Multiple oral papillomas after antiretroviral treatment resumption

Discussion

Oral manifestations in case of immunodeficiency, in particular due to HIV infection, are common and numerous. They can include oral candidosis, aphthous ulcerations, hairy leukoplakia, Kaposi’s sarcoma and HPV-associated oral lesions such as papilloma, condyloma acuminatum and multi-FEH. Concerning HIV, since the use of efficient antiretroviral therapy, the prevalence and incidence of all these oral manifestations have dropped, except from HPV oral lesions.4 5

In the APROCO (Antiproteases Cohort) cohort, which was a French cohort study set up in 1997 on HIV-infected patients who had started a HAART regimen including at least one protease inhibitor, only 31% of them remained compliant at each follow-up visit.6 When there a treatment is discontinued, opportunistic infections occur. Induced HPV lesions can be one of them. This is how oral lesions can reveal the non-adherence of certain patients to their treatment. Several psychosocial factors have been highlighted to explain the aetiologies of these treatment discontinuations.7 The challenge is above all to identify these patients and to try to guide them towards multidisciplinary care, particularly psychological and social, in order to help them regain optimal compliance with their medication.

However, these lesions are not always only a sign of a treatment disruption or a primary diagnosis of immunodeficiency, but they can also occur after resumption of a patient follow-up and treatment. While the exact pathophysiological explanation has not yet been established, the immune reconstitution inflammatory syndrome (IRIS) is the most frequently proposed hypothesis. IRIS is a known complication in HIV-infected patients. It is defined in HIV-positive patients treated with ART as clinical deterioration of an infectious or inflammatory condition temporally associated with ART, excluding the expected course of a previously recognised and treated infection, drug toxicity or side effect, treatment failure or complete non-compliance with ART.8 Studies show that IRIS occurs in patients with HIV who rapidly recover immunocompetence thanks to ART. Indeed, it appears that the greater the CD4+ T lymphopenia at the start of ART, the greater the risk of developing IRIS. The sudden increase in CD4+ T cells would result in significant inflammation against a latent infection.9 10 One possible explanation is that because the immune system is still partially functional, it may be less effective against HPV and induce its clinical expression.11 Another explanation focuses on the role of macrophages. After HIV infection, the patient’s immune system will produce large numbers of primed macrophages. However, in the absence of T cells, they cannot fulfil their effector role and will accumulate in the tissues of the patient. When the immune system is reconstituted after ART initiation, antigen-specific CD4+ T cells will interact with primed macrophages and cause the release of proinflammatory mediators.9 12

Another mechanism that may explain the development of multiple papillomas in HIV-positive patients after the initiation of ART is the regulation of HPV transcription by HIV. Examination of condyloma acuminata biopsies from HIV-positive patients has reported the presence of HIV RNA. Furthermore, in perianal condyloma biopsy specimens from HIV-positive patients, a negative correlation was observed between HPV E7 gene expression and CD1 (Langerhans cell) RNA levels. Thus, on reduction of viral load, the decrease in HIV RNA level would be accompanied by a reduction in HPV E7 gene expression in the mucosa, allowing a normalisation of CD1 RNA levels with an increase in the number of Langerhans cells (LCs) at the site of HPV infection. This local increase in LCs would then lead to the development of multiple papillomas.11

In our patient, even though the 2-month blood test after treatment showed a low CD4+ T cell count, it did not rule out an IRIS. As mentioned above, studies have shown that clinical signs may be caused by other immune cells and mechanisms. Apart from HPV oral lesions, similar cases have been described where latent infections become clinically evident after initiation of an antiretroviral treatment. HIV-infected patients can begin to show symptoms of tuberculosis, CMV retinitis, cryptococcal meningitis or hepatitis B because of a rapid viral load decrease.4 11

IRIS is a syndrome mostly described in patients with HIV, but that has also been observed in patients with HIV negative. One example is patients receiving tumour necrosis factor (TNF) blocking therapy, which sensitises them to various infections, particularly Mycobacterium tuberculosis. If the patient develops tuberculosis, the proper course of action is to start antibiotic treatment and immediately stop the anti-TNF therapy. In some individuals; however, an acute exacerbation of tuberculosis may occur rather than resolution of the disease. The same phenomenon has been observed in patients receiving natalizumab therapy who developed progressive multifocal leukoencephalopathy due to reactivation of polyoma John Cunningham (JC) virus in the brain. On discontinuation of treatment and after several plasma exchanges, symptoms were exacerbated. Finally, rare cases of IRIS have been reported in renal and liver transplant patients: discontinuation of immunosuppressive drugs resulted in a sudden exacerbation of symptoms against Cryptococcus neoformans.9

In total, in all these different reported cases with IRIS, a common feature is that immune responses that are normally involved in host protection become pathogenic.

Most studies in patients with HIV do not distinguish between the different clinical forms of oral HPV lesions. Instead, they are often lumped together as ‘oral warts’. It is, therefore, difficult to assess what percentage of patients has isolated or few condylomas or papillomas and what percentage have multiple papillomas. Case reports of patients with HIV with multiple oral papillomas lesions are rare. Some report FEH, the main differential diagnosis for multiple papillomas, based on HPV serotype found in biopsies.13

There is currently no consensus on how to treat multiple oral papillomas. Similar to the management of common oral warts, multiple options are available: laser or surgical removal of the lesions and photodynamic therapy are usually the most commonly used;14 15 some authors indicate using topical application of drugs such as antiproliferant or immunomodulator agents (podophyllin, imiquimod).13 16 Choice of the best treatment will depend on the medical context, the clinical situation, the evolution of the lesions and also the aesthetic and functional discomfort and the patient’s request. Above all, it must include an exploration of the patient’s immunocompetence.