Efficacy of tenofovir alafenamide- or tenofovir disoproxil fumarate-containing regimens in adults with treatment-naïve HIV-hepatitis B co-infection

Abstract

Background

Hepatitis B (HBV) infection affects 4%–14% of people with HIV infection in Turkey. Tenofovir alafenamide (TAF) is highly effective in treatment of HIV infection. While it is active against HBV, data on the use in HIV-HBV co-infection are limited.

Patients and Methods

We analyzed the efficacy of tenofovir disoproxil fumarate (TDF)- and TAF-containing regimens in patients with HIV-HBV co-infection from six centers in Istanbul, Turkey. The results of the cohort of 36 months were presented.

Results

259 patients were enrolled: 146 and 113 were receiving TAF- and TDF-containing regimens respectively. Baseline characteristics were comparable except TAF-containing group was older; had higher CD4 cell count and lower rate of CD4 count ≤200 cells/μL. Baseline HIV-RNA were 8.2 log copies/mL and 6.8 log in TAF- and TDF-containing groups, respectively (p = .059) and HBV-DNA levels were 8.1 log IU/mL in both groups. Thirty-eight and 39% of the patients were HBeAg-positive. After 36 months, undetectable HBV-DNA was noted in 88% and 87%, and undetectable HIV-RNA in 85% and in 83% of TAF and TDF-containing groups, respectively. The increase in mean CD4 cell was significant in both groups: Δ = 311 cells/μL in TAF- and Δ = 393 cells/μL in TDF-containing groups. Rates of HBeAg loss (63% vs 57%), HBeAg seroconversion (35% vs 29%), HBsAg loss (29% vs 27%), and HBsAg seroconversion (23% vs 16%) were comparable at 36 months of therapy.

Conclusion

This real-life study showed that both TAF- and TDF-containing regimens are effective in co-infected patients. The rates of HBsAg loss seemed higher than those in HBV-monoinfected patients.

Keywords

Hepatitis B virus human immunodeficiency virus co-infection tenofovir disoproxil fumarate tenofovir alafenamide

Introduction

Infections of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are global health care concerns. A considerable proportion of individuals are infected with both viruses. Co-infection with HIV and HBV is associated with increased morbidity and mortality, especially with higher risk of cirrhosis and liver cancer than people with HBV monoinfection. Co-infection carries also the increased risks of low response to the treatment, drug-induced liver damage and cross-drug resistance.^1,2

Tenofovir is an HBV-active antiretroviral drug and tenofovir disoproxil fumarate (TDF)-containing regimens have improved the outcome of people with HIV-HBV co-infection. TDF-based regimens are recommended for the treatment of HIV-HBV co-infection by main guidelines.^3–5 Tenofovir alafenamide (TAF) another prodrug of tenofovir, also has dual effects, against both HIV and HBV. Compared to TDF, TAF use results in 90% less tenofovir concentrations in the plasma and is associated with fewer adverse effects on kidney function and bone metabolism.⁶ TAF was found to be highly effective in the treatment of HIV infection in both treatment-naïve and switch trials. In HBV-monoinfected patients, switching from TDF to TAF was shown to be non-inferior to continuing TDF in terms of decline in quantitative HBsAg and ALT normalization.^7,8 Among HIV-HBV co-infected patients, studies using switch from TDF-containing to TAF-containing regimens showed durable viral suppression of both HIV and HBV.^9–12 Switch studies, however, represent using TAF-containing regimen in patients with already suppressed HIV and HBV replications. In treatment-naïve HIV and HBV infection, a recent randomized Phase 3 non-inferiority trial showed that co-formulated bictegravir/emtricitabine/TAF is non-inferior to dolutegravir, emtricitabine and TDF at week 48.¹³

Hepatitis B surface antigen (HBsAg) seroprevalence is 4% in Turkey.¹⁴ Although the prevalence of HIV infection is relatively low compared to global rates, it is steadily increasing in recent years.¹⁵ Hepatitis B virus infection affects 4%–14% of people living with HIV in the country.^16,17 Both TAF- and TDF-containing regimens are currently used in the treatment of co-infected individuals. There is no real life study comparing the efficacy of TDF- and TAF-containing regimens among naïve HIV-HBV co-infected patients. This study aimed to analyze the real life cohort of treatment outcomes in HIV-HBV co-infected individuals.

Patients and methods

Study design and participants

We analyzed patients treated with TDF- and TAF-containing regimens with HIV-HBV co-infections. It included 6 centers of university or education and training hospitals in Istanbul, Turkey.

Patients only receiving treatments including TAF of TDF were analyzed. Patients previously treated for either HIV or HBV infection were not included. The patients received the treatment at least for 1 month were included to the analysis. The results up to 36 months were presented.

