April 2002

HRSA Care ACTION

Oral Health and HIV Disease

Oral health problems were identified as a significant issue early in the AIDS epidemic, and they continue to be so today.¹  Oral manifestations of HIV disease, such as thrush, warts, and gum disease, occur in approximately 30 percent to 80 percent of people living with HIV/AIDS worldwide.²

Problems in the mouth not only may be the first symptom of HIV infection but also can signify clinical progression. Thus, access to oral health care, both for the person at risk for HIV infection and for the individual already living with HIV disease, is critical. Yet, care is often not available, not accessed, or both; reasons range from lack of funding and lack of willingness to treat, to geographic isolation and problems that are so devastating for the patient that those related to oral health seem relatively unimportant.

Lack of dental care among the HIV-positive population in the United States exists in the context of poor access to dental care for large segments of the general population. For the HIV-positive person who is unaware of his or her serostatus but for whom oral symptoms are developing, no access to dental care represents a lost opportunity for HIV screening, counseling and testing, and linkage to care. This scenario assumes, of course, access to not only a dentist but one who recognizes HIV risk factors, is familiar with oral symptoms of HIV infection, and is able to provide HIV screening. Oral health care is no less essential for the HIVpositive person already in care, because of its relationship to good nutrition. Highly active antiretroviral therapy (HAART), despite reducing the incidence of some oral health conditions, has been associated with increased incidence and frequency of other problems and is no panacea for poor access to oral health care.³

Oral manifestations of HIV are categorized as fungal, viral, and bacterial infections; neoplasms; and nonspecific presentations, such as salivary gland disease and apthous ulcers. The sections that follow describe some of the most common oral manifestations.

Oral candidiasis is the most common fungal infection seen in connection with HIV infection. Three types of oral candidiasis are commonly observed: 

Pseudomembranous candidiasis (PC) is also known as thrush. It appears as creamy white or yellowish patches on the tongue or inside the mouth that can be wiped off, leaving a red, raw, or bleeding surface. Even with the introduction of protease inhibitors and HAART, PC is still one of the most common oral manifestations of HIV disease. Mild to moderate cases are treated with topical therapies, such as nystatin or clotrimazole; more severe cases are treated with systemic therapy, such as fluconazole. To be effective, antifungal therapy should last at least 2 weeks.

Erythematous candidiasis (EC) presents as a red, flat lesion commonly found on the tongue or the hard or soft palate. Patients may complain of a burning sensation.  Although EC is a common oral manifestation, it is often underdiagnosed.⁴ Topical antifungal therapies are used in treatment.

Angular (candidal) cheilitis appears as cracks or fissures radiating from the corners of the mouth. If untreated, it can exist for a long period of time. Treatment consists of the application of a topical antifungal cream to the affected areas 4 times a day for 2 weeks.

Oral warts caused by humanpapilloma virus may be cauliflowerlike, spiky, or raised with a flat surface. Treatment usually involves surgical removal with scalpel, electrosurgery, or laser. Alternatives to surgery include topical application of a podophyllin resin. Even with treatment, oral warts have a high rate of recurrence. Researchers report a dramatic increase in oral warts associated with the use of HAART, the reasons for which are unclear. One hypothesis is that although immune function generally increases with the use of HAART, its function may be incomplete, leaving the body open to potentially pathogenic microorganisms.⁵

Herpes simplex virus Type 1, a fairly common problem, appears as blisters on the lips. It can also appear inside the mouth as blisters that may rupture and produce painful ulcerations. Although the ulcerations usually clear up on their own, antiviral medications, such as acyclovir or valacyclovir, may help clear up an outbreak.

Oral hairy leukoplakia (OHL) is caused by the Epstein-Barr virus. It is one of the most common oral manifestations of HIV and presents as white, vertically corrugated patches on the sides of the tongue. Treatment of OHL is usually unnecessary but is instituted if a lesion interferes with eating or talking or is visually unappealing. Acyclovir and topical application of a podophyllin resin are used in treatment; recurrences are common if treatment is stopped.

Herpes zoster (shingles) is a reactivation of the varicellazoster virus—the same virus that causes chicken pox. Oral lesions appear as blisters or bubbles, then burst, becoming ulcerations. Treatment consists of high doses of acyclovir or famciclovir.

