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1 Department of Oral and Maxillofacial Surgery, Oral Medicine and Oral Pathology, Dublin Dental School and Hospital, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland
2 Guy’s, King’s and St Thomas’ Dental Institute, Department of Oral Medicine and Pathology, Guy’s Hospital, London, UK
3 Louisiana State University Health Science Center, School of Dentistry, New Orleans, USA
4 Charité Zahnäartzliche Röntgenologie, Berlin, Germany; and
5 Department of Oral and Maxillofacial Pathology, Medicine and Surgery, Temple University School of Dentistry, Philadelphia, PA, USA
Correspondence: * corresponding author, stephen.flint{at}dental.tcd.ie
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KEY WORDS: HAART • HIV • oral lesions • mucosal lesions • oral manifestations
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Introduction |
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The US Department of Health and Human Services and the Henry J. Kaiser Family Foundation publishes regularly updated guidelines on the use of antiviral agents in HIV-1-infected adults and adolescents. These are available at http://AIDSinfo.nih.gov.
The aims of HAART are four-fold:
Successful treatment causes a sustained suppression of the virus, resulting in an undetectable viral load (< 50 copies/mL) at 4–6 months after initiation of therapy. A concomitant rise in the CD4+ count is also seen. However, HAART regimens are complex, may cause serious (potentially lethal) side-effects or drug interactions, pose difficulty with compliance, often entail large numbers of pills and tablets with frequent dosing, and carry serious potential consequences from the development of viral resistance (United States Department of Health and Human Services and Henry J. Kaiser Family Foundation, 2005).
Treatment failure (HAART failure) does occur and has been ascribed to the development of resistance by the virus to the combination of drugs used, non-compliance with the drug regimen, or suboptimal potency or blood levels of the drug combination.
This workshop addressed the morbidity aspect of therapeutic aim (4), since: oral co-morbidities in HIV infection were some of the first manifestations of the disease to be documented; these co-morbid oral conditions are numerous, prominent, easily diagnosed, occur early in the course of the disease, and may be virtually pathognomonic (such as oral hairy leukoplakia); and compatible classifications of these diseases have been published (Greenspan et al., 1992; EC-Clearinghouse, 1993). However, these classifications may not be entirely appropriate in resource-poor settings. Oral manifestations of HIV infection might therefore serve as good markers for monitoring not only restoration of immune function (along with the numerical parameters of viral load and CD4+ counts), but also HAART failure. These surrogate markers may give insight into the functionality of the immune system, as opposed to simple numerical biochemical and hematological counts on peripheral blood. Indeed, it has been shown that peripheral blood contains only 2% of the body’s lymphocytes, and that these are mostly naïve T-cells and NK cells, whereas the lymphoid tissues contain 98% of the lymphocytes, including activated T-cells, memory cells, and B-cells (Pakker et al., 1998; Roederer, 1998).
At the time this paper was written, anti-retroviral agents constituted 20 different drugs of 4 separate classes: fusion inhibitor (FI), nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) (Table 1
). In HAART therapy, combinations of (usually) three anti-retroviral agents are administered simultaneously to bring about a sustained block in viral replication and restore immune function. Since these drugs are administered for long periods of time, three drug combinations are used in an attempt to minimize viral resistance to the drugs, similar to the way treatment for tuberculosis was managed (Ho, 1995). A range of different combinations of drugs has been used, and each drug combination has advantages and disadvantages. Essentially, there are three commonly used combinations: one NNRTI + two NRTI; one or two PIs + two NRTIs; and three NRTIs. The fusion inhibitor, enfuvirtide (Fuzeon, T20), differs from the other classes of drug, in that it is given by injection and is currently the only drug in its class. It is given as an adjunct to standard regimens. Certain NRTI pairs, termed ‘backbone pairs’—e.g., zidovudine and lamivudine—work particularly well together (Ruane and DeJesus, 2004) and may be co-formulated to aid compliance. Other combinations should be avoided, such as abacavir, lamivudine, and tenofovir, due to poor clinical response (Gallant et al., 2003).
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Question 2: What is the time-course from the start of HAART therapy to any observed changes in incidence, prevalence, or characteristics of HIV-related oral diseases?
Question 3: What are the incidence, prevalence, and characteristics of HIV-related oral diseases in patients who experience HAART failure?
Question 4: Which oral lesions are useful as markers of immunodeficiency or HIV disease progression in patients on HAART therapy?
