years (0.6–10.4) for the mono-infected and 6.25 years (1–17) for the co-infected subjects (p < 0.001). The median time to a full treatment response for the whole cohort was 4.5 years. With only those in whom lamivudine treatment had failed taken into account, the estimated median time to full treatment response was 5.5 years (0.6–10.4) for the mono-infected and 6.25 years (1.9–17) for the co-infected subjects (p = 0.53). Yet, using Kaplan–Meier curves and the log-rank test, we found significant differences in the times to full treatment response between the mono-infected and the co-infected when considering lamivudine treatment alone, tenofovir treatment alone, and overall treatment in the entire study population and the subpopulation of patients that was unsuccessfully treated with lamivudine (see Figure 1). Cox regression modeling demonstrated that HIV co-infection was the singular significant predictor of overall treatment duration until full-treatment success (see Table 2).

Figure 1.

Kaplan–Meier curves comparing therapy duration amongst the mono- and co-infected (p values are results of the log-rank test).

Table 2.

Cox regression – Predictors of overall full treatment success.

	B	SE	Wald	Sig.	HR	95% CI for HR
	B	SE	Wald	Sig.	HR	Lower	Upper
HIV +	.714	.355	4.039	.044	2.042	1.018	4.095
HBeAg +	.189	.380	.247	.619	1.208	.574	2.541
Female gender	.472	.359	1.728	.189	1.604	.793	3.244
Age	−.014	.011	1.499	.221	.986	.965	1.008
High baseline viremia	.576	.539	1.143	.285	1.779	.619	5.113
Cirrhosis	.363	.283	1.643	.200	1.438	.825	2.505

HIV: human immunodeficiency virus.

As for HBs seroconversion as the ultimate treatment goal, our data showed that this feat was possible only if the HBV DNA became undetectable. HBsAg loss at the end of follow-up was more prevalent among the co-infected compared to the mono-infected (see Table 1). HBs seroconversion was also achieved in a higher proportion of the co-infected compared to the mono-infected (19% vs. 5.8%, p = 0.001). HBeAg loss was more frequently observed amongst the mono-infected (see Table 1)

When logistic regression modeling was implemented, no significant predictors of a full therapy response could be identified aside from age (see Table 3).

Table 3.

Predictors of full treatment success using logistic regression modeling.

	B	S.E.	Wald	Sig.	OR
Baseline viremia (log)	−.248	.150	2.748	.097	.780
Cirrhosis	1.637	1.028	2.535	.111	5.141
Female gender	.874	.701	1.556	.212	2.396
Age	.065	.027	5.672	.017	1.067
HIV +	1.352	.690	3.843	.050	3.865
HBeAg +	.261	.722	.131	.717	1.299
Constant	−3.495	1.913	3.339	.068	.030
Negelkere R² =0.308

OR: odds ratio; HIV: human immunodeficiency virus.

Notably, we did not observe HBV virologic breakthrough among those treated with tenofovir who had achieved a full treatment response. ALT serum activity normalization always followed a full treatment response.

Discussion

Our data show that the median time to a full treatment response for the whole cohort was 4.5 years and longer among HIV co-infected subjects. This interesting observation has not been demonstrated by other researchers. One explanation would be that HBV/HIV co-infected patients experienced HBV virologic breakthrough later than HBV mono-infected ones as was the case in our study. This might be a consequence of any number of factors – patient age, baseline level of liver fibrosis, baseline HBV viral load, the interaction between HBV and HIV, the effect of other antiviral drugs and immune reconstitution associated with HIV treatment. This requires further study.

On the other hand, it is possible that time of follow-up was not long enough to observe lamivudine failure because some of the patients that achieved a full treatment response were referred to regional hospitals for further follow-up. Yet, even if the “successfully lamivudine treated” subpopulation is not taken into account, the duration of treatment to full response was significantly longer amongst the co-infected. The duration of tenofovir-based treatment was similar among the subgroups (mono-infected and co-infected) and virologic breakthrough was not observed in a single patient.

