|Year : 2019 | Volume
| Issue : 4 | Page : 195-198
Absence of human leukocyte antigen-B*57:01 amongst patients on antiretroviral therapy in Nigeria: Implications for use of abacavir
Oche O Agbaji1, Maxwell O Akanbi2, Ihedinachi Otoh3, Patricia E Agaba4, Rolake Akinsola5, Victoria Okolie5, Placid O Ugoagwu3, Aliyu A Babadoko6, Adewumi Adediran7, Finomo O Finomo8, Jonah O Abah9, Haruna M Muktar6, Alani S Akanmu7
1 Department of Medicine, University of Jos/Jos University Teaching Hospital; Department of AIDS Prevention Initiative in Nigeria (APIN)–Supported HIV Treatment Centre, Jos University Teaching Hospital, Jos, Nigeria
2 Department of Medicine, University of Jos/Jos University Teaching Hospital; Department of AIDS Prevention Initiative in Nigeria (APIN)–Supported HIV Treatment Centre, Jos University Teaching Hospital, Jos, Nigeria; Health Sciences Integrated PhD Program, Center for Education in Health Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
3 Department of AIDS Prevention Initiative in Nigeria (APIN)–Supported HIV Treatment Centre, Jos University Teaching Hospital, Jos, Nigeria
4 Department of AIDS Prevention Initiative in Nigeria (APIN)–Supported HIV Treatment Centre, Jos University Teaching Hospital; Department of Family Medicine, University of Jos/Jos University Teaching Hospital, Jos, Nigeria
5 Department of Molecular Biology Research Laboratory, Lagos University Teaching Hospital, Lagos, Nigeria
6 Department of Hematology, Ahmadu Bello University/Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
7 Department of Hematology, College of Medicine, University of Lagos/Lagos University Teaching Hospital, Lagos, Nigeria
8 Department of Medicine, Federal Medical Centre, Yenagoa, Nigeria
9 Department of Family Medicine, Federal Medical Centre, Makurdi, Nigeria
|Date of Web Publication||4-Oct-2019|
Dr. Maxwell O Akanbi
Health Sciences Integrated PhD Program, Center for Education in Health Sciences, Feinberg School of Medicine Northwestern University, Chicago, Illinois
Source of Support: None, Conflict of Interest: None
Background: The presence of human leukocyte antigen (HLA) B*57:01 allele predicts hypersensitivity reaction (HSR) to abacavir (ABC), a nucleoside reverse-transcriptase inhibitor used for human immunodeficiency virus (HIV) treatment. However, the prevalence of this allele amongst Nigerians with HIV is yet to be established. We aimed to determine the prevalence of HLA-B*57:01 allele amongst Nigerians with HIV infection. Methods: We conducted a multicentre cross-sectional epidemiologic survey. Between April 2016 and April 2017, patients were enrolled across five HIV treatment facilities in Nigeria. Participants' demographic information and their history of ABC exposure were obtained, and venous blood was obtained for HLA typing. Results: One thousand five hundred and four (1504) adults were enrolled, with a mean age of 44.6 ± 10.7 years, 1078 (71.7%) were female. 1463 (97.3%) were on antiretroviral therapy. ABC use was reported by 12 (0.8%) participants and none reported HSR. Of 1500 blood samples that were processed, 1458 (97.2%) were successfully typed. Of these, 132 (9.1%) were HLA-B*57 positive using non-specific low-resolution HLA-B*5701 primer mix. On further analysis, none of the 132 samples (0%) had the HLA-B*5701 allele. Conclusion: HLA-B*5701allele is rare amongst Nigerians.