Question 5: Which changes in incidence, prevalence, and characteristics of HIV-related oral diseases are related to immune reconstitution, and which are related to direct effects of anti-retroviral medication?
Question 1: What are the incidence, prevalence, and characteristics of HIV-related oral diseases in patients on, as compared with those not on, successful highly active anti-retroviral therapy (HAART)?
There is consensus in published studies that the prevalence of HIV-related oral lesions reduces significantly with HAART. The reported percentage decrease varied from 50% in a Mexican study on selected 1000 HIV patients over a period of 12 years (Ramírez-Amador et al., 2003) to 10% in a USA study on 570 patients (Patton et al., 2000).
Studies around the world showed various degrees of reduction in the prevalence of oral manifestations with the use of anti-retroviral therapy. In a Spanish study on 154 subjects, Ceballos-Salobrena et al.(2000) showed a 30% reduction, while Tappuni and Fleming (2001) reported a reduction of 24% in a study on 284 patients in the United Kingdom. However, a straightforward comparison between the studies is inappropriate, since the study subject groups are heterogeneous and the methodology is diverse. Some looked at a particular oral manifestation (Cauda et al., 1999) as apposed to a range of oral lesions (Ceballos-Salobrena et al., 2000; Tappuni and Fleming, 2001; Eyeson et al., 2002; Ramírez-Amador et al., 2003).
Studies examining the effect of HAART on the prevalence of individual oral manifestations mainly reported on oral candidosis, oral hairy leukoplakia, HIV-related periodontal diseases, Kaposi’s sarcoma (KS), oral papillomata, and HIV-related salivary gland disease. A summary of the findings of these studies was presented in this workshop.
Oral candidosis (OC) has been shown to be one of the most common oral lesions in HIV patients. With the advent of HAART, most studies reported a decrease in the prevalence of OC. In a study on 93 patients, 7% of patients on protease inhibitors (PI) had OC, compared with 36% in non-PI-treated patients (Cauda et al., 1999). Schmidt-Westhausen et al.(2000) detected OC in 10/103 (9.7%) of their study subjects who had been on HAART for 4 weeks and in none after 6 months’ therapy (n = 61) (Schmidt-Westhausen et al., 2000). Tappuni and Fleming (2001) reported that the prevalence of OC was about 50% less in patients on therapy (n = 89) compared with drug-naïve patients (n = 195). Conversely, Patton et al.(2000) found no significant difference in the prevalence of oral candidosis (OC) with the use of PI (n = 507). In the same study, the prevalence of oral hairy leukoplakia (OHL) was found to decrease with therapy (Patton et al., 2000), in agreement with reports from other studies (Tappuni and Fleming, 2001).
The prevalence of HIV-associated periodontal diseases was reported to decrease significantly in an American cohort, from 4.8% to 1.7% with HAART (Patton et al., 2000), in concordance with findings in other studies (Ceballos-Salobrena et al., 2000; Tappuni and Fleming, 2001). Kaposi’s sarcoma is one of the oral manifestations that is strongly associated with HIV, although its prevalence is quite low in this group. Ceballos-Salobrena et al.(2000), looking at a Spanish HIV-positive population, found no cases of KS in patients on HAART (n = 154). Studies from the USA (Patton et al., 2000) and Mexico (Ramírez-Amador et al., 2003) found no significant change in the occurrence of KS with HAART.
Unlike most other oral manifestations of HIV, studies from the USA and the UK described an increase in the prevalence of oral warts with HAART (Patton et al., 2000; Greenwood et al., 2002), which may reach statistical significance (Greenspan et al., 2001). Others looking at a different population (Mexican) reported similar detection rates of oral warts in HIV-positive subjects on HAART compared with those not on therapy (Ramírez-Amador et al., 2003). Other lesions that are showing a trend of rising prevalence include HIV-related salivary gland disease (Patton et al., 2000). However, this was not supported by other studies (Ramírez-Amador et al., 2003).
There is limited evidence on the prevalence of oral lesions in HIV-infected children on HAART. In a study group of 40 children from Northern Thailand, aged 0-12 years, 12.5% were on HAART and 57.5% had oral lesions (Pongsiriwet et al., 2003). In 102 American vertically infected 3- to 15-year-olds on HAART, 2.9% had OC, 2.9% linear gingival erythema, 2% bilateral parotid enlargement, and 1% enlarged cervical lymph nodes (Okunseri et al., 2003). No OHL, oral papillomata, or KS was detected.
