Chronic hepatitis B, which is the leading cause of end-stage liver disease worldwide, is common in HIV type 1 (HIV)-infected individuals [1–5]. There are limited data on hepatitis B virus (HBV) treatment in HIV-infected patients from resource-limited settings where HBV endemicity is high. In most studies of HBV treatment from resource-rich settings, HIV–HBV co-infected individuals are usually positive for hepatitis B e antigen (HBeAg) and have high HBV DNA, characteristics associated with nearly all of these individuals having lamivudine-resistant HBV after 4 years of lamivudine [6,7]. For these reasons and because tenofovir disoproxil fumarate (TDF) is widely available, TDF-based antiretroviral therapy (ART) regimens are recommended for HIV–HBV co-infected patients in these locations. However, in many resource-limited settings, TDF, even though recommended by WHO for first-line treatment, is still not affordable and not universally recommended for HIV–HBV co-infected patients . In fact, 13 of 58 (22%) low or medium-income focus countries have not adopted TDF with lamivudine or emtricitabine as the preferred first-line antiretroviral regimen . Thus, ART regimens where lamivudine is the only drug active against HBV continue to be used.
HIV–HBV co-infection in resource-limited settings differs from that in resource-rich settings because there is a higher prevalence of HBeAg-negative disease and of individuals with HBV DNA levels below 20 000 IU/ml [9–12]. Thus, the long-term efficacy of lamivudine-based ART in resource-limited settings may be different than in resource-rich settings. A Thai study of 11 HBeAg-negative and 19 HBeAg-positive HIV–HBV co-infected patients taking lamivudine-based ART for up to 5 years found that all the HBeAg-negative patients maintained suppression (HBV DNA <150 IU/ml) and none developed lamivudine-resistant HBV . In contrast, of the HBeAg-positive patients, only seven of 19 (37%) maintained suppression, and 50% of those not suppressed developed lamivudine-resistant HBV.
To date, a comparison of lamivudine or emtricitabine-based ART versus TDF-based ART in HIV–HBV co-infected patients that includes resource-limited countries has not been performed. Previously, we reported on pre-ART characteristics of a subgroup of HIV–HBV co-infected patients from two randomized clinical trials (RCTs) conducted by the Adult AIDS Clinical Trials Group (ACTG) in diverse resource-limited settings. The first – ACTG A5175 (PEARLS) – enrolled HIV-infected men and women in nine countries to compare three initial ART regimens . The second – A5208 (OCTANE) – compared the response to first-line ART in women who had and had not received single-dose nevirapine for prevention of mother-to-child transmission of HIV in seven African countries . Using this predefined subgroup of HIV–HBV co-infected individuals from these two trials, we compared outcomes between those who received only one agent with anti-HBV activity (lamivudine or emtricitabine) to those who received two anti-HBV agents (TDF + lamivudine or emtricitabine) to test whether HBV outcomes differed between these groups and also within subgroups defined on baseline HBV DNA.
The present study included HIV–HBV co-infected individuals followed in either A5175 or A5208, as previously described (Table 1) [14,15]. In brief, HIV–HBV co-infected participants in this study were hepatitis B surface antigen (HBsAg)-positive at screening, negative for chronic hepatitis C, and met one of the following three criteria at the study entry visit: positive for HBeAg or HBe antibody (anti-HBe), or HBV DNA above 200 IU/ml. For the 85 (74%) participants from A5175, the anti-HBV agent(s) included either once-daily lamivudine, emtricitabine, or TDF + emtricitabine (often co-formulated). To complete their anti-HIV ART regimen, they also received either atazanavir or efavirenz, and if not assigned TDF + emtricitabine, then another NRTI (either zidovudine, stavudine, or didanosine). Randomization to the ART regimen did not account for the HBV infection status. However, sites could add a second anti-HBV agent if a co-infected patient was randomized to a regimen that included only emtricitabine or lamivudine (one patient added adefovir). Participants from A5208 received once-daily TDF + emtricitabine with either nevirapine or lopinavir/ritonavir. The pre-ART characteristics of the patients included in this study were described previously .
