Week 96 Results of Switching from Tenofovir Disoproxil Fumarate-Based Antiretroviral Therapy to Coformulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide among HIV/Hepatitis B Virus-Coinfected Patients

ABSTRACT Data regarding the durability of tenofovir alafenamide (TAF)-containing antiretroviral therapy (ART) in maintaining hepatitis B virus (HBV) viral suppression among HIV/HBV-coinfected patients are limited. Between February and October 2018, 274 HIV/HBV-coinfected participants who had achieved HIV RNA of <50 copies/mL with tenofovir disoproxil fumarate (TDF)-containing ART and switched to elvitegravir/cobicistat/emtricitabine/TAF were prospectively enrolled. Serial plasma HIV and HBV viral loads, HBV and hepatitis D virus (HDV) serology, renal parameters, metabolic profiles, and bone mineral density (BMD) were assessed through 96 weeks. At baseline and weeks 48, 72, and 96, 5.8%, 5.1%, 5.8%, and 5.1% of the participants had plasma HBV DNA of ≥20 IU/mL, and 0%, 0.7%, 1.5%, and 2.2% had HIV RNA of ≥50 copies/mL, respectively. Hepatitis B surface antigen (HBsAg) loss occurred in 1.5% of 274 participants, and hepatitis B e-antigen (HBeAg) loss or seroconversion occurred in 14.3% of 35 HBeAg-positive participants. Compared with baseline, the median urine protein-to-creatinine ratio (79 versus 63 mg/g, P < 0.001) and β2-microglobulin-to-creatinine ratio (165 versus 83 μg/g, P < 0.001) continued to decrease at week 96. BMD of the spine and hip slightly increased (mean change, +0.9% and +0.5%, respectively). The median triglycerides, total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol increased from baseline to week 96 (116 versus 141, 166 versus 190, 99 versus 117, and 42 versus 47 mg/dL, respectively; all P < 0.001), and most of the increases occurred in the first 48 weeks of the switch. Our study showed that switching from TDF-containing ART to elvitegravir/cobicistat/emtricitabine/TAF maintained HBV and HIV viral suppression through 96 weeks among HIV/HBV-coinfected patients. Proteinuria continued to improve, while fasting lipids increased and BMD stabilized at 96 weeks after the switch. IMPORTANCE Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide as a maintenance therapy showed durable and high rates of viral suppression for HIV/HBV-coinfected patients, with only 5.1% and 2.2% of patients having HBV DNA of ≥20 IU/mL and HIV RNA of ≥50 copies/mL, respectively, at 96 weeks. Our study fills the data gap on the long-term clinical effectiveness of tenofovir alafenamide-containing antiretroviral therapy in people living with HIV who have HBV coinfection.

1.This study analyse data of the continuation to 96wk of the same cohort HIV/HBV whose data they had already analysed and published Authors use an identical approach and even the same Figures adapted to 96 wk as in the work they previously published (Huang et . J AIDS 2021;86: 473-481 2.E/C/F/TAF is rarely used nowadays in Western countries.Patients on E/C/F/TAF are usually switched to BIC/C/F/TAF (Biktyarvy) avoiding cobicistat. Minor points 1.Could you report the weight changes after switching to E/C/F/TAF at 96 wk?. At 48wk there was a significant weight gain of 3 Kg (JAIDS 2021;86: 473-481). This is an interesting point to report in the present manuscript. 2.Could you explain the differences between HBeAg loss and HbeAg (negative) seroconversion?. They look very similar to me (Results section lines 175-176) 3.RPR titers were more elevated among anti-HDV-positive patients but not significantly (57.5% vs. 41.6%, p=0.061 not significant) Therefore there is a tendence but these data cannot confirm here that sexual contact is an important route of HDV transmission (Discussion section , lines 305-308) Reviewer #2 (Comments for the Author): 1. The drop outs should be discussed better in the beginning. 44 out of 274 did not complete the study but a full account is only given for 19 of them. 2. discuss long term impact of increased levels of fasting lipids for liver pathology in HBV infected people. 3. Shortcomings are reported but dampen impact of the study (eg no monitoring of lipid lowering drugs) Typo's Line 84 : having instead of had Line 319: were not included Reviewer #3 (Comments for the Author): Reviewer Comments to Author: The authors studied the efficacy and safety of switching from tenofovir disoproxil fumarate-based antiretroviral therapy to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (E/C/F/TAF) in HIV/hepatitis B virus (HBV)coinfected Asian patients from Baseline to Week 96.