The effect of therapy on oral manifestations in 38 HIV-positive American children was studied by Flanagan et al.(2000), and Khongkunthian et al.(2001) compared the prevalence of HIV-related oral lesions between Northern Thai children on HAART (n = 15) and children not on HAART (n = 30). Both studies reported no significant difference in HIV-related oral lesions in children on HAART compared with children not on therapy.
Published studies agree that the overall prevalence of HIV-related oral lesions decreases with therapy. However, some lesions, such as oral warts and salivary gland disease, are showing a trend of increasing with HAART. Further longitudinal studies are needed to confirm these findings.
Question 2: What is the time-course from the start of HAART therapy to any observed changes in incidence, prevalence, or characteristics of HIV-related oral diseases?
Three main aspects to answering this question were considered:
Incident oral opportunistic infections have been reported to occur only in patients who receive HAART if there is regimen adherence failure, or non-compliance (Manfredi, 2004). However, HAART itself has been associated with adverse reactions (Scully and Diz Dios, 2001), which may occur at any time after initiation of therapy, and some of these conditions are also seen in untreated HIV disease. It is therefore important to distinguish between a true HIV-related oral manifestation of disease and adverse events of HAART.
For example, the NRTIs have been associated with intra-oral ulcers in 3–30% of patients receiving zalcitabine (ddC) (McNeely et al., 1989), with mucocutaneous hyperpigmentation in patients receiving zidovudine (AZT) (Greenberg and Berger, 1990; Poizot-Martin et al., 1991), and with xerostomia in 30% of patients taking didanosine (ddI) (Allan et al., 1993). These adverse effects must be distinguished from "Not Otherwise Specified" ulcers (NOS), aphthous stomatitis, mucosal pigmentation, and xerostomia associated with HIV disease in the absence of HAART (Greenspan et al., 1992; EC-Clearinghouse, 1993).
Xerostomia and/or oral ulcerations can also be seen in 7% of patients taking protease inhibitors (Danner et al., 1995). Other adverse events include taste abnormalities in 20% of patients (Schiffman et al., 1999), circumoral paraesthesia in a quarter of patients receiving ritonavir (Scully and Diz Dios, 2001), parotid lipomatosis or facial lipoatrophy (as a feature of generalized lipodystrophy) in patients receiving ritonavir (Olive et al., 1998), and cheilitis in 57% of patients taking indinavir (Calista and Boschini, 2000).
Although NNRTIs have rarely been implicated in HIV-associated disorders, erythema multiforme with nevirapine treatment has been reported (Wetterwald et al., 1999; Fagot et al., 2001).
As to oral manifestations in long-term HAART and older patients, studies on an association with osteoporosis or osteodystrophy are inconsistent. Madeddu et al.(2004) described an increase in osteoporosis in patients with HAART, whereas Thomas and Doherty (2003) reported that osteoporosis may occur in patients with and without HAART. If this association is real, there may be implications for alveolar bone loss or periodontal disease (Yoshihara et al., 2004). Similarly, HAART-induced diabetes mellitus and dyslipidemia may predispose to periodontal disease in the long term (Cutler and Iacopino, 2003; Renvert, 2003).
A disproportionate increase in the incidence and prevalence of neoplasms like lymphoma and carcinoma (Manfredi et al., 2003a; Manfredi, 2004), due to persistent dysregulation of the immune system, has been surmised. One consistent observation, however, is an increase in benign HPV-associated oral neoplastic lesions (papillomas, condylomas, and focal epithelial hyperplasia) in patients on HAART (Patton et al., 2000; Schmidt-Westhausen et al., 2000; Greenspan et al., 2001). This raises the possibility of an increased incidence of HPV-related oral malignancies with long-term HAART, particularly if the HPV subtypes carried are high-risk subtypes (such as HPV-16) which have been associated with oral malignancy.
Question 3: What are the incidence, prevalence, and characteristics of HIV-related oral diseases in patients who experience HAART failure?
HAART failure may be defined as immunologic, virologic, or clinical failure. It is important to distinguish HAART failure from regimen failure due to poor adherence and compliance, toxicity, or suboptimal virologic potency. Guidelines (US Department of Health and Human Services and Henry J. Kaiser Family Foundation, 2005) for initiation of HAART suggest different start points, according to drug availability, fear of resistant strain generation, etc., but there is consensus that HAART is indicated at CD4+ counts of < 200 cells/mm3 (which defines ‘full-blown’ AIDS) and virological load of > 55,000 copies/mm3. In epidemiological studies, it is critical that the same inclusion criteria be used as for HAART failure studies.
