J Oral Pathol Med (2013) 42: 443–449 doi: 10.1111/jop.12032 © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
wileyonlinelibrary.com/journal/jop
HPV oral lesions in HIV-infected patients: the impact of long-term HAART
Gabriela Anaya-Saavedra1, Bertha Flores-Moreno1, Alejandro García-Carranca 2,3, Esther Irigoyen- Camacho1, Miriam Guido-Jim enez2,3, Velia Ramírez-Amador1
1Universidad Autonoma Metropolitana-Xochimilco, Ciudad de M exico, Mexico; 2Instituto Nacional de Cancerología (INCan), Ciudad de M exico, Mexico; 3Unidad de Virus y Cancer, Instituto de Investigaciones Biom edicas, UNAM, Ciudad de M exico, Mexico
BACKGROUND: Since the introduction of highly active Keywords: HAART; human papillomavirus; oral warts antiretroviral therapy (HAART), an increase in the frequency of human papillomavirus-associated oral lesions (HPV-OL) has been observed. Thus, the aim of this study was to determine the prevalence and factors associated with HPV-OL in Mexican HIV-infected patients, as well as its genotyping, in the HAART era. Introduction METHODS: In a cross-sectional study developed at an HIV/AIDS referral center in Mexico City, HIV-infected A hallmark of the HIV-associated oral lesion spectrum is the patients were consecutively included from 2004 to 2011. increase in the frequency of human papillomavirus-associ- An oral exam was performed; lymphocyte CD4+ count, ated oral lesions (HPV-OL), concurring with the introduc- HIV-viral load, CDC-stage, and HAART use were tion of highly active antiretroviral therapy (HAART) (1–3). recorded. HPV-OL samples were taken for routine histo- The term HPV-OL incorporates a group of benign oral pathological analysis (H-E) and HPV-DNA amplification/ lesions (squamous cell papilloma, verruca vulgaris, condy- sequencing. Logistic regression models were performed loma acuminatum, and multifocal epithelial hyperplasia) that and the interactions tested using the STATA software. has been described in HIV-infected patients as a result of RESULTS: Among 787 HIV patients, 55 (6.9%) showed diverse immunological abnormalities (4–6). HPV-OL. HPV-OLs were independently associated with Human papillomavirus-associated oral lesions in immu- age ( 40 years) and with a longer time of HAART use nocompromised patients may carry unusual HPV-types and ( 12 months). The most frequent lesion was squamous atypical clinical features (7). In most studies (8–14), low- cell papilloma in 22 (40%) cases, followed by multifocal risk HPV types have been associated with these oral benign epithelial hyperplasia in 15 (27.3%) cases. Labial mucosa disorders; however, some high-risk types (HPV-16, 18, 31) was the most common site involved (56.4%). Of the have also been identified (8, 9, 12, 15). sequences obtained, 65.4% corresponded to low risk and Although the benign nature of HPV-OL in HIV has been 11.5% to high risk. Mixed high- and low-risk infection were documented (16–18), it is relevant to consider the increased identified in 7.7% of the cases. incidence of diverse types of cancer with a known infectious CONCLUSIONS: Human papillomavirus-associated oral cause reported in HIV/AIDS patients, particularly HPV- lesions were associated with older age and longer associated oral and oropharyngeal cancer (4, 19–25). Thus, HAART use. All lesions were benign in nature and most the aim of this study is to determine the prevalence, clinical of the HPV sequences corresponded to low-risk types. characteristics, and factors associated with the presence of The rise of HPV-OLs in HIV patients on HAART may be HPV-OLs in Mexican HIV-infected patients, as well as its related with the longer life expectancy of individuals with genotyping in the HAART era. an impaired immune system rather than a direct effect of HAART. Material and methods J Oral Pathol Med (2013) 42: 443--449 A cross-sectional study was conducted from July 2004 to December 2011 in a primary care center for HIV/AIDS patients without Social Security, located in Mexico City Correspondence:Velia Ramírez-Amador Camino Sta. Teresa 277-9. Col. (Cl ınica Especializada Condesa [CEC]). The study protocol Parques del Pedregal Mexico D.F. 14010, Mexico.Tel: (5255) 5606-1781, was approved by