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© 2006 SAGE Publications (A3) HIV Phenotypes, Oral Lesions, and Management of HIV-related DiseasePresented at the Fifth World Workshop on Oral Health and Disease in AIDS, Phuket, Thailand, July 6–9, 2004, sponsored by Prince of Songkla University, Thailand, the International Association for Dental Research, the World Health Organization, the NIDCR/National Institutes of Health, USA, and the University of California-San Francisco Oral AIDS Center.
1 Dept. of Stomatological Studies, Faculty of Dentistry, University of Limpopo, MEDUNSA 0204, South Africa Correspondence: * corresponding author, eblignaut{at}medunsa.ac.za
Workshop participants discussed: the role of HIV subtypes in disease; the treatment of oral candidiasis; the relationship between and among viral load, CD4+ counts, oral candidiasis and oral hairy leukoplakia, pigmentation; and the development of a reliable oral index to predict disease progression. Regarding HIV, the literature revealed that Type I (HIV-I), in particular group M, is involved in the majority (90%) of documented infections, and groups N and O to a lesser extent. Viral envelope diversity led to the subclassification of the virus into nine subtypes, or clades—A–D, F-H, J, and K—each dominating in different geographical areas. HIV-2, currently occurring mostly in West Africa, appears to be less virulent. No evidence could be produced of any direct impact of type, subtype, or clade on oral lesions, and participants believed that further research is not feasible. Oral candidiasis in patients from resource-poor countries should be prevented. When the condition does occur, it should be treated until all clinical symptoms disappear. Oral rinsing with an antimicrobial agent was suggested to prevent recurrence of the condition, to reduce cost, and to prevent the development of antifungal resistance. Lawsone methyl ether, isolated from a plant (Rhinacanthus nasutus leaves) in Thailand, is a cost-effective mouthrinse with potent antifungal activity. Evidence from a carefully designed prospective longitudinal study on a Mexican cohort of HIV/AIDS patients, not receiving anti-retroviral treatment, revealed that the onset of oral candidiasis and oral hairy leukoplakia was heralded by a sustained reduction of CD4+, with an associated sharp increase in viral load. Analysis of the data obtained from a large cohort of HIV/AIDS patients in India could not establish a systemic or local cause of oral melanin pigmentation. A possible explanation was a dysfunctional immune system that increased melanin production. However, longitudinal studies may contribute to a better understanding of this phenomenon. Finally, a development plan was presented that could provide a reliable prediction of disease progression. To be useful in developing countries, the index should be independent of costly blood counts and viral load.
Key Words: HIV • phenotypes • hyperpigmentation • CD4 count • oral candidiasis • oral hairy leukoplakia
A variety of topics was addressed during this Workshop, with the purpose of providing a better understanding of factors underlying and contributing to the oral manifestations of HIV/AIDS and the subsequent improved management thereof. Highly active anti-retroviral therapy (HAART) has greatly decreased the prevalence of the majority of oral manifestations associated with HIV/AIDS among patients in developed countries (Patton et al., 2000; Schmidt-Westhausen et al., 2000). However, in developing countries, where the epidemic does not appear to be declining, and where HAART is not freely available, affordable mechanisms to predict disease progression and to prevent and treat oral manifestations associated with HIV-infection are continuously being sought. The desirability of obtaining clarity on contradicting findings, through longitudinal studies, was repeatedly expressed during the course of discussions.
Question 1: What are the influences of type, strain, and clade differences on the incidence and natural history of the oral manifestations of HIV disease? Question 2: What should be the optimal goal in treating oral candidiasis in developing countries? Are there any interventions to prolong the time to recurrence of the lesion? Question 3: Are oral candidiasis and hairy leukoplakia related to the CD4 and viral load kinetics during HIV infection? Question 4: What are the significance and relevance of oral melanocytic pigmentation in HIV infection? Question 5: Is it possible to develop a reliable oral index to predict disease progression?