Keywords: Abacavir, Africa, antiretroviral therapy, epidemiology, human immunodeficiency virus, hypersensitivity
|How to cite this article:|
Agbaji OO, Akanbi MO, Otoh I, Agaba PE, Akinsola R, Okolie V, Ugoagwu PO, Babadoko AA, Adediran A, Finomo FO, Abah JO, Muktar HM, Akanmu AS. Absence of human leukocyte antigen-B*57:01 amongst patients on antiretroviral therapy in Nigeria: Implications for use of abacavir. Niger Postgrad Med J 2019;26:195-8
|How to cite this URL:|
Agbaji OO, Akanbi MO, Otoh I, Agaba PE, Akinsola R, Okolie V, Ugoagwu PO, Babadoko AA, Adediran A, Finomo FO, Abah JO, Muktar HM, Akanmu AS. Absence of human leukocyte antigen-B*57:01 amongst patients on antiretroviral therapy in Nigeria: Implications for use of abacavir. Niger Postgrad Med J [serial online] 2019 [cited 2020 May 27];26:195-8. Available from: http://www.npmj.org/text.asp?2019/26/4/195/268597
| Introduction|| |
Abacavir (ABC) is a nucleoside reverse-transcriptase inhibitor used for the treatment of human immunodeficiency virus (HIV) infection. On account of its efficacy and favourable safety profile, antiretroviral therapy (ART) combinations which include ABC have become a preferred first-line treatment for HIV treatment.,, While few long-term adverse effects have been reported with the use of ABC, hypersensitivity to ABC still remains a major challenge. Hypersensitivity to ABC occurs in about 5%–8% of persons who initiate ABC,, and this incidence could vary based on the population as well as mode of diagnosis. The occurrence of hypersensitivity following exposure to ABC precludes the subsequent use of ABC as a treatment option. Re-exposure to ABC after an initial hypersensitivity reaction (HSR) often results in a more severe reaction which may be fatal.
The association between ABC HSR and the human leukocyte antigen (HLA) B*57:01 was first demonstrated amongst 200 Caucasians in an Australian HIV cohort in 2002. This association has been supported by other studies., Genetic screening for HLA B*57:01 prior to initiating ABC showed no cases of hypersensitivity to the drug in persons who tested negative to HLA-B*57:01., On account of this, HIV treatment guidelines now recommend screening for HLA-B*57:01 prior to initiating ABC, and persons who test positive should not receive ABC.
The prevalence of HLA-B*57:01 allele has been shown to vary widely amongst populations tested, with low prevalence rates reported amongst people of African descent.,, In North America, the prevalence has been reported to be higher amongst Caucasians (7.2%) than African-Americans (2.8%). Few prevalence studies have been carried out in sub-Saharan African where about 80% of persons living with HIV (PLHIV) reside and none has been done in Nigeria, the country with the second-highest number of PLHIV. The objective of this study was to determine the prevalence of the genetic marker HLA-B*57:01 amongst Nigerians living with HIV/acquired immune deficiency syndrome.
| Methods|| |
Ethical approval was obtained from all participating sites (Federal Medical Centre Yenagoa: From the Head of Clinical Services, dated: 4th November, 2014; Lagos University Teaching Hospital: From Health Research and Ethics Committee, dated 3rd November, 2014, Reference Number: ADM/DCST/HRC/2198; Ahmadu Bello University Teaching Hospital: the Health Research Ethics Committee, dated 18th November, 2014, Reference Number: ABUTH/HREC/L33/2014; Federal Medical Centre Makurdi: From the Health Research Ethics Committee, dated 29th October, 2014, Reference Number: FMH/FMC/MED.108/VOL.I/X and Jos University Teaching Hospital: From the Institutional Health Research Ethic Committee, dated 6th November, 2014, Reference Number: JUTH/DCS/ADM/127/XIX/6026). In addition, written informed consent was obtained from all the study participants and all the study data were treated with confidentiality.
We conducted a multicentre cross-sectional survey amongst adults with HIV-infection across five HIV treatment facilities in Nigeria. The study sites were chosen based on geographic distribution to capture the ethnic diversity of the country. The study locations were Jos (North-Central), Lagos (South-West), Makurdi (Middle belt), Yenagoa (South-South) and Zaria (North).
The minimum sample size for the study was obtained using an online sample size calculator (select-statistics.co.uk/calculators/sample-size-calculator-population-proportion), accessed on the 3rd of September 2013. A minimum sample size of 753 was required based on an estimated prevalence of HLA B27 01 allele of 2%, an error margin of 1% and a 95% confidence interval. Our target enrolment was to 1500 participants, with 300 participants recruited at each of the study sites.
Patient recruitment and data and sample collection
Eligible participants were adults >18 years, with confirmed HIV-infection. Between April 2016 and 2017, consecutive adults presenting to the study sites were approached to participate in the study during their routine clinic visits. Each study participant gave written informed consent prior to the study enrolment. Demographic information and history of ABC exposure were obtained from each participant, and 3 ml of venous blood was obtained from each participant in bottles with ethylenediaminetetraacetic acid for HLA typing. Blood samples at each study site were batched and transported once a week to a central laboratory for the analysis.
