Antiretroviral Treatment and Adherence

Introduction

Although treatment can greatly increase longevity and quality of life for HIV-infected patients, some HIV-infected adolescents are not receiving the benefits of this care. In line with recent guidelines from the U.S. Centers for Disease Control and Prevention (CDC),1 providers should make HIV testing a routine part of health care to help identify undiagnosed HIV-infected youth and link them to life-saving treatments and services. Once HIV-infected youth have been identified, clinical care for these patients should meet the following goals:

• Determine staging of HIV illness and health status
• Provide health care maintenance: HIV and primary care, treating concurrent medical problems
• Provide ongoing monitoring: immunologic, virologic, clinical
• Provide state-of-the-art treatment and therapies: antiretrovirals (ARVs), opportunistic infection (OI) prophylaxis, etc
• Educate patients about HIV disease
• Educate patients about ARV therapy (ART) and facilitate treatment adherence
• Establish linkages with appropriate clinical trials

This section highlights important issues that can facilitate culturally competent care; gives providers an overview of general clinical care considerations for treating HIV-infected youth; and addresses the challenges of initiating ARV medications in adolescent patients, including the medical, psychosocial, and cultural issues youth may face when initiating ART. It also illustrates how to assess for medication readiness and how to select a regimen that is compatible with patients' different lifestyles.

Learning Objectives:

Upon completing this module, participants will be able to:

1. Identify at least 3 sociocultural and religious barriers affecting the initiation of ART in adolescents (youth perspective).
2. Recognize at least 3 clinical factors unique to adolescents that impact the initiation of ART.
3. Identify 3 common reasons for virologic failure.
4. Identify and address 4 common barriers to ART adherence.
5. Identify 2 ARV drugs that can potentially decrease the effectiveness of estrogen-containing oral and transdermal birth control medications.
6. Identify 3 side effects of ARV medications most likely to result in poor adherence in adolescents and specify which side effects are perceived as severe by Black/African American teens.

Instructions

• The course may be navigated either by selecting the "Next Page" button at the bottom of each screen, or by using the course outline buttons in the left navigation column.

• All users will be asked to complete a final evaluation to help the sponsors assess the value of the course.

Authors

Ligia Peralta, MD

Ligia Peralta, MD, FAAP, is an associate professor of pediatrics and epidemiology, chief of the Division of Adolescent and Young Adult Medicine, and director of the Adolescent HIV Program at the University of Maryland Hospital for Children, University of Maryland School of Medicine. Dr. Peralta has more than 17 years of experience in adolescent health and HIV care. Dr. Peralta developed the "One-Stop Shopping" model of service for adolescents and young adults, which includes anonymous, confidential, and free HIV testing and counseling; advanced gynecological examinations, including colposcopy and cervical dysplasia screening using digital photographs; sexual and substance abuse counseling and treatment; and pharmacy, dental and legal services.

Dr. Peralta's areas of research include primary and secondary HIV prevention, innovative HIV testing technologies, HIV disease progression and spectrum of disease, AIDS fatigue and wasting, sexually transmitted infections, pregnancy, and expanding nontraditional ways of delivering care to special youth populations.

Dr. Peralta is currently the principal investigator of the Adolescent Trials Network for HIV/AIDS Interventions (ATN) Baltimore Unit. In addition, she is the principal investigator of a longitudinal study on biological factors impacting the acquisition of sexually transmitted diseases in adolescent women, funded by the National Institutes of Health, and various grants on secondary prevention of HIV. She is the national representative of the Society of Adolescent Medicine to the American Medical Association. She has spearheaded the National HIV Agenda in her native country, the Dominican Republic. Dr. Peralta serves on the National Pediatric and Family HIV Resource Center Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, and has been the recipient of numerous awards, including the 2000 Latinos of Distinction Award conferred by the U.S. Food and Drug Administration and the White House.

