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Liver damage in patients living with HIV on antiretroviral treatment with normal baseline liver function and without HBV/HCV infection: an 11-year retrospective cohort study in Guangxi, China

Objective To characterise the association between duration of exposure to antiretroviral treatment (ART) and liver damage in HIV patients with an initially normal baseline liver function and without hepatitis B virus (HBV)/hepatitis C virus (HCV) infection. Methods A retrospective cohort study was conducted in HIV-infected individuals with normal liver function parameters at ART initiation and without HBV/HCV infection, from 14 April 2004 to 13 April 2015 in Guigang city, Guangxi, China. The association between duration of ART and liver damage (grade II–IV liver enzyme elevation [LEE] and/or total bilirubin elevation [TBE]), was analysed. Cox regression was used to examine the factors related to liver damage. Results Of 2119 eligible patients, 12.41% (263/2119) developed liver damage (grade II–IV LEE/TBE) and contributed 4.11/100 person-years crude incidence rate. The highest liver damage incidence was observed in patients with 6–12 months’ ART (15.16/100 person-years). The incidence decreased to 5.56/100 person-years in patients with 12–18 months’ ART and 3.13/100 person years in patients with 18–24 months’ ART, and then maintained at a relatively low and stable level in patients with 2 years’ ART or longer (average of 3.65/100 person-years). Cox regression analysis revealed that current WHO disease stage II, III or IV (compared with stage I) were the risk factors for liver damage, while baseline disease stage II, III (compared with stage I) and current regimen 3TC+AZT+NVP were the protective factors for liver damage. Conclusions Liver damage always exists among HIV-infected patients on ART with normal baseline liver function and without HBV/HCV infection. Nevertheless, cumulative ART duration does not increase the risk of liver damage. ART could tend to be long-term, however, monitoring and management of liver damage among patients on ART are also important in clinical therapy.

(1) The manuscript is quite clear, but may benefit from being reread by someone fluent in English to check for grammar and spelling -for example, the word should be "median" with an "n" at the end.
(2) The primary definition of LEE was not exactly clear to me. On page 7, line 3 it talks about a single value of AST or ALT >40, but on the same page line 56 talks about the requirement for two values to be raised. It wasn't clear to me which definition was used when in the manuscript (3) Along the same lines -there is no information on the levels that these enzymes reached -what was the average value at the time of the event? If it is quite low, then this could be a concern. Could the early rate in the first six months be a result of regression to the mean -i.e. those entering the study with values just below the cutoff returning to values just above 40? (4) Are the results of the study sensitive to the use of other cut-offs for the definition of LEE? A value above 40 is still clinically quite low and other standard definitions such as >2.5 times the ULN or >5 times the ULN would be interesting sensitivity analyses (5) In the statistical analysis, the rates at different time points were compared using a chi-squared test. Would it be better to perform a test (such as by Poisson regression) to account for the use of person-time? Similarly, how were the confidence intervals for the rates calculated? (6) A number of time points have been compared in Figure 2. What adjustments were made for multiple testing and a high risk of a Type I error.
(7) It would be useful to provide information on the median and range follow-up per person, the median (range) number of AST/ALT/BIL measurements per person, and the time between measurements. (8) Table 1 stratifies characteristics by subsequent LEE/TBE. This is probably ok, but it should really include information on the length of follow-up of each group as the LLE group may have had an event simply because they were followed for longer (9) I would not agree with the beginning of the discussion (page 14, line 3) which states "indicating that the existence of hepatic damage was associated with ART". There was one time period early on with a very high rate, and then the rate was quite stable from then on.

