Adv Dent Res 19:5-9, April, 2006
© 2006 International and American Associations for Dental Research
Overview and Research Agenda Arising from the 5th World Workshop on Oral Health and Disease in AIDS
Stephen Challacombe,
Maeve Coogan,
David Williams, and
John Greenspan
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Overview
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At the start of this Workshop, Jay Levy made us aware that, over the past 20 years, research into AIDS has progressed very rapidly. The result of this endeavor is that the human immunodeficiency virus is now the best-understood agent that causes human disease. He emphasized the need to investigate approaches that target not only the causative agent of HIV, but also the host immune response. Although a great deal is known about the pathology of oral disease in HIV infection, research into oral conditions in HIV infection should continue and could assist with the control of this rapidly spreading pandemic.
The following questions regarding oral health and disease in HIV infection formed the basis of the individual Workshop discussions, and the consensus view can be found in the relevant sections in this issue. These questions were intended to clarify the current state of knowledge and to identify areas that required further research. Overall, the meeting and Workshops identified many areas that form part of an ongoing research agenda, and some of the issues raised are outlined below.
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Clinical Workshops
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Workshop A1: Identification of Oral Health Care Needs in Children and Adults, Management of Oral Diseases
- What is the role of the dental profession in the management of the HIV-infected individual?
- Identifying health care needs—what are the epidemiology and disparities of HIV-associated oral lesions in children from different continents?
- How effective is HIV treatment in controlling oral diseases?
- Could we develop basic inexpensive oral and dental care protocols for economically deprived HIV-infected patients?
- What is the best method of arranging resources to meet the oral health care needs of people with HIV disease?
Participants concluded that health care professionals working in resource-poor countries should be trained to recognize orofacial lesions that could be used to identify patients with HIV infection. The dental profession should assist HIV-infected patients by providing routine dental care and diet counseling and emphasize the importance of universal infection control. Cancrum oris and other orofacial lesions may be underreported in resource-poor countries. HIV anti-retroviral treatment reduces the occurrence of oral candidiasis, has little effect on hairy leukoplakia, but increases the prevalence of oral warts in patients on protease inhibitors. Gentian violet, chlorhexidine, and oil of melaleuca can be useful for the treatment of oral candidiasis.
Research agenda
- There is a need to re-target research efforts to resource-poor countries and to prioritize research efforts on children with HIV disease.
- Oral health research should be integrated into other health care research programs.
Workshop A2: Oral Health and General Health
- Does oral disease affect the general health of patients with HIV?
- Does the state of health in the oral cavity influence other anatomical regions of the body?
- What is the relationship among the nervous system, the brain, and oral tissues?
- Are neurological pathologies influenced by oral-systemic health?
- Do oral-systemic interactions influence social behavior?
- Do HIV-infected individuals have systemic diseases or conditions that have a unique direct or indirect effect on oral health?
- Does concurrent tuberculosis infection modify the oral manifestations of HIV infection?
- What is the role of Hepatitis B and C in HIV infection?
There is a growing need for efforts in primary prevention and integrated care. The most significant conclusion of this Workshop is the need for all involved in oral health research and oral health care to become essential partners in comprehensive care for patients and whole communities.
Research agenda
- Longitudinal cohort studies to determine the interrelation between oral and systemic diseases are required.
- The effect of dental treatment on general health and quality of life should be investigated.
- Improved animal models must be developed to explore the interrelation between the oral and other mucosal immune systems and the systemic immune responses.
- Quality-of-life measures using improved, well-validated, and internationally agreed instruments should be included in all clinical studies.
- The impact of oral symptoms and diseases on psychosocial functioning should be documented.
Workshop A3: HIV Phenotypes, Oral Lesions, and Management of HIV-related Disease
- What are the influences of type, strain, and clade differences on the incidence and natural history of the oral manifestations of HIV diseases?
- 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?
- Are oral candidiasis and hairy leukoplakia related to the CD4+ count and viral load kinetics during HIV infection?
- What are the significance and relevance of oral melanocytic pigmentation in HIV infection?
- Is it possible to develop a reliable oral index to predict disease progression?