The DNA from the blood samples was extracted using the Gentra Puregene Plus (1000 ml) Kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol. This kit was best suited for the study because of its high-volume sample processing and high DNA elution yield. The ratio of sample volume, lysis solutions, protein precipitation solution and wash buffers used were in accordance to the manufacturer's protocol. In addition, to completely eliminate all traces of RNA, RNase A solution was added during extraction, therefore yielding only pure DNA. The final elution volume of 300 μl was quantified with a spectrophotometer at A260/280 nm ratio (SmartSpec Plus, Bio-Rad, Spain). All samples were stored at −40°C prior to further analyses.
Human leukocyte antigen typing
Samples were initially assessed using non-specific low-resolution HLA-B*5701 primer mix containing various subtypes of the B57 gene (OLERUP GmbH, Vienna, Austria). The samples found to be HLA-B*57 positive were further subjected to a high-resolution screening using sequence-specific primer methodology. Low-resolution reaction included 30–60 ng/μl of DNA, bulk primer solution and polymerase chain reaction (PCR) Master Mix (OLERUP GmbH, Vienna, Austria) in accordance to the manufacturer's protocol. DNA samples with concentrations below 15 ng/μl were exempted from PCR amplification due to failed amplification revealed during our pilot analysis for this study.
For high-resolution analysis, PCR-sequence-specific-primer methodology was used. 50 ng/μl of DNA, PCR Master Mix complete with Taq (OLERUP GmbH, Vienna, Austria) and water were added to each well pre-aliquoted primer solutions in 0.2-ml well cut PCR plate. Thermocycling parameters for both low-resolution amplification and high-resolution amplification included initial denaturation at 94°C for 2 min followed by 10 cycles of 94°C for 10 s and 10 cycles of annealing and extension at 65°C for 60 s. Afterwards, the second phase of denaturation was carried out at 94° C for 10 sec, followed by 20 cycles of annealing at 61° C for 50 sec and extension at 72°C for 30 sec. Ramp rate of thermal cycler was reduced to 1°C/s at every step. PCR products were electrophoresed on a 2% agarose gel (Bio-Rad, Spain).
Demographic information was summarised using descriptive statistics. The prevalence of HLA-B*57:01:01 allele was reported as a percentage. Statistical analysis was carried out using STATA version 14, College Station, Texas, USA.
| Results|| |
A total of 1504 patients were enrolled in the study. The mean age was 44.6 ± 10.7 years, and 1078 (71.7%) were female. A total of 1463 (97.3%) patients were on ART. ABC use was documented in 12 (0.8%) patients. None of the patients reported a diagnosis of HSR to ABC. [Table 1] summarises demographic characteristics of the study population.
|Table 1: Demographic characteristics of 1504 Nigerians with human immunodeficiency virus evaluated for human leukocyte antigen-B*57 01 allele (n=1504)|
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One thousand and five hundred (1500) blood samples were suitable for the analysis (4 sample spilled) and 1458 (97.2%) were successfully typed. A total of 132 (9.1%) were HLA-B57* positive using non-specific low-resolution HLA-B*57:01 primer mix. On further analysis, none of the 132 samples (0%) had the HLA-B*57:01 allele. [Table 2] shows the frequency of HLA-B57* identified in our patient population.
|Table 2: Frequency of human leukocyte antigen-B*57 allele amongst 132 Nigerians with human immunodeficiency virus|
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| Discussion|| |
Our aim was to determine the prevalence of HLA-B*57:01 allele in the Nigerian population. To the best of our knowledge, this is the first published report of HLA-B*57:01 allele in Nigeria. None of the patients in our study population had the HLA-B*57:01, although other closely related alleles were identified. These closely related alleles are not associated with HSR to ABC. However, HLA-B*57:03 which was one of the most frequent alleles found is associated with slow progression of HIV. The clinical significance of the other identified alleles is yet to be determined.
Our results support emerging data indicating a low prevalence of HLA-B*57:01 allele amongst Africans. The PREDICT-1 study which enrolled 1956 participants across 19 countries reported a prevalence of 2.8% in Africans/African Americans and 7.2% amongst Caucasians in North America. In another large epidemiologic study in the UK which enrolled 1494 subjects, 770 (52%) were black, and the prevalence was 0.26% in blacks compared to 7.93% in whites. Few prevalence studies have been carried out in Africa; in Kenya, a prevalence of 0.8% was recently reported amongst 1004 samples analysed, whereas none (0%) of the 161 samples from HIV-infected patients in Uganda had the HLA-B*57:01 allele.
