Background
Buruli ulcer (BU), a necrotizing infection of the skin and soft tissues is caused by
Mycobacterium ulcerans (M. ulcerans)
. BU has been listed among the Neglected Tropical Diseases (NTD) and is the third most common extra pulmonary mycobacterial disease [
1]. Globally, BU is endemic in tropical and semitropical climates with cases reported from 33 countries [
2]. In 2015, 2037 new cases were reported worldwide and 94% of these cases were from sub-Saharan Africa [
2]. BU can be found in all age groups but in Africa, it is mostly reported in children [
2]. The organism produces a toxic macrolide, mycolactone, which has cytotoxic and immunosuppressive properties and is responsible for the extensive destructive lesions which characterize BU disease [
3]. Late presentation of the disease can result in large disfigurement, amputations and permanent disability [
4].
Human Immunodeficiency Virus infection (HIV) is a global public health issue that has led to the loss of 33 million lives since it was declared an epidemic [
5]. Sub-Saharan Africa is the most affected with a reported 25.6 million people living with the disease in 2015. The HIV prevalence among the adult Ghanaian population is 1.7% [
6].
In Ghana, the HIV prevalence in the age group 45–49 years is 1.9%; 35–39 years is 3.4% and 15–19 years is 0.7% [
7]. In Cameroon, HIV prevalence was 3–6 times higher in BU patients than the regional estimated prevalence (37% vs. 7% in women; 20% vs. 5% in men; and 4% vs. 0.7% in children) [
8]. In Benin, BU patients were 8 times more likely to have HIV infection than those without BU (2.6% vs. 0.3%), and in a small cohort in Ghana, HIV prevalence was 5 times higher in BU patients (5% vs. 0.9%) [
9].
Reports of the impact of HIV on the clinical presentation and severity of BU disease have indicated an increased incidence of multiple, larger and ulcerated BU lesions in HIV-infected individuals [
10]. It also appears that the presence and severity of BU may reflect the level of underlying immune suppression in an HIV-infected person. In Cameroon, 79% of patients with BU category 2 or 3 lesions had a CD4 count of ≤500 cells/mm
3 compared with 54% of those with category 1 lesions [
11].
There is increasing interest in the incidence of BU-HIV coinfection, management strategies applied, and the clinical outcome. Co-infection with HIV is thought to make Buruli ulcer disease more severe, and to negatively affect time to complete healing following treatment [
12]. In both diseases, the adaptive immune system is compromised during infection. HIV infects T helper cells (CD4
+ T cells), dendritic cells and macrophages [
13] leading to low levels of circulating CD4
+ T cells. In BU, mycolactone interferes with T-cell activation, down-regulating expression of the T-cell receptor [
14]. Production of various cytokines and chemokines is reduced, and mycolactone treated dendritic cells show reduced ability to activate T-cells [
8]. Hence, BU patients produce low levels of interferon-gamma (IFN-γ) [
15,
16]. Immune recovery in BU [
17] and HIV is driven by the adaptive immune system. Co-infection with HIV complicates the management of patients with BU [
18].
The WHO technical team has provided some guidance on how to manage BU-HIV coinfection based on limited data. There is a need for more published data to help guide patient management especially in countries where the disease burden is high [
18]. The present study aimed to describe the clinical spectrum of disease and the relationship between HIV viral load and lesion severity in patients with BU-HIV coinfection in central Ghana. We further aimed to assess any differences in the mycobacterial load in BU-HIV coinfected patients compared to age-matched BU patients without HIV infection.
Discussion
The median age of 42 years found in this BU-HIV coinfected population is higher than previously reported among coinfected patients from Ghana [
13] and Togo [
32]. Also, the estimated prevalence (1.7%) of HIV among the general adult Ghanaian population (15–49 years) is higher than in children [
33]; this may explain the low prevalence of BU-HIV coinfection in this cohort. The prevalence of HIV in Sub-Saharan Africa is 20–30% [
34]. In the current study cohort, the prevalence of HIV was 2.4% which is less than the 4.8% (of 83) reported from a study of BU patients in Togo [
32]. The prevalence of BU-HIV coinfection was not significantly differentiated by gender in the current study in contrast to a Togolese study where the prevalence was three times higher in females compared to males [
32]. In keeping with the known epidemiology of BU, most BU-HIV patients had their lesions located on the lower limbs.
HIV prevalence in the study population appeared to be comparable to the national HIV prevalence (2.4% vs 1.7% respectively). This is different from the findings in Cameroon [
11] where the prevalence of HIV infection in coinfected populations (29%) was significantly higher than the regional estimate. In that study, HIV prevalence among adult patients with PCR confirmed BU was 39 and 17% compared to the regional estimated prevalence of 6.9 and 5.3% for females and males respectively. It is known that some individuals in BU endemic areas develop antibodies to M. ulcerans without any evidence of clinical BU disease [
35‐
37]. Some patients had significant immunosuppression before antibiotic treatment for BU [patients 1, 4 and 8 (Table
1)] since they had high viral load and/or low CD4 counts before and/ or after BU treatment when done. Such patients who have significant immunosuppression when they are exposed to M. ulcerans may be more likely to develop BU disease, but it was difficult to fully investigate this with the limited access to viral load testing and CD4 counts in the current study.