the institutional review board of the Fax: (5255) 5483-7206, E-mails: [email protected]; rava1863@cor- reo.xoc.uam.mx participant institution, and the patients gave written consent Accepted for publication November 13, 2012 to participate in the study. Long-term HAART and HPV oral lesions Anaya-Saavedra et al. 444 Adult patients with known HIV infection, who attended a Genomic HPV-DNA amplification was carried out using routine visit at the Oral Medicine and Pathology Clinic of MY09/MY11 (30) and GP5+/GP6+ primers (31) that CEC were consecutively included. Information regarding amplify a large variety of HPV types, under the conditions age, HIV-transmission risk factors, and tobacco use was described by the manufacturer, as previously described (32). recorded. Lymphocyte CD4+ T-cell counts, HIV viral load, In every assay, water and DNA from the HeLa cell line was CDC stage (26), and the type and duration of HAART were used as a substitute for DNA and as a negative and positive retrieved from the medical records. HAART was defined as control, respectively. To visualize the PCR products after the concomitant use of three antiretroviral (ARV) drugs, amplification, a 5-ll aliquot of each sample was run on a either a combination of two types of ARVs (nucleoside 1.5% agarose gel staining with ethidium bromide (10 mg/ reverse transcriptase inhibitors [NRTIs], non-nucleoside ml) (Sigma Chemical Co., St. Louis, MO, USA); the reverse transcriptase inhibitors [NNRTIs], protease inhibitors expected sizes were ~450 bp for MY09/11 and ~150 bp for [PIs], or a fusion inhibitor [FIs]), or three NRTIs (27). GP5+/6+. Patients were considered to be on HAART if they received To minimize sample-to-sample contamination, special any of these combinations for more than 30 days; the precautions such as frequent changes of gloves and careful regimens were supervised by an infectious disease specialist. handling of samples were followed. All the reagents used in All the patients had a thorough clinical oral examination; the PCR assays were prepared and stored in an area that was HPV-OLs were identified by two oral pathology and free of PCR-amplified products. medicine specialists with experience in the recognition of Positive PCR products were purified using the QIAquick these lesions (VRA, GAS), based on visual inspection and PCR purification protocol and subsequently sequenced using according to predetermined clinical criteria (7, 28 ,29). The the Big Dye Terminator v3.1 cycle sequencing kit (Applied presence and clinical characteristics of each HPV-OL were Biosystems Life Technology, Foster City, CA, USA) by registered. Tissue from the HPV-OL was obtained using a using one of the PCR primers as a sequencing primer (GP5+ disposable punch, and divided into two sections: one was and MY09). Sequencing reactions were analyzed using the fixed in a formalin solution (10%) for subsequent routine ABI PRISM 3100 genetic analyzer system (Applied Biosys- histopathological analysis (hematoxylin–eosine stain); the tems Life Technology), and the obtained sequences were second piece was introduced in a collection tube that matched with Gene Bank-published sequences (National contained a cellular preservation solution (CytycCorp., Center for Biotechnology Information, Bethesda, MD, USA) Marlborough, MA, USA). using the BLAST program (33). Histopathological diagnosis was based on pre-established definitions (7, 29) that consider the morphology of the Statistical analysis epithelial surface, the degree of keratinization, basal cell The association between the presence of HPV-OL and the hyperplasia, mitosoidal body presence, vacuolization of variables considered in the study were analyzed by the squamous cells, and inflammation in the subjacent connec- U-Mann–Whitney, v2, or Fisher’s exact test, when neces- tive tissue. All studies were performed by oral pathology sary. Risk factors for HPV-OL were assessed using a and medicine specialists blinded to HPV testing. logistic regression model, and odds ratios and 95% confi- Specimens were vortexed to remove the cells from the dence intervals for the corresponding categories were bristles and then they were centrifuged at 3000 