Participants concluded that HIV type, strain, and clade diversity have little impact on HIV oral disease. There is little access to antifungal agents in developing countries, and a high rate of recurrence of oral candidiasis, even when treatment is available. The temporal dynamics of the interaction between CD4+ and viral load prior to oral candidiasis and hairy leuko-plakia confirms their use as early clinical markers of HIV progression.
Research agenda
- Studies on the antifungal activity of traditional medicines to combat oral candidiasis, and an index for monitoring of CD4 count and viral load, are needed in developing countries.
- More research on endogenous antimicrobial peptides with antifungal activity against Candida is warranted.
- Antimicrobial peptides should be made available at low cost to developing countries.
- Longitudinal studies should explore the reduction of CD4+, with associated sharp increase of viral load and the onset of oral candidiasis and oral hairy leukoplakia.
Workshop B1: Candida and Mycotic Infections
- What is more important in the development of oral candidiasis in HIV-infected patients, low CD4+ counts or high viral loads?
- Can the development of oral candidiasis serve as a marker for the level of viral load?
- Do Candida biofilms play a role in recalcitrance of oral candidiasis seen in HIV disease?
- How prevalent are exotic mycoses in HIV-infected patients in the developing world?
- Are typing and subtyping of Candida species important in clinical management?
- What is the effect of oral thrush on the post-natal acquisition of HIV?
The Workshop concluded that viral load is the best predictor of oral candidiasis status. Micro-organisms associated with biofilm are more resistant to antifungal than planktonic forms. Typing and subtyping of yeasts are not critical to the management of oral candidiasis. Oral thrush in infants is associated with an increase in the transmission of HIV infection.
Research agenda
- The predictive value of HIV viral load and oral candidiasis
- The effect of commensal bacteria on the pathogenesis of oral candidiasis
- Impact of epithelial cells, Candida virulence, the normal flora, and the host response on HIV infection
- Mechanisms of pathogenicity and virulence of Candida albicans in oral candidiasis
- The post-natal transmission of HIV in infants with oral candidiasis
Workshop B2: Periodontal Disease and Other Bacterial Infections
- What is linear gingival erythema? Is it prevalent only in HIV disease?
- Do periodontal pockets contribute to viremia in HIV infection?
- Do anti-viral drugs reach the sulcular fluid in significant concentrations? Is this important in view of our present understanding of the periodontal tissues?
- What pathogens are involved in periodontal disease in HIV infection?
- How can we diagnose the diseases seen in HIV infection?
- Does concurrent tuberculosis infection modify the oral manifestations of HIV infection?
No consensus could be reached about the prevalence of linear gingival erythema in HIV disease. HIV-related periodontitis seems to be a multifactorial, multimicrobial disease involving the same pathogens as periodontal diseases in HIV-negative populations. Analysis of data from developing countries suggests that there is an association between tuberculosis and oral candidiasis.
Research agenda
- Longitudinal studies should be undertaken to monitor the progression of periodontal disease with as many parameters as possible being measured at each stage.
Workshop B3: Markers of Immunodeficiency and Mechanisms of HAART Therapy on Oral Lesions
- 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)?
- 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?
- What are the incidence, prevalence, and characteristics of HIV-related oral diseases in patients who experience HAART failure?
- Which if any oral lesions are useful as markers of immunodeficiency or HIV disease progression in patients on HAART therapy?
- 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?
The overall prevalence of HIV-related oral lesions decreases with therapy; however, oral warts and salivary gland disease show a trend of increasing with HAART. There is growing evidence that HAART reduces the oral manifestations of HIV infection. No studies have investigated the recurrence of these manifestations with HAART failure. The effects of protease inhibitors on Candida virulence appear to be independent of immune reconstitution.
Research agenda
- The use of the oral manifestations of HIV as early markers of HAART failure
- Whether protease inhibitors diminish the usefulness of candidiasis as a marker of HAART success
- The increased risk of periodontal diseases and caries in patients on long-term HAART
- HPV-papillomas and diffuse infiltrative lymphocytosis syndrome as markers of immune reconstitution syndrome
- The risk of neoplasia in patients on long-term HAART
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Basic Science Workshops
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Workshop C1: Mechanisms of Expression of Viruses
- What is the role of Hepatitis B and C in HIV infection?
- What is the mechanism of interaction between HIV and HPV?