April L. Palmer, MD

April L. Palmer, MD, is an associate professor of pediatric infectious diseases at the University of Mississippi Medical Center in Jackson, Mississippi, where she heads the adolescent HIV clinic. Dr. Palmer graduated with distinction and honors in human biology at the University of Kansas before obtaining her MD degree from the University of Kansas Medical School. She completed her pediatric training at the University of Texas Southwestern Medical School in Dallas, Texas, where she was also chief resident, and then completed her pediatric infectious diseases fellowship at the University of Colorado School of Medicine. Dr. Palmer is certified by the American Board of Pediatrics in pediatrics and pediatric infectious diseases. She is a member of the American Academy of Pediatrics, Pediatric Infectious Disease Society, Southern Society of Pediatric Research, American Society of Microbiology, and the Louisiana/Mississippi Infectious Diseases Society. Her current research interests include antiviral medications, congenital viral infections, and adolescent HIV.

Marvin Belzer, MD, FACP

Marvin Belzer, MD, is an associate professor of clinical pediatrics and medicine at the University of Southern California (USC) Keck School of Medicine. He graduated from medical school at USC in 1986. He completed his internship and residency at the University of California Irvine in primary care internal medicine. He completed his fellowship in adolescent medicine at Children's Hospital Los Angeles in 1991. Since 1991, Dr. Belzer has been the medical director of the Risk Reduction Program, and he is the associate director of research at the Division of Adolescent Medicine. Dr. Belzer has one of the largest adolescent HIV clinics in the western United States. He has developed a clinical research program that is engaged in large multisite clinical trials for youth infected with HIV. Current research network affiliations include the Adolescent HIV/AIDS Trails Network, Pediatric AIDS Clinical Trials Group, and the Centers for Disease Control and Prevention's Project Legacy. Dr. Belzer has been involved in multiple studies evaluating medication adherence. He also is involved in HIV prevention studies for high-risk adolescent populations.

Valuing Cultural Competence

Public health experts now recognize that certain racial, ethnic, and cultural groups face disparities in availability of health care and access to health education. As a result, health care providers have become increasingly aware of the need to consider culture in the context of their work with patients and their families. Thus, cultural competence has become an important area of skill building for health care providers, and some believe it is an ethical imperative.23

• For example, Black/African American adults have high rates of hypertension, diabetes, and heart failure and may be taking medications for these illnesses, creating the potential for drug interactions. Lactose intolerance is common among most racial/ethnic minorities. These situations may need to be taken into account when making suggestions for foods to eat that make medications more palatable or easier on the stomach.

• Providers approach medication and treatment from a scientific, empirical viewpoint, whereas patients and their families may take an intuitive approach. Get to know what they think about the treatment regimen you are proposing. Do they have fears or hesitations? Do they believe the treatment plan will work? Are they willing to try? Have regular conversations about perceptions of treatment and its effectiveness. Encourage youth and their families to let you know when they feel a plan is not working.

• Many ethnic groups, including Blacks/African Americans, American Indians/Alaska Natives (AI/ANs), Asian Americans/Pacific Islanders (AA/PIs), and Latinos hold culturally specific spiritual beliefs and individuals may seek advice and intervention from ministers, Yoruba priests, spiritual readers, herbalists, voodoo priests, shamans, or others known for their healing abilities. Determine whether your patients are using herbal or other therapies that may interact with ARV medications or negatively influence treatment adherence.

Initiating Antiretroviral Therapy

Clinical Considerations

The natural history of HIV infection in adolescents has not been fully defined. Long-term survivors of perinatal infection may have a unique clinical course that differs from that of other adolescents.4 However, most adolescents are infected, by sexual contact or injection drug use, after their immune systems have developed to maturity. In these adolescents, the clinical course of HIV infection parallels that of adults rather than of children, though there may be subtle differences in the adolescent immune system.5

In identifying and addressing the clinical needs of each HIV-infected adolescent, the following 10 care domains form the basis of an effective treatment protocol.5 For a detailed description of each domain, see "Adolescent HIV Care Protocol" in the Toolbox.

1. Medical and physical history
2. Review of systems
3. Physical examination
4. Laboratory assessment
5. Immunizations
6. Medications/treatment
7. Access to clinical research
8. Entitlements/case management
9. Patient education and empowerment
10. Referral to support services

In terms of ART, currently recommended strategies strike a balance between initiating treatment early enough to preserve immune function yet waiting long enough to minimize the time a patient is taking medications, as most ARVs have potentially serious side effects. Although the issues involved in making decisions about implementing ART are complex, a number of guidelines from expert panels are available to help care providers select effective regimens for individual patients. All clinicians treating HIV-infected patients should be familiar with the most current versions of these treatment guidelines (see Toolbox).