Question 1: What are the influences of type, strain, and clade differences on the incidence and natural history of oral manifestations of HIV diseases? (Lauren L. Patton) HIV Type 2 (HIV-2), first identified in Cameroon in 1985, shows about 50% similarity to HIV-1 at the nucleotide level (Tatt et al., 2001). HIV-2, currently geographically confined to West Africa, is more similar to Simian Immunodeficiency Virus (SIV) than is HIV-1, and it is much less virulent, with lower viral loads (VL) usually not resulting in AIDS, but still potentially fatal. HIV-2 has epidemic clades A and B and non-epidemic clades C–G (Lemey et al., 2003). Published data proved extremely limited to address Question 1. Three systematic PubMed literature searches through June, 2004, in all languages, revealed no articles addressing oral disease by clade/subtype or strain for patients infected with HIV-1 or HIV-2, and seven articles reporting on oral lesions or HIV-associated periodontal disease in patients infected with HIV-2 (3 case reports; 5 cohort studies) (Kloser et al., 1989; Carballo et al., 1994; Labandeira et al., 1994; Ndiaye et al., 1997, 2002; Ndour et al., 2000). Case reports demonstrate that oral hairy leukoplakia (OHL) and oral candidiasis (OC) can also occur in individuals infected with HIV-2 (Kloser et al., 1989; Carballo et al., 1994; Labandeira et al., 1994). Two cohort studies from West African tuberculosis treatment centers add additional evidence of OC occurring with HIV-2 infection (Gnaore et al., 1993; Malkin et al., 1997). A third retrospective cohort comparison study was identified that compared opportunistic infections and malignancies of HIV-1- vs. HIV-2-infected patients (Ndour et al., 2000). This study involved 790 hospitalized AIDS (599 HIV-1-positive; 137 HIV-2-positive; 54 HIV-1 and two co-infected) patients from January, 1986–July, 1997, at Fann Hospital, Dakar, Senegal, who met the World Health Organization AIDS definition and had an ELISA and Western blot confirmed HIV antibody test (Ndour et al., 2000). Across all 3 HIV type-groups, OHL was reported between 0 and 2%, facial paralysis between 2 and 3%, herpes simplex virus infection between 11 and 13%, herpes zoster infection between 2 and 4%, Kaposi’s sarcoma between 1 and 2%, and lymphoma between 0 and 1%. Importantly, patients with HIV-1 (67%) were 1.46 times more likely to have OC (p = 0.05) than were patients with HIV-2 (58%), and this is in light of similar age, gender, and CD4 count means between groups. A fourth cohort comparison study followed 680 HIV-1-infected men and women and 115 HIV-2-infected men and women recruited from Infectious Disease and Dental Clinics at Fann Hospital, Dakar, over 2.5 years, to determine prevalence and risk factors for oral lesions (Ndiaye et al., 2002). Analyses revealed that HIV-1 patients had a higher risk of mucosal lesions than HIV-2 patients (ORadj = 2.5; 1.1–50) (Ndiaye et al., 2002). A fifth small cohort comparison of 27 HIV-positive and 65 HIV-negative female commercial sex workers in Senegal reported that HIV-associated periodontal lesions were seen in three of 27 HIV-seropositive subjects, compared with none of 65 HIV-seronegative workers. One of seven HIV-2- and one of one HIV-1+2-infected workers had linear gingival erythema, and one of 19 HIV-1-infected workers had necrotizing periodontitis (Ndiaye et al., 1997). Given the paucity of direct evidence from the literature for or against an effect of HIV type or clade on HIV oral disease, indirect evidence and biologic plausibility were explored. The relationship between HIV-1 subtype diversity and disease transmissibility and progression is poorly understood (Spira et al., 2003). Subtype diversity may affect modes of HIV transmission (Hu et al., 1999). HIV oral lesions may also differ by HIV transmission category (Ramirez-Amador et al., 1998; Patton et al., 2002). HIV virulence may differ by HIV-1 clade, but the impact on oral opportunistic infections is unknown. Clades may show differences in co-receptor usage and syncytia-inducing capacity that may affect HIV disease progression (Spira et al., 2003). Oral lesions are also more common as HIV disease progresses, in the absence of HAART (Glick et al., 1994; Begg et al., 1996). Anti-retroviral drug sensitivity and resistance are thought to differ by HIV type or clade (Tantillo et al., 1994; Pillay et al., 2000; Caride et al., 2001; Spira et al., 2003), and this may indirectly affect oral lesion incidence. In developed countries, HIV-1 clade B infections have been managed with highly active anti-retroviral therapy (HAART), resulting in reductions in oral lesion prevalence and incidence (Patton et al., 2000; Schmidt-Westhausen et al., 2000; Greenspan et al., 2004). Among populations infected with non-HAART-susceptible HIV types or clades, the oral disease profile may differ.
