Evidence Report/Technology Assessment: Number 37
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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Methodology / Inclusion/Exclusion Criteria / Reviewing and Abstracting the Articles / Findings / Conclusions / Future Research / Availability of Full Report
This is the second in a series of systematic reviews of critical oral health care issues collaboratively supported by the National Institute of Dental and Craniofacial Research (NIDCR) and the Agency for Healthcare Research and Quality (AHRQ).
Rather than focusing on a specific dental disease condition or a particular treatment approach, this report focuses on several aspects of the dental management of a special population subgroup—the estimated 900,000 persons in the United States infected with the human immunodeficiency virus (HIV) or living with the acquired immune deficiency syndrome (AIDS). These aspects include:
- Complications associated with invasive dental treatments.
- Dental conditions as markers or indicators of change in HIV serostatus and immunosuppression.
- The efficacy or effectiveness of available antifungal drugs to prevent or treat oral candidiasis.
This report was prepared to serve as a major element of a State of the Science Workshop that NIDCR held in December 2000 on the management of dental patients with HIV/AIDS.
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Reporting the Evidence
The key clinical questions to be addressed in this evidence report were proposed by the NIDCR staff involved in the planning of a State of the Science Workshop on this subject, and subsequently refined through discussions with the NIDCR staff and a Technical Expert Advisory Group (TEAG) assembled for this particular topic area. The questions reflect concerns that health care practitioners, and particularly dentists, may not be aware of the available research with respect to the treatment of persons who are HIV positive, and that the research may not be as comprehensive or definitive as it should be.
This report addresses three issues:
- Risks to HIV-positive patients related to invasive oral procedures.
- Oral conditions as markers or indicators of change in HIV status (i.e., seroconversion and immunosuppression).
- The efficacy or effectiveness of antifungal treatments (prophylactic and curative) for oral candidiasis in HIV-positive patients.
The latter two topics have been split to cover each of the aspects in parentheses separately; thus, we have five specific key questions.
- Key Question 1. Are HIV/AIDS patients at increased risk of complications (e.g., local infection, systemic infection, increased bleeding, delayed healing, or alveolitis) from intra-oral dental procedures (e.g., extractions, orthognathic surgery, periodontal therapy, endodontics, prophylaxis, scaling and root planing, and dental implants) as compared with similar patients without HIV/AIDS?
- Key Question 2A. What are the sensitivity, specificity, and positive and negative predictive values of hairy leukoplakia, oral candidiasis, necrotizing ulcerative periodontitis, oral ulcers, and parotid swelling as markers of recent HIV seroconversion (i.e., within 12 weeks after exposure)?
- Key Question 2B. What are the sensitivity, specificity, and positive and negative predictive values of hairy leukoplakia, oral candidiasis, necrotizing ulcerative periodontitis, oral ulcers, parotid swelling, linear gingival erythema, and Kaposi's sarcoma as indicators of severe immunosuppression—as measured by CD4 lymphocyte count and plasma viral load of HIV—in persons with HIV/AIDS?
- Key Question 3A. What is the efficacy of available antifungal agents—nystatin formulations, clotrimazole, amphotericin B suspension, ketoconazole, fluconazole formulations, and itraconazole formulations—as prophylactic measures for oral candidiasis in persons diagnosed with HIV/AIDS? This question is intended to examine the prevention of both recurrences and first-time infections, although the primary focus is on recurrences.
- Key Question 3B. What is the effectiveness of currently available antifungal drugs—nystatin formulations, clotrimazole, amphotericin B suspension, ketoconazole, fluconazole formulations, and itraconazole formulations—for the treatment of oral candidiasis in persons diagnosed with HIV/AIDS?
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Two automated databases were searched: MEDLINE® and EMBASE. The contents of the Cochrane Collaboration Library were reviewed manually. We also hand-searched the contents of the most recent 12 months (through spring 2000) of the five journals most likely to contain relevant articles:
- Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics.
- Journal of Oral Pathology and Medicine.
- Oral Diseases.
- Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology.