Informed consent for the parent RCTs was obtained from the study participants in their native language. This study was approved by the local institutional review boards and Johns Hopkins University IRB.
The following study entry variables were used in the current analysis: age, sex, race, BMI, history of liver disease, hemoglobin, HIV disease stage, plasma HIV RNA, CD4+ T-cell count, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). At 24-week intervals during follow-up, plasma HIV RNA and CD4+ T-cell count, and ALT/AST (only available from A5175) were extracted from the parent study database. During the same follow-up intervals, stored serum samples were tested for HBeAg, anti-HBe, and HBV DNA. HBV pol sequencing was performed on samples from the following scenarios: visits exhibiting evidence of rebound, defined as greater than 1 log10 IU/ml HBV DNA increase from nadir level or HBV DNA above 1000 IU/ml after being undetectable (<200 IU/ml); week 48 visit if HBV DNA decline from baseline was 1 log10 IU/ml or less.
All serum specimens were stored at −80°C. Serological testing for HBeAg (ETI-EBK Plus; Diasorin, Stillwater, Minnesota, USA) and anti-HBe (ETI-AB-EBK Plus; Diasorin) were performed according to the manufacturer's instructions. HBV DNA was determined with real-time PCR using either RealART HBV LC PCR v 3.0 (Qiagen, Valencia, California, USA) or Abbott RealTime HBV DNA (Abbott Molecular, Des Plains, Illinois, USA). The highest common lower limit of detection of these assays was 200 IU/ml, which is the value used as undetectable in the analyses. HBV genotype and drug-resistance mutations were determined by HBV pol sequencing, performed as previously described .
Comparison groups were defined as those who started two anti-HBV medications (primarily emtricitabine + TDF – dual-therapy group) versus those who started only one anti-HBV medication (emtricitabine or lamivudine – monotherapy group). The primary outcome was HBV DNA below 200 IU/ml at 24 weeks following treatment initiation and was compared in an intent-to-treat analysis between groups using Fisher's exact test. Associations between pretreatment characteristics and the primary outcome were tested using chi-square or Fisher's exact tests for discrete covariates and Wilcoxon rank-sum test for continuous covariates, and fit to logistic regression models one at a time (univariable). To adjust for possible confounding, multivariable logistic regression modeling included variables having P value less than 0.10 in univariable models, treatment comparison group, and covariates associated with treatment group. For significantly associated continuous covariates, linearity in the logit was graphically examined, and if rejected, categories were formulated as suggested by the data (e.g. quartiles).
Secondary outcomes included HBV DNA below 200 IU/ml at each 24-week follow-up time through week 144, ALT and AST normalization or elevations, HBeAg seroconversion, and durability of HBV DNA suppression. Longitudinal analyses of HBV DNA less than 200 IU/ml over time used marginal longitudinal modeling estimated via generalized estimating equations, with a logit link and an exchangeable log odds ratio (OR) structure for within-participant correlation. ALT and AST levels were graded according to standard ACTG definitions . Among the subgroup of HBeAg-positive patients at entry, the outcome of HBeAg seroconversion was defined as negative HBeAg and positive anti-HBe. Durability of HBV DNA suppression was formulated in two ways. First, for the subset who achieved HBV DNA below 200 IU/ml, it was examined as time to loss of HBV DNA below 200 IU/ml grouped in 24-week intervals. Second, durability was examined as time to loss of a 1 log10 IU/ml HBV DNA decline or time to loss of HBV DNA below 200 IU/ml (among those whose low HBV DNA at baseline did not permit a 1 log10 decline) grouped in 24-week intervals.
As-treated analyses, which excluded patients once they were no longer taking the same number of anti-HBV medications as assigned at entry (e.g. persons adding TDF when assigned to emtricitabine alone), were performed as sensitivity analyses to the primary, intent-to-treat comparisons, which did not consider treatment information after ART initiation. Subgroup analyses were performed according to the baseline HBeAg status and HBV DNA. Additionally, a post-hoc subgroup analysis was performed to further explore the hypothesis that monotherapy with lamivudine or emtricitabine may be effective in people with low baseline HBV DNA (<20 000 IU/ml) – a level chosen because there is a greater risk for poor liver outcomes above this level . We estimated the proportion of participants with baseline HBV DNA below 20 000 IU/ml who achieved HBV DNA below 200 IU/ml at 24-week intervals stratified by therapy group.
