• Users Online: 642
  • Print this page
  • Email this page


 
 
Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 1  |  Page : 15-18

Study of atazanavir-induced hyperbilirubinemia among HIV patients on second-line anti-retroviral therapy


Department of Medicine, BMCRI, Bengaluru, Karnataka, India

Date of Submission22-Jul-2019
Date of Acceptance11-Dec-2019
Date of Web Publication14-Jan-2020

Correspondence Address:
Dr. G N Devamsh
Department of Medicine, Victoria Hospital, Bangalore Medical College and Research Institute, K R Market, Bengaluru - 560 002, Karnataka
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJIM.AJIM_32_19

Rights and Permissions
  Abstract 

Introduction: Ritonavir-boosted atazanavir (ATV/r) is the preferred second-line protease inhibitor option for HIV patients as per the NACO guidelines. Atazanavir is a protease inhibitor with several advantages including once-daily dosing, low pill burden, and favorable effect on lipid profile compared with other protease inhibitors. Atazanavir-induced hyperbilirubinemia is not widely studied in the Indian population. Aim: The aim is to study the occurrence of atazanavir-induced hyperbilirubinemia in HIV patients receiving second-line antiretroviral therapy (ART) and its outcome. Materials and Methods: One hundred and ten HIV patients treated with ATV/r-based second-line anti-retroviral regimen at a tertiary care hospital were included in the study and followed up for at least 12 months. Liver function tests were measured at baseline (at the time of initiation of ATV/r), at 6 months and 12 months of second-line ART. Results: The cumulative incidence of hyperbilirubinemia in the study population was 42.72% (n = 47). However, atazanavir-induced hyperbilirubinemia was self-limiting and did not mandate change in regimen. Conclusion: A significant number of patients on ATV/r-based second-line ART developed indirect hyperbilirubinemia. There was no significant elevation in liver enzymes. Most of the patients tolerated ATV/r-based regimen well and there was no need for discontinuation/change of regimen. Patients on ATV/r-based regimen must be followed up closely and counseled regarding adherence to therapy.

Keywords: Atazanavir, HIV patients, hyperbilirubinemia


How to cite this article:
Ravi K, Devamsh G N, Umesh K J, Prashant B C. Study of atazanavir-induced hyperbilirubinemia among HIV patients on second-line anti-retroviral therapy. APIK J Int Med 2020;8:15-8

How to cite this URL:
Ravi K, Devamsh G N, Umesh K J, Prashant B C. Study of atazanavir-induced hyperbilirubinemia among HIV patients on second-line anti-retroviral therapy. APIK J Int Med [serial online] 2020 [cited 2020 Feb 24];8:15-8. Available from: http://www.ajim.in/text.asp?2020/8/1/15/275980




  Introduction Top


HIV is a retrovirus belonging to family retroviridae, subfamily lentiviridae. It was first recognized in the United States in 1981. Since then, HIV has become a global pandemic. HIV/AIDS is the world's sixth largest cause of death in humans, accounting 3.1% of all deaths.[1] Approximately 37 million individuals were living with HIV infection as per the 2016 Joint United Nations Programme on HIV/AIDS (UNAIDS) estimate. A large majority of people with HIV infection reside in low- or middle-income countries. However, the estimated global incidence of new HIV infections reduced between 2000 and 2016. This reduction can be attributed to efforts undertaken for the prevention and treatment of HIV. There has been a lot of advancement in the understanding of HIV pathophysiology, HIV treatment, and the treatment/prevention of opportunistic infections in people living with HIV.

The treatment of HIV with monotherapy was associated with high mutation rates and has been discontinued.[2] The first-line regimen consists of two nucleoside analogs and a nonnucleoside reverse transcriptase inhibitor. As per the NACO guidelines, the second-line regimen consists of two nucleoside analogs and a protease inhibitor.

Second-line antiretroviral therapy (ART) is considered in patients with immunological, virological, or clinical failure on first-line ART. The commonly used second-line ART includes tenofovir, lamivudine, and ritonavir-boosted atazanavir (ATV/r).