Question 2: What should be the optimal goal in treating oral candidiasis in developing countries? Are there any interventions to prolong the time to recurrence of the lesion? (Wipawee Nittayananta) Three distinct clinical presentations of OC are commonly observed in HIV/AIDS subjects; pseudomembranous, erythematous, and angular cheilitis (EC-Clearinghouse, 1993). Hyperplastic candidiasis, a less common type of OC, has also been reported (Ranganathan et al., 2000). OC may cause oral discomfort, pain, and loss of taste, and affects quality of life. Moreover, without treatment, the disease may spread to the esophagus, causing invasive esophageal candidiasis, which is categorized as an AIDS-defining illness (Centers for Disease Control and Prevention, 1992). Although different antifungal agents for treating OC—such as azoles, both topical (clotrimazole) and systemic (fluconazole, itraconazole)—can be easily obtained in developed countries, these medications are not affordable for most patients in developing countries. The cheapest antifungal agents used for treating OC in the developed world are nystatin 100,000 u/mL oral suspension ($70/200 mL), and clotrimazole 10 mg troche ($65 per 50 tablets) (Patton et al., 2001). However, the minimum payment for labor in Thailand is only $5 (200 Baht) per day. The access to potent anti-retroviral drugs, which improve the immune system and decrease the prevalence of OC, is also limited in this patient group. In addition, there is a lack of facilities to determine CD4+ cell counts and viral load (VL), used as guidelines for choosing appropriate antifungal agents (Powderly et al., 1999). Thus, strategies to treat OC in HIV/AIDS patients in developing countries may, of necessity, be quite different from those used in the developed world.
Although it is well-established that subjects with HIV/AIDS will develop OC during the course of the disease (EC-Clearinghouse, 1993), so far, no specific recommendations have been made for directing the prevention and management of the lesion among those in developing countries. In the developed world, where HAART is accessible, a marked decrease in the incidence of OC has been reported (Greenspan et al., 2004). This can be attributed to the improved immune and viremic status of the subjects (Nicolatou-Galtis et al., 2004). However, inaccessibility of the medication does exist in developing countries, and a high prevalence of OC among HIV/AIDS subjects is still reported in the recent literature (Bendick et al., 2002; Chidzonga, 2003). Thus, the optimal goal in dealing with OC in these developing countries is to prevent the occurrence of the lesion by educating patients on how to enhance their immunity, reduce predisposing factors that lead to further immune impairment, and perform self-assessment for the presence and control of the lesion (Fig. 1
An effective strategy for the prevention of OC should aim to reduce the numbers of oral Candida as well as their adherence to the mucosa. For example, improving oral hygiene (Hilton et al., 2004) and maintaining mechanical cleansing by rinsing the mouth with normal saline or home-made salt water, several times a day, may be helpful (Nittayananta et al., 2006b). These are practical, inexpensive ways that may minimize the development of candidal infection, since the first step of the infection is adhesion of Candida to the mucosa. Hyposalivation has been found to be significantly associated with the numbers of oral Candida, and xerostomia is commonly associated with late-stage HIV infection (Nittayananta et al., 2006a). Thus, rinsing the mouth with normal saline may help reduce Candida attachment, and make patients feel more comfortable with their dry mouth conditions. Due to the underlying immune deficiency, the relative ease with which OC can be treated is in contrast to the high rate of recurrence observed among HIV/AIDS subjects. Thus, interventions that prolong the time to recurrence of the disease are needed. Chlorhexidine mouthwash (0.12–0.2%) has been found to be useful in the prevention and treatment of OC, as well as in reducing recurrence of the lesions (Barasch et al., 2004). In Thailand, a mouthrinse of Lawsone methyl ether, isolated from the leaves of the Rhinacanthus nasutus plant, was found to exhibit antifungal activity with a minimal inhibitory concentration (MIC) of 512 µg/mL, and also possessed antibacterial activity against Staphylococcus aureus (Panichayupakaranant et al., 2000). In an in vitro study, Lawsone methyl ether mouthwash showed potent antifungal activity against oral Candida isolated from HIV/AIDS subjects and was comparable with 0.2% chlorhexidine mouthwash (Prasert et al., 2006). Of interest, Lawsone methyl ether in an oral base did not cause any skin irritation in rats, whereas, in a solution formulation, it produced erythema and papular skin lesions (Panichayupakaranant and Reanmongkol, 2002). In South Africa, Polygala myrtifolia L. leaves and Glycyrrhiza glabra L. rhizome extracts exhibited antifungal activity, with a MIC value of 1.56 mg/mL (Motsei et al., 2003). Other plants that show antifungal activity were reported from India: Allium sativum L. (garlic), Allium schoeoprasum L. (elephant garlic), Allium cepa var. cepa L. (onion), and Allium cepa var. aggregatum L. (multiple onion), with MIC values ranging from 1.15 to 37.5 mg/mL (Vaijayanthimala et al., 2000).