GENERAL COMMENTS
Although clearly written, the paper has some important limitations: 1) Was HBV/HCV testing routinely performed in all patients? It is unclear whether all patients included in the analysis tested negative for HCV/HBV or if those without an available test were included.
2) The end-point (any grade ALT/AST/bilirubin elevation) is not very clinically relevant. I suggest to assess the rate grade III elevation (or at least grade II) 3) Please clarify whether only formerly naive patients were included 4) NVP and higher CD4 count were associated, in this paper, with ALT elevations. Was NVP used according to manifacturer reccomendation (ie, avoided in women with CD4 count >250)? An interaction btw NVP and CD4 count and/or gender could be tested. Please also comment these results in light of results of another chinese paper on a similar topics (J Acquir Immune Defic Syndr. 2013 Apr 15;62(5):540-5.). Toxic-allergic reaction to NVP also explains why incidence of LEE was higher in the first 6 months of treatment 5) I dont think it is true that most of the previous study were not controlled for baseline transaminase level (It is quite the opposite) 6) A major limitation of the paper is the lack of info on common causes of transaminase elevations, such as alcohol consumption or metabolic syndrome. This should be commented 7) From the discussion "One possible reason for higher prevalence and overall incidence of LEE/TBE in our study is that we used three hepatic function indexes (AST, ALT, TB) to define liver dysfunction". I disagree, the main reason is the threshold chosen to define LEE. Most of the study use at least ALT and AST 8) Given the fact that total bilirubin elevation was included in the definition of "hepatotoxicity" I wonder whether ARV drugs that can inhibit UGTA1, such as atazanavir or indinavir Minor comments: -Please check "Mediam" instead of "Median" throughout the paper -Please cite (eg "a study by Carlo" instead of "Ti

GENERAL COMMENTS
The text must be justified in both sides. Table 1, Age (years) at diagnosis: first number "< 39", because the next range is 40-60, it is the same in: Age (years) at ART Initiation, the first number range "<39" In Table 1 Transmission Route, It would be interesting to know about the history of injection drug use if it was posible.
In Table 2 are included demographic characteritics wich are described in table 1, I think this table could start with the transmission route In respect of references, the first author is not necessary to be in bold.

GENERAL COMMENTS
This study conducted at one single HIV clinic in China examined retrospectively the incidence of liver enzymes elevations in 2230 HIV+ individuals wih no baseline liver damage attended during 11 years. The authors found that LEE occued in 27% of patients during he first 6 months of antiretroviral therapy, especially when having high CD4 counts and including d4T, EFV, NVP or LPV/r. The authors concluded that cumulative ART is not associated with hepatic damage.  (7):1187-8.