For youth experiencing developmental changes and growth spurt, drug dosing should be carefully monitored to avoid potential side effects and toxicities, as well as inadequate dosing (see "Pediatric ARV Guidelines" in the Toolbox). In general, pubertal changes may affect pharmacokinetics. Therefore, ARV dosing should be based on the Tanner puberty stage and not on age:

• Adolescents who have entered puberty or are early in puberty (Tanner stage I/II) should receive pediatric dosing based on pediatric guidelines.
• Adolescents who are in the middle of puberty (Tanner stage III/IV) should receive dosages based on whether they have completed their growth spurt.
• Adolescents who have completed puberty (Tanner stage V) should be given adult dosages.

Initiating Antiretroviral Therapy

When to Initiate ART

The guidelines for when to initiate antiretroviral treatment reflect a balance between: wanting to suppress HIV as much and as soon as possible to preserve immune function versus the long-term toxicity of current medications, as well as the challenge of long-term adherence. The "golden moment" to start ART is thus dependent on the properties of currently licensed medications. It is therefore crucial that providers check the most current ART guidelines before initiating therapy. Although there are clinical indications to begin treatment, it is also vital to assess the adolescent's treatment readiness as described below.

Let's begin with clinical guidelines for starting treatment.

Selecting ART Regimens

Initiation of ART is a critical decision that always should be made jointly between a collaborative physician and an informed patient. Generally, the decision should be made only after unhurried discussions (ideally, over the course of several patient visits), which can give the patient an understanding of the potential risks and benefits of alternative therapeutic approaches and can facilitate the patient's commitment to the ART regimen that is chosen.

The following recommendations are based on current DHHS Guidelines.

Once-Daily Dosing

Because challenges to adherence can compromise the long-term success of treatment, and because even modest inconveniences can become significant in the context of lifelong therapy, the focus of ART is shifting toward the use of simpler regimens. In addition to improving convenience and facilitating adherence, once-daily dosing permits the administration of ART as directly observed therapy (DOT), in which a provider observes the ingestion of medication. DOT has been shown to be successful in improving HIV treatment, especially among hard-to-reach populations, but is labor intensive. Providers may consider DOT during a 3-6 month period to improve patient education and medication self-administration.6

Initiating Antiretroviral Therapy

Assessing Patients' Medication Readiness

Identifying Barriers and Facilitators for ART

An array of negative and positive factors influence young people in ways that can either hinder them or help them in achieving success with their ART regimens. It is crucial that providers understand such factors for each patient in order to minimize the risk of nonadherence, which could lead to ARV resistance. A list of key barriers and facilitators to effective ART is provided below. A detailed assessment tool that can be used with patients can be found in the Toolbox.

Forming a Partnership

When assessments of young patients' medication readiness indicate that they are good candidates for initiating ART, it is then important that providers demystify for them the process of deciding when to begin taking medications and what medications are best suited to them. This investment of time engages patients as active partners in their own treatment. The best way to achieve this goal is to explain the process using simple language and visual aids, then involve each patient in making medication decisions to ensure that the chosen medication's characteristics and the patient's characteristics are compatible.

Part I of the partnership: Deciding when to start

• Inform the patient of the indications for ART, including CD4 count, symptoms, and comorbidities.
• Review the HIV staging table (see Toolbox) and point out the patient's stage.

Part II of the partnership: Deciding what to take

• Review the patient's resistance testing results.
• Show the patient a medication menu (see Toolbox) and walk the patient through available medication options, so that you can discuss pros and cons and make a joint decision about the appropriate regimen.
• Explain that there are simple regimens that combine multiple medications in a single pill that can be taken once a day. These simple regimens can be presented graphically (see Toolbox) to identify the components of a single pill and show the shape of the pill. It is helpful to show actual pill sizes or compare the size of the pill with a medication familiar to the patient (eg, vitamins, acetaminophen, ibuprofen). Metaphors that help the young person understand how the medications work also may be useful.
• Counsel the patient to provide a clear understanding of the number of medications in the pill and the risk of resistance if any doses are missed.