g for 10 min. constructed. Statistically significant (P < 0.05) variables in The cell pellets were resuspended in 200 ll of sterile PBS. the univariate analysis and those considered relevant based Both cellular and tissue specimens were immediately frozen on previous literature were included in the multivariate at À20°C until DNA extraction was performed. DNA was model. Interactions were tested. The statistical analysis was extracted using the DNA Wizard Genomic Purification kit carried out using the STATA statistical software release 10 (Promega, Inc., Madison, WI, USA) according to the (StataCorp 2007, College Station, TX, USA). manufacturer’s protocol. The proteins were removed by ° incubation at 65 C in a nucleic lysis solution for 3 h Results (brushings) or overnight (biopsies) with 17.5 ll of protein- ase K (20 mg/ml); then, 1.5 ll of RNase was added and As described in Table 1787 HIV-infected patients were incubated at 37°C for 30 min. One hundred microliters of included (735/93.4% males), with a median age of 33 years protein precipitation solution was added, vortexed for 20 s, (Q1–Q3:27–40), of which 50.1% were AIDS patients. A and kept in ice for 5 min. A white pellet was obtained after third of them (243/30.9%) were on HAART, with a median 4 min of centrifugation, washed with 300 ll of isopropanol, time of use of 358 days (Q1–Q3: 97.5–847.8); the most and then with 300 ll of 70% ethanol. Following ethanol frequent ARV scheme used was NRTI + NNRTI (142/ precipitation, the DNA was resuspended in 50 llofDNA 58.4%). One hundred and fifty-seven patients (from 421 rehydration solution. Finally, the obtained DNA was stored individuals in whom a viral load determination was at À20°Cin5-ll aliquots until analysis. available) had undetectable levels of HIV-RNA (37.3%). The total DNA concentration was determined by The median lymphocyte CD4+ count, from data available in 3 spectrophotometry, the ratio of 260/280 was measured to 439 patients, was 281 cells/mm (Q1–Q3:140–471. The evaluate the DNA purity using a Beckman DU-640 main transmission category was men who had sex with men spectrophotometer (Beckman Scientific Instruments, Fuller- (MSM) (562/82.8%), and 52% were current smokers. ton, CA, USA). To demonstrate the integrity of the purified The demographic and clinical characteristics of patients, DNA, a b-globin gene PCR assay (268-pb PCO4/6H20) with or without HPV-OL, are presented in Table 1. Fifty- was performed for all samples. five (6.9%) of the 787 patients showed HPV-OLs (two
J Oral Pathol Med Long-term HAART and HPV oral lesions Anaya-Saavedra et al. 445 Table 1 Demographic and clinical data of HIV-infected subjects with and without HPV-OL
With HPV-OL (n = 55) Without HPV-OL (n = 732) Total (n = 787) n n (%) n (%) (%) P
a Median age (Q1–Q3) years 40 (32–44) 33 (27–39) 33 (27–40) <0.001 Tobacco smoking Yes 30 (54.5) 337 (47.5) 367 (48.0) 0.311b No 25 (45.5) 373 (52.5) 398 (52.0) n = 55 n = 710 n = 765 Transmission category MSM 52 (94.5) 510 (81.7) 562 (82.8) 0.114c Heterosexual 3 (5.5) 100 (16.0) 103 (15.2) Blood transmission 0 (0.0) 5 (0.8) 5 (0.7) Unknown 0 (0.0) 9 (1.4) 9 (1.3) n = 55 n = 624 n = 679 CDC stage26 AIDS 36 (65.5) 289 (48.7) 325 (50.1) 0.023b No-AIDS 19 (34.5) 305 (51.3) 324 (49.9) n = 55 n = 594 n = 649 HAART use Yes 41 (74.5) 202 (27.6) 243 (30.9) <0.001b No 14 (25.5) 530 (72.4) 544 (69.1) HAART combination NRTIs+NNRTIs 28 (68.3) 114 (56.4) 142 (58.4) 0.119b NRTIs+IPs 8 (19.5) 67 (33.2) 75 (30.9) NNRTIs+IPs 2 (5.9) 12 (5.9) 14 (5.8) NRTIs+NNRTIs+IPs 3 (7.3) 4 (2.0) 7 (2.9) IPs 0 (0.0) 5 (2.5) 5 (2.1) n = 41 n = 202 n = 243 a Median HAART use (Q1–Q3) days 477 (224–1170) 327 (87–800) 358 (97–847) 0.031 n = 41 n = 202 n = 243 a Median viral load (Q1–Q3) log10 copies/ml 4.43 (3.97–4.97) 5.00 (4.41–5.39) 4.97 (4.38–5.38) 0.036 n = 51 n = 370 n = 421 + 3 a Median CD4 count (Q1–Q3) cell/mm 282 (191–525) 281 (123–464) 281 (140–471) 0.584 n = 53 n = 386 n = 439 HIV-viral load (copies/ml) Detectable 13 (25.5) 251 (67.8) 264 (62.7) <0.001b Undetectable 38 (74.5) 119 (32.2) 157 (37.3) n = 51 n = 370 n = 421 aU-Mann–Whitney, bChi-square, cExact Fisher’s test. MSM, men who had sex with men; HAART, highly active