Hyperbilirubinemia during atazanavir treatment in people living with HIV ( PLHIV ) , Sri Lanka

Introduction: Atazanavir (ATV) is an antiretroviral drug of the protease inhibitor class. It is used to treat HIV infection in combination with other HIV medications. Atazanavir was first introduced to National STD/AIDs control programme of Sri Lanka in 2014. Symptomatic hyperbilirubinemia is a common adverse effect associated with atazanavir use. Objective of this study was to see the significance of hyperbilirubinemia with ritonavir boosted atazanavir use among people living with HIV receiving antiretroviral therapy. Method: This was a descriptive cross sectional study carried out among all PLHIV started on retonavir boosted atazanavir based regimens, who were receiving care services at National STD/AIDS control programme, Sri Lanka. Results: Total of 40 PLHIV who had taken atazanavir more than 90 days during the study period (28 months) were analyzed. Cumulative incidence of hyperbilirunemia of grade 2 or above during the study period was 40% (n=16). Almost all PLHIV had isolated indirect hyperbilirubinemia. Conclusions: Significant proportion of patients (40%) developed grade 2 or more indirect hyperbilirubinemia following initiation of atazanavir based therapy and 25% (n=10) improved symptomatically and biochemically during follow up. But in 12.5% (n=5) patients antiretroviral regimen had to be substituted.


World
Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection 2016, recommends two nucleoside/ nucleotide reverse transcriptase inhibitors plus a non neucleoside reverse transcriptase inhibitor or an integrase inhibitor as first line antiretroviral therapy (ART).National guideline of antiretroviral drugs for treating and prevention of HIV infection 2014, Sri Lanka prefer tenofovir (TDF), emtricitabine (FTC) plus efavirenz (EFV) as first line ART regimen.There are instances, where we use protease inhibitor class in first line instead of efavirenz in some patients such as patients with psychiatric illness, history of suicidal attempts and who are engaged in shift duties especially night tasks, etc.When first line antiretroviral regimen failed, we prefer second line regimen constitute with a boosted protease inhibitor.In Sri Lanka, protease inhibitor class is also used as a switching drug to people who cannot tolerate non nucleoside reverse transcriptase inhibitor class.Ritonavir boosted atazanavir (ATV/r), lopinavir (LPV/r) and darunavir (DRV/r) are the available options in Sri Lanka.Darunavir

Method
A descriptive cross sectional study was conducted among all the PLHIV who initiated antiretroviral therapy (ART) with atazanavir (300mg per day) from May 2014 to August 2016 (28 months) and received care services at the Colombo, HIV clinic of the National STD/ AIDS control programme, Sri Lanka.PLHIV who were started on atazanavir based regimen at least 90 days prior to study period were included in the study.Forty (40) study subjects were included in the study.Atazanavir exposure was evaluated from records of all patients.The prescription of antiretroviral with the starting and ending dates were identified through patient's Papers __________________________________________________________________________________ records.Baseline liver profile tests, hepatitis B surface antigen and hepatitis C antibody screening test, which were carried out prior to initiation of antiretroviral therapy were studied and documented.Liver profiles were followed up at regular intervals of 1 month, 3 months, 6 months and thereafter in every 6 months following initiation of atazanavir.The total bilirubin level recorded at any point during the follow up was taken in to account in deciding the severity grading of toxicity.Data was collected using a data extraction sheet and data was processed and analyzed by using Microsoft excel 2013.

Results
In the study population (n=40), majority were males (68%).An overall mean CD4 cell count at the initiation of atazanavir was 481 cells/µl (Mdn=378 cells/µl) and the range 16 -960 cells/µl.Distribution of other baseline characteristics is tabulated in table 1.As baseline, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and serum bilirubin levels were measured prior to the initiation of atazanavir/ritonavir based therapy.All the study participants had total bilirubin levels less than upper limit of normal and liver enzyme levels less than twice the upper limit normal (ULN) before starting atazanavir.All the study subjects had been tested for hepatitis B and C coinfections prior to initiation of therapy and none were positive.(Table 1) They were followed up at monthly intervals and liver profiles repeated at 1 month, 3 months and 6 months after the initiation of antiretroviral therapy.Thereafter, in every 6 months if there were no other indications.Cumulative incidence of hyperbilirunaemia (toxicity grade 2 or above) during the period of 28 months was 40% (n=16) and of them 35% (n=14) were symptomatic with scleral icterus.In all cases hyperbilirubinemia was developed within first 90 days of initiation of therapy.
Among those who developed indirect hyperbilirubinemia, none showed elevations of AST, ALT, GGT, ALP more than twice the upper limit of normal.Hyperbilirubinemia due to unconjugated hyperbilirubinemia was seen among all study subjects.

Discussion
Several clinical studies demonstrated atazanavir induced hyperbilirubinemia.CASTLE was a randomized 96 weeks trial which demonstrated clinical significance of hyperbilirubinemia among HIV 1 infected patients treated with ritonavir boosted atazanavir.Overall 44% of patients receiving atazanavir/ritonavir had hyperbilirubinemia (grade 3-4) at any time during the 96 weeks study.Less than 1% of patients discontinued atazanavir due to hyperbilirubinemia, jaundice or scleral icterus (3).Atazanavir and other determinants of hyperbilirubinemia studied in a cohort of 1150 HIV positive patients of 9 year follow up period in Canada.Cumulative incidence of hyperbilirubinemia of grade 3 and 4 after 1, 5 and 8 years exposure to atazanavir were 30.1%, 73.4% and 83.6%, respectively (4).Findings among PLHIV in Sri Lanka were also supported by CASTLE and atazanavir and other determinants cohort study of 1150 patients in Canada.
This study provided information on use of atazanavir among Sri Lankan PLHIV.All the patients started on atazanavir based therapy since 2014 were included in the study.In this group 3 PLHIV had poor adherence and experienced virological failure while another PLHIV defaulted for follow up.Cumulative incidence of hyperbilirubinemia during 28 months period was 40%.Atazanavir associated hyperbilirubinemia was not related with elevations of other liver enzymes, but it led to discontinuation in 5 patients due to cosmetic reasons.However, there were few limitations which need to be mentioned.Firstly, small sample size is a concern.Monitoring of liver functions could be done at more regular intervals, if it was available consistently.

Conclusion
Significant proportion of study subjects (40%) developed isolated indirect hyperbilirubinemia during the period studied (28 months).However, none showed elevations of liver enzymes more than twice the upper limit normal.Cosmetic issues were a concern among study subjects and led to discontinuation of therapy in 12.5%.As our sample size is small we cannot conclude suitability of atazanavir as a first line therapy.We need to follow up larger cohort of patients to predict about adverse effects and outcome of atazanavir use.

table 2 ) Papers __________________________________________________________________________________ Sri Lanka Journal of Sexual Health and HIV Medicine (Sri Lanka JoSHH), Volume 2, December 2016 38Table 2 :
Distribution by level of toxicity