CASE STUDY:

Carlos

Carlos is an 18-year-old gay Latino. His initial HIV visit took place at a county clinic a year ago, shortly after he received a preliminary positive result from a rapid HIV test performed at a health fair. He reengaged in care last month, and HIV tests were performed at that visit. His CD4 count is now 150 cells/µL and his viral load is >300,000 copies/mL. Carlos travels 25 miles to Dr. Franklin's clinic by bus because he does not want to be seen walking into an HIV clinic by someone he knows from his neighborhood.

Family History

Carlos lives with his parents, but has not disclosed his HIV status to them or other family members. He tells Dr. Franklin that the only person he can talk to openly is his boyfriend, Jorge, who is also HIV positive. Jorge is 10 years older than Carlos and Carlos' parents strongly disapprove of their relationship. Carlos experiences episodic homelessness following arguments with his father about his sexual orientation. He is concerned about the stigmas of being gay and being HIV positive.

Social History

Jorge has advised Carlos never to take HIV medications because, he says, they will make him sicker and make him fat. Instead, he recommends that Carlos take several herbs his grandmother gives him. Additionally, Carlos' mother is giving him ventosas because she is concerned that he is losing weight. Carlos tells Dr. Franklin that some of his HIV-infected friends believe alternative HIV treatments are healthier than pharmaceutical medications. He has also commented that he doesn't think he could ever handle the number and size of ART pills some of his friends take, much less the potential side effects of the drugs such as nausea and loose bowel movements.

Current Situation

In broken English, Carlos explains to Dr. Franklin that he came back to the clinic because he is suffering from acute anxiety stemming from several HIV-related deaths among his peers, and says he does not want to die. Dr. Franklin recommends that Carlos start taking ART, but Carlos does not understand why he needs to take medicine when he does not feel sick. He reports that he does not have medical insurance and cannot afford to purchase the medications on his own. However, after Dr. Franklin convinces him that the medications can improve his health, he indicates that he will try to take the medications as prescribed if doing so will keep him alive and healthy.

Carlos reports a lack of privacy at home and states that he will have to take the pills in the bathroom. He asks Dr. Franklin for an envelope in which to store the drugs, fearing that a pillbox would cause them to rattle and prompt his friends and family members to ask questions.

Discussion

1. What are some of the barriers to medication initiation that Dr. Franklin should address with Carlos?

• Lack of HIV status disclosure
• Cultural beliefs about alternative therapies
• Family disapproval of his sexual orientation
• Lack of support from partner and family regarding ART
• Fear of side effects and of commitment to long-term medication use
• Distance to the clinic; refusal to use local resources (eg, a clinic where family members receive care) because of fear and stigma
• Lack of insurance
• Periodic homelessness

2. Does Carlos seem motivated to adhere to an ARV regimen?

• Although the death of several friends from HIV-related complications may motivate Carlos to seek care, he must also understand how HIV is affecting him personally. It is important for patients to have an understanding of the stages of disease progression. Many youth have difficulty comprehending why they need to take medications when they have no symptoms of illness. A clear understanding of patients' perceptions of their illness is important for determining where HIV ranks on their lists of priorities. Having this knowledge is critical in assessing their medication readiness.

3. What cultural influences should Dr. Franklin address with Carlos to improve his chances of medication adherence?

• All the people to whom Carlos has disclosed his HIV status place more trust in alternative HIV treatments than in standard treatments with ARVs. Assessment of patient, family, and peer perceptions about ART efficacy and toxicity is an essential step in tailoring an ideal treatment plan for each patient. Dr. Franklin should explore the family members' and peers' beliefs related to medications, long-term treatment, and alternative therapies, including spiritual healing methods.

4. What are the negative experiences with medications alluded to by Carlos that Dr. Franklin should explore in order to minimize the chances of nonadherence?

