Although human immunodeficiency virus (HIV) and hepatitis B virus (HBV) share the same transmission routes, coinfection is common, especially in areas where both diseases are prevalent. A recent retrospective multicenter study in China discovered that chronic HBV coinfection occurs in 12% of HIV-infected Chinese patients.1 Tenofovir (TDF)+lamivudine (3TC) or TDF+emtricitabine (FTC)-based combination antiretroviral therapy (cART) is recommended for treatment of HIV/HBV coinfected patients2 because they are both highly active against HIV and HBV viral replication. In addition, TDF is efficacious against 3TC-resistant HBV in HBV monoinfection.3 Despite this, TDF remains unavailable or expensive in some resource-limited areas; thus 3TC-based cART for HBV coinfection is given. Unfortunately, 3TC monotherapy has lower potency and genetic barrier to resistance, with around 20%–25% mutation rate per year in HIV/HBV coinfected subjects4; however, most of the subjects from whom resistance rate data come have high levels of HBV DNA before cART and resistance to 3TC does not usually develop when baseline HBV DNA levels are low. In a recent study from Côte d'Ivoire with treatment-naïve HIV/HBV coinfected subjects, those with high-level persistent HBV viremia and/or 3TC-associated HBV Pol mutations had high baseline HBV DNA levels (>6 log IU/mL).5 In most studies from developing countries,6,7 including our previous report,8 a majority of HIV/HBV coinfected subjects had baseline HBV DNA <20,000 IU/mL, which is the treatment threshold for HBV mono-infection.9 It is unknown whether 3TC-based cART has similar efficacy against HBV in comparison with TDF+3TC-based cART in people with this low level of HBV DNA.
Before 2012, 3TC-based cART (zidovudine or stavudine plus 3TC as backbone) was the first-line treatment for all HIV-infected treatment-naive patients in China,10,11 including those with HIV/HBV coinfection. Since 2012, all newly treated HIV patients, including HIV/HBV coinfected patients, receive a TDF+3TC-based cART regimen. Thus, China is an ideal place to compare HBV outcomes between those who receive 3TC-based or TDF+3TC-based cART to determine whether 3TC-based cART is efficacious with low baseline HBV DNA.
SUBJECTS AND METHODS
The subjects in this study were previously enrolled in one of the following 4 multicenter HIV cohorts in China: (1) 10th five-year (10-5) cohort (recruited between 2005 and 2007, reported in12); (2) 11th five-year (11-5) cohort (recruited between 2008 and 2010, reported in8); (3) 12th five-year cohort 4 (12-5-4, recruited between 2012 and 2014); (4) 12th five-year (12-5) cohort 6 (12-5-6, recruited between 2012 and 2014); (5) outpatient clinics (OP, recruited between 2012 and 2014) (Fig. 1). The Institutional Review Board of Peking Union Medical College Hospital (PUMCH) approved the parent studies and each participant provided written informed consent. Inclusion criteria for the HIV cohorts were described previously,8,12 including: (1) CD4 cell count lower than 350 cells per microliter in 10th five-year cohort and 11th five-year cohort, CD4 cells lower than 500 cells per microliter in 12th five-year cohort and outpatient clinics (CD4 >500 cells per microliter can still be enrolled as long as adherence can be guaranteed in 12th five-year cohort 6 and outpatient clinic); (2) alanine transaminase (ALT) and aspartate aminotransferase (AST) lower than 3 times upper limit of normal (ULN, which is 40 IU/mL for both ALT and AST); (3) not pregnant. Enrollment criteria relevant to this study included: (1) HBV surface antigen positivity at baseline; (2) uninfected with hepatitis C virus (HCV) (anti-HCV negative or anti-HCV positive with negative HCV RNA); (3) no previous history of cART or anti-HBV treatment. All subjects from cohorts 10-5 and 11-5 received 3TC-based HBV-active cART (zidovudine or stavudine or didanosine plus 3TC plus nevirapine), whereas those from 12-5-4 received TDF+3TC-based HBV-active cART (TDF plus 3TC plus efavirenz or lopinavir/ritonavir). Subjects from cohorts 12-5-6 and OP received either 3TC-based or TDF+3TC-based HBV-active cART, which was determined by the standard of care at the time and locations they were enrolled. Thus, subjects from these cohorts contributed to both treatment arms.