Cytomegalovirus (CMV) infection, an HIV-related opportunistic infection, presents on rare occasions as a large, painful ulcer that may be on any part of the mouth. Biopsy and histologic confirmation are needed for diagnosis; treatment is with oral acyclovir. The presence of CMV in the mouth, however, indicates that it is present in the body. Systemic treatment, with either oral or intravenous ganciclovir or intravenous foscarnet, is indicated.

Necrotizing ulcerative periodontitis (NUP) and necrotizing ulcerative gingivitis (NUG) are both periodontal diseases.  NUP is a marker for severe immunosuppression; it causes severe pain, bleeding of the gums, and rapid destruction of gum tissue and bone, which can lead to tooth loss.⁶  People with NUP often describe a deep jaw pain. Treatment consists of a professional cleaning and use of a chlorhexidine rinse. Antibiotic therapy may also be instituted for severe cases. NUG refers to destruction of gum tissue and soft tissue and is associated with mild pain and occasional bleeding. Treatment is the same as for NUP. 

Linear gingival erythema (LGE) presents as a red band where the gums and teeth meet and may be accompanied by occasional bleeding. Treatment for LGE consists of a thorough professional cleaning and use of a chlorhexidine rinse.

Kaposi’s sarcoma (KS) is still the most common oral malignancy seen in connection with HIV infection. The incidence, however, has dropped dramatically since the introduction of HAART.⁷  Oral lesions, which can be raised or flat and range in color from red to purple, may be the first sign of KS. Oral KS is most commonly found on the roof of the mouth, but it also can appear on the gums and tongue and at the back of the mouth. As a KS lesion grows, it can cause problems with chewing, talking, or swallowing. Treatment of oral lesions ranges from injections of a chemotherapeutic agent, such as vinblastine sulfate, to surgical removal. If KS lesions are present in other parts of the body, systemic chemotherapy may be carried out.

Non-Hodgkin’s lymphoma occasionally presents as a large, ulcerated mass on the palate or gums. Diagnosis must be confirmed with a biopsy. Patients should be referred to an oncologist for treatment.

Salivary gland disease presents clinically as parotid gland enlargement; xerostomia, or dry mouth, is also present. Salivary gland disease may occur at any time during the course of HIV disease and as a side effect of medications. Increases in salivary gland disease have been reported with the use of HAART; this effect may be due to an immune reconstitution syndrome.⁸

Xerostomia, which occurs frequently in people living with HIV disease, has a variety of causes. As stated above, swollen salivary glands can cause a reduction in the amount of saliva in the mouth. In addition, dry mouth can occur as a result of medications used in HAART or antidepressants. Besides being uncomfortable, the lack of saliva in the mouth can lead to gum and tooth decay as well as other problems. Xerostomia can be relieved by sucking on sugarless candy or chewing sugarless gum. Commercial artificial saliva, available by prescription, also may alleviate the discomfort.

Apthous ulcers—commonly known as canker sores—are small, round ulcers that appear on the soft tissue in the mouth (e.g., the inside of the cheeks, the sides of the tongue, or the throat). Typically, such ulcers have a red halo of inflammation and are covered by a yellow-gray membrane; pain may increase with eating and drinking. Generally, apthous ulcers take 7 to 14 days to heal. Although apthous ulcers are common in the general population, people with HIV disease may have ulcers that are large and painful and take a long time to heal. Treatment may involve topical use of steroids such as a dexamethasone elixir. In severe cases, systemic steroids (e.g., prednisone) may be needed.

For ulcers that do not heal, an experimental treatment, thalidomide, may be used. Studies have shown thalidomide to be effective in treatment of major apthous ulcerations, but it comes with some important warnings. Side effects may include fatigue and peripheral neuropathy (a painful tingling and numbness in the hands and feet). Thalidomide is associated with serious birth defects if used during pregnancy; health care providers should warn pregnant women and women who are of childbearing age about the serious consequences of using thalidomide.