antiretroviral therapy; NRTIs, nucleoside reverse transcriptase inhibitors, NNRTIs, non- nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; Q1–Q3, interquartile range. females and 53 males); 52 of the 53 males (94.5%) were P < 0.001) than those with a shorter time on HAART. MSM. The patients with HPV-OLs were significantly older Other variables significantly associated with the presence of (40 years [Q1–Q3:32–44]) than those without lesions these lesions were age (>40 years old) and undetectable (33 years [Q1–Q3:27–39]) (P < 0.001). Also, the subjects viral load. To explore the independent effect of the variables with HPV-OLs were in more advanced stages of HIV that were significantly associated in the univariate analysis, infection than those in the non-HPV-OLs group a multivariate analysis indicated that the group with HPV- (P < 0.023). More patients in the group with HPV-OLs OLs was independently associated with age ( 40 years) were on HAART in comparison with the other set of and longer time of HAART use ( 12 months). patients (74.5% vs. 27.6%, P < 0.001), with NRTIs + Of the 55 HPV-OLs, 22 (40%) were squamous cell NNRTIs being the most frequent HAART combination papilloma (SCP), 15 (27.3%) multifocal epithelial hyper- prescribed in both groups. The duration of HAART use was plasia (MEH), and three (5.5%) verruca vulgaris (VV). In longer in the HPV-OL group than in patients without HPV- seven patients (12.7%), the lesions shared clinical and OL (477 vs. 327 days, P = 0.031). The proportion of histopathological characteristics of SCP and VV, so they individuals with an undetectable viral load was significantly were defined as oral warts (OW). Eight patients (14.5%) higher among the HPV-OLs patients (P < 0.001), but the showed concurrent MEH and OW lesions. Oral condyloma median CD4+ cell counts was comparable in both groups. acuminatum cases were not found in this study. The univariate analysis described in Table 2 reveals that The most frequent HPV-OL location was the labial the patients on HAART were more likely (OR = 7.7) to mucosa in 31 (56.4%) cases, followed by the tongue in nine present HPV-OLs (95% CI 4.10–14.39, P < 0.001). Also, (16.4%), and the buccal mucosa in eight (14.5%) cases. those with more than 12 months under HAART were 5.1 Other affected sites were the palate (n = 3) and the gingiva times as likely to present an HPV-OL (CI 95% 2.84–9.03, (n = 3) (5.5% each one). One lesion was found in the floor
J Oral Pathol Med Long-term HAART and HPV oral lesions Anaya-Saavedra et al. 446 Table 2 Results of the univariate and multivariate logistic regression Table 3 HPV types identified in HPV-OL samples from HIV-infected models fitting HPV-OL and selected variables patients
OR (95% CI) P HPV-OL (n = 26) Univariate analysis n (%) Types of HPV-OL Age Reference: 40 years 1.00 Low-risk HPV types > – 40 years 3.13 (1.78 50.50) 0.001 HPV-1 1 (3.8) 1 MEH+OW On HAART HPV-6 2 (7.7) 2 OW Reference: no 1.00 HPV-11 3 (11.5) 2 SCP, 1 VV – < Yes 7.68 (4.10 14.39) 0.001 HPV-13 8 (30.8) 5 SCP, 1 OW, 1 MEH, Time under HAART 1 MEH+OW Reference: 12 months 1.00 HPV-32 2 (7.7) 2 MEH >12 months 5.06 (2.84–9.03) <0.001 26 HPV-74 1 (3.8) 1 SCP CDC stage Low- and high-risk HPV types Reference: no-AIDS 1.00 HPV-13 & 16 1 (3.8) 1 MEH+OW – AIDS 1.10 (0.99 1.22) 0.0494 HPV-13 & 18 1 (3.8) 1 SCP Undetectable viral load High-risk HPV types Reference: no 1.00 HPV-16 1 (3.8) 1 MEH – < Yes 6.16 (3.16 12.01) 0.001 HPV-31 2 (7.7) 2 OW Multivariate analysis Multiple HPV infections Age 4 (15.4) 2 SCP, 2 MEH Reference: 40 years 1.00 >40 years 2.51 (1.38–4.56) 0.002 CDC stage26 HPV-OL, human papillomavirus-associated oral lesion; SCP, squamous = Reference: no-AIDS 1.00 cell papilloma; VV, verruca vulgaris; OW, oral warts; OW SCP/VV; AIDS 1.09 (0.98–1.22) 0.096 MEH, multifocal epithelial hyperplasia. Time under HAART Reference: 12 months 1.00 HAART; moreover, patients with more than 12 months >12 months 3.14 (1.72–5.74) <0.001 under HAART showed a threefold risk of having an HPV- OL. The observed prevalence was higher than the 0.4% fi OR, odds ratio; CI, con dence interval, HAART, highly active antiretro- reported by our working group for the period 