For all analyses, missing data were ignored and significance was set at 0.05 without adjustment for multiple comparisons.
Of the 115 HIV–HBV co-infected patients, 56 (49%) received either lamivudine (n = 25) or emtricitabine (n = 31) as the only anti-HBV drug (monotherapy), and 59 (51%) received dual therapy, with 58 of 59 patients receiving TDF and emtricitabine, and one receiving adefovir and emtricitabine. At least 88% of the expected HBV DNA results were available among participants in follow-up through week 144 (n = 89).
All the participants in the monotherapy group and 28 (47%) in the dual-therapy group were from A5175. Of the demographic and HIV pretreatment characteristics, the two comparison groups differed by sex (P = 0.001), country of origin (P = 0.001), CD4+ T-cell count distribution (P = 0.06), plasma HIV RNA (P = 0.02), and hemoglobin (P = 0.009) (Table 1). The differences in sex and country of origin were expected due to the distribution of the participants from the two RCTs. None of the HBV characteristics were significantly different between the monotherapy and the dual-therapy groups, with 50% being HBeAg-negative (Table 1). The median HBV DNA in the monotherapy and the dual-therapy groups was 5.2 and 4.9 log10 IU/ml, respectively. Forty-eight (41.8%) patients had HBV DNA below 20 000 IU/ml prior to ART, whereas in 46 (45.2%), it was above 2.0 × 107 IU/ml. Genotype A HBV was the most common (60%) followed by genotype D (13%); the genotype distributions in the two comparison groups were similar.
Hepatitis B virus DNA below 200 IU/ml
The proportion of patients achieving HBV DNA below 200 IU/ml was 60% [66/100; 95% confidence interval (CI) 50–69%] for the primary outcome at week 24 and 79% at week 144 (62/78; 95% CI 69–88%) (Fig. 1). In the comparison groups at week 24, 57% (30/53; 95% CI 42–70%) in the monotherapy and 63% (36/57; 95% CI 49–76%) in the dual-therapy group (exact P = 0.56) achieved HBV DNA below 200 IU/ml. However, the estimated proportion with HBV DNA below 200 IU/ml increased more over time in the dual than in the monotherapy group (P = 0.007) (Fig. 1). This between-group difference over time remained statistically significant (P = 0.02) when adjusted for baseline HBV DNA and HBeAg. The as-treated analysis, which included 98.5% of the expected visits, was similar to the intention-to-treat analysis.
Initial multivariable models included pretreatment characteristics associated with HBV comparison groups or with the primary outcome. Sex, HIV-1 RNA, hemoglobin, CD4+ T-cell count, and HDV status were all associated with HBV comparison groups (Table 1), whereas AST, HBeAg, and HBV DNA were associated with the primary outcome. Hemoglobin was removed from the multivariable model due to co-linearity with sex and CD4+ T-cell count. The linearity in the logit was rejected for CD4+ T-cell count and AST; therefore, these variables were grouped in quartiles. In the multivariable model for the primary outcome, HBV therapy group was not associated (OR 1.8, 95% CI 0.5–7.9; Table 2). Participants with baseline CD4+ T-cell count below 70 cells/μl were 14.8-fold (95% CI 1.9–201.7) more likely to achieve HBV DNA below 200 IU/ml at week 24 compared to those with above 140 cells/μl. However, change in CD4+ T-cell count from baseline to 24 weeks was not associated with the primary outcome. Higher AST (>44 U/l) compared to lower levels (<33 U/l) was associated with HBV DNA below 200 IU/ml at 24 weeks (OR 14.1, 95% CI 1.9–228.6), as was lower baseline HBV DNA (OR 4.6/log10 HBV DNA decrease, 95% CI 2.7–10.9). Lower baseline HBV DNA was the only variable that remained significantly associated longitudinally (P < 0.0001).