Very few participants in our study cohort (0.8%) had prior exposure to ABC and none reported symptoms suggestive of HSR. The low frequency of exposure to ABC in this population may be related to the uncertain risk of ABC hypersensitivity. Given the strong association between HLA-B*57:01 and ABC HSR, our study suggests that the risk for ABC HSR in our population is low. While the current guidelines recommend routine screening for HLA-B*57:01 prior to ABC initiation, the cost-effectiveness of this recommendation needs to be evaluated in Nigeria and other countries with very low prevalence of HLA-B*5701.
Our study had some limitations. While our study sites were chosen to capture the ethnic diversity of Nigeria, we cannot confirm that our participants included members of the over 250 ethnic groups in Nigeria. However, with the large sample size and the diverse locations, we believe our findings are generalizable to the whole population.
| Conclusion|| |
Our findings show that HLA-B*57:01 allele is very rare amongst Nigerians. While the current guidelines recommend routine screening for HLA-B*5701 prior to ABC initiation, the cost-effectiveness of this recommendation needs to be re-evaluated in Nigeria and other countries with very low prevalence of HLA-B*5701.
Financial support and sponsorship
The study was supported by a research grant from Viiv/GSK. M.O.A was supported by a Fogarty International Center training grant, NIH grant D43TW009575- Murphy/Lifang Hou (PIs). The contents of this article are solely the responsibility of the authors and do not necessarily represent the views of ViiV/GSK, NIH or Fogarty International Center. The funding agencies had no role in the study design, data collection, data analysis, interpretation of results or write-up of the study.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Comi L, Maggiolo F. Abacavir+dolutegravir+lamivudine for the treatment of HIV. Expert Opin Pharmacother 2016;17:2097-106.
Rodriguez-French A, Boghossian J, Gray GE, Nadler JP, Quinones AR, Sepulveda GE, et al.
The NEAT study: A 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 2004;35:22-32.
DeJesus E, Herrera G, Teofilo E, Gerstoft J, Buendia CB, Brand JD, et al.
Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 2004;39:1038-46.
Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, et al.
Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 2001;23:1603-14.
Clay PG. The abacavir hypersensitivity reaction: A review. Clin Ther 2002;24:1502-14.
Carolino F, Santos N, Piñeiro C, Santos AS, Soares P, Sarmento A, et al
. Prevalence of abacavir-associated hypersensitivity syndrome and HLA-B*5701 allele in a Portuguese HIV-positive population. Porto Biomed J 2017;2:59-62.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al.
Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727-32.
Phillips EJ, Wong GA, Kaul R, Shahabi K, Nolan DA, Knowles SR, et al.
Clinical and immunogenetic correlates of abacavir hypersensitivity. AIDS 2005;19:979-81.
Hughes AR, Mosteller M, Bansal AT, Davies K, Haneline SA, Lai EH, et al.
Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics 2004;5:203-11.
Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 2006;43:99-102.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al.
HLA-B*5701 screening for hypersensitivity to abacavir. N
Engl J Med 2008;358:568-79.
Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA, et al.
Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the infectious diseases society of America. Clin Infect Dis 2014;58:1-0.
Sun HY, Hung CC, Lin PH, Chang SF, Yang CY, Chang SY, et al.
Incidence of abacavir hypersensitivity and its relationship with HLA-B*5701 in HIV-infected patients in Taiwan. J Antimicrob Chemother 2007;60:599-604.
Bannister WP, Friis-Møller N, Mocroft A, Viard JP, van Lunzen J, Kirk O, et al.
Incidence of abacavir hypersensitivity reactions in euroSIDA. Antivir Ther 2008;13:687-96.
Nahirya-Ntege P, Musiime V, Naidoo B, Bakeera-Kitaka S, Nathoo K, Munderi P, et al.
Low incidence of abacavir hypersensitivity reaction among African children initiating antiretroviral therapy. Pediatr Infect Dis J 2011;30:535-7.
Young B, Squires K, Patel P, Dejesus E, Bellos N, Berger D, et al.
First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS 2008;22:1673-5.
McLaren PJ, Ripke S, Pelak K, Weintrob AC, Patsopoulos NA, Jia X, et al.
Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans. Hum Mol Genet 2012;21:4334-47.
Shah R, Nabiswa H, Okinda N, Revathi G, Hawken M, Nelson M. Prevalence of HLA-B*5701 in a Kenyan population with HIV infection. J Infect 2018;76:212-4.
Munderi P, Snowden WB, Walker AS, Kityo C, Mosteller M, Kabuye G, et al
. Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART. Trop Med Int Health 2011;16:200-4.
[Table 1], [Table 2]