1999–2001 viral therapy. CDC=HIV/AIDS stage according with the CDC staging system.26. (34), and is consistent with the increased trend of HPV-OL in HIV/AIDS patients described by other authors (1–3, 18). of the mouth (1.8%). Twenty-six (47.3%) patients presented The study by Patton et al. (3) was the first to report that HPV-OLs in multiple sites on the oral mucosa. human papillomavirus lesions increased among HIV-positive DNA was purified and amplified from 30 HPV-OLs. In patients from 2.2% in 1995–1996 to 4.0% in 1996–1999, 25 patients, it was not possible to obtain a tissue sample although the difference did not reach statistical significance. because (i) the patient did not give his consent to the Another study described the increase of oral warts from 5% in procedure, (ii) lesions were small, flat, and did not cause any individuals without ARVs, to 15% in patients on antiretroviral discomfort, and (iii) patient’s systemic conditions were not therapy other than HAART, and to 23% in those on HAART favorable to perform a surgical procedure (thrombocytope- (2). Similarly, Greenwood et al. (1) showed an increase of the nia). All 30 samples were positive for a b-globin PCR prevalence of HPV-OL over time (1996–1998), mainly in reaction, but there was insufficient DNA to determine the patients taking ARVs (4.6%). In addition, King et al. (18) genotype in four biopsy samples. As shown in Table 3, of noted an increase in the cumulative incidence of oral warts in a the 26 included samples, high-risk HPV types (16 and 31) 3-year study period. In recent years, although there is some were detected in three (11.5%) and low-risk (types 1, 6, 11, information regarding the prevalence of HPV-OL in HIV/ 13, 32, and 74) were found in 17 (65.4%) samples. Two AIDS patients derived from cross-sectional studies varying lesions (7.7%) showed mixed high- (16, 18) and low-risk from 0.5% (35) to 4.6% (36), there are no longitudinal studies HPV (13) infection, and multiple HPV infection was found that could bring additional evidence related to the increase of in four (15.4%) samples. Human papillomavirus type 13 HPV-OL in patients on HAART. was the most frequent type identified in 10 patients (38.5%), Even though the aforementioned reports (1–3, 18) two of whom also showed HR-HPV (one HPV-16 and one proposed that HAART might be an important factor that HPV-18). HPV-32 was identified in two MEH samples influences the development of HPV-OL, to date, there is not (7.7%). Cutaneous HPV types (HPV-1, 6, 11) were enough scientific evidence to conclude that this therapy identified in six samples (one MEH+OW, one VV, two could be a risk factor for the development and progression OW, and two SCP). of these lesions. It is important to highlight that in our findings the Discussion development of HPV-OL was associated with older age and a longer duration of HAART use. Thus, the rise of HPV-OL In this study, we found that from 2004 to 2011, 6.9% of in treated HIV patients may be related to the fact that 787 HIV/AIDS patients seen at a referral center in Mexico HAART is an enduring therapy that offers extended survival City exhibited HPV-OL. These lesions were associated to HIV patients. It is probable that the long-lasting with older age (>40-years old) and with a longer time on immunosuppression in HIV-infected individuals placed on
J Oral Pathol Med Long-term HAART and HPV oral lesions Anaya-Saavedra et al. 447 HAART has already exceeded some critical threshold for An interesting finding in this study was the presence of developing HPV-related disease that cannot be reversed HPV multi-infection in four HPV-OL samples (7.3%). The with therapy (6). HPV-specific immunity may not recover presence of multiple infections may be associated with the fully after the immune response is restored, which may inability of the severely impaired cell-mediated immune explain the relatively limited beneficial effect of HAART on response to clear HPV infection in HIV patients (57). On the HPV-OL (37). To explain the rise of HPV-OL in the other hand, even though we cannot differentiate between HAART era, another aspect to be considered may be the transient, persistent, or reactivated