Virological failure manifests as failure to achieve HIV RNA levels of < 400 copies/mm3 by 24 weeks, or < 50 copies/mm3 by 48 weeks (although ideally by 24 weeks) in a treatment-naïve patient, and suggests an incomplete response to HAART. However, account must be taken of the fact that high baseline levels may affect the time-course and the slope of the monitored virological response. Most patients with an adequate virological response have at least 1 x log10 copies/mm3 reduction in viral load at 4 weeks.
Immunological failure represents a failure to increase the CD4+ count by 25–50 cells/mm3 per month above baseline in the first year, or a decrease in CD4+ count below baseline levels. Low baseline CD4+ count may be associated with a slower response to therapy. Successful therapy achieves a mean increase of 150 cells/mm3 in the first year. However, absolute cell counts take no account of the functionality of the CD4+ cells.
Clinical failure is defined as the occurrence of HIV-related clinical events after 3 months of HAART therapy, and thus, in combination with absolute cell counts, gives an indication of the functionality of the cells measured. Since many oral manifestations of HIV occur early in the course of HIV disease, these may become important markers of early HAART failure. Several publications (Pakker et al., 1997; Gorochov et al., 1998; Notermans et al., 1999) have indicated a return of immune function with HAART, but there is less information about the different combinations of HAART and specific functionality against oral pathogens. A single report (Nielsen et al., 1994) assessed cell-mediated lymphocytic function against Candida using mitogen stimulation. Skolasky et al.(2001) have suggested that parameters such as presence or absence of fever and thrush (including oral pseudomembranous candidosis) may represent markers of immune competence with HAART.
A further complication in defining clinical failure is the so-called immune reconstitution syndrome—or ‘HAART Attack’ (Kunimoto et al., 1999). The re-invigorated inflammatory component of immune reconstitution can have a deleterious effect on quiescent or latent infection, whereby recrudescence of the disease causes damage to the host. The immune reconstitution syndrome (French, 1999) has been described for infections with: tuberculosis, cerebral cryptococcosis, cytomegaloviral retinitis or uveitis, Pneumocystis carinii pneumonia, microsporidial keratoconjunctivitis, and visceral leishmaniasis. The oral equivalent is perhaps represented by the reported increase in HPV lesions (Greenspan et al., 2001) and salivary disease, particularly the diffuse infiltrative lymphocytosis syndrome (DILS) (Patel and Mandel, 2001). It is obviously important that immune reconstitution syndrome be excluded before clinical failure is diagnosed.
There is a growing body of evidence that HAART reduces oral manifestations of HIV infection (Margiotta et al., 1999; Ceballos-Salobrena et al., 2000; Patton et al., 2000; Schmidt-Westhausen et al., 2000; Tappuni and Fleming, 2001; Eyeson et al., 2002; Greenwood et al., 2002; Greenspan et al., 2004; Kerdpon et al., 2004; Nicolatou-Galitis et al., 2004), but none of these investigations addressed the issue of recrudescence of oral manifestations of HIV in HAART failure. There is a single case report of multiple opportunistic AIDS-associated disorders that paralleled immunodeficiency levels in a girl with congenital HIV infection, which documented opportunistic infections following virological failure (Manfredi et al., 2003b).
Since many oral manifestations of HIV occur early in the disease, these may become important markers of early HAART failure in the future, but at the time this paper was written, there were no cohort studies in the literature. It is vital, however, that any future studies take account of the definition of HAART failure and thereby have the same inclusion or end-point criteria.
Question 4: Which, if any, oral lesions are useful as markers of immunodeficiency or HIV disease progression in patients on HAART therapy?
Although there are no documented studies demonstrating an increase in the prevalence of any oral lesion following the failure of HAART therapy, by analyzing current data on oral lesions since the introduction of HAART, it may be possible for investigators to predict which oral lesions may return with a rise in HIV viral load and/or a decrease in immune function following failure of HAART. For an oral lesion to be a useful marker of increased HIV viral load or disease progression, there are four basic criteria that need to be met:
Although many oral lesions were recorded in HIV disease prior to the advent of HAART therapy, not all of those described decreased upon the advent of HAART. The prevalence of several oral lesions (oropharyngeal candidosis [OPC], oral hairy leukoplakia [OHL], Kaposi’s sarcoma [KS], and HIV-associated periodontal diseases) decreased in the presence of HAART, suggesting that these lesions are the most sensitive to immune reconstitution and/or decrease in HIV viral load (Patton et al., 2000; Schmidt-Westhausen et al., 2000; Greenspan et al., 2001; Tappuni and Fleming, 2001).