In conclusion, efforts to prevent OC should be emphasized in HIV-infected subjects in developing countries. However, for those who develop the disease, the optimal goal should be to treat the lesion with available antifungal agents until it has completely disappeared. Antifungal treatment may be followed by mouthrinsing (Fig. 2
Question 3: Are oral candidiasis and hairy leukoplakia related to the CD4 and viral load kinetics during HIV infection? (Velia Ramírez-Amador) An association between oral candidiasis (OC) and/or oral hairy leukoplakia (OHL), with a decreased CD4+ lymphocyte count, has been clearly demonstrated in several studies (Birnbaum et al., 2002; Greenspan and Greenspan, 2002). Recently, an association with increased viral load (VL) levels has also been shown in cross-sectional studies (Margiotta et al., 1999; Ramírez-Amador et al., 2003; Nicolatou-Galitis et al., 2004). In 250 HIV-infected subjects, individuals with OHL or OC were 2 and 1.5 times, respectively, more likely to have a VL > 20 000 copies/mL than were individuals without OC or OHL, independent of CD4+ counts and anti-retroviral therapy (Patton et al., 1999). Others have suggested a threshold level (from 30,000 to 40,000 viral copies/mL) above which it was more likely that a patient would develop either OC or OHL (Ramírez-Amador et al., 2001). Also, patients with a VL higher than 10,000 copies/mL had an 11-fold greater frequency of OC than patients with an undetectable VL (Campo et al., 2002). A recent study has shown, in a group of HIV-infected individuals, that OC and OHL occurring concurrently have an important predictive value for immune suppression, and a moderate predictive value for high VL (> 20,000 copies/mL) (Patton, 2000). However, several researchers have shown a significant relationship between OHL and high VL, but not CD4+ counts (Greenspan et al., 2000; Margiotta et al., 2000). Although a recent prospective study in HIV-1-infected women has shown a significant relationship with high VL for both OHL and OC incidence (Greenspan et al., 2004), evidence from more longitudinal studies is needed. Dr. Ramírez-Amador presented data from a prospective, longitudinal, collaborative study that was carried out at the AIDS Clinic of the Instituto Nacional de Ciencias Médicas y Nutrición, between April, 1999, and August, 2002, to determine the VL and CD4+ lymphocyte kinetics associated with the development of OC and OHL in HIV-infected Mexican patients. Participants were adult HIV-infected individuals, without a history of previous or current OC or OHL, and not receiving HAART, who were able to sign the written informed consent and attend the follow-up visits. Patients were examined according to established clinical criteria (EC-Clearinghouse, 1993) for clinical evidence of OC or OHL at baseline and during monthly follow-up visits. Clinical data, CD4+ cell counts, and VL levels were determined at baseline and at six-month follow-up visits, and when OHL or OC was first identified. When possible, patients were offered additional laboratory tests and a clinical examination two months after oral lesions were first detected. Of the 99 individuals, 76.8% were male. This dropped to 70.7% in pre-AIDS qualifying stages, and to 67.7% without exposure to anti-retroviral drugs. Almost 50% of the patients had a CD4+ cell count higher than 350 cells/mm3. VL levels were widely variable, with seven patients displaying a baseline value below the detection level of 50 copies/mL, and about a quarter (23.2%) had levels above 55,000 copies/mL. The group that developed OC and/or OHL (late-OL group) and the group that did not develop OC and/or OHL (NA group) showed similar demographic and clinical characteristics at baseline. The median follow-up period for the study cohort was 178 (31–924) days. Forty-seven patients were excluded at some point, due to starting HAART, loss to follow-up, or death. During follow-up, 31 (31.3%) patients developed oral lesions. OC developed in 18 (58.1%) of the patients, nine presenting with the erythematous type, five with the pseudomembranous, and four with both clinical varieties. Three individuals (9.7%) presented with OHL, and 10 individuals (32.2%) with both target lesions, namely, OC and OHL. Median CD4+ cell