Our review of the Cochrane materials indicated related topics that were under study but not currently available as published reports. No search was made through the "gray" literature (i.e., unpublished materials).
Separate MEDLINE® searches were conducted for each of the five key questions, but all five searches began with the terms "HIV" or "HIV infection" or "acquired immunodeficiency syndrome" and were limited to humans and the English language. Beyond these similarities, the searches were customized except that the search terms for Key Questions 2A and 2B were similar to each other up to a point, as were the search terms for Key Questions 3A and 3B.
We did the searches without restriction on the year of publication, but we found no relevant publications dated before 1983. All five of the MEDLINE® searches started with 83,962 articles on human HIV or AIDS in the English language. Inclusion and exclusion criteria used by the reviewers are set out in the next subsection.
For Key Question 1, the search then included a list of dental procedures of interest—dental care, tooth extraction, dental procedure, gingivoplasty, periodontitis, periodontal surgery, dental implants, gingivectomy, oral surgical procedures, orthognathic surgery, dental scaling, dental prophylaxis, root scaling, root planing, root canal therapy, and pulpectomy.
We identified 145,292 articles on these topics. When cross-checked against with the English-language articles on HIV/AIDS, 767 articles were common to both search results. These were further winnowed down to 201 articles by eliminating nonresearch articles and clinical case reports. We only included studies described in such terms as controlled clinical trials, randomized controlled trials, multicenter study, epidemiologic research design, comparative study, evaluation study, outcome and process assessment, outcome assessment, or treatment outcome.
For Key Question 2A, the departure point from the first search was to specify the oral conditions of interest—mouth diseases, periodontal diseases, oral infections, hairy leukoplakia, oral leukoplakia, oral candidiasis, necrotizing ulcerative gingivitis, oral ulcers, parotid diseases, parotid gland, parotitis, or parotid swelling. This resulted in 1,719 articles when cross-checked against the English-language articles on HIV/AIDS. These were reduced further to 297 articles by restricting them to mention of HIV seropositivity, seroconversion, or AIDS serodiagnosis.
The search for Key Question 2B included searching for the same oral condition as in Key Question 2A, but restricted the studies to those mentioning immunosuppression or CD4 lymphocyte count. This yielded 133 articles.
For Key Question 3A, the search was limited to oral candidiasis and to a list of antifungal agents—fluconazole, ketoconazole, nystatin, itraconazole, clotrimazole, amphotericin B, or drug therapy. This resulted in 223 articles, a number that was further reduced to 18 studies by restricting the search with the terms primary prevention, prevention, preventive medicine, health promotion, disease prevention, dental prophylaxis, or prophylaxis.
The search strategy for Key Question 3B was similar to the search done for Key Question 3A to the point of specifying the condition and the drugs. It then restricted the articles to those dealing with drug therapy, therapy, intervention studies, intervention, treatment outcome, or treatment and yielded 143 articles.
Subsequent to the MEDLINE® searches, we conducted additional searches on EMBASE. EMBASE is somewhat more limited than MEDLINE® in the time period covered (only since 1988) and in the search terms available to customize queries. For this latter reason, we did only three customized searches for the five questions: Key Questions 2A and 2B were combined into a single search, as were Key Questions 3A and 3B. The vast majority of articles uncovered in these searches were duplicative of those found in the MEDLINE® searches. The EMBASE searches resulted in the addition of only three articles to the bibliography.
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The basic screening criteria for inclusion and exclusion that applied to articles for all of the questions were as follows:
- Include: Only research manuscripts published in English reporting on the human population.
- Exclude: Literature reviews (except to check references for additional articles), letters, commentaries, editorials, clinical case reports, or practice or treatment guidelines.
For Key Question 1 on the differences in outcomes and complications of intra-oral procedures between HIV-positive and HIV-negative patients, the criteria used were as follows:
- Include: Studies reporting on complications of any or all of the following set of intra-oral dental procedures—surgical interventions, including orthognathic, periodontal, extractions, endodontics, prophylaxis, scaling and root planing, and implants in which patient HIV status was confirmed by test results and the complications reported for both groups (infected and uninfected) are local infection, systemic infection, increased bleeding, dry socket (alveolitis), or delayed healing.