- What is the role of HHV-8 in salivary secretions in the pathogenesis of Kaposi’s sarcoma?
- What is the role of the oral epithelium in HIV acquisition and transmission?
- Is there a genetic susceptibility of the HIV-infected host to viral oral infections?
Although the Workshop agreed that much progress had been made, the questions should still form the basis of a future research agenda.
Workshop C2: Saliva, Breast Milk, and Mucosal Fluids in HIV Transmission
- Are there oral fluid markers—for example, neopterin—for predicting disease progression?
- Can oral fluids be used for diagnostics in the HIV-infected individual?
- What are the routes of HIV transmission via breast milk? Are tonsillar and gastrointestinal tissues the primary sites of initial infection?
- How do other conditions in infants and mothers affect post-natal transmission?
- What are the benefits and safety of ART, especially nevirapine, given to mothers and infants to prevent the transmission of HIV associated with lactation?
- What is the rate of infectivity of HIV associated with oral sex?
Participants concluded that CD4+ lymphocyte counts and HIV RNA levels in blood provide a measure of disease progression. Attempts to find a biologic agent that provides prognostic value in oral fluid and secretions have not been successful. Insight into the pathogenesis of HIV in the oral cavity has assisted with understanding HIV disease transmission during breastfeeding and possibly the intra-partum transmission of HIV. Viral characteristics of HIV differ in breast milk and plasma.
Research agenda
- How does the presence of drug resistance mutations in breast milk affect the transmission of HIV or disease progression?
- Understanding minimal risk associated with oral sex to develop HIV prevention methods
Workshop C3: The Oral Epithelial Cell and First Encounters with HIV-1
- Does HIV-1 translocate and integrate into oral mucosal epithelial cells or other mucosal cells during clinical disease or in vitro?
- Can intrinsic differences between oral and other mucosal epithelial cells explain, in part, why oral mucosae appear to be less-favored routes of infection?
- Can infectious or inactive virus be found in saliva?
- Can primary infections be explained by a plausible route of HIV-1 transfer from unbreached oral mucosa to the systemic immune system?
- What are the factors that minimize infection of target T-cells in the oral mucosa?
- What is the fate of HIV-1 upon exposure to oral tissues in animal models?
The primary encounter between HIV and the oral mucosa requires additional investigation to be properly understood. Passage across the oral mucosa could be a potential route of infection in adults, and this pathway of entry may have great significance in mother-to-child transfer.
Research agenda
- Recognize the limitations of existing in vitro approaches, and develop more rigorous in vitro models to test hypothetical HIV-1 interactions with oral mucosa.
- Characterize the mechanisms of encounter and transmission to identify novel, important targets for intervention and HIV vaccines.
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Research Agenda
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The questions above constituted the framework questions for the 5th World Workshop on Oral Health and Disease in HIV infection. As expected, some questions could be answered fully, some questions could be answered partially, some questions could not be answered at all, and some questions raised other research issues, which need to be addressed. Elsewhere in this issue, reports of the Workshops will indicate the answers to these questions. Overall discussion at the meeting and Workshops identified many areas, which form part of an ongoing research agenda, and some of the issues raised are outlined below.
Overall major areas of research include:
- Health services research and health promotion
- Oral lesions in initiation, progression, and treatment of HIV worldwide
- Key insights into some basic interactions in HIV infection
- Specific infections associated with HIV
- Research capacity-building, international collaboration and calibration
(A) Health Services Research and Health Promotion
Toward a research agenda: health care research
- Ensure that oral aspects of HIV disease are taken into account in medical programs, integrate oral health skills.
- Education and training of all health care workers (dental as well) about the relevance of oral needs, and lesions as surrogate markers
- Assess LOCAL needs, and ensure that resources are distributed where needed.
- Co-ordinate research efforts in randomized clinical trials, and standardize protocols.