One case of paradoxical reaction (PR) was reported at week 16 (after antibiotic therapy) and healed completely by week 20 in our BU-HIV coinfected patients (patient 6) but in Cameroon, a severe PR was reported 6 months after antibiotic therapy [
12]. Both BU and HIV are associated with impaired adaptive immune function which may hinder an early immune response, even though immune reconstitution syndrome which resembles PR, is common in HIV patients beginning antiretroviral therapy. Also, multiple lesions are associated with PR but in this study, only one BU-HIV coinfected patient presented with multiple lesions. High bacterial loads at baseline tend to affect healing and is a risk factor to the development of paradoxical reactions [
38]. Our results indicated that though our cohort of BU-HIV coinfected patients had high baseline bacterial loads, it was comparable to that of the age-matched controls without paradoxical reaction episodes. The healing time in both groups was shorter than reported in studies on lesions with high bacterial load [
38]. Although the PR developed by patient 6 was also characterised by lesion enlargement and inflammation as was the case in the report by Wanda et al. [
12], the PR occurred after completion of antibiotics for BU and the patient was on ART even before specific antibiotic therapy for BU was initiated. It has been suggested that significant baseline immune suppression [
12,
39], early commencement of ART [
12,
39] and a good response to ART (evidenced by the increase in CD4 counts and suppressed HIV viral load) [
12] might be important contributory factors to the development of PR in BU-HIV coinfection. The small sample size of the current study and the challenges to ART initiation made it difficult to ascertain the impact of these factors on the development of PR.
The majority of our study participants presented with single, mostly category II and I lesions. We also identified that 88.9% of the lesions presented by BU
+HIV
+ coinfected patients healed after treatment with a median (IQR) healing time of 14 [
8‐
28] weeks. The median time to wound healing in our study is shorter compared to 37 weeks (IQR: 36–37) reported by Tuffour et al [
13] and that reported in the recent WHO BU drug trial [
19]. This difference in median healing times is most likely because all the 7 patients in the series studied by Tuffour et al. had category III lesions (compared to the current study which had most patients presenting with category II disease). Also, the patients in the study by Tuffour et al. had much lower haemoglobin at baseline compared to those included in the present study and this might have further contributed to the observed differences in the median healing time.
In our study, we could not ascertain a clear relationship between the viral load and the BU lesion severity of the BU
+HIV
+ patients at baseline. This was due to number reasons including the very small number of co-infected patients, the difficulty in obtaining baseline viral loads in all BU-HIV infected individuals, the incomplete ART history and incomplete CD4 counts. It was suggested that the severity of BU disease did not necessarily reflect the level of underlying immune suppression, especially when using CD4 as the marker as a case with CD4 counts below 300 had no multifocal disease, while another case with CD4 counts above 500 developed multiple lesions [
13]. There are however reports of severe BU lesions like osteomyelitis occurring in patients with severe immune suppression from HIV [
13]. Further studies are needed to establish a clearer relationship between BU severity and the level of immune suppression.
In our study, one patient (patient 4) had an increase in the HIV viral load while another (patient 8; no viral load available at baseline) also had a very high viral load after antibiotic therapy. Patient 8 was known with HIV before BU diagnosis but was not adherent to ART. Further questioning revealed the patient doubted the HIV diagnosis, so was re-counselled and tested for reconfirmation followed by subsequent re-enrolment in ART clinic after completion of BU treatment. The very high viral load post BU treatment may be reflective of non-compliance which has the potential to lead to the development of drug-resistant HIV strains. Patient 4 had antiretroviral therapy (ART) initiated rather late due to refusal to enrol in the HIV clinic. The initial challenges encountered with the enrolment of these patients in the ART programme was probably indicative of a significant mental health burden; the assistance of appropriate mental health expert was sought and this helped resolve the difficulties. This also highlights the need to evaluate further the burden of mental health in BU patients especially those with BU+HIV+ coinfection.
There were challenges with the initiation of ART in the BU
+HIV
+ coinfected patients resulting in the start of ART occurring at different times in different patients. Patients had to enrol in HIV clinics which were distant from the BU clinics. Such logistical and programmatic challenges present obstacles for these patients in accessing care and may further hamper adherence to treatment for both BU and HIV infections. Such challenges in the management of BU-HIV coinfection are not peculiar to the current study. In a previous study [
13], some patients were referred to ART centres away from the centre of the study only after BU lesions had healed after some 6 months of follow-up because no ART centre was established at the district hospital at the time of management. This calls for efforts to better integrate the care of patients with BU-HIV coinfection.
The prevalence of HIV-HBV and HIV-HCV coinfection in Ghana are 13 and 3.6% respectively [
40]. In this study, 1 patient was BU-HIV-HBV positive with another one being BU-HIV-HCV positive. Immune response and haemoglobin levels were not different among the BU-HIV positive regardless of the Hepatitis B or C status before and after treatment in this study. Anaemia was reported among BU-HIV coinfected patients in a previous study [
32]. The low haemoglobin levels observed in some BU
+HIV
+ coinfected patients after antibiotic treatment for BU was likely related to delayed initiation of ART.
The burden of BU-HIV disease was shown in IFN-γ production where age-matched BU-HIV negative cases mounted significantly higher responses compared to BU-HIV coinfected cases. This difference in IFN-γ responses may be attributed to the impact of HIV on the immune system of BU patients. After BU antibiotic therapy, there was a slightly non-significant improvement in the IFN-γ response of the BU-HIV coinfected patients. It is known in BU immunology that TH1 response improves after treatment [
29,
30] therefore HIV infection may have a bigger impact on the overall immune status of the coinfected patients.
The small sample size and inability to measure CD4 counts in patients at baseline notwithstanding, our study contributes important data on BU-HIV coinfection and highlights the need for further research in this area.
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