A subgroup analysis to determine if achieving HBV DNA below 200 IU/ml differed on the basis of the pretreatment HBeAg status demonstrated that a greater proportion of HBeAg-negative patients achieved HBV DNA below 200 IU/ml at week 24 (47 of 53, 89%) than HBeAg-positive patients (18 of 56, 32%). This finding was true over both HBV therapy groups, and this difference significantly increased over time (P = 0.04).
Hepatitis B e antigen seroconversion
Overall, 16 of the 53 (30%) HBeAg-positive patients had HBeAg seroconversion, with 10 occurring in the first 48 weeks. These seroconversions were maintained throughout follow-up in 11 (69%) patients. A significant difference was not observed between the monotherapy and the dual-therapy groups, with 27 and 33% seroconversions, respectively. Seroconversion was associated with higher baseline AST (median 47 versus 33 U/l; P < 0.001), a lower baseline HBV DNA (median 2.30 versus 3.26 log10 IU/ml; P < 0.001), and trended towards a lower baseline CD4+ T-cell count (median 63 versus 139 cells/μl; P = 0.07). Multivariable models were not informative due to the small number of outcomes.
Alanine aminotransferase and aspartate aminotransferase outcomes
Of the 23 participants from A5175 with grade 1–4 ALT or AST at baseline, only three did not experience normalization (one died at week 9 from bacterial pneumonia and two were lost to follow-up after weeks 4 and 16). Normalization occurred between weeks 2 and 34. Of the 74 participants from A5175 with grade 0 ALT or AST at baseline, 45 (61%) experienced an elevation to grades 1–4 during follow-up. Only two experienced a severe elevation (grade 3) and one was life-threatening (grade 4). All three participants normalized after the elevation. The life-threatening elevation required temporary discontinuation of ART, but was later successfully restarted.
Durability of hepatitis B virus DNA suppression or of 1 log10 hepatitis B virus DNA decline
Of the 105 patients with at least 48 weeks of follow-up, 85 (81%) achieved HBV DNA below 200 IU/ml and were followed for durability of this outcome. Nineteen (22.4%) of them did not maintain an HBV DNA below 200 IU/ml and the time to rebound was similar between the monotherapy and the dual-therapy groups (log-rank P = 0.8). In particular, nine of 36 (25%) patients in the monotherapy group compared to 10 of 49 (20%) patients in the dual-therapy group did not have a durable HBV DNA below 200 IU/ml response. Of the 19 individuals, only 4 had HIV RNA above 400 copies/ml at the same time as the HBV DNA rebound, and these individuals came from both the monotherapy and the dual-therapy groups. Of the 66 patients who maintained HBV DNA below 200 IU/ml throughout their follow-up, 53 (80%) did so for at least 24 months.
One hundred and one participants met the criteria for inclusion into the analysis for durability of at least l log10 IU/ml HBV DNA decline from baseline. In patients whose baseline HBV DNA was below 2000 IU/ml, achieving HBV DNA below 200 IU/ml was considered a 1 log10 decline. Of the 101 participants, 21 (20.8%) did not have a durable 1 log10 decline, with the majority of failures (n = 16) occurring within 18 months of having an initial response. In the monotherapy group, 17 of 47 (36.2%) individuals failed to maintain this outcome, compared to four of 54 (7.4%) in the dual-therapy group. Interestingly, the failures in the monotherapy group were primarily in those with HBV DNA above 20 000 IU/ml (Fig. 2).
Hepatitis B virus resistance
For 22 patients, HBV pol sequencing was performed, with 12 having emergence of known lamivudine-resistance mutations including 1 rtM204V/I, 8 rtM204V/I + rtL180M, 2 rtV173 + rtL180M + rtM204V/I, and 1 rtM204V/I + rtM250L. These mutants all emerged in patients in the monotherapy group (seven on lamivudine, four on emtricitabine, and one changed from lamivudine to emtricitabine).