Of these four lesions, the most two most common, both pre- and post-HAART, are OPC and OHL (Patton et al., 2000; Schmidt-Westhausen et al., 2000; Greenspan et al., 2001, 2004; Tappuni and Fleming, 2001). Both candidosis and OHL can occur early in the course of HIV disease, with CD4+ T-lymphocyte numbers as high as 400 cells/mm3, which has made them good indicators of early immune dysfunction. However, unlike OPC, OHL has a greater prevalence in males than females (Shiboski et al., 1996; Patton et al., 2000). Candidosis has the added diagnostic benefit that it can present in one of two clinical forms, depending on CD4+ cell count. Erythematous candidosis presents at higher CD4+ cell counts (~ 400 cells/mm3) compared with the pseudomembranous form, which more commonly occurs when CD4+ cells decrease further (~ 200 cells/mm3) (Greenspan et al., 1992). Studies have also demonstrated a significant correlation of OPC and increased viral load (Campo et al., 2002; Greenspan et al., 2004). However, an increase in erythematous candidosis was observed in a Spanish cohort, despite a decrease in the pseudomembranous form (Ceballos-Salobrena et al., 2000).
Thus, OPC fulfils three of the criteria for a useful marker of HIV disease progression following HAART failure, in that it is not gender- or race-specific, it occurs early in immune dysfunction in the erythematous form, and the prevalence correlates to HIV viral load. Confounding this, however, is the impact of protease inhibitors on both the carriage of Candida albicans and the occurrence of OPC (Cassone et al., 2002), suggesting that there may not be an increased incidence of OPC in individuals receiving PIs, even in a failing regimen.
Question 5: Which changes in incidence, prevalence, and characteristics of HIV-related oral diseases are related to immune reconstitution, and which are related to direct effects of anti-retroviral medication?
As discussed above, the prevalence of several oral lesions differs in patients on HAART compared with those not on HAART. For most oral lesions, this difference is generally attributed to improved or altered immune system function. However, evidence is mounting that oral candidosis may be directly inhibited by protease inhibitors: Unexpected resolution of antifungal-unresponsive oral candidosis, shortly after initiation of protease inhibitor use and before substantial reconstitution of the immune system would be expected, has been reported. For example, a 34-year-old male with severe immunosuppression (4–10 CD4+ cells/mm3) had a two-year history of oral candidosis refractory to high-dose fluconazole, itraconazole, or oral amphotericin B (Zingman, 1996). Two weeks after he started saquinavir therapy, his candidosis improved and then resolved within two months. That his immune system remained severely depressed (20 CD4+ cells/mm3) suggests a direct inhibitory effect of PI therapy.
This apparent ability of protease inhibitors to inhibit growth of Candida may be related to similarities between candidal-secreted aspartic proteinases (SAPs) and HIV proteinase (Munro and Hube, 2002). SAPs are key virulence factors for Candida albicans, and their highly conserved active-site sequences (Asp-Thr/Ser-Gly) and 3-D structures closely resemble those of HIV proteinase (also an aspartic proteinase, with the same active-site sequence). In vitro studies found that therapeutically relevant concentrations of indinavir, saquinavir, and ritonavir could inhibit some of the SAPs involved in Candida virulence, suggesting that a fortuitous cross-reaction may enable HIV proteinase inhibitors to prevent episodes of clinical candidosis directly.
Further evidence comes from prospective and cross-sectional clinical studies (Cassone et al., 2002). In the prospective study, two groups of HAART-naïve patients began either a PI-based HAART or a NNRTI-based HAART regimen and were followed for 180 days. Significant decreases in episodes of oral candidosis and Candida carriage were observed in the PI group but not in the NNRTI group. Additionally, there was a rapid decrease in SAPs isolated from saliva of Candida carriers in the HAART-PI group but not in the HAART-NNRTI group. That there was no significant difference in CD4+ cell count increases or HIV viremia decreases between the two groups during study suggests that the decreases in oral candidosis and Candida carriage were due to a direct effect of PI use, rather than to differences in the extent of immune system reconstitution. In the cross-sectional study, Candida carriers who had been on a stable HAART-NNRTI or HAART-PI regimen for a year were examined. Those on HAART-NNRTI had SAPs in their saliva, but those on HAART-PI did not, although there was no significant difference between regimens as to CD4+ cell count increases and HIV-viral load decreases. This suggests that the effect of PI use on Candida virulence is independent of immune reconstitution. Whereas a decrease in episodes of candidosis benefits HIV-seropositive patients, PI use may lessen the usefulness of oral candidosis as a marker for HAART success or failure.