Chronic hepatitis B was defined as HBsAg and HBV-DNA positive ≥6 months.

“HBeAg loss” refers to HBeAg negativity without the development of anti-HBe after the baseline visit. “HBeAg seroconversion” refers to the HBeAg negativity and anti-HBe positivity after the baseline visit. “HBsAg loss” refers to HBsAg negativity without the development of anti-HBs after the baseline visit. “HBsAg seroconversion” refers to the HBsAg negativity and anti-HBs positivity after the baseline visit.

Procedures

Baseline was defined as the initiation of ART. Participants were seen at baseline, and month 1, and every 3 months thereafter. Laboratory studies included complete blood count, urea, creatinine, liver function tests, fasting lipid parameters, CD4 count, HIV-RNA, HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV-DNA. Hepatocellular carcinoma screening using abdominal ultrasound was introduced every 6 months.

Statistical analysis

Primary efficacy endpoints were the rate at month 12 with HIV-RNA <50 copies/mL (FDA snapshot analysis) and HBV-DNA <29 IU/mL.

Secondary endpoints were the rate at months 6, 12, 24, and 36 with HIV-RNA <50 copies/mL (FDA snapshot analysis) and HBV-DNA <29 IU/mL with HBsAg loss and HBeAg loss (of those with baseline HBeAg-positive), with HBsAg-to-anti-HBs seroconversion and HBeAg-to-anti-HBe seroconversion, with ALT normalization (of those with baseline abnormal ALT). For ALT normalization, American Association for the Study of Liver Diseases (AASLD) criteria of ≤25 U/L (females), ≤35 U/L (males) were used.¹⁸

Continuous and categorical variables in every treatment period were compared with t test and chi-square test, respectively. CD4 cell count change in each group from baseline to month 36 was tested by repeated measures t test. p values <0.05 were considered statistically significant.

Results

A total of 256 patients were enrolled: 146 and 113 were under TAF- and TDF-containing regimens respectively. Baseline characteristics were comparable in both groups except the TAF-containing group was older, had higher mean CD4 cell levels and the rate of CD4 cell count ≤200 cells/μL was lower (Table 1).

Table 1.

Baseline characteristics of HIV-HBV co-infected patients given TAF- or TDF-containing regimens.

	TAF-containing (n = 146)	TDF-containing (n = 113)	p
Age, years (mean ± standard deviation)	44.5 ± 10.7	41.8 ± 10.1	<.05
Gender (M/F/TG)	143/2/1	102/11/0	NS
HIV-1 RNA, copies/mL	156,945,133 ± 3,223,138	6,516,806 ± 32,366,090	NS (0.059)
HIV-1 RNA, log10 copies/mL	8.20 ± 6.51	6.81 ± 7.51	NS (0.059)
HIV-1 RNA ≥100,000 copies/mL, n (%)	29/146 (19.9%)	28/113 (24.8%)	NS
CD4 cells/μL	426 ± 321	285 ± 217	<.001
CD4 count ≤200 cells/μL, n (%)	33/140 (23.6%)	47/106 (44.3%)	<.001
Mean HBV DNA, IU/mL	131,468,479 ± 249,795,393	135,982,300 ± 370,239,363	NS
Mean HBV DNA, log10 IU/mL	8.11 ± 8.40	8.13 ± 8.57	NS
HBV DNA ≥8 log10 IU/mL, n (%)	36/146 (24.7%)	22/113 (19.5%)	NS
HBeAg-positive, n (%)	56/146 (38.4%)	44/113 (38.9%)	NS
ALT (U/L, mean ± standard deviation)	136 ± 340	142 ± 374	NS
ALT >ULN, n (%)^a	70/140 (50.0%)	45/104 (43.3%)	NS
AST (U/L, mean ± standard deviation)	84 ± 202	93 ± 223	NS
Platelets (/mcL, mean ± standard deviation)	231 ± 66	231 ± 63	NS
Albumin (g/dL, mean ± standard deviation)	4.67 ± 0.29	4.65 ± 0.26	NS
Cirrhosis	2 (1.3%)	2 (1.8%)	NS
Other antiretrovirals	EVG + FTC: 80 (55%)	EVG + FTC: 51 (45%)
	EVG + FTC: 80 (55%)	DTG + FTC: 28 (25%)
	BIC + FTC: 66 (45%)	RAL + FTC: 23 (20%)
	BIC + FTC: 66 (45%)	EFV + FTC: 11 (10%)

^aAmerican Association for the Study of Liver Diseases (AASLD) criteria: normal ≤25 U/L (females), ≤35 U/L (males). TAF; tenofovir alafenamide, TDF; tenofovir disoproxil fumarate, M; male, F; female, TG; transgender. ULN; upper limit of normal, ALT; alanine aminotransferase, AST; aspartate aminotransferase, EVG; Elvitegravir, FTC; Emtricitabine, BIC; Bictegravir, DTG; Dolutegravir, RAL; Raltegravir, EFV; Efavirenz.