Subjects visited local medical centers for clinical evaluation and blood collection before cART and at the following weeks after cART initiation: 4, 8, 12, and then every 12 weeks. In this study, we retrieved clinical data before cART (within 2 weeks of cART initiation), at week 24, and at week 48.
Primary and Secondary Endpoints
The primary endpoint of this study was HBV DNA suppression (<20 IU/mL, the lower limit of detection) at week 48. Secondary endpoints included HBV DNA suppression at week 24, median HBV DNA at weeks 24 and 48, quantification of HBV surface antigen decline, HBV e antigen (HBeAg) loss and seroconversion, and HBsAg loss and seroconversion.
Clinical and Laboratory Data
At each visit, HIV RNA (COBAS Ampliprep/TaqMan48 real-time RT-PCR; Roche Diagnostics, Indianapolis, IN), CD4 cell count (flow cytometry; Beckman-Coulter, Brea, CA), ALT, and AST were measured (reported in our previous study8).
HBV DNA Measurement and HBsAg Quantification
HBV DNA levels were measured using COBAS Ampliprep/TaqMan48 real-time PCR Test (Roche Diagnostics) with a detection range of 20–110,000,000 IU/mL. Quantification of HBV surface antigen (qHBsAg) may reflect HBV reservoir size13 and is associated with treatment response14; therefore, we assessed qHBsAg using the Abbott Architect i2000 platform (Abbott Diagnostics, Abbott Park, IL). This assay was performed according to the manufacturer's instructions, with a detection range of 0.05–124,925 IU/mL. HBV DNA, qHBsAg, and HBeAg were measured from frozen stored (−80°C) plasma samples.
Continuous variables were summarized with median and interquartile ranges (IQR) and analyzed by the Kruskal–Wallis test. Categorical variables were analyzed by χ2 test or Fisher exact test. To determine whether TDF+3TC is superior to 3TC-based regimen at lower HBV DNA levels, we stratified statistical analyses by baseline HBV DNA (<20,000 vs. ≥20,000 IU/mL), a level chosen based on prior studies.15 Relative risks (RR) of factors associated with HBV DNA suppression (HBV DNA <20 IU/mL) were determined by Poisson regression with a robust error variance.16 Sex (male and female), age (categorical, 18–30, 31–40, 41–50, and 51–65 years), routes of transmission [men who have sex with men (MSM), heterosexual, blood and others/unknown], cART regimens (3TC-based or TDF+3TC-based), baseline HBV DNA (continuous), and baseline CD4 cell count (≤200 or >200 cells per microliter) were forced into the multivariate models; other factors with P values <0.15 in univariate models were also adjusted for in the multivariate models. Mann–Whitney U test was used to determine whether difference of qHBsAg between the baseline and 48 week value was significant. Stata 13 (StataCorp, College Station, TX) was used for all analyses. P values < 0.05 were considered statistically significant.
This study included 151 HIV/HBV coinfected subjects, of whom 60 received 3TC-based regimens (3TC group) and 91 subjects received TDF+3TC-based regimens (TDF group). Of these subjects, 48 were from cohort 11-5, 6 were from cohort 10-5, 45 were from 12-5 cohort 4, 40 were from 12-5 cohort 6, and 12 were from outpatient cohort. Most of patients were male, 30–40 years old, and infected via sexual transmission (Table 1). Median CD4 cell count was 150 cells per microliter in the 3TC group and 229 cells per microliter in the TDF group (P < 0.001), whereas HIV RNA, HBV DNA, and qHBsAg were comparable in these 2 groups (Table 1). Notably, 23 patients (15.2%) had undetectable HBV DNA before cART, whereas 69 patients (45.7%) had baseline HBV DNA ≥20,000 IU/mL; these participants were equally distributed between the 2 treatment groups. Thirty-nine patients (25.8%) were HBeAg positive.