- Exclude: Studies in which treatment is not rendered concurrently to HIV-positive and HIV-negative patients or complications are not reported according to patient group and procedure.
For Key Question 2A on the use of oral lesions as markers for seroconversion, the criteria were as follows:
- Include: Reported presence of any of the following selected oral lesions—hairy leukoplakia, oral candidiasis, necrotizing ulcerative periodontitis, oral ulcers, or parotid swelling—within the 3-month window for primary HIV infection; reporting of the specificity, sensitivity, or positive or negative predictive values of the selected oral lesions as markers for seroconversion, or information from which these values can be calculated.
- Exclude: No reasonable or firmly established time of exposure to HIV.
The criteria for Key Question 2B addressing the use of selected oral lesions as indicators of change in immunosuppression were as follows:
- Include: Presence of any of the following oral lesions—oral hairy leukoplakia, oral candidiasis, necrotizing ulcerative periodontitis, oral ulcers, parotid swelling, Kaposi's sarcoma, or linear gingival erythema—in HIV-positive patients; the HIV status of the patients at the time of the oral lesion is reported by CD4 cell count or plasma viral load; and reporting of the specificity, sensitivity, or positive or negative predictive values of the selected oral lesions as indicators of severe immunosuppression (CD4 <200 cells/mm3), or information from which these values can be calculated.
For Key Question 3A, addressing the use of available antifungal agents to prevent initial or recurrent oral candidiasis, the criteria were as follows:
- Include: Studies of the following available antifungal agents—nystatin formulations, clotrimazole, amphotericin B suspension, ketoconazole, fluconazole formulations, or itraconazole formulations; studies of the prevention of initial infection or recurrence of oropharyngeal candidiasis; and studies whose results are reported separately for initial infection or recurrence.
- Exclude: Studies on non-HIV/AIDS patients only or studies not reporting results separately for HIV/AIDS patients, studies without laboratory confirmation of oral candidiasis status at start of study period and after apparent infection, studies of mixed-site candidiasis where results are not reported separately for oropharyngeal candidiasis, or studies without a concurrent control or comparison group.
The criteria for Key Question 3B, on the effectiveness of available antifungal agents to treat oral candidiasis, were as follows:
- Include: Studies of available antifungal agents—nystatin formulations, clotrimazole, amphotericin B suspension, ketoconazole, fluconazole formulations, and itraconazole formulations—and their use in treatment of oropharyngeal candidiasis.
- Exclude: Studies without a concurrent control or comparison group, studies comparing different formulations of the same drug, studies on non-HIV/AIDS patients only or studies not reporting results separately for HIV/AIDS patients, studies without laboratory confirmation of oral candidiasis status at time of diagnosis and after treatment, or studies of mixed-site candidiasis where results are not reported separately for oropharyngeal candidiasis.
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Reviewing and Abstracting the Articles
Determining which articles identified in the literature searches were to be included in the review involved a number of steps:
- First, the titles of articles for each of the questions received independent dual review by two of the authors, with copies obtained of any abstracts suggested by either one of them.
- Copies of the abstracts were reviewed by two of the authors.
- Articles were identified for abstraction only when both reviewers agreed. The abstracts of all of the excluded articles were independently reviewed by another of the authors to ensure that no articles were incorrectly excluded from the review.
- Eligible articles were given to one of three trained abstractors who extracted the data to be included in the evidence tables using specially designed forms.
- Authors then checked the abstracted data against the articles as they prepared their sections of the report and the corresponding evidence tables.
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Complications of Oral Procedures
The data from five articles were abstracted for the review of Key Question 1 comparing the complication rates associated with dental treatment in HIV-positive persons to the complication rates for similar dental treatment in individuals who are HIV negative. Only two of the seven dental procedures specifically mentioned in Key Question 1 were the objects of study in the five articles. One article examined endodontic procedures (root canal treatment), while four studies examined tooth extraction. None reported on orthognathic surgery, periodontal surgery, prophylaxis, scaling and root planing, or implants.