GENERAL OBSERVATIONS
• Similar study, as also mentioned in Ref 12, has already been conducted and published. In terms of results, you observed in this new unpublished paper same virologic, serologic and biochemical responses compared to the published study; although, in this new paper, you kept observing patients up to 96 weeks. Considering these results, this new paper should be re-adapted in a form that includes a brief summary of the previous study (by reporting the observed results at 24 and 48 weeks), and the new results related with follow up at 72 and 96 weeks. Repeating all the work already done in the published paper (from baseline to 48 hours) is unnecessary and can be confusing (e.g. LINE 144, LINE 341). In conclusion, it is recommended to edit this manuscript by making a summary of the results obtained so far (baseline and week 48 from the study of REF. 12)  • LINE 132-133: Reference required; please add one or more references related with the low evaluation of the virologic and serologic parameters in the co-infected patients.
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Huang et al report here the 96wk results of switching from a TDF-based regimen to coformulated E/C/F/TAF in 274 HIV/HBV coinfected Chinese patients. The authors conclude that switching to E/C/F/TAF can maintain HBV and HIV suppression and lead to improvement in proteinuria and BMD. This observational study is interesting because brings forward virological data after switching to E/C/F/TAF of a large HIV/HBV coinfected cohort with a long follow-up.
This work has some problems that I need to point out: Major points 1.This study analyse data of the continuation to 96wk of the same cohort HIV/HBV whose data they had already analysed and published Authors use an identical approach and even the same Figures adapted to 96 wk as in the work they previously published (Huang et . J AIDS 2021;86: 473-481 2.E/C/F/TAF is rarely used nowadays in Western countries.Patients on E/C/F/TAF are usually switched to BIC/C/F/TAF (Biktyarvy) avoiding cobicistat.
Minor points 1.Could you report the weight changes after switching to E/C/F/TAF at 96 wk?. At 48wk there was a significant weight gain of 3 Kg (JAIDS 2021;86: 473-481). This is an interesting point to report in the present manuscript.
2.Could you explain the differences between HBeAg loss and HbeAg (negative) seroconversion?. They look very similar to me (Results section lines 175-176) 3.RPR titers were more elevated among anti-HDV-positive patients but not significantly (57.5% vs. 41.6%, p=0.061 not significant) Therefore there is a tendence but these data cannot confirm here that sexual contact is an important route of HDV transmission (Discussion section , lines 305-308)

Reviewer Comments to Author:
The authors studied the efficacy and safety of switching from tenofovir disoproxil fumarate-based antiretroviral therapy to coformulated elvitegravir, cobicistat,  Lines 211-220 (underlined): "BMD assessment was performed in 138 participants at week 96. Among these participants, the mean BMD of the spine and hip increased and peaked at week 48 (+2.0% and +1.5%, respectively), and slightly declined but still higher at week 96 than those at baseline (+0.9% and +0.5%, respectively) ( Fig. 4A and Table S4). For the participants who had paired   Figure 4 in the revised manuscript: We re-analyze the changes of bone mineral density by excluding the participants who did not have paired BMD assessments at baseline and week 96. In addition, the evolution of T-score category after 5 switching to E/c/F/TAF is analyzed. Figure 4A presents the mean percentage change in BMD. Figure 4B shows the changes of T-score categories (normal, osteopenia and osteoporosis) of the spine and hip from baseline to week 96.  participants completed the 96 weeks of follow-up (Fig. S1). Thirteen (4.7%) and 31 (11.3%) participants dropped out of the study before and after week 48, respectively.
After week 48, 31 participants withdrew from the study because of withdrawal of consent (n=12), drug-drug interaction with E/c/F/TAF (n=8), loss to follow-up (n=8), and adverse effects (n=3, including hyperlipidemia, occurrence of non-ST-elevation 8 myocardial infarction, and depression). Six participants switched to other TAF-containing ART after 48 weeks and continued in the study." Comment 2. Discuss long term impact of increased levels of fasting lipids for liver pathology in HBV infected people.
Reply: Thank you for the comment. We agree with the reviewer that impacts of increased fasting lipids on liver pathology is an important issue and should be discussed for PLWH with HBV coinfection. We add several sentences in the fourth paragraph of Discussion (lines 302 to 309, underlined) to discuss this point, as follows: "Another concern is the impact of increased fasting lipids on the liver.
Hyperlipidemia was found to be associated with fatty liver disease in PLWH with HBV coinfection. Steatosis alone was independently correlated with higher ALT after adjustment for HBV DNA level. Prior studies revealed that use of TAF or integrase   191-196 (underlined): "The UPCR and urine β2-microglobulin-to-creatinine ratio continued to decline from week 48 to week 96, whereas the decrement of urine albumin-to-creatinine ratio (UACR) were similar between week 48 and week 96 (-15.3% vs. -12.5%) ( Fig. 2A). The prevalence of proteinuria by urine dipstick tests decreased from 19.0% at baseline to 3.9% at week 96. Similarly, the proportion of the participants with UPCR ≥150 mg/g decreased from 12.1% at baseline to 7.9% at week 96 (Fig. 2B)." participants at week 96. Among these participants, the mean BMD of the spine and hip increased and peaked at week 48 (+2.0% and +1.5%, respectively), and slightly declined but still higher at week 96 than those at baseline (+0.9% and +0.5%, respectively) ( Fig. 4A and Table S4). For the participants who had paired BMD assessments at baseline and week 96, we inspected the changes of T-score categories after switching to TAF-containing ART. At week 96, 44.8% of the 1 2 participants who had osteopenia of the spine before switch regressed to normal T-score, and 33.3% of those who had osteoporosis of the spine regressed to osteopenia. Similar proportions of changes were observed for T-score of the hip (Fig. 4B)."  Figure 1: We remove the data observed at week 24 and Figure 1A and 1B are merged into one figure to make it simple.
 Figure 2: After consideration, we preserve the change in quantitative proteinuria at each time point to better depict the trends (Figure 2A). However, we add a new figure ( Figure 2B in the revised manuscript) to show the change in the proportion of the participants with abnormal UPCR or UACR.
 Figure 3 in the revised manuscript: The change in fasting lipids is separated into  Figure 4 in the revised manuscript: We re-analyze the changes of bone mineral density by excluding the participants who did not have paired BMD assessments at baseline and week 96. In addition, the evolution of T-score category after switching to E/c/F/TAF is analyzed. Figure 4A presents the mean percentage change in BMD. Figure 4B shows the changes of T-score categories (normal, osteopenia and osteoporosis) of the spine and hip from baseline to week 96.