With use of HAART, the pattern of oral manifestations in people living with HIV disease has changed. The prevalence of OHL has significantly declined, and rates of KS appear to be diminishing as well. The prevalence of HIV-related salivary gland disease, however, has increased significantly, and oral warts are increasingly common.⁹  Although the demographic characteristics of people with HIV disease have changed over time, the sudden, profound reduction in viral burden and improvement in cellular immunity achieved with HAART are most likely responsible for the observed alteration in oral disease patterns.¹⁰  The pattern of oral manifestations in HIV disease may continue to shift as a result of differential access to therapy; problems with adherence to medications, including side effects; and prevalence of drug-resistant HIV strains among people with HIV.¹¹

Many providers are noticing the changes in their practices. David Reznik, D.D.S., chief of the dental service for the Grady Health System in Atlanta, GA, observes, "I’m seeing an increase in root caries [cavities] which cause the teeth to fracture. Patients call it 'brittle teeth syndrome.’ The problem appears to be related to xerostomia."

Although treatment has reduced the prevalence of many oral health conditions among patients living with HIV, problems remain. "Even with decreases in a number of HIV-related oral lesions, severe or life-threatening lesions are still present, says Mark Nichols, D.D.S., director of Bering Dental Clinic in Houston, TX. "Oral health care professionals must still be prepared to diagnose and treat these lesions."

Oral health problems in patients living with HIV can be more complicated and harder to treat than in the general population and often require the attention of both dental and medical providers. As Jill Young, an HIV/AIDS case manager who works with Western Community Health Resources in northwest Nebraska and with the Nebraska AIDS Project, states, "It is important to have accepting, knowledgeable providers of HIV care who are experienced and comfortable in working with HIV-positive people."

According to Michael Collins, RN, AIDS Certified RN (ACRN), and a licensed alcohol and drug counselor (LADC), "One of the most effective ways to deal with HIV disease is to maintain good nutrition. Because of the increased burden placed on the metabolism of HIV-positive people, their caloric intake needs to be higher." Although HAART and other anti-HIV drugs have helped reduce HIVrelated morbidity and mortality in recent years, oral manifestations of HIV are still common, and they can affect patients’ quality of life and disease progression. For example, for people living with HIV, meals are not just a focus of social activity—they are a fundamental part of their care plan. Oral pain or discomfort, however, can lead to problems with eating, both reducing patients’ intake of nutrients and impeding an important life activity. Thus, routine visits to dental care providers for cleanings and oral health assessment are important for all patients with HIV, regardless of whether the disease has produced oral manifestations.

Many disparities in access to oral health care exist in the United States. A 2000 report on oral health care from the Surgeon General describes shortages of primary oral health care providers in areas generally lacking in health care services (i.e., underserved areas) and a decrease in the proportion of underrepresented minorities in the dental profession.¹²

People living with HIV disease often have even more limited access to oral health care than their counterparts without the disease do. The HIV Cost and Services Utilization Study examined the need for oral health care among a nationally representative sample taken from an estimated 230,900 HIV-positive adults receiving medical care in the contiguous United States. Interviews conducted in 1996 indicated that an estimated 19.3 percent had an unmet need for dental treatment in the 6 months before the interview.¹³  Another study found that approximately 25.1 percent of people living with HIV had unmet needs for dental or medical services in the 6 months prior to the survey. Unmet dental needs were twice as prevalent as unmet medical needs for this cohort.¹⁴

Provider availability, willingness to treat, insurance, and geography all affect access to dental care. Financially, the cost of oral health care can be prohibitive for HIV-positive people, many of whom do not have insurance. According to Lynn Meyerkord of the AIDS Project of the Ozarks in Springfield, MO, "Costs sometimes run into the thousands of dollars and somehow, we have to decide how the funds can be equitably distributed. . . . Once we were able to make more dental care money available through Title III, clients definitely took advantage of it."

Looking at HIV care in rural areas, it is clear that people with HIV disease face a number of obstacles. Jeff Tracy, Title III coordinator for Western Community Health Resources in northwest Nebraska, says, "In rural areas, distance, shortage of providers, willingness to treat, lack of insurance, and stigma all play a part in accessing care. Our project contracts with Panhandle Community Health Services, a community health center [CHC], for provision of oral health care. The CHC has become an incredible magnet because most providers don’t take Medicaid."