• Medication experience is a very important part of the assessment for medication readiness. This assessment may give the clinician a sense of how the patient can handle pill burden, dosing schedules, and lifestyle barriers.
• Carlos indicated to Dr. Franklin that he does not have health insurance and cannot afford to purchase ARVs on his own. Dr. Franklin should refer Carlos to a case manager who can help him apply for government-sponsored medication assistance. A patient's citizenship status can be a barrier to adherence, as many aliens are unaware that they are eligible for assistance or fear that accessing government-sponsored programs could put them at risk of deportation.
• Identifying needs and offering intervention to assist with pill swallowing and memory deficits are critical components in the process of selecting an ARV regimen. In addition, helping Carlos with issues about disclosing his HIV status and identifying a support person or persons before initiation of therapy are among the most important factors in helping reduce future adherence problems. Reminder tools are useful when used in combination with family/friend support, rather than in isolation.
• The success of reminder tools usually depends on many factors, including level of disclosure, motivation to carry a device and use it in public, and the patient's level of comfort with technology.

Addressing Adherence

The Importance of Adherence

This section will review how to assess adherence, particularly in those adolescents whose HIV viral load is not suppressed by ART; examine the common adherence barriers youth experience; and explore ways providers can work with youth to improve adherence.

ART regimens require strict adherence in order to prevent the emergence of resistant HIV. Unfortunately, most HIV-infected youth find it extremely difficult to adhere to their dosing schedules consistently. Drug combinations that can be administered once or twice daily make ART easier but do not eliminate adherence issues, especially in youth. Common reasons for adolescents to miss doses include:

• Aversion to medication side effects
• Inconvenience of taking multiple pills
• Forgetfulness and distractions caused by the complications of daily life
• Negative perception of medications as a constant reminder of HIV infection
• Lack of disclosure to persons who might facilitate better adherence

Helping young patients integrate medications into their daily lives is one of the most crucial and challenging tasks for providers. Providers can improve their patients' success with adherence when they approach this issue with the understanding that adherence to HIV/AIDS treatment involves more than simply remembering to take medications. Rather, it is a complex issue involving social, cultural, economic, and personal factors.7

Providers are well aware of how good adherence facilitates viral suppression, but it is useful to find out how important patients think adherence is to their well-being. You might ask youth and their families, "How do you feel about taking breaks from your medication?" "How do you believe it might affect you if you miss one dose of your medication?" "On a scale of 1 to 10, how important do you think it is to take the medication as prescribed?" Metaphors can be very useful in describing how medications work and what happens when a dose is missed. Providers also should find out what youth and their families may have heard about the medications and assess any myths that may affect their perceptions and behavior.8 It will be important to determine whether parents and youth believe the same myths, as youth are very likely to be influenced by significant adults in their lives.

Addressing Adherence

Top 3 Reasons for Virologic Failure

1. Medication Nonadherence

Medication nonadherence is the leading cause of viral resistance, as described below. In some situations, however, virologic failure may occur without resistance, if youth are taking so few of their ARVs that no selective pressure is exerted on the HIV.

2. Inadequate Drug Levels

When a youth who is taking ARVs does not have adequate suppression of HIV viral load, providers should first determine whether the medication dosages are adequate.

• Subtherapeutic drug levels may occur because of inadequate adherence with the ARV regimen; this is the most common reason for virologic failure.
• As youth grow, their dosage requirements may increase; ARV doses may not be adjusted adequately.
• Numerous drug-drug interactions must be assessed carefully (eg, tenofovir can reduce drug concentrations of unboosted atazanavir to subtherapeutic levels).
• Diarrheal illness can adversely affect drug absorption.
• Poor drug absorption may occur if atazanavir is given with acid-blocking medications. It also may occur more frequently with other ARVs that require food for absorption, as youth often do not follow the food-requiring instructions because of busy lifestyles or irregular schedules.

3. Resistance to ARVs

Youth for whom ART regimens are failing may harbor HIV that is resistant to one or more of their medications. They may have been infected with a resistant virus; in one study, 20% of newly infected youth had HIV that had at least one significant resistance mutation.9 IHowever, the most common reason for the development of new resistance is inadequate adherence to ART, with the emergence of resistance in the setting of inadequate drug levels.

