Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide as Maintenance Treatment in HIV/HBV-coinfected Patients

Yu-Shan Huang, MD; Chien-Yu Cheng, MD; Bo-Huang Liou, MD; Po-Liang Lu, MD, PhD; Shu-Hsing Cheng, MD, PhD; Yuan-Ti Lee, MD; Chun-Eng Liu, MD; Hsin-Yun Sun, MD; Chia-Jui Yang, MD; Hung-Jen Tang, MD; Shih-Ping Lin, MD; Mao-Wang Ho, MD; Sung-Hsi Huang, MD; Hung-Chin Tsai, MD, PhD; Chen-Hsiang Lee, MD; Chien-Ching Hung, MD, PhD

Disclosures

J Acquir Immune Defic Syndr. 2021;86(4):473-481. 

In This Article

Discussion

In this cohort of HIV/HBV-coinfected Asians who were switched from TDF-based regimens to E/C/F/TAF, 89.8% and 94.2% of participants maintained HBV and HIV suppression at week 48, respectively. Seroconversion occurred in 5.7% of HBeAg-positive participants, and 1.1% of all participants lost HBsAg. After switch to E/C/F/TAF, the participants had improved proteinuria and BMD. All components of the fasting lipid profile increased, including HDL-cholesterol. E/C/F/TAF was well tolerated, with only 2.6% of the participants discontinuing the treatment because of drug-related adverse events.

Our results confirm the efficacy of TAF in maintaining HBV viral suppression in HIV/HBV-coinfected patients. In the study of Gallant et al,[20] 91.7% of 72 patients had HBV DNA <29 IU/mL at 48 weeks after switch from TDF-containing ART to E/C/F/TAF. Using the same cutoff value (<29 IU/mL), up to 91.2% (250/274) of our participants achieved HBV suppression at week 48. Another study of HBV-monoinfected patients with suppressed HBV DNA (<20 IU/mL) found that 96.3% (234/243) of patients switching from TDF to TAF maintained HBV DNA <20 IU/mL at 48 weeks,[27] and the study concluded that TAF can be a substitute for TDF in HBV-infected patients. In contrast to the report of Gallant et al,[20] in which no individual with baseline undetectable HBV DNA became detectable at week 48, 17 (6.6%) of 258 participants with baseline undetectable HBV DNA in our cohort had HBV DNA ≥20 IU/mL at weeks 24 or 48. All of these 17 participants had HIV RNA <50 copies/mL (data not shown), and 5 participants had a 2-fold or greater elevation of ALT (1 had HDV superinfection; 2 due to concurrent use of health supplement or herbal medicine that might have affected the bioavailability of E/C/F/TAF; 1 acute HCV infection; and 1 with no specific causes identified). A detectable HBV DNA during TDF-based therapy is not unusual.[28] Of patients reporting good ART adherence, suboptimal HBV suppression might be due to the genetic variability of HBV or a stricter adherence requirement for HBV than HIV suppression.[29] Transient HBV viral blips might also represent random assay variability.[30] In our study, patients who did not achieve primary end points had low-level HBV viremia. Previous clinical studies showed that the percentage of patients with HBV viremia declined over long-term TDF treatment,[31] and the emergence of HBV resistance to TDF or TAF was rare.[19,30] Although more studies are warranted to investigate the long-term outcomes of HIV/HBV-coinfected patients who had HBV viremia on TAF treatment, currently available data suggest that low-level HBV viremia at 48 weeks of TAF-containing therapy does not indicate an increased risk of virologic failure or development of TAF resistance, and TAF treatment could be continued.[19,30,31] In our study, 14 of the 17 participants whose HBV DNA became detectable continued E/C/F/TAF and all had HBV DNA <20 IU/mL at week 96. No liver-related morbidity or mortality occurred up to week 96 (data not shown).

Seropositivity for HBeAg was recognized as a surrogate marker of active HBV replication.[32] In our study, HBeAg-positive patients had a higher rate of detectable HBV DNA at week 48 than HBeAg-negative patients (96.0% vs 85.7%, P = 0.027). HBeAg positivity has also been associated with failure to achieve HBV suppression in patients who received TDF therapy.[31,33] The loss of HBeAg and HBeAg seroconversion occurred infrequently in our cohort (8.6% and 5.7%), which is similar to the low rates observed in HBV-monoinfected patients (8% and 3%).[27]

Switch from TDF-containing to TAF-containing regimens lead to favorable changes in proteinuria and BMD in HIV/HBV-coinfected patients. These findings are consistent with those of the studies on HIV-monoinfected or HBV-monoinfected populations.[14,27,34,35] In a pooled analysis including only 6% of Asians, virologically suppressed HIV-infected patients taking a TAF-containing regimen had a decrease in the median UACR and urine β2-microglobulin-to-creatinine ratio by 5.4% and 25.8%, respectively, at week 96.[34] In this study consisting of participants of ethnic Chinese, we showed a greater improvement of proteinuria (15.3% and 38.5% at week 48), which could be attributed to the fact that Asians are characterized by a smaller body weight relative to people in North America and Western Europe and low body weight has been shown to be associated with higher plasma tenofovir trough concentrations and an increased risk of TDF-related renal dysfunction.[11,12,36–38] A subanalysis of trials evaluating E/C/F/TAF in Asian participants showed no renal adverse events leading to E/C/F/TAF discontinuations in ART-naive and experienced Asians, whereas discontinuations due to renal adverse events occurred in non-Asians.[39]