For people without private insurance, finding providers who accept Medicaid or who will treat at a reduced cost is an obstacle to receiving care. In many states, Medicaid does not include dental benefits, although some studies suggest that one way of increasing access is to have dental benefits added to all state Medicaid programs.¹⁵  Even when providers are willing to treat and funding is available, however, care may not be possible. Collins, a former co-chair of the Ryan White Title I Planning Council for the Las Vegas, NV, Eligible Metropolitan Area, offers a good example: "Our planning council took action to improve access to oral health care. It was identified as one of the top three priority areas, and funds were allocated to meet the need. Unfortunately, a statewide shortage of dentists kept us from meeting our goal, and the funds had to be reallocated." 

Transportation issues play an important role in access to oral health care in both urban and rural settings. "In Houston," Nichols says, "transportation is still a barrier to accessing care. In a city without a good public transportation system [like Houston], HIV-positive people without cars struggle to reach dental appointments. It is also difficult to staff a dental clinic dedicated to HIV care. Bering Dental Clinic is high volume, and turnover is an issue for the clinic, as it is for other dental clinics."

Patients infected with HIV are living longer, and their care is presenting new challenges for dental practitioners. Regular, ongoing dental visits and treatment are critical to minimizing long-term dental complications for people living with HIV disease. Thus, consideration of the need for dental services in the context of Ryan White CARE Act planning and spending has never been more crucial.

Continued educational and training opportunities for dental health care providers will enhance providers’ knowledge, attitudes, and capacity to provide quality care to people living with the disease. The Dental Reimbursement Program (DRP) of the Ryan White CARE Act supports access to oral health care for people with HIV infection. The program compensates dental schools, hospitals, and other institutions with dental education programs for unreimbursed costs they incur in treating people living with HIV/AIDS. By offsetting the costs of nonreimbursed HIV care in dental education institutions, the DRP improves access to oral health care and provides training to new generations of dentists and dental hygienists in managing the oral health care of people with HIV. In 2000, the DRP supported dental services for almost 29,000 clients.

The CARE Act-funded AIDS Education and Training Centers (AETC) program also is an important resource for providers of HIV-related oral health care. Through a network of regional and national training centers, the AETC program provides state-of-the-art treatment education, training, consultation, and clinical decision support to health care professionals treating HIVinfected people. Further information about both programs is available on the HIV/AIDS Bureau website, http://hab.hrsa.gov.  

References

1. Capilouto EI, Piette J, White BA, et al. Perceived need for dental care among persons living with acquired immunodeficiency syndrome. Med Care. 1991;29:745-54; Centers for Disease Control. Task force on Kaposi's sarcoma and opportunistic infections. Epidemiologic aspects of the current outbreak of Kaposi’s sarcoma and opportunistic infections. N Engl J Med. 1982;306:248-52.

2. Arendorf TM, Bredekamp B, Cloete CA, et al. Oral manifestations of HIV infection in 600 South African patients. J Oral Pathol Med. 1998;27(4):176-9; Diz Dios P, Ocampo A, Miralles C, et al. Changing prevalence of human immunodeficiency virus-associated oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(4):403-4; Patton LL, McKaig R, Strauss R, et al. Changing prevalence of oral manifestations of human immunodeficiency virus in the era of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;89(3):299-304.

3. Patton, et al. 2000; Felefli S, Flaitz CM. Oral warts in HIV-infected individuals. Res Initiat Treat Action. 2000; 6(3):19-22; Greenspan D, Canchola AJ, MacPhail LA, et al. Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet. 2001;357(9266):1411-2; King MD, Reznik DA, O’Daniels CM, et al. Human papillomavirus-associated oral warts among HIV-seropositive patients in the era of highly active antiretroviral therapy: an emerging infection. Clin Infect Dis. 2002;34:641-8.

4. Tappuni AR, Flemming GJ. 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. 2001;92(6):623-8. 

5. Patton et al. 2000; Felefli et al. 2000; Greenspan et al. 2001; King et al. 2002.

6. Glick M, Muzyka BC, Salon LM, Luric D. Necrotizing ulcerative periodontitis: a marker for severe immune deterioration. J Periodontol. 1994;65:393-7.

7. Tappuni and Flemming 2001.

8. Patton et al. 2000.

9. Patton et al. 2000; Felefli et al. 2000; Greenspan et al. 2001; King et al. 2002.

10. Patton et al. 2000.

11. Project Inform. HIV and the mouth. [Project Inform website]. January 2001. Available at: http://www.projinf.org/fs/oral.html.