Post-hoc subgroup analysis
Since most of the patients who did not maintain a 1 log decline in HBV DNA over time were in the monotherapy group with HBV DNA above 20 000 IU/ml, a post-hoc analysis was designed to test the hypothesis that when pretherapy HBV DNA levels are below 20 000 IU/ml, lamivudine or emtricitabine monotherapy can achieve and maintain HBV DNA below 200 IU/ml. Among the 21 patients in the monotherapy group and 25 in the dual-therapy group with baseline HBV DNA below 20 000 IU/ml, all were below 200 IU/ml at week 24 and they were likely (>89%) to have HBV DNA below 200 IU/ml at all follow-up time points regardless of whether they received monotherapy or dual HBV therapy.
This is the largest multinational HIV–HBV co-infected study to compare HBV outcomes between lamivudine/emtricitabine monotherapy versus TDF-based dual therapy as part of ART through 144 weeks of treatment. Another unique aspect is that approximately 40% of the participants had HBV DNA below 20 000 IU/ml, a group that is not included in clinical trials of anti-HBV therapies since they do not meet treatment criteria . Overall, we found no difference in becoming undetectable at 24 weeks between treatment groups, but a higher proportion on TDF-based dual therapy achieved an undetectable HBV DNA over time, a finding driven primarily by those with higher baseline HBV replication. In the subgroup analysis, individuals with HBV DNA below 20 000 IU/ml responded well regardless of treatment regimen through 144 weeks of therapy. In addition, the patients in the monotherapy group who failed to maintain a response to therapy over time had HBV DNA at least 20 000 IU/ml. Taken together, our data support that when possible, TDF-based dual ART should be used to treat HIV–HBV co-infected patients, but in resource-limited settings where TDF may not be universally available, baseline HBV replication status, as measured by HBV DNA or HBeAg, may help determine whether lamivudine or emtricitabine monotherapy for HBV is a therapeutic option.
In many resource-limited settings, the transition from stavudine-based to TDF-based ART has been slow. One challenge in phasing out stavudine is uncertainty about how to prioritize the phase-out. In resource-limited settings, studies demonstrate that HIV–HBV co-infected patients who have HBeAg-negative disease are likely to have low HBV DNA [9,19]. This fact, taken together with our current findings demonstrating that the patients with HBV DNA below 20 000 IU/ml on lamivudine-based therapy were able to maintain HBV DNA suppression through nearly 3 years of therapy suggests that one potential strategy is to phase out stavudine in the HIV–HBV co-infected patients who are HBeAg-positive since they will derive the most benefit. Also, our data support that for patients with known renal insufficiency where TDF is not an option, lamivudine or emtricitabine as the only HBV-active drug may be a reasonable alternative if they are HBeAg-negative or have a pretreatment HBV DNA below 20 000 IU/ml.
Lower baseline HBV DNA was the only factor in multivariable analysis that was associated with achieving HBV DNA below 200 IU/ml throughout follow-up, which is consistent with other studies [20–22]. In the ALLRT (AIDS clinical trials group longitudinal linked randomized trials) cohort, 68 treatment-naive HIV–HBV co-infected patients received either lamivudine or TDF-based HAART, and baseline HBV DNA was the only factor associated with HBV DNA suppression at 48 weeks . Interestingly, that study did not find a difference in HBV DNA suppression between the 21 patients on TDF-based dual therapy and the 47 patients on lamivudine monotherapy (OR 1.42, P = 0.63). Similar to our study, but different from other clinical trials, the ALLRT cohort included participants with low HBV DNA. Due to the smaller number of participants, they could not stratify response by baseline HBV DNA.
The difference between the therapy groups in the durability of HBV DNA suppression outcome was only observed with the greater than 1 log10 decline in HBV DNA and not with the HBV DNA below 200 IU/ml outcome. This discrepancy is likely a result of including more patients with higher HBV DNA levels in the greater than 1 log10 decline outcome compared to the HBV DNA below 200 IU/ml durability outcome.
It is also important to note that at 48 weeks only 69% had undetectable HBV DNA, and that even amongst those receiving TDF-based dual therapy, only 76% were undetectable, a proportion that is comparable to studies of HBV-monoinfected patients on entecavir or TDF [23–26]. Even at 144 weeks, 11% of those on TDF-based dual therapy still had a detectable HBV DNA, which is consistent with long-term data of HIV–HBV co-infected patients from resource-rich settings . Notably, those who did not suppress had baseline HBV DNA at least 20 000 IU/ml.