Participants with HBV DNA ≥20,000 IU/mL had marginally lower median CD4 cell count (175 vs. 211 cells per microliter, ≥ vs. <20,000 IU/mL, respectively P = 0.067), higher median HIV RNA (4.76 vs. 4.58 log copies per milliliter, P = 0.030), higher median qHBsAg levels (4.04 vs. 2.88 log IU/mL, P < 0.001), and a higher proportion of HBeAg positivity (55.1% vs. 1.2%, P < 0.001). Of the HBeAg-positive participants, 97.4% had HBV DNA ≥20,000 IU/mL compared with 27.7% of the HBeAg-negative participants (P < 0.001).
HBV DNA Response
The primary endpoint, HBV DNA suppression to <20 IU/mL after 48 weeks of cART, was achieved in 78.8% of subjects overall, but it was higher in the TDF than the 3TC group (86.8% vs. 66.7%, P = 0.003). When baseline HBV DNA was <20,000 IU/mL, both the TDF and 3TC groups had similar HBV DNA suppression rates at week 48 (Fig. 2B) even after excluding subjects with undetectable HBV DNA at baseline (95.2% and 97.4% in the 3TC and TDF groups, respectively, P = 0.66). However, when baseline HBV DNA was ≥20,000 IU/mL, the TDF group was associated with higher viral suppression at week 48 (Fig. 2A). HBV DNA suppression for the secondary endpoint of 24 weeks was similar (Figs. 2A, B).
Similarly, analysis of median HBV DNA demonstrated that when baseline HBV DNA was <20,000 IU/mL, the median value was <20 IU/mL at weeks 24 and 48 in both the 3TC and TDF groups. However, when baseline HBV DNA was ≥20,000 IU/mL, median HBV DNA in TDF group was <20 IU/mL (IQR <20 IU/mL to 1.87 log IU/mL) at week 48, whereas the median HBV DNA was 3.26 log IU/mL (IQR <20 IU/mL to 4.51 log IU/mL, P < 0.001) in the 3TC group.
We also evaluated the association between HBeAg and HBV DNA suppression (see Figure S1, Supplemental Digital Content, http://links.lww.com/QAI/A782). In HBeAg-negative participants, the HBV DNA suppression rates were >90% at 48 weeks in both the 3TC and TDF groups (P = 0.20). In contrast, in HBeAg-positive participants, the 3TC group was less likely to achieve HBV DNA suppression than the TDF group (11.1% vs. 52.4%, respectively, P = 0.006).
Factors associated with HBV DNA suppression at 48 weeks of HBV-active cART were determined with regression models stratified by baseline HBV DNA (Table 2). In univariate models, TDF use and lower baseline HBV DNA were the only variables significantly associated with HBV DNA suppression when baseline HBV DNA ≥ 20,000 IU/mL (Table 2). In multivariate models, neither TDF use nor baseline HBV DNA levels were significantly associated with HBV DNA suppression in subjects with baseline HBV DNA <20,000 IU/mL. However, in subjects with baseline HBV DNA ≥20,000 IU/mL, TDF use was associated with HBV DNA suppression [adjusted RR (aRR) 1.98, 95% confidence interval (CI) 1.18–3.34, P = 0.010] as was lower baseline HBV DNA (aRR 0.74 per 1 log IU/mL increase, 95% CI 0.63–0.87, P < 0.001). Interestingly, higher baseline CD4 cell count was associated with poorer HBV DNA suppression (aRR 0.66 for CD4 cell count >200 cells per microliter compared with ≤200 cells per microliter, 95% CI 0.46–0.96, P = 0.028). When baseline HBeAg status or qHBsAg was included in the multivariable model in place of HBV DNA, both were associated with HBV DNA suppression only when baseline HBV DNA is ≥20,000 IU/mL (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A782). In particular, being HBeAg positive at baseline was associated with a 62% decreased likelihood for suppression (aRR 0.38, 95% CI: 0.23 to 0.63, P < 0.001). Higher baseline qHBsAg was also associated with decreased likelihood for suppression (aRR 0.49 per log IU/mL increase in qHBsAg, 95% CI: 0.37 to 0.66, P < 0.001).