Specifically, it was agreed that there is further need for:
- Objective data on caries risk
- Objective data on periodontal changes
- Natural history in HIV disease
- Response to therapy
- Microbiology, especially in regard to recent techniques for identification
- Systemic implications and associations of periodontal disease in HIV
(B) Oral Lesions in Initiation, Progression, and Treatment of HIV Worldwide
Previous work has established the importance of oral lesions in the identification and management of HIV disease. Many of these associations are detailed elsewhere in this issue. The Workshop identified further important research and social issues in relation to oral lesions in HIV, particularly with regard to resource-poor countries. These included:
- Oral lesions related to quality of life
- Resource implications of oral disease
- The role of oral lesions in prevention
- The role of oral lesions in diagnosis
- Tobacco effects and the mechanisms involved
- Treatment of oral lesions and response to systemic HIV treatment
- Treatment trials and cost-effectiveness; treatment guidelines for resource-poor environments. Crucial for oral physicians to be included in emerging networks (ACTG/HIVNET successor) to contribute knowledge of oral lesions as markers of response/lack of response
- The identification of unmet needs/access
- An understanding of the significance/value in resource-poor environments
- The need for professional acceptance of the role and importance of oral lesions as contributing to HIV knowledge and management.
Toward a research agenda: effect of anti-HIV therapy on oral health and lesions
The full effects of HAART and other therapies on the oral mucosa and oral mucosal diseases in HIV infection need to be understood.
- Oral warts:
- Real increase in HAART and other therapies?
- If so, why? What are the mechanisms?
- What are the HPV types involved, and are they oncogenic?
- Oral and other cancers? Are they increased or decreased on HAART therapy? What are the mechanisms?
- What are the effects of HAART on DILS (diffuse infiltrative lymphocytosis syndrome/HIV SGD [salivary gland disease]), linear gingival erythema, and other oral lesions, and what are the mechanisms?
- Immune reconstitution inflammatory syndrome after inititation of HAART therapy: effect on oral lesions
Toward a research agenda: specific HIV-related oral lesions, conditions, diseases
It was recognized that there are still various HIV-related oral diseases that we do not fully understand and that, with the numbers available from international collaboration, can be studied more fruitfully. These include:
- - DILS/HIVSGD
- - CD8 subsets
- - CD8 anti-HIV factor?
- - Effects of HAART
- - Real prevalence in children
- - Long-term outcomes, predictive value in different continents
(C) Key Insights into Some Basic Interactions in HIV Infection
Basic biology of the oral cavity in health and disease
- The salivary milieu: Further characterization of saliva and its role—saliva is not just spit!
- The significance of the secretory immune system
- The oral cavity as a surrogate marker for other mucosal tissues
- The salivary proteome and its significance in HIV
- Innate defense and protection molecules: SLPI, lactoferrin, mucins, etc.
- The use of saliva for analyzing HIV: transmission, monitoring
- The use of saliva in diagnosis of HIV, analysis of anti-HIV factors
- Identification of co-infecting viruses: HCV
- The oral mucosa: its role in defense and response to infection
- Oral mucosa is not just stratified epithelium; further characterization required
- Identification and significance of regional variation in permeability
- Characterization of intra-epithelial non-keratinocyte populations:
- Langerhans cells, mononuclear cells, dendritic cells, lymphocytes and their subsets
- comparison with other mucosal tissues, including gut and lung
- In considering diversity of mucosa, include lymphoid aggregates and the mucosal immune system
- The oral flora
- Characterization of ‘unculturables’ and their association with oral lesions
- Virological issues, including strain variation and mutation and habitat
- Potential co-pathogenicity and enhanced effect on oral epithelium
- Oral mucosal vaccination
Oral researchers play an important role in understanding mucosal immunity and its potential role in the immunological inhibition of HIV. There needs to be much more integrated research to harness the enormous potential.
- Is the oral mucosa infected by HIV, and is it a reservoir for the virus?
- Oral mucosa: although plausible, little direct evidence for infection.
- What do we mean by oral mucosa, biology of different types?
- What does infection mean in terms of oral mucosa?
- Transcytosis is a mechanism by which virus may cross epithelium without entering keratinocytes.
- How might transcytosis occur through epithelial cells by HIV?
- How does HIV get into the saliva? Shed from lymphocytes?
- Uptake of HIV-1 into tonsillar keratinocytes and transfer to PBMCs can be shown in vitro. Does it occur in vivo?
- How do oral mucosal cells respond to, and defend themselves against, virus?
