Prevalence of HIV related oral lesions in people living with HIV and on combined antiretroviral therapy: a Nigerian experience

Introduction oral lesions comprise significant clinical features of HIV infection and are often indicators of immune suppression. However, the advent of antiretroviral therapy has significantly reduced its prevalence. The aim of this study was to relate the prevalence of oral lesions of HIV to treatment outcome of Combined Antiretroviral Therapy (cART) in a Nigerian HIV adult population. Methods a cross- sectional study was conducted on 491 People Living with HIV (PLWHIV) on cART from two HIV centres in Lagos state, Nigeria. The EC-clearing house guidelines were employed to categorise oral lesions. Presence or absence of these lesions was reconciled with CD4+ cell count as a measure of efficacy of cART treatment. Results a total of 491 PLWHIV on cART were enrolled, 366 (74.5%) were females and 125 (25.5%) were males. Age ranged between 18-80 years, with a mean of 41.2 ± 9.1 years. On examination, 12 (2.4%) patients presented with HIV oral lesions. Oral hyperpigmentation (10, 2.0%) was the most common lesion seen, followed by oral ulcers (2,0.4%). Majority (75%) of the affected patients were on a Lamivudine containing regimen. 7 out of the 12 patients with oral lesions had CD4+ cell count between 200-500 cell/mm3 prior to cART initiation. Eleven (92%) of the patients with oral lesions had significant improvement of their CD4+ cell count after cART administration. Conclusion the prevalence of oral lesions in HIV patients on cART therapy in Lagos is low. Oral hyperpigmentation and oral ulcers are the most frequent lesions seen. The presence or absence of oral lesions were not associated with CD4+ cell count. Therefore, we conclude that the oral lesions seen in HIV patients on cART may not be a direct manifestation of the disease.


Introduction
Oral lesions form significant early clinical features of HIV infection [1].
These lesions are often indicators of immune suppression and can be used for early testing, diagnosis and management of patients with HIV/ AIDS. Oral lesions therefore contribute largely to patients' morbidity, affecting the psychological and economic functioning of the individual and community [2]. They may be classified into infections such as fungal, viral and bacterial infections, neoplasms such as Kaposi's sarcoma and non-specific presentations such as aphthous ulcerations and salivary gland diseases [3,4]. The overall prevalence of oral lesions in HIV infected patients has changed since the advent of combination Anti-Retroviral Therapy (cART). For instance, several studies have shown considerable reduction in prevalence of herpes labialis and periodontal diseases along with other oral lesions from 80% to about 30% after the institution of cART [5] and in HIVassociated opportunistic infections [6,7]. Oral candidiasis (OC) has been shown to be the most common oral lesion seen in HIV infected patients, however with the advent of cART, most studies reported a decline in its occurrence. In a study of 93 patients, 7% of patients on protease inhibitors (PI) had oral candidiasis, compared with 36% in non-PI treated patients [8]. Schmidt-Westhausen et al. (2000) detected OC in 10 out of 103 (9.7%) of their study subjects who had been on cART for 4 weeks and in none after 6 months of therapy (N=61) [9]. Unlike most other oral manifestations of HIV, which decrease with use of cART, studies from the USA and the United Kingdom (UK) have described an increase in the prevalence of oral warts with cART [10][11][12], which may reach statistical significance.
Other lesions that are showing a trend of rising prevalence include HIV-related salivary gland disease [10]. The goal of cART should be maximal and durable viral suppression, restoration and preservation of the immune system with resultant resolution of opportunistic illnesses and improvement in the quality of life through ease of use of the regimen with minimal side-effects to enhance adherence. This should translate to a reduction of HIV-related morbidity including oral manifestations. Reduction of viral load will prevent progressive immunodeficiency, decrease the risk of the emergence of resistant viruses and decrease the risk of viral transmission [13]. The potent combination therapies have proven effective in suppressing plasma-HIV viral load below detectable limits and elevating CD4+ lymphocyte cell counts. Consequently, the immune status for the therapy adherent patients improves significantly. However, some patients fail to achieve complete viral suppression [14,15]. It has been shown in various studies that the prevalence of HIV-related oral lesions reduces significantly with cART. The reported percentage decrease varied from 10% in a USA study on 570 patients [10] to 50% in a Mexican study on selected 1000 HIV patients over a period of 12 years [16].
In a Nigerian study about 80% of the lesions cleared with use of cART [7]. However, cART sometimes achieves suboptimal results with less than fifty percent of patients achieving therapeutic goal. This is due to a variety of reasons such as medication intolerance/ side effects, prior ineffective antiretroviral therapy and infection with a drugresistant strain of HIV. However, non-adherence with antiretroviral therapy is the major reason most individuals fail to benefit from cART [17]. Nearly all the reported studies had been conducted in Fisher's exact test was used for 2 × 2 tables or where the requirements for test could not be met. Paired T test applied to compare mean CD4 cell count at initiation of cART and on examination at recruitment. The 5% significance level was used. acknowledged the use of other medications along with cART to treat the lesions. The median duration of oral lesions was 9 ±(1-36) months and recurrence was reported in 18(26%) of the respondents ( Table   2). Distributions of oral lesions are shown in Table 2

Discussion
Various studies have shown prevalence of HIV-related oral lesions reduced significantly with the use of cART. The reported percentage decrease varied from 10% in a USA study [11], 50% in a Mexican study [16] and 84% in a previous study in Lagos, Nigeria [7]. Studies examining the effect of cART on the prevalence of individual oral manifestations such as oral candidiasis, oral hairy leukoplakia, HIVrelated periodontal diseases, Kaposi's sarcoma (KS), oral papilloma, and HIV-related salivary gland disease showed reduction in the prevalence of these lesions [4,9,10,16]. The current study also agrees with these findings, as 40% of study participants with history  [20]. Reported prevalence of hyperpigmentation varies from as low as 5.2% in children in Tanzania to as high as 38% in Venezuela [21,22].
Although it could not be fully ascertained when the oral pigmentation occurred during the course of cART administration, majority of the patients were certain the pigmentation was not present before cART therapy except in one patient who had oral hyperpigmentation prior to cART administration. It was also observed that majority of participants with hyperpigmentation were either on Lamivudine, Tenofovir or nevirapine containing regimen, none of which is known to be associated with hyperpigmentation. The major ARV which has been associated with oral hyperpigmentation is regimen containing zidovudine. [23] Zidovudine has an established adverse drug reaction of hyperpigmentation of the skin and nails [24]. Though antiretroviral drugs could be responsible for some of the oral hyperpigmentation seen in some studies [25,26], other research findings suggest some other drugs used in treating concomitant associated diseases such as clofazimine and ketoconazole could increase the α-melanocyte stimulating hormone. On the other hand, some researchers could not find any systemic or local cause for the oral hyperpigmentation and have suggested it may be idiopathic [27,28]. There was no association between the patients who smoked and those with oral lesions particularly oral hyperpigmentation. Aphthous-like ulcers were seen in 2 of our patients; this condition is seen in HIV patients and These patients gave no prior history of oral lesions related to HIV before initiation of HAART. This further supports our suspicion that the hyperpigmentation may not be a direct manifestation of the disease, but perhaps is a side effect of medications used.

Conclusion
The prevalence of oral lesions in people living with HIV on cART therapy in Lagos is low. Oral hyperpigmentation and oral ulcers are the most frequently observed lesions. As the presence of oral lesions in PLWHIV in this study had no association with their CD4+ cell count; this study therefore infers that oral lesions seen in HIV patients on cART may not be a direct manifestation of the disease.

Competing interests
The authors declare no competing interests.  Table 1: demographic data of HIV patients on HAART