We also performed a multivariable analysis stratified by HBeAg status (see Table S2, Supplemental Digital Content, http://links.lww.com/QAI/A782) and found that TDF+3TC was associated with better HBV DNA suppression only in HBeAg-positive group (aRR 10.07, 95% CI: 2.30 to 44.22, P = 0.002), but not in HBeAg-negative group (aRR for TDF use 1.08, 95% CI: 0.97 to 1.21, P = 0.16).
Changes in qHBsAg
Median qHBsAg before therapy was 3.49 (IQR 2.76–4.13, n = 151) and was 3.24 (IQR 2.24–3.74, n = 137) after 48 weeks of cART (P = 0.015). Overall, the median decrease of qHBsAg was 0.11 log IU/mL (IQR −0.029 to 0.40). The median decrease of qHBsAg was 0.086 log IU/mL (IQR −0.040 to 0.52 log IU/mL, n = 47) in 3TC group and 0.12 log IU/mL (IQR −0.015 to 0.37 log IU/mL, n = 90) in TDF group (P = 0.92). When stratified by baseline HBV DNA levels, subjects in 3TC and TDF groups had comparable qHBsAg decline in both strata (data not shown).
HBeAg and HBsAg Antigen Loss/Seroconversion
Thirty-five HBeAg-positive subjects had HBV serology data at week 48, of whom 10 (28.6%) had HBeAg loss and seroconversion. In the 3TC group, 1/14 (7.1%) of subjects had HBeAg seroconversion, whereas 9/21 (42.9%) of subjects in TDF group had HBeAg seroconversion (P = 0.028).
Of the 137 participants who had HBsAg obtained at week 48, 5 experienced HBsAg loss (2 from 3TC group and 3 from TDF group) of whom 4 developed hepatitis B surface antibody. The 2 treatment groups had comparable rates of HBsAg loss and seroconversion.
HIV RNA Suppression
After 48 weeks of cART, HIV RNA <400 copies per milliliter was achieved in 96.7% and HIV RNA <50 copies per milliliter was achieved in 86.1%. TDF and 3TC groups did not differ in HIV suppression rates (P = 0.39 and P = 0.52, at HIV RNA <400 copies per milliliter and <50 copies per milliliter, respectively).
This is the largest multicenter cohort study to compare the efficacy of 3TC-based versus TDF+3TC-based cART against HBV infection in subjects with HIV/HBV coinfection stratified by baseline HBV DNA level. Because most HBV treatment guidelines use 20,000 IU/mL as a cutoff for treatment, there are limited data available on the response to 3TC monotherapy in those with low pretreatment HBV DNA. We demonstrated that in HIV/HBV coinfected participants with baseline HBV DNA levels <20,000 IU/mL, 3TC-based and TDF+3TC-based cART regimens had comparable efficacy for HBV treatment at 48 weeks, whereas in those with HBV DNA levels ≥20,000 IU/mL at baseline, TDF+3TC was more efficacious. These data are most applicable to resource-limited countries where TDF may not be universally available or affordable. They are also important for patients who cannot use TDF because of its nephrotoxicity.
At baseline, we found that over 50% of HIV/HBV coinfected subjects had HBV DNA <20,000 IU/mL, the treatment threshold for HBV infection.9,17 This finding is similar to other studies in developing countries where 30%–50% had baseline HBV DNA <20,000 IU/mL.6,15,18 It is in these people with HBV DNA <20,000 IU/mL that our study demonstrates >95% HBV suppression rates for 48 weeks in both the 3TC and the TDF+3TC HIV/HBV coinfected groups. This is compared with other HIV/HBV coinfection studies, which did not stratify by baseline HBV DNA, that have shown approximately 30%–60% achieving HBV DNA suppression with 3TC monotherapy at 48 weeks.19–21 A recent study from China with a small number of HIV/HBV coinfected subjects demonstrated that 3TC monotherapy was associated with higher rates of 3TC-resistant HBV compared with TDF+3TC,22 but in this study, the authors did not stratify their analyses with baseline HBV DNA levels. Our multivariable analysis demonstrates that TDF is associated with HBV DNA suppression when HBV DNA ≥20,000 IU/mL (Table 2) or when HBeAg is negative (see Table S2, Supplemental Digital Content, http://links.lww.com/QAI/A782) at baseline. In a recent multicenter study, Thio et al15 reported that in subjects with baseline HBV DNA <20,000 IU/mL, monotherapy (3TC or FTC) and dual therapy (TDF+3TC or FTC) had similar efficacy in terms of HBV DNA suppression during 144 weeks of follow-up. Taken together, these studies suggest that 3TC-based monotherapy might be considered in patients with HBV DNA <20,000 IU/mL or HBeAg negative when TDF cannot be safely used or accessed. Since not all countries are able to determine HBV DNA levels, HBeAg status can also be used as a surrogate marker for HBV DNA level and a predictor of response to HBV-active cART, since we found that HBeAg-negative patients had a similarly high response to either TDF+3TC-based or 3TC-based cART. However, HBeAg-positive subjects responded better to TDF+3TC.