and VL levels were similar between the NA and late-OL groups at baseline. At 6 months of follow-up, before the onset of OC or OHL, the late-OL group showed significantly lower CD4+ counts (230 cells/mm3) in comparison with the NA group (442 cells/mm3 ) (p = 0.011). At 12 and 18 months, the late-OL group showed reduced CD4+ values compared with the NA group, but this difference was statistically significant only at 12 months (p = 0.041). VL levels at 6 months were comparable in both groups of patients, but the late-OL individuals showed higher VL values at 12 (45,353 copies/mL) and 18 months (18,700 copies/mL), compared with the NA group (4280 and 2150 copies/mL, respectively); the difference was significant (p = 0.006 and p = 0.038, respectively). From the results of a univariate Cox proportional hazards analysis, apart from advanced stage, the only significant variables for either oral lesion or OC in our study were CD4+ counts and VL; the other potential confounder variables did not show a prognostic significance. Although, for OHL, no variable was significant, a prognostic role for VL in OHL development could not be definitively ruled out, given the wide confidence interval (0.88 to 3.31) for VL and the small sample size. In the multivariate Cox proportional hazards model analysis, serial CD4+ counts were significant, independent of serial VL, for both oral lesions and OC. After adjustment for clinical stage and anti-retroviral use, the main factor associated with the development of either oral lesion and OC was CD4+ count.
Question 4: What are the significance and relevance of oral melanocytic pigmentation in HIV infection? (K. Ranganathan) Oral hyperpigmentation in HIV-infected persons, due to antifungal and anti-retroviral drugs, has been reported by Langford et al.(1989) and Tadini et al.(1991), while oral hyperpigmentation as a result of adrenocortical destruction by Mycobacterium avium-intracellulare infection has been reported by Porter et al.(1990). Ficarra et al.(1990) have reported development of hyperpigmentation over a period of two years in a cohort of 217 HIV-positive patients.
In HIV disease, the immune system is dysregulated, leading to the elevation of interleukins (IL-1 and 6) and tumor necrosis factor-alpha, which leads to the release of alpha melanocyte-stimulating hormone ( Dr. Ranganathan presented data on the prevalence of hyperpigmentation in a cohort of HIV-seropositive patients in India. The study group consisted of 1700 consecutive HIV/AIDS patients attending the YRG CARE, Chennai, India, over a period of 6 years (1998–2004). Confirmation of HIV serostatus for all patients was by ELISA and Western blot. A detailed history was taken, an oral and systemic examination performed and recorded, and photographs were taken. The oral lesions were diagnosed according to EC-Clearinghouse and WHO (1993) criteria, as described in detail in an earlier report (Ranganathan et al., 2000). Racial pigmentation was excluded in these patients on the following basis: (1) recent onset, and (2) sites unlikely to be racial pigmentation (e.g., buccal mucosa). An incisional biopsy of the hyperpigmented area of the buccal mucosa was carried out on 20 HIV-seropositive patients, in whom other possible causes of hyperpigmentation—e.g., habits, drugs, and other causes—were excluded, as well as in a normal control group presumed HIV-seronegative (n = 10). Ipsilateral mucosal biopsies were taken when the patients were undergoing extraction or periodontal surgery. Tissues were embedded in paraffin and stained with hematoxylin and eosin, as well as by the Masson-Fontana staining technique, so that the nature of distribution of melanin pigments in the tissues could be evaluated. The study showed that there was a statistically significant increase in the prevalence of pigmentation in the HIV-seropositive group, both clinically and histopathologically. Histologically, this pigmentation was due to increased melanophores in the epithelium and increased melanin in the connective tissue. The increase in melanin histologically confirmed the increased pigmentation seen clinically. No known cause could be ascertained for the pigmentation except in one patient, who was on medication that could induce pigmentation.