When a patient does not take medications regularly and at appropriate dosages, viral replication occurs in the presence of subtherapeutic drug levels. This leads to selective pressure for the virus to mutate and become resistant to the medications currently being used. Even worse, some viral mutations can lead to cross-resistance to other antiretroviral agents. Once a mutation occurs in the HIV virus within an individual, most experts believe it will remain there forever.

Inadequate adherence can take various forms. Youth may not take any of their medications, may avoid a single medication they see as having bad side effects, or may randomly or predictably skip doses of the regimen. Partial viral suppression commonly leads to further viral resistance and greater increases in viral load over time.

Addressing Adherence

Top 4 Barriers to ART Adherence

1. Patient Characteristics

Patient characteristics are the most common and complex factors affecting adherence.

• A diagnosis of depression is commonly associated with nonadherence and has been documented in 49% of HIV-infected youth.10 Other common psychiatric diagnoses, such as bipolar disorder and schizophrenia, also are likely to affect adherence. Substance abuse is another factor that often contributes to nonadherence. Recent unpublished research on adolescent adherence to ART indicates that greater self-efficacy and, to a lesser extent, better outcome expectancy were associated with improved adherence.11
• Though yet to be evaluated in research, adolescent developmental factors are believed to affect adherence. Younger and more impulsive patients are more likely to forget or not prioritize taking their medications. Adolescent patients may be more easily distracted by issues of daily life.
• Some adolescents are extremely concerned that taking medications might inadvertently reveal their HIV status, and this can have profound impact on their adherence.
• Many adolescents have limited social support. In some cases, cultural or other factors may hinder youth from disclosing to their families, and some youth may be estranged from their families as a result of a variety of issues.
• One common phenomenon seen with perinatally infected children is that adherence starts waning during adolescence.
• Health care providers speculate that the normative adolescent tasks of separation and individuation lead adolescents to use control over medication adherence as a method of self-assertion. Clinicians can combat this surge in nonadherence by establishing better communication with the adolescent, exploring healthy ways for youth to express their independence, gradually handing responsibility for medication use from parents to teens, and being vigilant in recognizing parent-youth conflict over medication use and intervening early in the process.

2. Adverse Regimen Characteristics

Negative characteristics of particular medication regimens are common barriers to adherence. Youth who feel healthy before starting ARVs will be very unlikely to accept having significant side effects, especially if they last more than a week or two. Side effects such as diarrhea, rashes, or jaundice may be particularly troublesome because youth frequently worry that friends and contacts may assume they have HIV. Suggesting and rehearsing responses that patients can give to their friends if they experience side effects may help (eg, "I got this rash from a medication my doctor gave me for an infection.").

3. Health Care System

Ensure that the health care system works for each patient. Help prevent lapses in patients' insurance coverage. Loss of coverage may be prevented by assigning case managers to monitor insurance status closely. Additionally, as mix-ups and delays of prescription deliveries are common, unplanned lapses in a patient's supply of medications can be avoided by establishing a regular delivery schedule with a pharmacy that is good at notifying the clinic when there is a potential problem.

4. Patient-Provider Relationship

Research has demonstrated that adherence can be facilitated when a patient-provider relationship incorporates trust, good communication, adequate education about medications, and an overall perception of caring, including a culturally and linguistically appropriate approach to the relationship.12

Addressing Adherence

Strategies for Improving Adherence

Providers can improve adolescent adherence by:

Anticipating nonadherence

• In the REACH study, only 41% of youth claimed good adherence and 18% admitted that they had never taken their prescribed ARV drugs.13
• Adopt proven tactics that help patients adhere:
  • Select the best regimen for each patient's lifestyle
  • Assess patients' ability to adhere to regimens by using practice "pills" such as vitamins or candies
  • Evaluate patients' willingness to have family members or friends provide reminders
  • Use dosing cues such as meals or toothbrushing, and have patients place medications where they see them during regular activities
  • Provide pillboxes or unit dosing packaging, which helps if patients need to take their medications with them when they are away from home
  • Remind patients to take medications via alarms on cell phones or pagers