Atazanavir is a protease inhibitor with once-daily dosing, low pill burden, and fewer effects on patient's lipid profile compared with other protease inhibitors.[3] It was approved by the Food and Drug Administration in 2003. Common side effects include nausea, vomiting, diarrhea, dizziness, jaundice, abdominal pain, and flu-like illness. Atazanavir-induced hyperbilirubinemia is a common side effect and it was defined as hyperbilirubinemia developing after the initiation of atazanavir therapy in absence of other causes for hyperbilirubinemia. According to the WHO consolidated guidelines 2016, indirect hyperbilirubinemia due to atazanavir is a clinically benign but stigmatizing side effect. It occurs due to inhibitory effect of atazanavir on uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) enzyme and prevents conversion of bilirubin to soluble glucuronide form. This side effect is more in ritonavir boosted regimen due to increased atazanavir plasma concentration.

Atazanavir is commonly used in second-line regimen for patients in India. However, there are not many studies conducted to assess the occurrence of hyperbilirubinemia in the Indian population on ATV/r combination regimen.

This study was done to know the occurrence of hyperbilirubinemia and its outcome in patients on second-line ART with ATV/r at a tertiary care hospital.


  Materials and Methods Top


This study was a longitudinal observational study conducted at a tertiary care hospital. The study was approved by the Institutional Ethical Committee and written informed consent was obtained from all patients who were included in the study. A total of 110 patients were included in the study. All patients in the study population were initiated on second-line ART containing tenofovir, lamivudine, and ATV/r at a dose of 300/100 mg/day. The patients on first-line ART who had treatment failure were examined by State AIDS Clinical Expert Panel and started on second-line regimen. Patients who had preexisting liver disease, hepatitis B, hepatitis C, and history of significant alcohol consumption were excluded from the study.

Liver function tests were performed at the time of initiation of second-line ART and at the end of 6 and 12 months of therapy.

Hyperbilirubinemia was graded from Grades I–IV in accordance with the AIDS Clinical Trials Group guidelines for total bilirubin levels [4]: Grade I (1.3–1.9 mg/dl); Grade II (1.9–3.1 mg/dl); Grade III (3.1–6.1 mg/dl); and Grade IV (>6.1 mg/dl).

Statistical analysis was performed using IBM ® Statistical Package for the Social Sciences (SPSS) software for windows and the analyzed data were expressed in percentages.


  Results Top


A total of 110 patients were included in the study. The age distribution of the study population is as follows: 5.45% (n = 6) belonged to 15–24 years, 33.63% (n = 37) belonged to 25–34 years, 40% (n = 44) belonged to 35–44 years, and 20.9% (n = 23) were above 45 years of age [Figure 1]. Majority of the patients belonged to the age bracket of 25–45 years with the mean age of the study population being 38.04 years.
Figure 1: Age distribution

Click here to view


Among the study population, 33% (n = 35) were females and 67% (n = 65) were males. Three patients on second-line ART died within 12 months of the initiation of therapy. One patient was lost to follow-up within 6 months of the initiation of second-line ART. There were no other dropouts from the study.

It was observed that 42.72% (n = 47) of the total study population on ATV/r regimen developed indirect hyperbilirubinemia. All the patients developed hyperbilirubinemia within the first 6 months of the initiation of second-line ART. Of the 47 patients, 35 were males and 12 patients were females [Table 1].
Table 1: Gender and hyperbilirubinemia

Click here to view


As per the AIDS clinical trials group guidelines, hyperbilirubinemia was graded from Grade I to Grade IV. Grade I was bilirubin 1.3–1.9 mg/dL; Grade II (1.9–3.1 mg/dL); Grade III (3.1–6.1 mg/dL), and Grade IV (>6.1 mg/dL). It was observed that at the end of 6 months, 40.42% (n = 19) of patients with hyperbilirubinemia belonged to Grade II [Figure 2].
Figure 2: Grades of hyperbilirubinemia

Click here to view


It was observed that 36.17% (n = 17) of patients who developed hyperbilirubinemia belonged to the age group 35–44 years [Table 2].
Table 2: Age distribution of hyperbilirubinemia

Click here to view


At the end of 12 months of follow-up, 10 had Grade I, 14 had Grade II and 11 had Grade III hyperbilirubinemia. The dose response relationship could not be assessed in the study since all the patients in the study population were treated with the same dose of 300 mg atazanavir boosted with 100 mg of ritonavir as per NACO.