We observed unexpectedly that those with the lowest baseline CD4+ T-cell count were more likely to achieve an undetectable HBV DNA at 24 weeks, but not at later time points. This may be due to differences in the robustness of the immune reconstitution in the period immediately after ART initiation. However, change in the CD4+ T-cell count in the first 24 weeks was not associated with HBV DNA suppression. Since CD4+ T-cell count increase is a crude measure of immune reconstitution with ART, it is possible that those with a lower baseline CD4+ T-cell count had greater change in a different arm of the immune response in the first 24 weeks or in a specific subset of CD4+ T cells. Further studies of immune reconstitution with ART are needed to explore these hypotheses.
The rates of HBeAg seroconversion and ALT normalization did not differ between therapy groups, as is consistent with prior studies . We also found that drug-resistant HBV only emerged in those on lamivudine or emtricitabine monotherapy, which is consistent with data showing no resistance with TDF-based therapy [22,28,29].
There are several limitations to this study. First, this was not a RCT in terms of HBV therapy, so there were differences in baseline characteristics between the groups; however, none of these differences were in HBV parameters. Second, participants were only followed through 144 weeks, so whether other differences occur between therapy groups with longer follow-up is not known. Third, we did not have data on adherence; however, as stated in the ‘Results’ section, few patients who did not have a durable HBV DNA response also lost HIV RNA suppression. Thus, adherence did not explain a large proportion of the HBV relapse.
In summary, for HIV–HBV co-infected patients in a multinational setting, TDF/emtricitabine dual therapy for HBV as part of ART should be the first-line therapy if available and cost-effective, especially in patients with HBV DNA levels at least 20 000 IU/ml or with HBeAg-positivity. For patients with lower levels of replication, lamivudine or emtricitabine-based monotherapy is a possible alternative at least through 144 weeks of therapy. In resource-limited settings, these data may inform strategic plans regarding which patients to transition to or to initiate on TDF-based ART.
Author contributions: Study design (C.T., J.H., M.N., U.L., S.L., T.C., J.C.), data analysis (C.T., L.S., K.H., J.C.), data collection (M.S., H.S., S.S., S.K., H.I., A.M.), drafting of manuscript (C.T., L.S., K.H., J.C.), and critical reading of the manuscript (all authors). The authors would like to acknowledge the efforts of the investigators at each of the sites participating in this study, Amanda Zadzilka and James Tutko for managing the database, and the A5175 and A5208 study participants.
Funding support: The work was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [R01 AI071820 (C.T.), K24 AI56933 (J.C.), AI068636 (AIDS Clinical Trials Group), AI69450 (T.C.), U01 AI068634 (Statistical and Data Management Center of the AIDS Clinical Trials Group), R01CA120206 (A.M.), R01CA136607 (A.M.)]. It was also supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health (NIMH), and the National Institute of Dental and Craniofacial Research (NIDCR). Study drugs were provided by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, GlaxoSmithKline, and Merck & Co. Inc.