Minimizing adherence barriers

• Help establish a solid therapeutic alliance between the patient and clinic staff based on respect, trust, and honesty. Clinicians working with the Adolescent AIDS Program at Montefiore facilitate patient adherence to HIV regimens by "using their EARS" (see Toolbox).
• Utilize the lessons learned from Project TREAT to identify each patient's stage on the Stages of Change and their medication adherence (see Toolbox).14
• Address mental health issues:
  • Nonadherent patients should be given a brief depression screening with a tool (see Toolbox) and should be referred for psychiatric or psychological evaluation and treatment when appropriate.
  • Substance-using patients should be referred for treatment services and may need detoxification and residential treatment before initiation or reinitiation of ART.
  • Patients with poor self-efficacy or low outcome expectancy may benefit from referral for cognitive behavioral counseling or motivation interviewing treatment before initiation of ART.

Understanding potential adverse characteristics of antiretroviral regimens

• Pill burden affects adherence. Pill burden includes the number, size (some youth have a particularly hard time with large capsules), and taste of the medications.
• For ease of dosing, consider once-daily regimens with low potential for side effects. Many clinicians recommend that all youth initiate a once-daily, boosted protease inhibitor (PI) with two nucleoside reverse transcriptase inhibitors (NRTIs) as backbone. Boosted PIs have low probability for development of resistance, even when adherence is poor.
• Avoid medications with food requirements if possible. Youth may not have reliable sources of food, or may fail to eat at regular times.
• Make the ARV dosing schedule friendly to the individual. ARV doses should be taken at times that fit an adolescent's schedule. For example, it is often inconvenient to take medications during school hours or at work. Also, some youth have trouble with adherence to efavirenz, because it should be taken at bedtime, and doses may be missed when youth stay out late.
• Efavirenz is not recommended for women who may become pregnant, because it may cause birth defects. It also may cause failure of oral contraceptives.
• Nevirapine can cause severe liver impairment; this occurs more frequently in women.

Addressing Adherence

Video: Janelle's Adherence Counseling

Janelle is a 17-year-old African American with perinatally acquired HIV. Her mother is deceased, and she lives with her grandmother and younger siblings. Janelle has been on numerous ARV regimens in the past, but for 2 years she has been stable on lopinavir/ritonavir (twice daily) and abacavir/lamivudine (Epzicom) taken once daily.

Three months ago, she had an undetectable viral load, but it was measured at 4,000 copies/mL at her most recent visit. When Janelle returned for her lab results, she reported taking 26 of 28 medication doses since her previous visit.

Because of the spike in Janelle's viral load, her provider, Dr. Rollins, ordered another viral load test, which measured 8,000 copies/mL. When Janelle returned for the results of the second test, she again claimed good adherence. However, a genotypic assay found several new resistance mutations. Dr. Rollins also ordered a test of Janelle's serum lopinavir level, which was undetectable.

ART Adverse Events and Interactions

When starting adolescent patients on ART, drug-drug interactions and medication side effects should be among the determining factors that help you and the patient decide which ARV drugs are appropriate. Important questions to answer before starting ARVs include:

• What side effects are or would be most troubling to the patient?
• Is the patient taking other medications?
• Is the patient using oral contraception?

ART Adverse Events

Assessing Side Effects

ARV medication can be associated with mild to potentially life-threatening side effects or adverse events (AEs). AEs are among the most common reasons for switching regimens or discontinuing therapy, and for medication nonadherence. AEs may occur soon after a patient starts taking a medication, or they may develop years later. Some AEs occur more frequently with certain classes of ARVs. For example, diarrhea is a common side effect of PIs. Other AEs occur more frequently among patients from certain racial groups, such as emtricitabine-related hyperpigmentation in Blacks/African Americans.15

Because even mild side effects may compromise patient adherence, it is important to explain the potential AEs of specific ARVs before a patient begins therapy to determine whether any particular AEs would be intolerable for the patient. Once therapy has begun, providers should take time during each visit to explore whether the patient may be experiencing AEs. If a patient complains of side effects related to ART, there are several options:

• Some ARVs have AEs that decrease in intensity within days to weeks. For these, one may reassure the patient that the side effects often subside over time.
• Provide symptomatic treatment for the side effect.
• Change the medications that are causing the AEs.