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were considered by the workshop to be those questions on which the profession might focus future research effort, since these were important questions which may have clinical relevance and significant influence on patient care. Several participants stressed that, in future observational studies (in both resource-rich and resource-poor settings), if we are to monitor oral manifestations in HIV in HAART-treated patients, it is critical that the definition of HAART failure be consistent (and if not consistent, documented).
Furthermore, criteria for entry into and cut-off in studies should be carefully documented and raw data retained, in case the need arises to re-work the data, should criteria or definitions change in the future. In the collection of tracking data, documentation of not just current drug use but also past drug history is important, because the analysis will be very complex, since there are 4 different drug classes and 20 different drugs. Factors that may affect current observations are previous drug therapy, compliance, drug holidays, and toxicity.
Finally, increased collaboration with medical colleagues was seen as highly desirable, and all efforts should be made to have a dental input to future major studies of HAART.
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Calista D, Boschini A (2000). Cutaneous side effects induced by indinavir. Eur J Dermatol 10:292–296.[Medline]
Campo J, Del Romero J, Castilla J, Garcia S, Rodriguez C, Bascones A (2002). Oral candidosis as a clinical marker related to viral load, CD4 lymphocyte count and CD4 lymphocyte percentage in HIV-infected patients. J Oral Pathol Med 31:5–10.[Medline]
Cassone A, Tacconelli E, De Bernardis F, Tumbarello M, Torosantucci A, Chiani P, et al. (2002). Antiretroviral therapy with protease inhibitors has an early, immune reconstitution-independent beneficial effect on Candida virulence and oral candidosis in human immunodeficiency virus-infected subjects. J Infect Dis 185:188–195.[Medline]
Cauda R, Tacconelli E, Tumbarello M, Morace G, De Bernardis F, Torosantucci A, et al. (1999). Role of protease inhibitors in preventing recurrent oral candidosis in patients with HIV infection: a prospective case-control study. J Acquir Immune Defic Syndr 21:20–25; comment 22:105–106.[Medline]
Ceballos-Salobrena A, Gaitan-Cepeda LA, Ceballos-Garcia L, Lezam Valle D (2000). Oral lesions in HIV/AIDS patients undergoing highly active antiretroviral treatment including protease inhibitors: a new face of oral AIDS? AIDS Patient Care STDs 14:627–635.[Medline]
Cutler CW, Iacopino AM (2003). Periodontal disease: links with serum lipid/triglyceride levels? Review and new data. J Int Acad Periodontol 5:47–51.[Medline]
Danner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, Gonzales J, et al. (1995). A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. N Engl J Med 333:1528–1533.
EC-Clearinghouse on oral problems related to HIV infection and WHO Collaborating Centre on oral manifestations of the human immunodeficiency virus (1993). Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 22:289–291.[Medline]
Eyeson JD, Tenant-Flowers M, Cooper DJ, Johnson NW, Warnakulasuriya KA (2002). Oral manifestations of an HIV positive cohort in the era of highly active anti-retroviral therapy (HAART) in South London. J Oral Pathol Med 31:169–174.[Medline]
Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, Naldi L, Viboud C, Roujeau JC, et al. (2001). EuroSCAR Study Group. Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. AIDS 15:1843–1848.[Medline]
Flanagan MA, Barasch A, Koenigsberg SR, Fine D, Houpt M (2000). Prevalence of oral soft tissue lesions in HIV-infected minority children treated with highly active antiretroviral therapies. Pediatr Dent 22:287–291.[Medline]
French MA (1999). Antiretroviral therapy. Immune restoration disease in HIV-infected patients on HAART. AIDS Read 9:548–562.[Medline]
Gallant JE, Rodriguez A, Weinberg W (2003). Early non-response to tenofovir, abacavir and lamivudine in a randomized controlled trial compared to efavirenz, abacavir and lamivudine (abstract). Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL.
Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, et al. (1998). Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med 4:215–221.[Medline]
Greenberg RG, Berger TG (1990). Nail and mucocutaneous hyperpigmentation with azidothymidine therapy. J Am Acad Dermatol 22(2 Pt 2):327–330.[Medline]
Greenspan D, Canchola AJ, MacPhail LA, Cheikh B, Greenspan JS (2001). Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet 357:1411–1412.[Medline]
Greenspan D, Gange SJ, Phelan JA, Navazesh M, Alves ME, MacPhail LA, et al. (2004). Incidence of oral lesions in HIV-1-infected women: reduction with HAART. J Dent Res 83:145–150.