There was an increase in the mean serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) of the study population. The baseline mean SGOT and SGPT levels were 33.46 and 28.65, respectively. At the end of 12 months follow-up, the mean SGOT and SGPT of the study population was 43.33 and 37.78, respectively. The trends of liver enzymes are shown in [Figure 3]. Although there was some elevation in the liver enzymes, it was within the laboratories upper limit of normal. None of the patients in the study population had hepatitis B or hepatitis C co-infection.
Figure 3: Trends of liver enzymes

Click here to view


There was a significant increase in the CD4 count of patients started on second-line ART with ATV/r. The mean baseline CD4 count of the study population was 136.87. The mean 12-month CD4 count was 334.27. There was a significant increase in CD4 count at 6 and 12 months as shown in [Figure 4].
Figure 4: CD4 count trend over 12 months

Click here to view


It was observed that the viral load of the study population was on the declining trend after initiation of second-line ART with ATV/r-based regimen. The baseline viral load was 202543.52 ± 288139.7. The mean viral load at the end of 12 months was 5811.2 ± 970.2 as shown in [Figure 5].
Figure 5: Viral load trend over 12 months

Click here to view


The mean CD4 count and viral load of the entire study population at baseline, 6 months and 12 months is compiled in [Table 3].
Table 3: CD4 count and viral load (mean±standard deviation)

Click here to view



  Discussion Top


HIV is no more a terminal illness. It has become a chronic infection that can be managed with highly active antiretroviral therapy. Due to the advent of several drugs, highly effective regimen, convenient dosage and low pill burden, patients are able to achieve sustained viral suppression with fewer side effects. However, there are several reports of multidrug-resistant virus in treatment experienced patients. These patients may not respond to first-line regimen. Second-line regimen containing ATV/r is advised as per the NACO guidelines. There are few studies conducted to assess hyperbilirubinemia and its outcome in patients on ATV/r.

In our study, 110 patients receiving atazanavir containing ART regimen were studied. The mean age of the study population was 38.04 years which was comparable to the mean age of 41 years in Choe et al.[5] and Subashini et al.[6] where mean age was 36 years. A study conducted by Savithri et al.[7] also had a mean age of 39 years.

Following the initiation of second-line ART, the study population showed a significant increase in the mean CD4 count. The median increase in CD4 count over 12 months was 197.4 cells/cu. mm. Pujades-Rodrígues et al.[8] showed an average CD4 gain of 135 cells/cu. mm. Similar results were observed in studies conducted by Savithri et al.[7] and Guha et al.[9] indirect hyperbilirubinemia was a common finding observed in our study population. Out of 110 patients started on ATV/r based regimen, 42.72% (n = 47) of patients included in the study developed hyperbilirubinemia. This was comparable to several other studies conducted. Castle study [10] and Rotger et al.[11] showed a cumulative incidence of 44% and 67%, respectively. A Sri Lankan study conducted by Rajapaksha et al.[12] showed an incidence of 40%.

In the present study, Grade I and II hyperbilirubinemia was more common, whereas Grade III and IV were more common in Castle study [10] and Choe et al.[5] study. Grade I and Grade III hyperbilirubinemia was more common in Savithri et al. study.[7]

Less than 1% of patients included in the Castle study discontinued atazanavir due to hyperbilirubinemia. In a study conducted by Rajapaksha et al.,[12] five patients discontinued therapy due to cosmetic reasons.

In our study, only one patient was initiated on third-line ART due to immunological failure on atazanavir-based regimen. All other patients were continued with ATV/r. The mechanism behind atazanavir-induced hyperbilirubinemia is the inhibition of UGT1A1 enzyme. This prevents conversion of bilirubin to soluble glucuronide form. This side effect is more in ritonavir-boosted regimen due to increased atazanavir plasma concentration.

