Prevalence of human leukocyte antigen HLA-B*57:01 in individuals with HIV in West and Central Africa

According to UNAIDS, new HIV infections have been reduced by 23% since 2010, largely due to a substantial 38% decrease in Eastern and Southern Africa [1]. Despite this reduction in new HIV infections, there were 690,000 AIDS-related deaths in 2019 [1]. The rollout of combination antiretroviral therapy (ART) has significantly changed the natural history of HIV infection [2]. Advances in treatment strategies have led to a spectacular drop in the mortality rate of people living with HIV (PLHIV) worldwide [3]. However, of the 38 million people living with HIV worldwide, only 25.4 million are on treatment [1]. Abacavir, a nucleoside HIV reverse transcriptase inhibitor, is one of the drugs used in the management of HIV infection. It is a key component of the first-line antiretroviral (ART) regimens recommended by the US Department of Health and Human Services (DHHS) [4]. A randomized, double-blind study from 2015 called for positioning the dolutegravir/abacavir/lamivudine regimen as a first-line option for treatment-naïve HIV-positive patients [5]. Indeed, of the 833 randomized participants, 71% in the dolutegravir/abacavir/lamivudine group and 63% in the efavirenz/tenofovir/emtricitabine group maintained viral loads of < 50 copies per milliliter up to 144 weeks after initiation of treatment (P = 0.01) [5]. The higher efficacy was mainly due to fewer dropouts due to adverse events in the dolutegravir/abacavir/lamivudine group [dolutegravir/abacavir/lamivudine group, 13 (3%); efavirenz/tenofovir/emtricitabine group, 48 (11%)] [5]. Several studies have provided clear benefits and recommended abacavir-based treatment regimens [6‐8]. According to the recent World Health Organization (WHO) guidelines in low-income countries, especially in West and Central Africa, abacavir is recommended as an alternative to first-line regimens in children and, in special circumstances in adults [9].

The main limitation to the use of abacavir is a frequent, early and potentially fatal Type IV hypersensitivity reaction [10]. Data from several clinical trials suggest that an abacavir-induced hypersensitivity reaction occurs in 2.3–9% of patients exposed to abacavir [11‐13]. In a cohort of 14,310 individuals with HIV-1 examined in 93 centers across Europe, Israel and Argentina, 2101 (64.1%) were forced to abandon abacavir treatment [14]. For 167 (5.1%) patients, the reason for discontinuing treatment was the occurrence of a hypersensitivity reaction, and the overall incidence of hypersensitivity reactions in the study was estimated at 22.1 (95% confidence interval [CI] 18.7–25.4) per 100 person-years [14].

Human leukocyte antigen (HLA)-B*57:01, an allele of the major histocompatibility complex, has been strongly associated with the risk of an abacavir hypersensitivity reaction [15]. A prospective, randomized, multicenter, double blind, prospective study has shown that screening for HLA-B*57:01 can reduce the incidence of hypersensitivity reactions to abacavir [16].. Several studies have been conducted to estimate the prevalence of HLA-B*57:01 in many populations around the world. A meta-analysis by the Clinical Pharmacogenetics Implementation Consortium (CPIC) of data published between 1950 and 2011 allowed the mapping of the distribution of HLA-B*57:01 in different ethnic populations [17]. The combined analyses covered 35,630 Europeans, 1321 South Americans, 8570 Africans, 1029 Middle Easterners, 3391 Mexicans and 12,501 Asians. Europeans recorded the highest frequency of HLA-B*57:01, with proportions up to 14.1% [17]. Among South Americans and Mexicans, 2.6 and 2.2%, respectively, were carriers of HLA-B*57:01 [17]. This proportion was 2.5% for Middle East residents and 12.6% for Asian residents [17]. African populations recorded the lowest prevalence with an estimated overall frequency of 1.0% [17].

The majority of HLA-B*57:01 prevalence surveys among people from Africa are conducted among African Americans [18‐21]. However, some studies have been carried out in sub-Saharan Africa, notably in Nigeria, Kenya, South Africa and Uganda [22‐26], but data on the distribution of HLA-B*57:01 in the population of Sub-Saharan Africa remain scarce.

In Burkina Faso, according to a study carried out in 2014 among 51 HIV sero-discordant couples, 78% of individuals with HIV were carriers of the HLA-B*57:01 gene [27]. This high frequency, in contrast to what is generally reported in African populations, has led the authors of this Burkinabe study to recommend large cohort studies to confirm their results [27]. In the Ivory Coast, Gabon and Togo, to our knowledge, there are no data on the prevalence of the HLA-B*57:01 gene. The objective of this study was to estimate the prevalence of the HLA-B*57:01 gene in individuals with HIV in four West and Central African countries (Burkina Faso, Ivory Coast, Gabon and Togo) and to measure the association between HLA-B*57:01 gene carrying and ethnic subgroups in West and Central Africa.

A multicounty, multicentric cross-sectional study was conducted from January 2016 to February 2020 in four countries in Central and West Africa: Togo, Burkina Faso, Ivory Coast and Gabon (Fig. 1).

