Abstract
In the 1970s, human papillomaviruses (HPV) were ascertained as the aetiologic agents of cervical carcinoma. Subsequently, an association with HPV was established in other epithelial tumours, including squamous cell carcinoma of the head and neck (HNSCC). HPV has demonstrated a high potential for inducing oropharyngeal tumours, with HPV-16 infection posing a significant oncogenic risk. People living with HIV (PLWH) are identified as being at a higher risk of HPV infection and the subsequent development of HPV-associated tumours of the oropharynx. We present two patients under the care of the Department of AIDS with long-term HIV infections who were newly diagnosed with HPV-associated carcinomas of the tonsils. Both patients had been on antiretroviral therapy (ART) for over 15 years, achieving optimal viral suppression for more than 10 years. Chemotherapy and radiation therapy were employed in the treatment of the carcinomas. Throughout the neoplastic disease treatment, both patients maintained optimal viral suppression for HIV. The presented cases underscore the fact that despite achieving long-term optimal viral suppression of HIV, people living with HIV remain susceptible to the development of HPV-associated neoplasms.
Introduction
Human papillomavirus (HPV) infection underlies a spectrum of conditions from benign condylomas to invasive carcinomas. 1 Oncogenic HPV persistence significantly contributes to invasive carcinoma development. Additionally, oropharyngeal squamous cell carcinoma (OPSCC) exhibits a higher prevalence in people living with HIV (PLWH).2–4 HIV-induced immune activation and chronic inflammation may contribute to carcinogenesis. 5 Immunosuppression, along with higher-risk sexual behaviours, increases the risk for HPV persistence and associated cancers among PLWH.6–8
We present two patients with long-term HIV infection who have been diagnosed with HPV-associated tonsil malignancy.
Case 1
A 59-year-old man diagnosed with HIV in 1997 initiated ART in 2002, presenting with severe immune deficiency (CD4+ cell count: 13/µl) and disseminated candidiasis, meningoencephalitis and Aspergillus otitis. His treatment regimen has changed multiple times over the years, currently being on a dolutegravir/rilpivirine single tablet. Since 2015, the patient has sustained viral suppression and achieved CD4 recovery exceeding 500 cells/µl by early 2021. However, in August 2021, he was diagnosed with HPV-associated low-grade squamous cell carcinoma of the left tonsil with regional lymph node metastases (Figure 1). (a) Axial head CT - poorly marginated, homogeneous lesion on the right side with displacement. (b) Head PET/CT with pathologically increased glucose metabolism in the retromolar region on the left, submandibular lymph nodes with a metastatic appearance.
The patient underwent 8 cisplatin/5-fluorouracil chemotherapies and 11 radiotherapies. Due to suboptimal tumour response, chemotherapy with docetaxel followed. Despite optimal viral suppression, the CD4 T-cell count remained below 200/µl. After a year of remission, in November 2023, the patient has suffered disease recurrence with regional lymph node metastasis.
Case 2
A 37-year-old woman diagnosed with HIV in 2005 was lost to follow-up until 2011. Admitted in May 2011 with severe immune deficiency (CD4: 71/µl, viral load: >2,000,000), she had disseminated tuberculosis involving cervical lymph nodes. After two months of treatment, she initiated ART with emtricitabine/tenofovir disoproxil fumarate with lopinavir/ritonavir. Post-tuberculosis treatment, she has maintained viral suppression and immune recovery (>500 CD4+ cells/µl) since 2012. In 2010, the patient underwent cervical conization for CIN3 associated with HPV. In November 2022, the patient developed right-sided cervical lymphadenopathy. A biopsy confirmed HPV-associated moderately differentiated metastatic squamous cell carcinoma originating from the right tonsil (Figure 2). (a) PET/CT evidence of a metabolically active proliferative tumour involving the soft tissues of the right palatine arch and right palatine tonsil. (b) PET/CT demonstrating a very good structural-metabolic effect at the level of the primary tumour formation.
The identified HPV strain was genotype 16. Subsequently, the patient underwent extensive treatment, including 33 radiation sessions and 7 cetuximab infusions. Eight months post-radiotherapy, the patient is in remission. Current ART comprises emtricitabine/tenofovir disoproxil fumarate and raltegravir. Recent HIV assessments demonstrated a CD4+ cell count 203/µl and an undetectable viral load.
Discussion
These cases feature individuals with a long-standing controlled HIV infection and sustained viral suppression for over a decade. With improved life expectancy, the number of HIV and HPV co-infected individuals at risk for OPSCC is anticipated to increase. 8 Over a 10-year study, the persistence of oncogenic oral HPV (oncHPV) was examined, revealing rapid clearance for most incident infections, but approximately half of the prevalent oncHPV cases persisted for ≥5 years 9 Persistence is associated with specific risk factors, including prevalent oncHPV, HIV infection, older age, male sex, smoking, taking ART and being on ART for an increased time.4,5,9 Key predictors of incident oral HPV acquisition included HIV infection, low CD4 cell count, and a high number of oral sex partners.7,10
HIV heightens susceptibility to oral HPV, hampering clearance, particularly in those with lower CD4+ T-cell counts and individuals aged over 46 years. Those with a nadir CD4+ T-cell count below 200/mm3 and higher viral load at diagnosis exhibit reduced clearance of high-risk HPVs and had significantly poorer prognosis.5,11 CD8+ T-cell counts have also gained significance, with higher CD4+/CD8+ ratios (>0.5) negatively impacting overall survival. 5 Better prognosis is linked to ART treatment, undetectable HIV viral load, and high CD4 count.4,12
As PLWH with HPV-positive OPSCC have improved survival compared to HPV-negative OPSCC, treatment de-intensification is sought due to detrimental effects on the immune system and potential drug interactions with ART.2,13 Cetuximab, a recombinant chimeric monoclonal antibody that binds to epidermal growth factor receptors (EGFR), explored as a cisplatin alternative, showed poorer survival outcomes in two studies without altering toxicity.14,15 Despite its success in HPV-negative cases, cetuximab’s inefficacy in HPV-positive disease may be linked to differing EGFR expression in oropharyngeal squamous cell carcinoma. 2 Although EGFR is expressed in most HNSCC, 16 mutations associated with resistance to EGFR-targeted therapies are more prevalent in HPV-positive OPSCC. 14 However, cetuximab resistance in HNSCC cell lines reveals that resistant cells surprisingly induce a more robust antibody-dependent cellular cytotoxicity response by NK cells, offering insights into overcoming cetuximab resistance through combined immunotherapies and targeted approaches in HNSCC. 17 Concurrently, one of our cases demonstrates a favourable response to cetuximab, aligning with existing data indicating positive outcomes in PLWH and various neoplasms. 18 This highlights the potential for continued use and advancements in cetuximab-based targeted immunotherapeutic approaches for PLWH and associated neoplasms.
Conclusions
Our cases emphasize the persistence of HPV and the development of related carcinomas in individuals with well-controlled, long-standing HIV infection. Contrary to expectations, ART does not seem to preclude persistent HPV infection or reduce the risk of HPV-related malignancies. However, effective ART, associated with undetectable HIV viral loads and maintaining high CD4 counts, correlates with an improved outlook in HNSCC. Furthermore, continued exploration of targeted immunotherapies also holds promise for improved outcomes in the growing population of HIV and HPV co-infected individuals.
Footnotes
Author’s note
All authors meet the ICMJE authorship criteria.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