Greenspan JS, Barr CE, Sciubba JJ, Winkler JR (1992). Oral manifestations in HIV infection. Definitions, diagnostic criteria, and principles of therapy. The USA Oral AIDS Collaborative Group. Oral Surg Oral Med Oral Pathol 73:142–144.[Medline]
Greenwood I, Zakrzewska JM, Robinson PG (2002). Changes in the prevalence of HIV-associated mucosal disease at a dedicated clinic over 7 years. Oral Dis 8:90–94.[Medline]
Ho DD (1995). Time to hit HIV, early and hard. N Engl J Med 333:450–451.
Kerdpon D, Pongsiriwet S, Pangsomboon K, Iamaroon A, Kampoo K, Sretrirutchai S, et al. (2004). Oral manifestations of HIV infection in relation to clinical and CD4 immunological status in northern and southern Thai patients. Oral Dis 10:138–144.[Medline]
Khongkunthian P, Grote M, Isaratanan W, Piyaworawong S, Reichart PA (2001). Oral manifestations in 45 HIV-positive children from Northern Thailand. J Oral Pathol Med 30:549–552.[Medline]
Kunimoto DY, Chiu L, Nobert E, Houston S (1999). Immune mediated ‘HAART’ attack during treatment for tuberculosis. Highly active antiretroviral therapy. Int J Tuberc Lung Dis 3:944–947.[Medline]
Madeddu G, Spanu A, Solinas P, Calia GM, Lovigu C, Chessa F, et al. (2004). Bone mass loss and vitamin D metabolism impairment in HIV patients receiving highly active antiretroviral therapy. Q J Nucl Med Mol Imaging 48:39–48.[Medline]
Manfredi R (2004). HIV infection and advanced age emerging epidemiological, clinical, and management issues. Ageing Res Rev 3:31–54.[Medline]
Manfredi R, Calza L, Chiodo F (2003a). Multiple AIDS-related malignancies just in the era of potent antiretroviral therapy. A rare but intriguing finding. Infez Med 11:153–156.[Medline]
Manfredi R, Calza L, Chiodo F (2003b). Multiple opportunistic AIDS-associated disorders strictly related to immunodeficiency levels in a girl with congenital HIV infection. Int J STD AIDS 14:638–639.
Margiotta V, Campisi G, Mancuso S, Accurso V, Abbadessa V (1999). HIV infection: oral lesions, CD4+ cell count and viral load in an Italian study population. J Oral Pathol Med 28:173–177.[Medline]
McNeely MC, Yarchoan R, Broder S, Lawley TJ (1989). Dermatologic complications associated with administration of 2',3'-dideoxycytidine in patients with human immunodeficiency virus infection. J Am Acad Dermatol 21:1213–1217.[Medline]
Munro CA, Hube B (2002). Anti-fungal therapy at the HAART of viral therapy. Trends Microbiol 10:173–177.[Medline]
Nicolatou-Galitis O, Velegraki A, Paikos S, Economopoulou P, Stefaniotis T, Papanikolaou IS, et al. (2004). Effect of PI-HAART on the prevalence of oral lesions in HIV-1 infected patients. A Greek study. Oral Dis 10:145–150.[Medline]
Nielsen H, Bentsen KD, Hojtved L, Willemoes EH, Scheutz F, Schiødt M, et al. (1994). Oral candidiasis and immune status of HIV-infected patients. J Oral Pathol 23:140–143.
Notermans DW, Pakker NG, Hamann D, Foudraine NA, Kauffmann RH, Meenhorst PL, et al. (1999). Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults. J Infect Dis 180:1050–1056.[Medline]
Okunseri C, Badner V, Wiznia A, Rosenberg M (2003). Prevalence of oral lesions and percent CD4+ T-lymphocytes in HIV-infected children on antiretroviral therapy. AIDS Patient Care STDs 17:5–11.[Medline]
Olive A, Salavert A, Manriquez M, Clotet B, Moragas A (1998). Parotid lipomatosis in HIV positive patients: a new clinical disorder associated with protease inhibitors [letter/case report]. Ann Rheum Dis 57:749.[Medline]
Pakker NG, Roos MT, van Leeuwen R, de Jong MD, Koot M, Reiss P, et al. (1997). Patterns of T-cell repopulation, virus load reduction, and restoration of T-cell function in HIV-infected persons during therapy with different antiretroviral agents. J Acquir Immune Defic Syndr Hum Retrovirol 16:318–326.[Medline]
Pakker NG, Notermans DW, de Boer RJ, Roos MT, De Wolf F, Hill A, et al. (1998). Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med 4:208–214.[Medline]
Patel S, Mandel L (2001). Parotid gland swelling in HIV diffuse infiltrative CD8 lymphocytosis syndrome. NY State Dent J 67:22–23.