- In the study of endodontics, the immediate (1- to 3-month followup) postoperative complication rate was exceedingly low in the HIV-positive group and nonexistent in the control group. Only 1 of 48 patients experienced any postoperative complications; an asymptomatic HIV-positive male was found to have pain and swelling following the initial root canal treatment. He received local debridement and antibiotics, and no further complications occurred. Otherwise, no complications associated with endodontic therapy were noted in any of the patients regardless of whether they did or did not receive prophylactic antibiotics. The authors did not detect a clinically significant difference in complication rates between the two groups.
- Three of the four studies in the review of dental extractions found no statistically significant difference in complications between the HIV-positive and HIV-negative groups, although the HIV-positive groups tended to have more postoperative complications. The final study found that the HIV-positive groups had a statistically significantly higher complication rate, but with adjustment for risk factors, the difference was no longer significant. Postextraction complications included persistent bleeding, persistent pain, localized alveolitis, local wound infection, or delayed wound healing.
Nevertheless, across all studies, the postoperative complications that were experienced were rather minor, and when they occurred, were treated on an outpatient basis. Finally, based on their findings, none of the four studies called for the need to take special precautions in HIV-positive patients who do not have a coagulopathy (e.g., hemophilia, thrombocytopenia, or other known bleeding disorders) and are sufficiently healthy to be seen on an outpatient basis.
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Oral Conditions as Markers of Seroconversion
Only one study was abstracted in the review for Key Question 2A. The question asked for evidence on a set of specific oral conditions—oral candidiasis, hairy leukoplakia, necrotizing ulcerative periodontitis, oral ulcers, and parotid swelling—as markers for recent HIV seroconversion. The study investigated the prevalence of a variety of signs and symptoms (including oral candidiasis) among two groups of initially seronegative hospital patients. All of the patients received blood transfusions for a variety of reasons, but half were transfused with seropositive blood while the "matched controls" received seronegative blood.
The question uses the medical "testing" dimensions of sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) of the oral conditions as a marker of recent seroconversion as the way of evaluating their usefulness. Positive enzyme-linked immunosorbent assays (ELISAs) and Western blot tests for HIV, obtained from patients who were confirmed previously seronegative for up to 3 months after the presumed time of infection/exposure, were considered evidence of recent seroconversion. No special conditions were imposed on the diagnosis of the oral conditions.
- The majority of patients with oral candidiasis had seroconverted by the end of 3 months (PPV = 82 percent), but only a small proportion of those who had seroconverted had oral candidiasis (Sn = 14 percent). Very few who did not seroconvert had oral candidiasis (Sp = 97 percent), and most of those who did not have oral candidiasis did not seroconvert either (NPV = 57 percent).
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Oral Conditions as Indicators of Severe Immunosuppression
Key Question 2B involved assessing evidence supporting the use of selected oral conditions as indicators of the progression of HIV infection to the stage of severe immunosuppression and a diagnosis of AIDS. The question suggests the use of the CD4 lymphocyte cell count as a measure of immunosuppression. The question identified the following seven oral conditions of interest: hairy leukoplakia, oral candidiasis, necrotizing ulcerative periodontitis, oral ulcers, parotid swelling, linear gingival erythema, and Kaposi's sarcoma.
The data from 10 articles were abstracted and included in the review for this question. All 10 articles reported CD4 count alone as their measure of immunosuppression.
This question also uses the medical "testing" dimensions (Sn, Sp, PPV, and NPV) of the oral conditions as an indicator of immunosuppression to evaluate their usefulness. In this context, an oral condition with high sensitivity would represent a screening tool for identifying HIV disease that has progressed to the next stage.
- When Sn (sensitivity) is high, it means that a large proportion of the persons whose HIV disease has progressed to the next stage also have the particular oral condition. Thus, when you find the oral condition, you are likely to find a more advanced stage of HIV.
- High Sp (specificity), on the other hand, indicates that a large proportion of persons whose HIV disease has not progressed to the next level also do not have the particular oral condition. In the absence of high Sn, high Sp is not particularly useful.