latent infections, it is proliferative capacity of keratinocytes provided by HIV-tat necessary to point out the possibility of transient infections, and other HIV genes (rev and vpr) that stimulate the particularly in the set of immunocompromised individuals expression of HPV genes (L1, E1, and E6) (16, 38). (16). Also, it has been recognized that sexual behavior is a In this study, patients with an undetectable viral load had risk factor for the presence of oral HPV in HIV infection (8, a sixfold risk of presenting HPV-OL, which was expected 15, 58–60). considering the long time under HAART spent by the HPV- This study has some limitations because it was conducted OL individuals. An earlier report (18) described an associ- as a cross-sectional study, so it lacks information on the ation between the presence of HPV-OL and a drop of at behavior or progression of HPV-OL over time. Longitudinal least one log in the peripheral HIV viral load in the previous studies should be carried out to clarify the possibility of 6 months, proposing that oral warts may represent a form of malignant changes in the presence of HR-HPV types. immune reconstitution inflammatory syndrome (IRIS) Nevertheless, it is important to mention that the detection of occurring in response to improved cell-mediated immune high-risk sequences in tissues does not necessarily prove a function (18). Likewise, a recent review (39) suggested that causal association with malignancy, thereby reinforcing the HPV disease in HIV infection after HAART might represent high frequency of oral HPV infection in the healthy oral a persistent immunodysregulation, and a form of immune mucosa of HIV patients (61). reconstitution-associated disease (IRAD), a term that also Even though, in this study, oral HPV infection was not encompasses IRIS. assessed, it is important to highlight that, in HIV-patients; According to the IRIS Definition criteria proposed by the oral HPV infection frequency could be as high as 80% (61). AIDS Clinical Trial Group (40), the onset of new skin/ Interestingly, despite the high prevalence of oral HPV genital warty lesions, as well as the rapid growth of infection found in these studies, HPV-OL have not been previously stable warts has been observed during immune described (57, 61–63). Some of the risk factors associated restoration (41–45). In addition, in a subset of HIV-infected with oral HPV infection, include tobacco consumption, patients, the clinical appearance of HPV-OL is characterized immunological factors, and sexual behavior (8, 63, 64). by a florid onset, with a rapid and uncontrolled course, In conclusion, it is suggested that the increasing incidence refractory to conventional treatments (5, 46–49). Neverthe- of HPV-OL in the post-HAART era may be associated with less, a tissue analysis performed in 14 oral warts revealed the longer life expectancy of individuals who also have an that HAART had no demonstrable effect on local immune impaired immune system rather than a direct effect of responsiveness; consequently, in agreement with their HAART. In HIV-infected patients, the high frequency of HR- results, oral warts could not be classified as IRIS (50). HPV infection, added to their increased susceptibility to Future studies, performed in compliance with international developing malignancies and the rise in oropharyngeal HPV- standards for IRIS case definition, may be helpful in associated cancer emphasizes the need for adequate screening clarifying the role of HPV-OL as part of IRIS. programs and timely interventions in HIV-infected patients. The most frequent HPV-OL identifiedin this study was SCP (40%), followed by MEH (27.3%), in agreement with recent References case reports of SCP (15, 48) and MEH (14, 17, 51) in HIV patients. Also, oral condyloma acuminatum, which has been 1. Greenwood I, Zakrzewska JM, Robinson PG. Changes in the reportedelsewhere(10,11,13,49),wasnotfoundinthisreport. prevalence of HIV-associated mucosal disease at a dedicated HPV-OL biopsies from HIV-AIDS individuals have clinic over 7 years. Oral Dis 2002; 8:90–4. demonstrated a range of low- and high-risk HPV geno- 2. 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