For bone safety, we observed an increase in the mean BMD of the spine by 1.77% at week 48 of switch to E/C/F/TAF, which is comparable with 1.56% and 1.74% increase in BMD of the spine among HIV-monoinfected and HBV-monoinfected patients, respectively.[14,27] In our study, the median serum creatinine increased significantly from 0.94 to 1.00 mg/dL at week 48. This could be attributed to the high proportion (65%, including 43.4% and 5.8% received efavirenz-based and nevirapine-based regimens, respectively) of our participants who switched from an ART regimen without a creatinine transport inhibitor, such as rilpivirine, dolutegravir, bictegravir, cobicistat, or ritonavir, to a regimen containing cobicistat.[40,41] In subgroup analysis, the median serum creatinine increased significantly in patients taking ART regimens not containing creatinine transport inhibitors (baseline vs week 48, 0.94 mg/dL vs 1.00 mg/dL, P < 0.001) but not in patients taking creatinine transport inhibitor-containing ART at baseline (baseline vs week 48, 1.00 mg/dL vs 0.96 mg/dL, P = 0.170) (data not shown).

Published data have shown that TAF-containing regimens had a less favorable effect on lipids than TDF-containing regimens,[19,35,42] and the increases in lipids when switching from TAF-containing to TDF-containing regimens could be reversible if switch back.[43] Although most studies reported a stable TC/HDL-cholesterol ratio,[14,27,35] we found a small but significant increase in TC/HDL-cholesterol ratio among our participants. The clinical significance of this alteration in lipid parameters remains uncertain, however. In a 96-week study, lipid changes with TAF did not affect cardiovascular disease risk profiles in comparison with TDF.[44]

InSTIs have recently been shown to be associated with more weight gain than protease inhibitors or non-nucleoside reverse transcriptase inhibitors;[42,45] moreover, weight gain on InSTIs could be accompanied by worsening of lipid and glucose profiles.[42,46] In our study, we observed a significant but modest weight gain (3 kg) in 89 patients with follow-up measurements, yet no correlation between the changes in weight and lipids was found over the 48-week follow-up. In patients with chronic HBV infection, metabolic syndrome may increase the risk of liver fibrosis progression.[47,48] Therefore, the metabolic derangements among HBV/HIV-coinfected patients taking TAF-containing or InSTI-containing regimens warrant more attention and should be actively managed to prevent potential liver and cardiovascular adverse effects.

In this study, 14% of participants had HDV seropositivity, and HDV viremia was detected in 20%–25% of anti–HDV-positive participants. Studies in Taiwan had shown a higher prevalence of HDV infection in HIV/HBV-coinfected patients than HBV-monoinfected patients,[49] with an increasing trend of recent HDV infection.[24] Infection with HDV often presents as hepatitis flares and may accelerate liver fibrosis.[50] For HIV/HBV-coinfected patients, it is necessary to consider the anti-HDV antibody and HDV RNA testing when clinical hepatitis is evident. It is also important to maintain long-term HBV suppression because a decrease in the HBsAg level has been shown to be associated with decreases of HDV RNA.[51,52]

The strength of the study is the relatively large number of HIV/HBV-coinfected individuals in whom the efficacy of E/C/F/TAF on HBV suppression is prospectively evaluated in a country that is hyperendemic for HBV infection. There are several limitations to our study, however. First, this was a single-arm study without a comparator group. Second, our study excluded HIV/HBV-coinfected patients who had an eGFR less than 30 mL/min/1.73m2 or decompensated cirrhosis; therefore, the results cannot be generalized to patients with severe renal or hepatic impairment. Third, only 89 participants had serial weight measurements, and the weight change observed in this study might not be representative. However, a moderate amount of weight gain (+1.75 kg) was also reported by Kuo et al[42] in a study including 693 HIV-infected Taiwanese who were switched to E/C/F/TAF from TDF-containing regimens. Fourth, the duration of this study (48 weeks) is short. The long-term impact of switch to E/C/F/TAF on renal function, BMD, and lipids warrants attention. Finally, we only measured HDV RNA in participants who tested positive for anti-HDV IgG. Therefore, the prevalence of HDV viremia might have been underestimated.

In conclusion, in HIV/HBV-coinfected patients, switch to E/C/F/TAF is well tolerated and can maintain HBV and HIV suppression and lead to improvements in proteinuria and BMD. Long-term investigations are needed to determine the clinical relevance of changes in lipids and weight after switch to E/C/F/TAF.

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