Additional funding for each site includes: UZ-Parirenyatwa CRS (Site 30313) CTU Grant: 1U01AI069436-01; Wits HIV CRS (Site 11101) CTU Grant: 1U01AI069463-01; University of North Carolina Project, Kamuzu Central Hospital (Site 12001) CTU Grant: 1U01AI069518-01; Durban Adult HIV CRS (Site 11201) CTU Grant: 1U01AI069426-01; YRG CARE Medical Ctr., VHS CRS (Site 11701) CTU Grant: 1U01AI069432-01; Instituto de Pesquisa Clinica Evandro Chagas CRS (Site 12101) CTU Grant: 1U01AI069476-01; College of Med. JHU CRS (Site 30301) CTU Grant: 1U01AI069518-01; Chiang Mai Univ. ACTG CRS (Site 11501) CTU Grant: 1U01AI069399-01; Hospital Nossa Senhora da Conceicao CRS (Site 12201) CTU Grant: 1U01AI069401-01; Les Centres GHESKIO CRS (Site 30022) CTU Grant: 1U01AI069421-01; NARI Pune CRS (Site 11601) CTU Grant: 1U01AI069417-01; Asociacion Civil Impacta Salud y Educacion, Sede Barranco (Site 11301) CTU Grant: 5U01 AI069438; Walter Reed Project – Kenya Med. Research Institute (Site 12501) CTU Grant: IAA#Y1-AI-8374-01; AMPATH at MOI Univ. Teaching Hosp. Eldoret CRS (Site 12601) CTU Grant: IAA#Y1-AI-8374-01; Kalingalinga Clinic CRS (Site 12801) CTU Grant: 1U01AI069518-01; Gaborone and Molepolole Prevention/Treatment Trials CRSs in Botswana (Sites 12701 and 12702) CTU Grant: 1U01AI069456-01; (Site 12401) CTU Grant: 1U01AI069456-01; San Miguel CRS (Site 11302) CTU Grant: 5U01AI069438; Molepolole Prevention/Treatment Trials CRS (Site 12702) CTU Grant: 1U01AI069456-01; University of Texas Southwestern Medical Center (Site 3751) Grant: AI 046376; NARI Clinic at NIV CRS (Site 11603) CTU Grant: 1U01AI069417-01; University of Cincinnati (Site 2401) CTU Grant: AI-069513; Univ. of California Davis Med. Ctr., ACTU (Site 3851) Grant: AI38858-09S1; NARI Clinic at Gadikhana Dr Kotnis Municipal Disp (Site 11602) CTU Grant: 1U01AI069417-01; University of Colorado Hospital CRS (Site 6101) CTU Grant: AI69450; The Ohio State University (Site 2301) CTU Grant: AI069474; Northwestern University CRS (Site 2701) CTU Grant: AI069471; University of Minnesota (Site 1501) CTU Grant: AI27661; Washington U CRS CTU (Site 2101) Grant: 1U01AI069495; Beth Israel Med. Ctr., ACTU (Site 2851) CTU Grant: AI46370; The Miriam Hospital (Site 2951) CTU Grant: AI069472-01; Duke University Medical Center CRS (Site 1601) CTU Grant: AI069484-06; University of Southern California CRS (Site 1201) CTU Grant: AI069428; Harbor-UCLA Medical Center (Site 603) CTU Grant: U01-A1 069424; UNC AIDS CRS (Site 3201) CTU Grant: AI069423; RR 025747; AI050410; Hospital of the Univ. of Pennsylvania CRS (Site 6201) CTU Grant: U01-AI- AI69467-05; CFAR Grant: P30-AI-045008-12; HIV Prevention & Treatment CRS (Site 30329) CTU Grant: 1U01AI069470; Vanderbilt Therapeutics CRS (Site 3652) CTU Grant: U01-AI069439; Rush Univ. Med. Ctr. ACTG CRS (Site 2702) CTU Grant: 1U01AI069471-01; University of Texas, Galveston (Site 6301) Grant: AI32782; New York University/NYC HHC at Bellevue Hospital (Site 401) CTU Grant: Al-27665; Al069532; Christine Hurley, RN and Roberto Corales, DO- AIDS Care CRS (Site 1108) CTU Grant: U01AI069511-02 (as of 2/12/08); CTSI: UL1 RR 024160; UCLA CARE Center CRS (Site 0601) CTU Grant: 1U01AI069424-01; University of Rochester (Site 1101) CTU Grant: U01AI069511-02 (as of 2/12/08); CRC: UL1 RR 024160; Cook County Hosp. CORE Ctr. (Site 2705) CTU Grant: 1U01AI069471-01; SSTAR, Family Healthcare Ctr. (Site 2954) Grant: AI46381; Wake County Health and Human Services Clinical Research Site (Site 3206) CTU Grant: AI25868; University of Hawaii at Manoa, Leahi Hosp. (Site 5201) Grant: AI34853; Todd Stroberg, R.N., and Christina Megill, PA-C. -Cornell CTU (Site 7804) CTU Grant # AI069419 CTSC# RR024996.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.
Conflicts of interest
None of the authors have a potential conflict of interest.
1. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection
. J Hepatol
2. Zhou J, Dore GJ, Zhang F, Lim PL, Chen YM. Hepatitis B and C virus coinfection in The TREAT Asia HIV Observational Database
. J Gastroenterol Hepatol
3. Nyirenda M, Beadsworth MB, Stephany P, Hart CA, Hart IJ, Munthali C, et al. Prevalence of infection with hepatitis B and C virus and coinfection with HIV in medical inpatients in Malawi
. J Infect
4. Diop-Ndiaye H, Toure-Kane C, Etard JF, Lo G, Diaw P, Ngom-Gueye NF, et al. Hepatitis B, C seroprevalence and delta viruses in HIV-1 Senegalese patients at HAART initiation (retrospective study)
. J Med Virol
5. Lee HC, Ko NY, Lee NY, Chang CM, Ko WC. Seroprevalence of viral hepatitis and sexually transmitted disease among adults with recently diagnosed HIV infection in Southern Taiwan, 2000–2005: upsurge in hepatitis C virus infections among injection drug users
. J Formos Med Assoc
6. Matthews GV, Bartholomeusz A, Locarnini S, Ayres A, Sasaduesz J, Seaberg E, et al. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy
7. Benhamou Y, Bochet M, Thibault V, Di MV, Caumes E, Bricaire F, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients
9. Thio CL, Smeaton L, Saulynas M, Hwang H, Kumarasamy N, Flanigan T, et al. Characterization of HIV-HBV coinfeciton in a multinational HIV-infected cohort
10. Idoko J, Meloni S, Muazu M, Nimzing L, Badung B, Hawkins C, et al. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria
. Clin Infect Dis
11. Hoffmann CJ, Charalambous S, Martin DJ, Innes C, Churchyard GJ, Chaisson RE, et al. Hepatitis B virus infection and response to antiretroviral therapy (ART) in a South African ART program
. Clin Infect Dis
12. Ive P, MacLeod W, Mkumla N, Orrell C, Jentsch U, Wallis CL, et al. Low prevalence of liver disease but regional differences in HBV treatment characteristics mark HIV/HBV co-infection in a South African HIV clinical trial
. PLoS One
13. 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
14. Campbell TC, Smeaton L, Kumarasamy N, Flanigan TP, Klingman KL, Firnhaber C, et al. Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings
. PLoS Med
15. Lockman S, Hughes MD, McIntyre J, Zheng Y, Chipato T, Conradie F, et al. Antiretroviral therapies in women after single-dose nevirapine exposure
. N Engl J Med
17. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load
18. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009
19. Idoko J, Meloni S, Muazu M, Hawkins C, Badung B, Gwamzi N, et al. Hepatitis B virus co-infection impacts baseline HIV parameters and HAART-related hepatotoxicity risk in an HIV-infected Nigerian cohort
. Clin Infect Dis
20. Childs K, Joshi D, Byrne R, Bruce M, Carey I, Agarwal K, et al. Tenofovir-based combination therapy for HIV/HBV co-infection: factors associated with a partial HBV virological response in patients with undetectable HIV viraemia
21. Kang M, Hollabaugh K, Pham V, Koletar SL, Wu K, Smurzynski M, et al. Virologic and serologic outcomes of mono versus dual HBV therapy and characterization of HIV/HBV coinfection in a US cohort
. J Acquir Immune Defic Syndr
22. Boyd A, Gozlan J, Maylin S, Delaugerre C, Peytavin G, Girard PM, et al. Persistent viremia in human immunodeficiency virus/hepatitis B coinfected patients undergoing long-term tenofovir: Virological and clinical implications
23. Marcellin P, Heathcote EJ, Buti M, Gane E, De Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B
. N Engl J Med
24. Chang TT, Gish RG, De Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B
. N Engl J Med
25. Wong DK, Kopaniszen M, Omagari K, Tanaka Y, Fong DY, Seto WK, et al. Effect of hepatitis B virus reverse transcriptase variations on entecavir treatment response
. J Infect Dis
26. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B
. N Engl J Med
27. 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
. J Viral Hepat
28. 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
. Clin Infect Dis
29. Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B