- The oral/salivary milieu is enormously important in preventing access of virus to the mucosa. It contains numerous innate factors, which act in concert. It includes SLPI, lactoferrin, chemokines, etc. These are constitutively expressed and are relatively unchanged in HIV infection. Oral mucosal defense works most of the time but is not invincible: breach in mucosal barrier, interaction with epithelial cells (GalCer) and transcytosis, traverse mucosa via M cells, dendritic cells. HIV-1-infected (inflammatory) cells can be detected in inflamed oral mucosa in situ. This says nothing about where the virus comes from, or which cells contain virus. HIV-1-infected cells can be demonstrated in salivary glands and in saliva itself.
- Oral mucosa and host defenses: toward a research agenda
The encounter between HIV and mucosa needs to be properly understood. Not only is it potentially an important route of infection in adults, but also it may have great significance in mother-to-child transfer. This approach may help to identify novel, important targets for HIV vaccines. We have produced a set of theoretical models amenable for testing. We need to recognize the limitations of existing in vitro approaches. There is a real need for good in vitro models of oral mucosa to enable many of our propositions to be tested. The practical issues to be surmounted are not underestimated. We need to develop a more physiological approach. This is more complex than current strategies, but probably more relevant.
- How does the oral commensal flora interact with the mucosa to enhance protection?
Up-regulation of innate biological modifiers, such as human beta defensins (HBDs), in keratinocytes. HBDs can induce mononuclear cells. F. nucleatum is one of the ‘good guys’, inducing HBD-2, and blocking subsequent infection of keratinocytes by P. gingivalis. P. gingivalis is one of the ‘bad guys’, and does not stimulate HBD expression. Is there any evidence for super-induction? Candida albicans: blastospore vs. hyphae in terms of HBD production.
(D) Specific Oral Infections Associated with HIV Infection
Toward a research agenda: Candida and infections
What is the role of commensal bacteria in the pathogenesis of oral candidiasis? Are the mechanisms of the pathogenicity of oral candidiasis altered in HIV infection? We must gain a better understanding of the geographic variations of Candida and the other mycoses in HIV disease. Does co-infection up-regulate either virulence factors or host response cytokines?
Toward a research agenda: oral viruses
Interactions between and among viruses, and effects of virus interactions on subsequent resistance or susceptibility (i.e., up-or down-regulation of immune factors) must be studied. Sequential studies are needed in numerous areas to understand host-virus interactions. Does the oral environment change the clade and infectability of viruses separately from blood? Should we be looking more at exposed and uninfected individuals as examples of natural resistance? Examine the role as reservoirs of oral lymphoid aggregates and minor salivary glands.
(E) Research Capacity-building—International Collaboration and Calibration
An international Workshop reveals the importance and value of establishing common criteria for lesions. It also reveals the wealth of clinical material and opportunities available to the international community to contribute significant research. However, significant research capacity-building is required for this opportunity to be exploited and the vision to be fulfilled. Such capacity-building will involve substantial investment by governmental and philanthropic funding agencies. Approaches that have been initiated but that must be significantly enhanced include the following:
- International training programs. The Fogarty International AIDS Training Program, funded by the US PHS/NIH, includes several sites in the US where small numbers of oral and craniofacial scientists have received training. These programs are modest in scope, are not well-known, and their impact has been limited to a small number of albeit-successful individuals in a few developing countries. This program should be expanded, providing more training slots for dentists and allied health care workers/scientists, and should be more widely publicized. Similar programs should be initiated under the aegis of WHO, EU, and other governmental agencies. Their impact should be assessed.
- Funding: Support should be sought from national and international philanthropic foundations and other agencies for support of training for those studying oral lesions of HIV infection and their impact on general health, as well as for support of those who will manage these complications. Again, careful monitoring and evaluation of such capacity-building for metrics of successful improvement in oral health and/or impact on the pandemic are required.
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Summary: Agenda for Future Research
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- Proper multi-center studies of the epidemiology of oral lesions
- Integration of oral-based research into general studies of HIV
- Studies needed with and without therapeutic intervention
- Epidemiology: What are the true figures for HIV in China, for India, for emerging countries?
- Define the scientific priorities around innate immunity and host defense.
- Address the dissemination of information and research findings.
- Gain wide ownership of the Phuket Declaration.
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Overview
Clinical Workshops