12. U.S. Department of Health and Human Services. Oral Health in America: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health;2000.

13. Marcus M, Freed JR, Coulter ID, et al. Perceived unmet need for oral treatment among a national population of HIV-positive medical patients: social and clinical correlates. Am J Public Health. 2000;90:1059-63.

14. Heslin KC, Cunningham WE, Marcus M, et al. A comparison of unmet needs for dental and medical care among persons with HIV infection receiving care in the United States. J Public Health Dent. 2001;61(1):14-21.

15. Marcus et al. 2000; Heslin et al. 2001.

Adherence: Taking Medication Seriously

Antiretroviral medications control HIV disease only if patients take them.

That claim sounds simple, but its implications are vast. Many people with HIV must take dozens or more pills every day and take them at the right time, under the right conditions, and for the rest of their lives. Although they offer people with HIV the hope of continued good health, the pills themselves often cause serious side effects. To control replication of the virus, medical care providers ask people with HIV who may feel well to take pills that may make them feel sick.

Along with access to medical care, adherence to medical regimens—taking medications exactly as prescribed—is a tremendous challenge facing people with HIV and the clinicians and medical care teams who treat them. Medicaid, the AIDS Drug Assistance Program (ADAP), and private insurance allow medications to be available to most HIVpositive people in the United States. Highly active antiretroviral therapy (HAART) places a tremendous burden on people taking the medications, a burden that many cannot sustain without help.

Difficulties with adherence are not unique to HIV. Studies of other chronic diseases have shown that people with diabetes, elevated blood pressure, and high levels of cholesterol often miss doses of their medications. HIV disease is different from those other diseases in some very important ways, however, and the consequences of skipping even a few doses of HIV medication may be quite serious.  Missing a few doses of high blood pressure medication, for example, may result in high blood pressure until the medication is resumed; skipping a few doses of antiretroviral medication may result not only in a higher level of virus in the blood but also in antiretroviral medications that no longer work. To achieve therapeutic success, defined as suppression of viral load, patients generally must take more than 95 percent of their medication doses, a tremendously difficult challenge.

When it comes to HIV disease, nonadherence is particularly concerning because it may result in higher viral loads and in viral resistance, which is the development of virus that will not respond to medication (see box). Nonadherence, therefore, can lead not only to uncontrollable disease progression for the patient but also to public health consequences, because it may foster the growth of resistant virus that could infect others. 

Studies have shown that adherence to HAART regimens averages about 70 percent.¹  That figure is higher than for many other chronic diseases, but it is well below the 95-percent level necessary to hold the virus in check. Patients give many reasons for missing doses of their medication. The most common explanations offered are that they forgot, that the medications interfere with meals and other activities, that they were feeling sick or experiencing side effects, that they slept through the time the dose was due, that they were too busy, that they were pessimistic about their disease, or that they did not have their medication with them.²  Whatever the reasons, the consequences are dangerous both for the patient and for the public health.  Before starting HAART, patients must have the information they need to evaluate both the potential benefits and the effects of HAART on their daily lives because the consequences of nonadherence are so severe.

Factors in Successful Adherence

Several factors seem to play a role in adherence, including the characteristics of the patient, the characteristics of the medical team and the team’s relationship with the patient, and the specific regimen prescribed for the patient.³

Race, ethnicity, gender, age, and socioeconomic status generally have not been found to predict adherence.⁴  Higher levels of education and literacy, however, are positively correlated with adherence. As a result, patients with lower levels of education should receive special attention. Other characteristics that make patients less likely to adhere to medication regimens include heavy alcohol use, current injection drug use, and depression. The stability or chaos in a patient’s social situation, as well as his or her motivation and beliefs about the effectiveness of the medication, also affect adherence. All of these areas should be explored before a patient starts therapy. Patients who use alcohol or drugs or who have mental health needs should be offered ongoing treatment for those conditions, which will improve the likelihood of successful adherence.

It also is important to take into account sources of the patient’s social support and to help the patient identify others who can help reinforce adherence. A family member, a friend, or another person taking HAART could be enlisted to support the patient. Other techniques includ e suppor t groups, educat ional sessio ns, and counseling. For some patients who find adherence difficult, directly observed therapy, long a mainstay of treatment for tuberculosis, can be effective. The medical care team must remember to integrate support for adherence into ongoing clinical care. Every patient visit and client contact is an opportunity to strengthen adherence.