VERSION 1 -AUTHOR RESPONSE
Reviewer #1: 1. The manuscript is quite clear, but may benefit from being re-read by someone fluent in English to check for grammar and spelling -for example, the word should be "median" with an "n" at the end.
Response: Thank the reviewer for this suggestion. This manuscript has been thoroughly checked in English grammar and spelling by a researcher fluent in English.
2. The primary definition of LEE was not exactly clear to me. On page 7, line 3 it talks about a single value of AST or ALT >40, but on the same page line 56 talks about the requirement for two values to be raised. It wasn't clear to me which definition was used when in the manuscript.
Response: We appreciate this important comment. According to this suggestion together with comments 3, 4 of reviewer 1 and comment 2 of reviewer 2, we have used a stricter standard to define hepatic dysfunction (liver damage) in the revised paper, which is comparable to the definitions of several similar studies in the field ( The upper level of normality (ULN) was defined as AST=40 U/L, ALT=40 U/L, and TBIL=20 μmol/L. Any one index exceeding the ULN was considered as abnormal levels (grade I-IV LEE/TBE). Grade I-IV LEE are defined when elevation reaches 1-2.5, 2.5-5.0, 5.0-10.0, >10.0 times as high as the ULN, respectively; and grade I-IV TBE are defined when elevation reaches 1-1.5, 1.5-2.5, 2.5-5.0, >5.0 times as high as the ULN, respectively. In the revised paper, we defined liver damage (hepatic dysfunction) when grade II-IV LEE/TBE occurred. The normal hepatic function group included patients who did not have LEE/TBE or only had grade I LEE/TBE, and liver damage group included patients who had grade II or III or IV LEE/TBE. We have clearly shown these standard and definitions in the revised paper (Page 6, Para 4).
Due to the changed standard to define liver damage (hepatic dysfunction), we have reorganized and reanalyzed the data in the revised paper. Although the incidence of liver damage decreased compared to the original one, and the identified influencing factors are difference, the main conclusions are still consistent with those of the original paper.
3. Along the same lines -there is no information on the levels that these enzymes reached -what was the average value at the time of the event? If it is quite low, then this could be a concern. Could the early rate in the first six months be a result of regression to the mean -i.e. those entering the study with values just below the cut-off returning to values just above 40?
Response: We appreciate this comment. Similar to the response to the previous comment of reviewer 1, we have changed the standard and used a stricter one to define liver damage (hepatic dysfunction). Liver damage was defined when grade II-IV LEE/TBE occurred. This new standard avoided the concerns that the reviewer mentioned in this comment. In addition, using new standard, the early incidence rates in the first 6 months and 6-12 months were still greatly higher than those in the subsequent time intervals (revised Figure 2), which is also consistent with the results in the original paper.
4. Are the results of the study sensitive to the use of other cut-offs for the definition of LEE? A value above 40 is still clinically quite low and other standard definitions such as >2.5 times the ULN or >5 times the ULN would be interesting sensitivity analyses Response: Thank the reviewer for this excellent suggestion. In the revised paper, we used >2.5 times as high as AST/ALT ULN or >1.5 times as high as TBIL ULN for the definition of liver damage (hepatic dysfunction), which increases sensitivity and convincing of the analyses. Using these new cut-offs, we reorganized and reanalyzed the data and got the similar conclusions as the original paper. In addition, detailed responses to this concern can also be seen in the responses to the last two comments of reviewer 1.
5. In the statistical analysis, the rates at different time points were compared using a chi-squared test.
Would it be better to perform a test (such as by Poisson regression) to account for the use of persontime? Similarly, how were the confidence intervals for the rates calculated?
Response: Thank the reviewer for this comment. Poisson regression, we understood, is not suitable for the analysis of censored data. In our study, some patients did not develop to the "endpoints" (grade II-IV LEE/TBE) until the end of the study, which could be categorize into censored data. Therefore, we considered that Poisson regression is not suitable for analyzing our data. In fact, in the revised paper, we used Log-rank test rather than Chi-squared test for the comparison of crude incidence rates at different ART duration time groups (revised Figure 2). The Chi-squared test (χ2 linear trend test) was used to verify the linear trend of incidence rate between 0.5-2 and ≥2 years ART duration. In the original paper, this information was not explained clearly and thus led to misunderstanding. In the revised paper, the results were described (Page 12, Para 1) along with the introduction of statistical method used (Page 7, Para 4).
As for the confidence intervals for the rates calculated, because the cohort in this study is actually a kind of open cohort, we used "incidence density (ID)" (person-year) to calculate incidence rate, with a 95% confidence interval (CI). In the revised Figure 2, the incidence densities with their 95% CI were shown, which were also clearly explained in the Figure legend (revised Figure 2 and its legend). Figure 2. What adjustments were made for multiple testing and a high risk of a Type I error.

A number of time points have been compared in
Response: Thank the reviewer for this comment. We agreed with that multiple comparing of rates at different time points may result in the increase of Type I error. In the revised paper, we used χ2 linear trend test to analyze the linear trend of the incidence rates at different time points, to avoid the high risk of Type I error of multiple testing of different groups.
7. It would be useful to provide information on the median and range follow-up per person, the median (range) number of AST/ALT/BIL measurements per person, and the time between measurements.
Response: Thank the reviewer for this comment. In the revised paper, we have shown the median (IQR) of baseline AST/ALT/TBIL, median AST/ALT/TBIL during follow-up and duration of ART in normal hepatic function group and liver damage group (please seer result section "Clinical characteristics of study population" and Table 2).
8. Table 1 stratifies characteristics by subsequent LEE/TBE. This is probably ok, but it should really include information on the length of follow-up of each group as the LLE group may have had an event simply because they were followed for longer.
Response: Thank the reviewer for this comment. In the revised paper, we have shown the follow-up length of each group in Table 2 ("during of ART"). Also, as the reviewer guessed, liver damage group actually had longer follow-up time than normal hepatic function group (Nonparametric test of the two groups shows a significantly difference). Therefore, we used Cox regression analysis, to assess the related factors of liver damage, which could take the length of follow-up into account and exclude the influence of different follow-up period. In the revised paper, we have included this information in Result Section (Page 12, Para 3).
9. I would not agree with the beginning of the discussion (page 14, line 3) which states "indicating that the existence of hepatic damage was associated with ART". There was one time period early on with a very high rate, and then the rate was quite stable from then on.