- High PPV (positive predictive value), on the other hand, is a measure that represents how closely the presence of the oral condition is associated with the progress of HIV to the next stage. When PPV is high, it indicates that a large proportion of the persons who clinically present with the oral condition also have HIV disease that has progressed to the next stage.
- A high NPV (negative predictive value), on the other hand, indicates that a large proportion of those without the oral condition also do not have HIV that has progressed to the next stage. In the absence of a high PPV, high NPV is not particularly useful.
The oral conditions on which studies reported were quite varied. None of the articles reported on parotid swelling; however, all 10 articles reported on oral candidiasis, six reported on hairy leukoplakia, and four on oral ulcers. Only two studies reported on linear gingival erythema, two on necrotizing ulcerative periodontitis, and three on Kaposi's sarcoma.
- There is little apparent consistency in Sns across the 10 studies of oral candidiasis. They range from 20 to 77 percent, with a small cluster of five study groups in the lower end of the range from 20 to 41 percent. The situation with respect to Sps is somewhat more consistent. They range from 65 to 97 percent, with a cluster of eight study groups in the upper end of the range from 79 to 97 percent. The PPVs range from 34 to 88 percent with eight clustered at the low end of the range from 34 to 58 percent. The range of NPVs was from 61 to 90 percent; however, all but four of the NPVs were clustered between 84 and 90 percent.
- Across the six studies of hairy leukoplakia, Sns and Sps were fairly consistent. The Sns ranged from 13 to 24 percent and the Sps ranged from 83 to 95 percent. PPVs ranged from 29 to 70 percent, with four below 50 percent, and NPVs ranged from 51 to 86 percent.
- The Sns reported in the two studies of necrotizing ulcerative periodontitis were very low, ranging from 0 to 16 percent, whereas the Sps were very high (92 to 99 percent). With the exception of one study group that had no cases of this condition, the PPVs ranged from 80 to 95 percent. The NPVs ranged from 52 to 70 percent.
- In the four studies examining oral ulcers, Sns ranged from 0 to 21 percent, while the Sps ranged from 88 to 100 percent. PPVs ranged from 0 to 100 percent and NPVs ranged from 52 to 84 percent.
- The two studies of linear gingival erythema had low Sns (13 to 34 percent) but relatively high Sps (62 to 90 percent). The PPVs ranged from 18 to 55 percent, while the NPVs ranged from 61 to 82 percent.
- Sns across the three studies of Kaposi's sarcoma were low and ranged from 7 to 12 percent. However, the Sps were extremely high, ranging from 99 to 100 percent. The PPVs were high as well, ranging from 73 to 100 percent Also, the NPVs were also reasonably high, ranging from 61 to 84 percent.
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Efficacy of Antifungals as Prophylaxis for Oral Candidiasis
There were six clinical trials that examined the efficacy of available antifungals to prevent oral candidiasis in persons who are HIV positive. Only two of the six available antifungals were studied in this context. There were five studies of fluconazole and one of nystatin pastilles.
- Fluconazole was statistically significantly more efficacious than placebo in preventing recurrences or new infections over a range of 3 to 17 months, when studied at doses from 100 mg/day to 100 mg/week. Gastrointestinal disorders were the most common, but tolerable, side effects.
- Nystatin pastilles at 200,000 units/day and 400,000 units/day were efficacious at preventing new or recurrent oropharyngeal candidal infections, with the higher dose being more effective. Few side effects were reported.
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Effectiveness of Antifungals as Treatment for Oral Candidiasis
Twelve clinical trials evaluated the effectiveness of the six available antifungal drugs in the treatment of oral candidiasis in persons with HIV/AIDS. No studies included an evaluation of amphotericin B suspension, and fluconazole was the most studied of the five remaining.
- Fluconazole appears to be from 88 to 100 percent effective in obtaining a complete clinical response after 14 days of therapy and from 53 to 76 percent effective in obtaining a culture negative for Candida species.
- Itraconazole appears to be roughly equivalent in effectiveness to fluconazole, with ketoconazole achieving the same or slightly lower response rates.