Of the 1700 patients, 95% had acquired the infection through heterosexual contact. There were 1251 males and 449 females, aged between 7 months and 72 years. Forty-three percent of the patients were in the age group 21–30 years. CD4+ cell counts were available for 790 patients, of whom 339 (42.9%) had a CD4+ count < 200. A total of 1412 (83%) of the 1700 patients presented with one or more oral lesions upon examination. Gingivitis (69%) and pseudomembranous candidiasis (13.2%) were the most common oral lesions. The other oral lesions seen were hyperpigmentation (24.6%), erythematous candidiasis (2.8%), periodontitis (28.5%), angular cheilitis (7.7%), oral ulcers (3%), OHL (2%), hyperplastic candidiasis (1%), 12 cases of oral submucous fibrosis (OSF), and 17 cases of OHL. Anti-retroviral therapy was taken by 267 (15.7%), of whom 213 were males and 54 females. When the hyperpigmentation was compared with the other oral lesions by chi-square analysis, a statistically significant correlation was seen with OSF (p < 0.01), OC (p < 0.01), and, in particular, with angular cheilitis (p < 0.001). When CD4+ counts and hyper-pigmentation were correlated, it was seen that patients with a CD4+ < 200 (104/190; 54.7%) displayed pigmentation significantly (p < 0.05) more often than those with a CD4+ > 200 (86/190; 45.3%). There was no single group of drugs associated with the pigmentation in this patient cohort. Table 1
Tables 2  and 3 show that there was increased production of melanin in the basal layer, which, to some extent, was incorporated into the suprabasal epithelial cells. Eighty percent was focally distributed in the underlying connective tissue.
Although no significant association was found between drugs and hyperpigmentation in the present Indian cohort, further research is needed to determine whether medications may cause hyperpigmentation. Evaluation of cortisol levels in future studies may cast some light on the possible hormonal imbalances. Although cortisol levels were not determined for this cohort, none of these patients displayed overt clinical symptoms of Addison’s disease. Histologically, the lesions observed in this study were associated with both basal and subepithelial connective tissue melanin pigments, similar to what was reported by Langford et al.(1989). The pigmentation was also seen more frequently in patients with a CD4+ < 200, raising the possibility of an association between immunosuppression and hyperpigmentation (Goldstein et al., 1997). Interestingly, the hyperpigmentation was more prevalent in patients with OC, raising the possibility of the role of Candida, directly or indirectly, in the pathogenesis of the hyperpigmentation.
Question 5: Is it possible to develop a reliable oral index to predict disease progression? (Amit Chattopadhyay) HIV-associated oral diseases (HIV-OD) include, among others, OC and OHL as two primary lesions. Recently, some studies have reported incidence densities and incidence density ratios for OC and/or OHL (Chattopadhyay et al., 2004, 2005a; Greenspan et al., 2004), and associations with potential markers based on predictive models for prevalent and incident OC and OHL (Greenspan et al., 2004; Mulligan et al., 2004; Chattopadhyay et al., 2005a,b). Pre-HAART-era studies evaluated OC, OHL, and other oral diseases for their value in predicting the progression of HIV/AIDS (Birnbaum et al., 2002; Greenspan and Greenspan, 2002) and immune suppression (Glick et al., 1994; Patton, 2000). Most studies that have evaluated HIV/AIDS-associated outcomes have tried to test if risk/hazard for these outcomes was different between those having and those not having OC, or OHL, or all HIV-OD. One study tested differences between different sets of oral lesions in predicting HIV/AIDS outcomes (disease progression) (Begg et al., 1997), and suggested that the prognostic value of the core lesion set (OC and OHL) was enhanced by the addition of other lesions, such as necrotizing ulcerative gingivitis and linear gingival erythema, that are not usually included in HIV staging systems. However, it was not clear from the study if there was any substantial contribution by the additional factors that went beyond a routine increase in predictability by the addition of a variable in a model. The approach to the development of an index involves the following steps: development of a conceptual model; identification of dimensions and potential factors of value that may contribute to the index; testing and finalizing the model and index factors; formulation of the index and development of a scoring method for its use; fine-tuning and finalizing the index; and evaluation of the index for validity and reliability.