HBeAg positivity was more prevalent among the co-infected compared to the mono-infected (71.4% vs. 32.9%, respectively), which was associated with higher pre-treatment (in the context of tenofovir treatment) viremias (199,526 vs. 63,096, respectively). A similar proportion of HBeAg-positive patients among the HBV/HIV co-infected was also observed by other authors such as the 78.8% reported by Alvarez‐Uria et al.⁸ The authors of the aforementioned study did not report the baseline HBV DNA levels. HBeAg positivity had no significant effects on full treatment success in our study as seen in Table 3. Kosi et al. showed that suppression of HBV replication was not more common among the HBeAg-positive patients compared to HBeAg-negative ones (p = 0.81).⁹

Advanced liver disease was slightly more prevalent in our study population (10.9% in the co-infected and 13.5% in the mono-infected) than in the study published by Alvarez‐Uria et al. (7.1%) possibly reflecting a delay in the diagnosis of HBV infection and/or therapy initiation. The prevalence of cirrhosis was higher among mono-infected patients, which might be an age-related effect, bearing in mind that those co-infected were significantly younger (40.8 ± 10.7 vs. 49.8 ± 16.5; p < 0.01), meaning they had probably been infected with HBV for a shorter period of time.

The median baseline CD4 cell count recorded in our patients (213 cells/µL) was similar to that reported by European (266 cells/µL) and Chinese authors (200 cells/µL).^9,10 Almost two-thirds (62.2%) of the patients in our study had AIDS. Li et al. reported a lower incidence of AIDS in their cohort of HBV/HIV co-infected patients (50.3%) which probably reflects the fact that many of our patients were late presenters.¹¹

Less than a fifth (17.9%) of co-infected patients in our cohort were able to achieve and maintain viral suppression while on lamivudine-based ART which is similar to what Li et al. reported.¹⁰ The median follow-up of co-infected patients in our study was relatively short at 3.17 years (0.3–14), which was probably not long enough for the development of lamivudine resistance to be observed. In addition, pre-treatment HBV viral loads were not determined in our patients, so we speculate that a significant proportion had less than 20,000 IU HBV DNA/mL, which would predispose them for successful lamivudine-based treatment as Thio et al. had demonstrated previously.¹² The EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection as well as Chu et al. presented similar results.^13,14

The proportion of patients with a full treatment response at the end of follow-up was higher among the mono-infected, yet the HBs seroconversion rate was more readily observed amongst the co-infected at 19%. This percentage was higher compared to data published thus far as summarized by EASL.¹⁴ We have no explanation for this phenomenon and further follow-up of our patients may provide some answers.

Tenofovir partial virologic treatment response was more common in our cohort than in those analyzed by other authors such as the data presented in a meta-analysis by Price et al.¹⁵ This could be the consequence of rather strict criteria for full treatment success we had selected, such as HBV DNA levels below 20 IU/mL (close to the limit of detection of modern sensitive PCR tests), while other authors often considered levels lower than 200 IU HBV DNA/mL optimal HBV replication suppression.¹⁶ This was certainly not always the case, because some authors did indeed consider undetectable HBV DNA to be the only marker of a full therapy response.¹⁵ A partial virologic response to tenofovir was more prevalent among co-infected subjects. Since it occurred after a median of 3.95 years of tenofovir treatment, it could be possible that full treatment response according to the criteria we selected is actually “around the corner” and will eventually be achieved. Du Jeong et al.¹⁷ also demonstrated that the vast majority of CHB patients with partial virologic response achieved optimal treatment response through prolonged tenofovir therapy. Furthermore, patients with a partial virologic response in the context of HBV infection did not have any significant recorded failure in the context of the HIV viral load (p = 0.363). Hence, poor adherence is not likely to be the cause of the partial response of the HBV viral load.

Note that our data clearly showed that only undetectable viremia could lead to HBs seroconversion as the most favorable treatment goal, thereby justifying the very strict criteria we selected for a full antiviral therapy response.