To our knowledge, this study is the first large multicountry study conducted in four countries in the West (n = 3) and Central (n = 1) African regions of the prevalence of the HLA-B*57:01 allele among individuals with HIV. According to the latest epidemiological data, West and Central Africa is home to 4.9 million people living with HIV. HIV prevalence among adults is 1.4%, which is relatively low compared to East and Southern Africa. In this region, the number of people accessing treatment rose significantly from 860,000 in 2010 to 2.9 million in 2019. HLA-B*57:01 is a generic marker of clinical importance used in several countries, specifically in developed countries, to decrease abacavir-related hypersensitivity reactions. Guidelines in North America and Europe recommend routine screening for HLA-B*57:01 prior to initiation of abacavir therapy [28]. Ideally, since HLA-B*57:01 varies among different populations, it is ascertaining HLA-B*57:01 prevalence before decoding or not performing systematic screening before initiating abacavir-based ART regimens. In our study, we screened HIV-positive patients on ART or not for HLA-B*57:01 carriage.

We estimated an overall HLA-B*57:01 prevalence rate of 0.07%, ranging from 0% in Togo to 0.2% in Burkina-Faso. A similar survey was conducted in Nigeria, located in the West African region between April 2016 and April 2017 in five HIV treatment facilities. In this study, 1504 adults were enrolled. Of these, 132 (9.1%) were HLA-B57 positive using a nonspecific low-resolution HLA-B*57:01 primer mix. On further analysis, none of the 132 samples (0%) had the HLA-B*57:01 allele [22]. Another survey was conducted in a different population and reported a high prevalence of HLA-B*57:01. This is the case in Colombia, with a prevalence rate of 2.7% in Colombian HIV-infected individuals. The prevalence was 4% for whites, 2.6% for other races, and 1.9% for Afro-Colombians [29]. Other studies have confirmed a low prevalence of HLA-B*57:01 in the African population. In the United States, there is a lower frequency of the HLA-B*57:01 allele in African Americans, with a reported frequency between 2.3 and 4% [20, 30, 31]. Among White subjects, prevalence was 7.93%. Among black subjects, only two (both Ugandan) were HLA-B*57:01 positive, giving a rate of 0.26% [32].

Our study had a few limitations. We did not conduct an analysis based on race in our survey. Other races are indeed rare in individuals with HIV in West and central Africa, and this variable is not collected routinely in databases. Further studies should explore including race (i.e., mestizo), as in our sample, one person in Gabon with the mestizo race was screened positive. Some studies have reported that the heterogeneity of HLA-B*57:01 prevalence is mostly dependent upon race and ethnicity heritage [16, 33]. Another limitation is that we did not perform logistic regression with the low prevalence observed to identify factors associated with the presence of HLA-B*57:01. Another limitation to the study is that HLA typing were performed on patients mostly already on ART. This design could induce some bias towards excluding patients already having had hypersensitivity reaction to abacavir. Finally, HLA-B*57:01-negative patients starting abacavir-containing regimens (3%) were not followed up; therefore, the incidence of HSR was not assessed.

Since abacavir is included in the first-line regimen, the question of hypersensitivity to abacavir should be important to document. However, to our knowledge, there are no guidelines for screening patients before ART initiation in Africa. Before abacavir should be wisely used in Africa, it is necessary to explore the prevalence of HLA-B*57:01. The application of routine HLA-B*57:01 testing to other racial populations deserves further investigation. In these four countries, antiretroviral therapy is available and free of charge for patients. Currently, the first-line regimen includes 2 NRTIs and dolutegravir in accordance with the WHO guidelines or 2 NRTIs and efavirenz. An optimized NRTI backbone should be used, such as zidovudine (AZT), tenofovir or abacavir (ABC), and vice versa.

In addition, HLA-B*57:01 screening was not performed routinely because of the lack of equipment and reference laboratories specializing in immunologic tests in the four countries. This is the main reason all-immunological analyses were performed in Belgium, which is specialized in this analysis to avoid heterogenicity between the tests.

Recently, the value of HLA-B*57:01 screening prior to prescribing abacavir is a concern in areas where its prevalence is low [34, 35]. In the context of low-income countries where pharmacogenetic screening is not available and based on this result with a low prevalence of HLA-B*57:01, we could not recommend the testing of HLA-B*57:01. Despite the low prevalence of HLA-B*57:01, clinical follow-up of patients starting an abacavir-based regimen is mandatory. It is therefore important to educate the patient about the possible symptoms of a hypersensitivity reaction, especially at the beginning of treatment, so that the patient can easily identify them and return for further consultation. Any suspicion of hypersensitivity to abacavir should lead to discontinuation of treatment and the initiation of rigorous clinical follow-up [36, 37]. Screening for HLA-B*57:01 prior to initiation of any therapy with abacavir has been shown to be beneficial [38, 39].

HLA-B*57:01 is rare in people living with HIV, in the four countries participating to this survey, and there are no significant differences among countries. HLA-B*57:01 screening may not be a cost-effective strategy to reduce the risk associated with abacavir hypersensitivity in these countries. Indeed, the prevalence of HLA-B*57:01 allele positivity was low in the study population. These results cannot be generalized to the West and Central African region as prevalence may be much higher in other countries and among other ethnicities in the same regions of Africa.

However, despite the low prevalence of the HLA-B*57:01 allele, rigorous monitoring should be maintained in any patient on ABC since the possibility of occurrence of HSR to this drug should not be definitively ruled out.