To develop an oral index for HIV/AIDS disease progression, Dr. Chattopadhyay created a conceptual model (excerpt in Fig. 3
HIV+ individuals (both sexes, white/black racial groups) were followed prospectively for two years in Chapel Hill, NC, USA, after written informed consent was obtained (Chattopadhyay et al., 2005a,b). The study sample was evaluated for some of the outcomes indicative of HIV/AIDS disease progression. Blood CD4+ cell count (CD4+ count) outcomes, as actual counts and as changes in CD4+ counts over time, and occurrences (prevalence and incidence) of OC, OHL, and HIV-OD (EC-Clearinghouse, 1993) were studied. Given the limitations of the study design, predictive modeling of the outcomes from the prospectively collected data was used to guide the analysis strategy, with hierarchically well-formulated linear and logistic regression methodology for development of the multivariable explanatory models. Outcomes utilized as indicative of HIV/AIDS disease progression included: CD4+ cell counts, changes in HIV/AIDS disease class, time to first occurrence of CD4+ count < 200 cells/mm3, first occurrence of CD4+ count < 100 cells/mm3, blood plasma VL, first occurrence of opportunistic infection/malignancy, and HIV-related death. Possible oral factors that may have a role to play in the development of such an index include: occurrence of OC and Candida carriage, OHL, all oral diseases associated/potentially associated with HIV/AIDS, and salivary measures such as SLPI and defensins. In the overall scheme of index development, these analyses help in establishing the clinico-epidemiologic factors that may be useful in developing the index. This analysis suggested the following:
Efforts toward the development of a reliable oral index to predict disease progression should explore the possible usefulness of frequency of OC episodes, Candida carriage rates, changes in salivary constitution, salivary VL, antiviral factors, and oral co-morbidities, with additional consideration of anti-retroviral drug use, drug resistance patterns, and immune reconstitution. Statistical evidence suggests that frequency of OC episodes may be a promising marker contributing to an oral prediction index for HIV/AIDS disease progression.
Question 1 The workshop participants were unable to identify additional studies on this topic and believed that the issue of the impact of HIV type, strain, and clade diversity on HIV oral disease was not critical to advancing the field of oral HIV research at this time. However, further alterations in the HIV genetic code, as a result of suboptimal anti-retroviral therapy and resultant mutations, may result in the need to re-address this topic at a future time (Wainberg, 2004). It was not deemed necessary for future oral epidemiological observational research studies to classify HIV type for all subjects, or to identify the clades of HIV-1-infected populations. Furthermore, it was not believed that a large population of patients with HIV-1 and HIV-2, organized in a West African multi-center study, was needed to verify the significant difference in oral lesions/candidiasis seen in the Dakar study (Ndour et al., 2000). Nonetheless, the potential influence of type, strain, and clade differences on the incidence and natural history of oral manifestations of HIV diseases is a theme that merits continued monitoring as the HIV epidemic evolves globally.
Question 2 To combat OC in HIV/AIDS patients in developing countries, there is clearly a need to develop inexpensive means of treatment. More research on endogenous antimicrobial peptides exhibiting antifungal activity against Candida—including defensins (Dale, 2002), SLPI (Chattopadhyay et al., 2004), histatins (Lupetti et al., 2002), lactoferrin, and lysozyme (Masci, 2000)—is warranted before the mechanisms of action, production, and applications for clinical use can be understood. Antimicrobial peptides, which can easily be made synthetically or by recombinant technology in the developed world, should be made available at low cost to developing countries, to make them affordable for HIV/AIDS subjects. The exogenous administration of these peptides may be helpful in restoring the low level of the endogenous peptides present at the site of infection in these immunocompromised persons (Lupetti et al., 2002), and may play a significant role in the prevention of the disease.
Question 3
Question 4
Question 5
The contributions of colleagues S. Ponce-de-León and G. Anaya-Saavedra to the data presented by Dr. Velia Ramirez-Amador are greatly appreciated.
Advances in Dental Research, Vol. 19, No. 1,
122-129 (2006) This article has been cited by other articles:
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Abstract
Introduction
-MSH) from the anterior pituitary. IL-1 up-regulates 