Clearly, adherence is difficult for patients; it also is clear that members of medical care teams have an important role to play in helping patients adhere to their drug regimens. Team members can educate clients about the benefits and side effects of medications and help them select regimens that they can follow. The education should start before the first pill is prescribed. Before initiating treatment, the physician, nurse, or case manager should first assess the client’s readiness to begin therapy. Once the decision is made to start, conversations with clients should include discussions about dosing times, relationship to meals, the number of pills to be taken, pill storage, side effects, symptom management, and any other concerns of the patient. It also is important to know whether the client has a permanent home where medications can be safely and, if necessary, privately stored and whether he or she has access to meals at regular times. Members of the medical team also must ensure the basics: Does the client have the prescription? Was the prescription filled? When are refills needed? 

Studies have shown that good adherence to a complex medical regimen, like any important behavioral change, requires ongoing and multifaceted interventions.⁵  In other words, adherence must be supported over time and in an assortment of ways. Written instructions and pictures, in addition to discussions, can help educate and engage clients. It is important to help clients identify cues in their daily life that can serve as reminders to take medication, such as television shows, dinner, or bedtime. Patients should have medication supplies at home, at work, and wherever they regularly spend time. Pillboxes, written medication logs, and timers with alarms also can be helpful.

A positive relationship between the patient and the medical care team, in which the patient feels supported, can increase adherence. The team should actively work to develop such a bond. Listening to the patient, answering questions, and offering educational materials all strengthen the relationship. It also is important for the medical team to remember that lack of adherence is just one cause of treatment failure and not to reflexively hold the patient responsible should treatment fail. Other causes of treatment failure include prior use of antiretroviral therapy, interactions among drugs, and difficulty absorbing medication. Listening to the patient, encouraging him or her to discuss side effects and other difficulties with the medications, and frequent contacts are important in building a trusting relationship that will support adherence.

Finally, the complexity of a medication regimen can act as a barrier to adherence. Too many pills, too many different medications, and too many intricate rules about how to take them all make good adherence less likely. To the extent possible, medications should be selected that have the fewest side effects, that are simple to take, and that fit the patient’s lifestyle and schedule. Side effects, such as nausea, diarrhea, and pain, should be anticipated and managed.  When more than one treatment choice is available, the patient should be involved in selecting the medications that would work best for him or her. Generally, the first drug regimen a patient uses is the most successful, so patients must understand that excellent adherence is essential from the start. Once a regimen is chosen, it is critical to make sure that patients understand how to follow it and how to manage any expected side effects.

Adherence in Children

Less research has been conducted on adherence in children with HIV than in adults, but children seem to need 90- percent adherence to medication in order to suppress the virus in their bodies. Children’s issues concerning adherence differ from those of adults. The primary distinction is that children must rely on their parents or other caretakers to obtain and administer their medications. Often those caregivers are HIV infected themselves and must contend with their own illnesses and medications. Data have shown that caregivers who cannot name their child’s medications or who do not take their child to scheduled medical appointments generally do not adhere to the child’s medication schedule. Even among caregivers who are familiar with their child’s medications and who do take their child to medical appointments, however, the degree of adherence is less than optimal. Further research is needed to identify barriers to adherence among children with HIV and AIDS. 

The silver bullet for AIDS—a single, easy-to-take pill that will defeat the disease—seems a long way off. For now, HAART and adherence to HAART are the most effective tools that people with AIDS have to lead long and healthy lives. Even while scientists are searching for better therapies, attention must be paid to ensuring that we use current drug regimens as effectively as possible. The consequences of failure—disease progression and viral resistance—are too serious to do otherwise.

References

1. Stone VE. Strategies for optimizing adherence to highly active antiretroviral therapy: lessons from research and clinical practice. Clin Infect Dis. 2001; 33:865-72.

2. Chesney M. The challenge of adherence. BETA. 1999;12:10-3; Andrews L, Friedland G. Progress in HIV therapeutics and the challenges of adherence to antiretroviral therapy. Infect Dis Clin North Am. 2000;14:901-28.

3. Andrews and Friedland 2000.

4. Stone 2001.

5. Andrews and Friedland 2000.

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