Baseline HIV viral load seemed higher in TAF-containing group, although it was not statistically significant (p = .059).

Baseline HBV-DNA levels and the rates of HBeAg-positive and normal ALT were comparable in both groups.

Mean follow-up duration under treatment was 66.4 ± 36.7 months and 64.1 ± 43.3, for TAF- and TDF-containing groups, respectively (p > .05).

Both regimens controlled HIV and HBV infection, and resulted in a significant increase in CD4 cell counts. After 36-month of therapy, the rate of HIV RNA <50 copies/mL was 85% and 83% and HBV-DNA <29 IU/mL was obtained in 88% and 87% in TAF- and TDF-containing groups, respectively (Figure 1). HIV and HBV treatment outcomes during 36-month of treatment was given in Table 2.

Figure 1.

The rates of HBV-DNA <29 U/mL after 36 months.

Table 2.

HBV and HIV infection outcomes following TAF- or TDF-containing regimens.

	TAF-containing (n = 146)	TDF-containing (n = 113)	p
6 months, HBV-DNA <29 IU/mL	81/140 (58%)	63/108 (58%)	NS
12 months, HBV-DNA <29 IU/mL	86/132 (65%)	66/104 (64%)	NS
24 months, HBV-DNA <29 IU/mL	97/120 (81%)	80/98 (82%)	NS
36 months, HBV-DNA <29 IU/mL	97/110 (88%)	71/82 (87%)	NS
36 months, ALT normal^a	94/110 (85%)	65/82 (79%)	NS
36 months, HIV RNA <50 copies/mL	94/111 (85%)	78/94 (83%)	NS
36 months, mean CD4 cells/μL increase	426 to 737 (Δ = 311), p < .0001**	285 to 678 (Δ = 393), p < .0001**

^aAmerican Association for the Study of Liver Diseases (AASLD) criteria: normal ≤25 U/L (females), ≤35 U/L (males), **Repeated measures t test.

TAF; tenofovir alafenamide, TDF; tenofovir disoproxil fumarate.

HBsAg loss was seen in 29% and 27% in TAF- and TDF-containing regimens respectively, while HBs seroconversion rates were 23% and 16% after 36 months of therapy. HBsAg loss was observed mainly among HBeAg-positive patients: 21 out of 32 in TAF-containing group and 13 out of 22 in TDF-containing group were baseline HBeAg-positive patients.

HBeAg loss was observed in 63% and 57% in TAF- and TDF-containing regimens respectively, while HBe seroconversion rates were 35% and 29% after 36 months (Table 3, Figure 2).

Table 3.

The rates of HBsAg (−), anti-HBe (+), HBeAg (−) and anti-HBe (+).

			6 mo^a	12 mo^a	24 mo^a	36 mo^a
TDF-containing	All TDF (n = 113)	HBsAg (−)	9 (8%)	10 (10%)	12 (12%)	22 (27%)
	All TDF (n = 113)	Anti-HBs (+)	5 (5%)	6 (6%)	6 (6%)	13 (16%)
	TDF with HBeAg(+) (n = 44)	HBeAg (−)	12 (28%)	14 (35%)	16 (42%)	20 (57%)
	TDF with HBeAg(+) (n = 44)	Anti-HBe (+)	7 (14%)	10 (25%)	12 (32%)	14 (29%)
TAF-containing	All TAF (n = 146)	HBsAg (−)	14 (10%)	15 (11%)	22 (18%)	32 (29%)
	All TAF (n = 146)	Anti-HBs (+)	7 (5%)	7 (5%)	15 (13%)	25 (23%)
	TAF with HBeAg(+) (n = 56)	HBeAg (−)	10 (19%)	16 (33%)	20 (44%)	25 (63%)
	TAF with HBeAg(+) (n = 56)	Anti-HBe (+)	6 (12%)	10 (21%)	12 (27%)	14 (35%)

^aIn all four time points, the comparisons of the rates of HBsAg (−), anti-HBs (+), HBeAg (−) and anti-HBe (+) were non-significant.

mo; months.

Figure 2.

HBsAg loss and HBs serconversion after 36 months of therapy.