In the multivariate analyses stratified by baseline HBV DNA, higher baseline HBV DNA was associated with lower HBV DNA suppression only when baseline HBV DNA was ≥20,000 IU/mL, which further supports that the precise level below 20,000 does not alter the response to treatment. HBeAg-positive status was also a strong independent predictor for HBV DNA suppression. This finding together with the fact that 97% of the HBeAg-positive participants and only 28% of the HBeAg-negative participants had high HBV DNA supports the use of HBeAg testing to determine who is most likely to have a HBV DNA level that would require TDF+3TC-based cART.
As has been shown in HBV mono-infected subjects, the HBsAg seroconversion rate and the decrease in qHBsAg are small regardless of treatment group. In HBV mono-infected subjects treated with ETV, the qHBsAg decline rate was 0.084 log IU/mL per year.23 Another study from France with HIV/HBV coinfected subjects reported that only 39% of subjects had constant decline in qHBsAg when they received TDF-based cART.24
The strengths of our study are the following: first, it is the first multicenter longitudinal study to compare the efficacy of 3TC-based and TDF+3 TC-based cART in HIV/HBV coinfected patients from a resource-limited setting designed to examine HBV treatment responses stratified by high and low baseline HBV DNA levels. Second, in addition to HBV DNA, we also stratified our findings by HBeAg status because HBV DNA requires more specialized equipment; thus, it cannot be obtained in all settings. Third, we determined whether decline in HBsAg levels differed by treatment group or by HBV DNA level.
One limitation to our study is that subjects from the 2 treatment groups were selected from cohorts established in different years; despite this, their baseline characteristics were well-balanced, except for CD4 cell count, which we adjusted for in the models. A second limitation is that the data to date are from 1 year; longer follow-up is warranted to evaluate HBV resistance and changes in qHBsAg in both treatment groups. Third, subjects with liver enzymes >3xULN were excluded from the parent HIV cohorts; therefore, it would be difficult to generalize this result to subjects who have high baseline ALT/AST.
In conclusion, HIV/HBV coinfected subjects with higher baseline HBV DNA (≥20,000 IU/mL) or HBeAg positivity should receive TDF+3TC-based cART because it is associated with higher HBV DNA suppression rates. However, in coinfected subjects with lower HBV DNA levels or HBeAg negative, 3TC-based cART could be considered whether TDF is not readily available or affordable or is contraindicated. Further studies are warranted to determine whether this stratification strategy can also be extrapolated to HBV mono-infected patients.
The authors thank our HIV/HBV coinfected subjects for their participation. They also thank Doctor Shaoxia Xu from Department of Clinical Laboratory of Peking Union Medical College Hospital for his assistance with qHBsAg assays. The following clinical institutions or hospitals participated in this study: Northeastern centers included Peking Union Medical College Hospital, Beijing Youan Hospital, Beijing Ditan Hospital, 302 Hospital in Beijing, China Medical University and Zhengzhou Sixth Hospital. Northwestern center included Tangdu Hospital. Southeastern centers included Guangzhou Eighth People's Hospital, Shanghai Public Health Clinical Center, Shenzhen Third People's Hospital, Fuzhou Infectious Diseases Hospital. Southwestern centers included Chengdu Infectious Diseases Hospital, Changsha First Hospital, District CDC in Nanning, Longtan Hospital in Nanning, Nanning Forth People's Hospital, Yunnan AIDS Care Center, Kunming Third People's Hospital, and Honghe First People's Hospital.
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