Limitation of the study was small sample size and only 12 months of follow-up.


  Conclusion Top


It is noted that a sizeable number of patients receiving atazanavir/ritonavir in ART regimen develop indirect hyperbilirubinemia. This side effect is not associated with significant elevation of liver enzymes. There is a sustained viral suppression with atazanavir-containing second-line regimen. Although stigmatizing to the patient, hyperbilirubinemia due to atazanavir is not an indication to change the ART regimen. Patients should be regularly followed up and counseled regarding adherence to therapy. Discontinuation of regimen due to cosmetic concerns should be discouraged. No life-threatening hepatic dysfunction has been reported. Discontinuation of ATV/r is advised only when there is a life-threatening complication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Top 10 Causes of Death, WHO. Available from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html. [Last accessed on 2019 Jul 15].  Back to cited text no. 1
    
2.
Coffin JM. HIV population dynamics in vivo: Implications for genetic variation, pathogenesis, and therapy. Science 1995;267:483-9.  Back to cited text no. 2
    
3.
Havlir DV, O'Marro SD. Atazanavir: New option for treatment of HIV infection. Clin Infect Dis 2004;38:1599-604.  Back to cited text no. 3
    
4.
Fellay J, Boubaker K, Ledergerber B, Bernasconi E, Furrer H, Battegay M, et al. Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet 2001;358:1322-7.  Back to cited text no. 4
    
5.
Choe PG, Park WB, Song JS, Kim NH, Song KH, Park SW, et al. Incidence of atazanavir-associated hyperbilirubinemia in Korean HIV patients: 30 months follow-up results in a population with low UDP-glucuronosyltransferase1A1*28 allele frequency. J Korean Med Sci 2010;25:1427-30.  Back to cited text no. 5
    
6.
Subashini D, Dinesha TR, Boobalan J, Samuel LC, Poongulali S, Pradeep A, et al. Incidence of atazanavir- associated adverse drug reactions in second-line drugs treated south Indian HIV-1 infected patients. Indian J Pharmacol 2016;48:582-5.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Desai S, Bagewadi HG, Harinika G. Hyperbilirubinemia during atazanavir treatment in HIV/AIDS patients taking second line ART drugs. Int J Res Pharmacol Pharmacother 2018;7:01-6.  Back to cited text no. 7
    
8.
Pujades-Rodríguez M, O'Brien D, Humblet P, Calmy A. Second-line antiretroviral therapy in resource-limited settings: The experience of Médecins Sans Frontières. AIDS 2008;22:1305-12.  Back to cited text no. 8
    
9.
Guha SK. Effectiveness of Addition of Zidovudine to Second line Antiretroviral Regimen of Tenofovir, Lamivudine and Lopinavir/Ritonavir in Patients Failing Thymidine Analogue Based First Line Atiretroviral Therapy in India; 2011. Available from: http://Pag.ias2011.org/Abstracts.aspx?AID=3419. [Last accessed on 2018 May 20].  Back to cited text no. 9
    
10.
McDonald C, Uy J, Hu W, Wirtz V, Juethner S, Butcher D, et al. Clinical significance of hyperbilirubinemia among HIV-1-infected patients treated with atazanavir/ritonavir through 96 weeks in the CASTLE study. AIDS Patient Care STDS 2012;26:259-64.  Back to cited text no. 10
    
11.
Rotger M, Taffe P, Bleiber G, Gunthard HF, Furrer H, Vernazza P, et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis 2005;192:1381-6.  Back to cited text no. 11
    
12.
Rajapaksha DI, Azraan A, Rajapaksa LI. Hyperbilirubinemia during atazanavir treatment in people living with HIV (PLHIV), Sri Lanka. Sri Lanka J Sexual Health HIV Med (Sri Lanka JoSHH) 2016;2:35-9.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed105    
    Printed1    
    Emailed0    
    PDF Downloaded28    
    Comments [Add]    

Recommend this journal