Discussion

This first real-life study showed that both TAF- and TDF-containing regimens are effective in controlling HIV and HBV infections in treatment-naïve, co-infected patients. Efficacy of TDF-containing regimens against both HIV and HBV was demonstrated in HIV/HBV co-infected patients.^19,20 Since the introduction of TAF, several switch studies have demonstrated that transitioning from TDF-based regimens to TAF-based regimens is both effective and safe.^9–11 Then, a recent randomized controlled trial, comprising treatment-naïve individuals with HBV/HIV co-infection demonstrated higher control rates of both HIV and HBV infection by either TDF- or TAF-based treatment¹³: At week 48, 113 (95%) of 119 participants in the TAF-based group and 111 (91%) of 122 participants in the TDF-based group had HIV-1 RNA < 50 copies/mL and 75 (63%) of 119 participants in the TAF-based group versus 53 (43%) of 122 participants in the TDF-based group had HBV DNA suppression.

HIV-HBV co-infection showed different HBV viral kinetics from HBV monoinfection. The rate of HBeAg-positive patients is 38%–39% in this cohort, while this rate is about 25% in the HBV-monoinfected patients in the country.^21,22 Higher rates of HBeAg positivity suggest more “fresh HBV infection” in HIV-HBV co-infected patients.

The rates of HBsAg loss seem higher than those in HBV-monoinfected patients. In HBV monoinfected patients, HBsAg loss was reported in 3% after 48-week use of TDF in the pivotal study.²³ HBsAg loss was reported 0% with TDF and 3%–4% with TAF after 96 weeks²⁴ in another study. In this cohort of co-infection, the rates of HBsAg loss were 29% (with TAF) and 27% (with TDF). A recent randomized study comparing the efficacy of TAF- and TDF-based regimens in HIV-HBV co-infected patients found the rates of HBsAg loss as 12.6% with TAF and 5.8% with TDF after 48 weeks of the therapy.¹³ A review of literature with 14 studies with HBV monoinfection and 13 studies with HIV-HBV co-infection reported the median rates (range) of HBsAg loss during treatment of CHB as 0.37 (0–1.06) per 100 person-years for HBV monoinfection and 2.39 (0.6–10.46) per 100 person-years for HIV-HBV co-infection within 5 years of therapy.²⁵ These higher HBsAg loss rates among HIV-HBV co-infected patients were explained by immune restoration. In addition to the determinant of HBsAg loss in HBV-monoinfected patients (including specific phase of HBV infection, HBV subtypes/genotypes, HBeAg-negative variants, and genetics of the host), CD4 cell counts and AIDS-defining illness appear as additional determinants in HIV-HBV co-infected patients.²⁵ In a recent study of HBsAg kinetics, long-term TDF therapy resulted in a significant decline in HBsAg and correlated with an increase in CD4 cell count in HIV-HBV co-infected patients.²⁶ Correlation with HBsAg kinetics and CD4 cell count suggested the effect of immune restoration. Similarly our study showed a significant increase in CD4 cell count and HBsAg loss in 27%–29% of the patients in 3 years therapy.

In the above-mentioned randomized, non-inferiority trial, TAF-containing regimen (TAF/bictegravir/emtricitabine) resulted in comparable HIV-RNA decline while it lead to a significantly more HBV DNA suppression than TDF-containing regimen (TDF, dolutegravir and emtricitabine) (63% vs 43%) at 48 weeks, but suppression rate was comparable at week 96 (75% vs 70%) (27). HBsAg loss was significantly higher at weeks 24 and 36 with the TAF-containing regimen. It tended to be higher with TAF-containing regimen, while it was not statistically significant at week 96 (22.7% vs 14.0%). HBsAg seroconversion rates at week 96 (9.2% vs 6.6%) were comparable. Our cohort study showed similar efficacies of TAF- and TDF-containing regimens in HIV-HBV co-infected patients in aspects of the kinetics of either virus in all time points through 36 months.

This study has limitations mainly inherent from its retrospective cohort nature. Some medical records are partially incomplete. Either HIV or HBV parameters or both might be lacking in a given visit. Since it is not a randomized study, the groups have varying baseline characteristics. The TAF-containing group was older, had higher CD4 cell counts and lower rates of those with CD4 counts ≤200 cells/μL which may affect the outcomes. There might be a bias that since the clinicians are more familiar with the TDF-containing regimens with their efficacy and safety studies, real-life reports, they may have preferred TDF-containing regimens for those with lower CD4 cell counts.

This study represents the first real-life data on a multicenter cohort of naïve HIV-HBV co-infected patients with longest (36 months) follow-up time. It demonstrates that both TAF-and TDF-including regimens control the infections of both viruses. The functional cure of HBV infection - HBsAg loss - is obtained in higher rates than that observed in HBV-monoinfection.

Footnotes

Declaration of conflicting interests

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

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

ORCID iDs

Fehmi Tabak

Hayat Kumbasar Karaosmanoğlu

Esra Canpolat Ünlü

Bilgul Mete

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