A major limitation of our study was the high number of missing data points. A number of patients (mostly with HBV mono-infection) were lost to follow-up due to a decentralized HBV treatment model utilized in Serbia. Financial constraints significantly influenced the quality of the data available to us mostly due to the fact that PCR testing was not always available. Since this study is retrospective, it was difficult to assess possible confounders due to the inherent flaws of this methodological approach.

Conclusion

HIV/HBV co-infected patients could take longer to achieve a full virologic response compared to mono-infected patients in the context of initial lamivudine-based therapy with tenofovir switching if failure occurs. The prevalence of a full treatment response was higher amongst the mono-infected in the time frame in which we observed our patients. Also, a partial virologic response was more common amongst the co-infected. A higher proportion of co-infected patients achieved HBs seroconversion. Only if undetectable viremia is achieved will it be justified to expect seroconversion as the most favorable treatment outcome.

Supplemental Material

STD879843 Supplemental Material - Supplemental material for The treatment outcome of chronic HBV infection among HBV/HIV co-infected and HBV mono-infected patients

Supplemental material, STD879843 Supplemental Material for The treatment outcome of chronic HBV infection among HBV/HIV co-infected and HBV mono-infected patients by Uroš Karić, Ivana Milošević, Ivana Pešić-Pavlović, Dubravka Salemović, Milan Stojković and Djordje Jevtović in International Journal of STD & AIDS

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Ministry of Education and Science of Serbia [grant III 41019 and grant 175024].

References

Kazeil

Peters

MG.

Viral hepatitis in HIV infection. N Engl J Med 2007; 356: 1445–1454.

Deinstg

JL.

Hepatitis B virus infection.

N Engl J Med 2008; 359: 1486–1500.

Sun

Sheng

Tsai

, et al. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: a review. World J Gastroenterol 2014; 20: 14598–14614.

Thio

CL.

Hepatitis B and human immunodeficiency virus coinfection. Hepatology 2009; 49: S138–145.

Khamduang

Gaudy-Graffin

Ngo-Giang-Hong

, 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: e42184.

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, 2011, pp. 111–113.

World Health Organization (WHO). Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Geneva, Switzerland: Author, 2010

Alvarez-Uria

Ratcliffe

Vilar

Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohort. HIV Med 2009; 10: 269–273.

Kosi

Reiberger

Payer

, et al. Five-year on-treatment efficacy of lamivudine-, tenofovir- and tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients. J Viral Hepat 2012; 19: 801–810.

10.

Xie

Han

, et al. Lamivudine Monotherapy-Based cART Is Efficacious for HBV Treatment in HBV/HIV Coinfection When Baseline HBV DNA <20,000 IU/mL. J Acquir Immune Defic Syndr 2016; 72: 39–45.

11.

Matthews

Avihingsanon

Lewin

, et al. A randomized trial of combination hepatitis B therapy in HBV/HIV coinfected antiretroviral naïve individuals in Thailand. Hepatology 2008; 48: 1062–1069.

12.

Thio

Smeaton

Hollabaugh

, et al. Comparison of HBV-active HAART regimens in an HIV-HBV multinational cohort: outcomes through 144 weeks. AIDS 2015; 29: 1173–1182.

13.

Chu

Keeffe

Han

, et al. U.S. HBV epidemiology study group. Prevalence of HBV precore/core promoter variants in the United States. Hepatology 2003; 38: 619–628.

14.

European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67: 370–398.

15.

Price

Dunn

Pillay

, et al. Suppression of HBV by tenofovir in HBV/HIV coinfected patients: a systematic review and meta-analysis. PLoS One 2013; 8: e68152.

16.

Kim

Rodriguez

Van Rompaey

, et al. Factors associated with delayed hepatitis B viral suppression on tenofovir among HBV-HIV coinfected patients in the CNICS cohort. J Acquir Immune Defic Syndr 2014; 66: 96–101.

17.

Du Jeong

Jung

Park

, et al. Clinical course of partial virologic response with prolonged tenofovir therapy in Nuclos(t)ides-naïve patients with chronic hepatitis B. Dig Dis Sci 2017; 62: 2908.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.01 MB