- Fluconazole and itraconazole are more effective at managing oropharyngeal candidiasis than are nystatin or clotrimazole, particularly when mycological response rates and relapse rates are taken into account.
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There is limited evidence on the risks of oral procedures among persons with HIV/AIDS. Very few studies have been reported, and only two types of procedures—root canal therapy and extractions—have been investigated. From this meager base, there is little evidence of unusual rates or severity of complications for these procedures among persons with HIV/AIDS.
Evidence for the utility of selected oral lesions as markers for seroconversion is limited to a single study of a single oral condition—candidiasis. While most of the persons who had candidiasis had seroconverted (high PPV), only a small proportion of the seroconverters had candidiasis (low Sn). This review does not suggest the use of oral conditions as markers for seroconversion. While there is a greater amount of evidence with respect to using a similar set of oral conditions as indicators of progress to severe immune suppression (CD 4 counts < 200 cells/mm3), the conclusions are not dissimilar. They are generally not good to use in place of a test to detect HIV progression to the next stage, and, with the exception of Kaposi's sarcoma which has a very high PPV, are of little benefit in a clinical setting.
The evidence with respect to the efficacy of fluconazole to prevent oropharyngeal candidiasis is good, but for other antifungal agents there is no evidence. The situation is different with respect to the effectiveness of antifungals as treatments for oropharyngeal candidiasis. With the exception of amphotericin B, the evidence is good that they are all effective, although not equally.
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To advance our understanding of differences in oral complication rates associated with patient HIV status, the number of studies on extractions and endodontics must be increased, and the types of dental treatments that are studied need to be expanded to include periodontal procedures, implants, orthognathic surgery, and oral prophylaxis. The study designs need to be more sophisticated, the samples large, and the analyses multivariate. Important variables that need to be better measured and reported include complications, postprocedural compliance, and antibiotic and antiretroviral use.
Furthering our knowledge of oral conditions as markers of recent seroconversion will require a large commitment of professional manpower and resources to monitor large at-risk cohorts over time. It will require that attention be given to the full range of oral conditions implicated in the seroconversion process, their consistent diagnosis, and frequent HIV testing.
As with future research on oral conditions as markers of seroconversion, more intensive study and consistent diagnosis of the suspected oral conditions (in addition to oral candidiasis and hairy leukoplakia) are needed to ascertain their value as indicators of changes in the level of immunosuppression. Additionally, the role of antiretroviral therapy—especially the newer, highly active agents—needs to be considered in future analyses, and viral load should be measured in addition to CD4 lymphocyte counts to measure changes in levels of viral replication and immunosuppression.
Large gaps remain to be filled in our knowledge with regard to the efficacy of ketoconazole, clotrimazole, itraconazole, nystatin suspension, and amphotericin B oral solution when used prophylactically against initial and recurrent oropharyngeal candidiasis in HIV patients. Studies using these drugs need to be performed, and more needs to be done using nystatin.
Future studies need to follow well-defined cohorts and control for immunological and clinical HIV status, HIV viral replication rates, prior history of oropharyngeal candidiasis, prior use of antifungals, and current antiretroviral therapy. Observations are needed of patient compliance with the drug regimen, fungal speciation, and resistance to the drug (via susceptibility testing).
Although much more research already exists regarding treatment effectiveness of available antifungals against oral candidiasis than on their prophylactic use, there is a need for studies of amphotericin B if it is to be included in the array of antifungal drugs used. The same methodological conditions mentioned in the context of research on the prophylactic use of antifungals also apply in the context of treatment.
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Availability of Full Report
The full evidence report from which this summary was derived was prepared for the Agency for Healthcare Research and Quality by the Research Triangle Institute-University of North Carolina at Chapel Hill Evidence-based Practice Center under contract No. 290-97-0011. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requestors should ask for Evidence Report/Technology Assessment No. 37, Management of Dental Patients Who Are HIV Positive.
The Evidence Report is also online on the National Library of Medicine Bookshelf.
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AHRQ Publication No. 01-E041
Current as of March 2001