Patton LL, McKaig R, Strauss R, Rogers D, Eron JJ Jr (2000). Changing prevalence of oral manifestations of human immuno-deficiency virus in the era of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89:299–304.[Medline]
Poizot-Martin I, Lafeuillade A, Dhiver C, Xeri L, Bouabdallah R, Gamby T, et al. (1991). Cutaneo-mucosal hyperpigmentation in AIDS. 4 cases. Presse Med 20:632–636.[Medline]
Pongsiriwet S, Iamaroon A, Kanjanavanit S, Pattanaporn K, Krisanaprakornkit S (2003). Oral lesions and dental caries status in perinatally HIV-infected children in Northern Thailand. Int J Paediatr Dent 13:180–185.[Medline]
Ramírez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, Anaya-Saavedra G,Gonzalez-Ramírez I, Ponce-de-Leon S (2003). The changing clinical spectrum of human immunodeficiency virus (HIV)-related oral lesions in 1,000 consecutive patients: a 12-year study in a referral center in Mexico. Medicine (Balt) 82:39–50.[Medline]
Renvert S (2003). Destructive periodontal disease in relation to diabetes mellitus, cardiovascular diseases, osteoporosis and respiratory diseases. Oral Health Prev Dent 1(Suppl 1):341–357; discussion 358–359.[Medline]
Roederer M (1998). Getting to the HAART of T cell dynamics. Nat Med 4:145–146.[Medline]
Ruane PJ, DeJesus E (2004). New nucleoside/nucleotide backbone options: a review of recent studies. J Acquir Immune Defic Syndr 37(Suppl 1):S21–S29.[Medline]
Schiffman SS, Zervakis J, Heffron S, Heald AE (1999). Effect of protease inhibitors on the sense of taste. Nutrition 15:767–772.[Medline]
Schmidt-Westhausen AM, Priepke F, Bergmann FJ, Reichart PA (2000). Decline in the rate of oral opportunistic infections following introduction of highly active antiretroviral therapy. J Oral Pathol Med 29:336–341.[Medline]
Scully C, Diz Dios P (2001). Orofacial effects of antiretroviral therapies. Oral Dis 7:205–210.[Medline]
Shiboski CH, Hilton JF, Neuhaus JM, Canchola A, Greenspan D (1996). Human immunodeficiency virus-related oral manifestations and gender. A longitudinal analysis. The University of California, San Francisco Oral AIDS Center Epidemiology Collaborative Group. Arch Intern Med 156:2249–2254.[Abstract]
Skolasky RL, Phair J, Detels R, Riddler S, Margolick J, Jacobson LP (2001). Thrush and fever as markers of immune competence in the era of highly active antiretroviral therapy. AIDS Res Hum Retroviruses 17:1311–1316.[Medline]
Tappuni AR, Fleming GJ (2001). The effect of antiretroviral therapy on the prevalence of oral manifestations in HIV-infected patients: a UK study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 92:623–628.[Medline]
Thomas J, Doherty SM (2003). HIV infection—a risk factor for osteoporosis. J Acquir Immune Defic Syndr 33:281–291.[Medline]
US Department of Health and Human Services and Henry J. Kaiser Family Foundation (2005). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://AIDSinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Wetterwald E, Le Cleach L, Michel C, David F, Revuz J (1999). Nevirapine-induced overlap Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol 140:980–982.[Medline]
Working group on antiretroviral therapy and medical management of HIV-infected children, National Resource Centre, UMDNJ, the Health Resources and Services Administration, National Institutes of Health (2005). http://AIDSinfo.nih.gov.
Yoshihara A, Seida Y, Hanada N, Miyazaki H (2004). A longitudinal study of the relationship between periodontal disease and bone mineral density in community-dwelling older adults. J Clin Periodontol 31:680–684.[Medline]
Zingman BS (1996). Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir [case report/letter]. N Engl J Med 334:1674–1675.
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