Nausea frequently improves when medicine is taken with food. If a patient becomes nauseous because of an ARV that needs to be taken on an empty stomach, modification of the regimen may be needed. If a patient on medications that must be taken with food is unable to eat at a certain time of day (eg, in the morning), the dosing schedule may need to be changed so that medications can be taken at mealtimes.

For diarrhea that is mild, without significant frequency or urgency, reassurance that the symptom may improve is usually a sufficient initial response. If the diarrhea is impacting the patient's daily routine (eg, requiring frequent trips to the bathroom while in school), dietary changes (eg, a gluten-free, lactose-free, or high-fiber diet), palliative medication (eg, calcium supplements), or a change in the ART regimen may help. Start with the safest and easiest treatment modality for the patient.

Physical appearance is very important for adolescents. Therefore, minor to severe dermatologic effects of medication may be very distressing to a young man or woman and can lead to poor medication adherence. Common dermatologic changes associated with specific ARVs include:

• Skin rashes: nevirapine, efavirenz, abacavir, darunavir, fosamprenavir, and many other drugs (these typically occur in the early weeks of treatment)
• Nail and mucocutaneous hyperpigmentation: zidovudine
• Hyperpigmentation of palms and soles: emtricitabine
• Jaundice: atazanavir, indinavir
• Retinoid-like side effects (alopecia, dry lips and skin, ingrown nails): indinavir

Other appearance-related AEs that may impact adherence include:

• Lipoatrophy or lipoaccumulation (alteration of body fat distribution): many ARVs
• Injection site reaction: enfuvirtide

ART Adverse Events

Drug-Drug Interactions: Focus on Hormonal Contraceptives

There are significant drug-drug interactions between ARVs and numerous other medications. These interactions may result in therapeutically significant increases or decreases in levels of either ARVs or interacting drugs. It is important to consider potential interactions carefully before any ARVs or other medication is prescribed.

An important example of drug-drug interactions is that of ARVs with oral hormonal contraceptives. PIs and NNRTIs may affect the hepatic metabolism of oral contraceptive agents. Depending on the specific antiretroviral medication, this may result in:

• Higher levels of ethinyl estradiol or norethindrone, possibly resulting in increases in contraceptive side effects such as nausea, vomiting, and breakthrough bleeding
• Lower levels of ethinyl estradiol or norethindrone, possibly resulting in contraceptive failure (pregnancy)

It is also important to understand that oral contraceptive medication may lower levels of some antiretrovirals, including fosamprenavir, ritonavir, and tipranavir, possibly resulting in subtherapeutic dosing and risk of virologic failure.

As an alternative to oral contraception, depomedroxyprogesterone acetate (DMPA) offers several advantages; however, its side effects also must be considered.

Pregnancy, whether resulting from adverse drug-drug interactions, ineffective contraceptive use, or a desire to become pregnant, commonly occurs among both behaviorally and perinatally HIV-infected adolescent women. When starting patients on ART, care providers should be aware of which medications are contraindicated during pregnancy and avoid using those drugs for adolescent women who may be using unreliable contraception.

In addition, there are significant drug-drug interactions between antiretrovirals and numerous other medications. It is important to consider these carefully before any new medication is prescribed.

CASE STUDY:

Leticia

Leticia is a 16-year-old African American who was diagnosed with HIV infection after she was raped at age 13. Her current CD4 count is <200 cells/µL and her HIV viral load is 50,000 copies/mL; she has never taken ART. Leticia does not have hepatitis B or renal insufficiency. She is sexually active with a male partner and currently uses birth control pills for contraception. At a recent visit, she tells you that she is considering starting ART but is very concerned about experiencing nausea, vomiting, and diarrhea--especially during school hours.

Anticipating Leticia's Side Effects and Drug Interactions

Based on what you know about Leticia, answer the following questions:

Clinical Trials

As with adults, young people may benefit from participating in clinical trials. Some youth may not be open to discussion of clinical trials in their initial visits, but some patients may have had experience with research and may want to engage in this discussion. In this case, the clinician should be prepared to assess the youth's interest and discuss general concepts about clinical trials. For example, at the end of a visit, a doctor could assess a patient's familiarity with and interest in research, and start the dialogue by providing an introduction about research:

Doctor: This conversation has been very helpful. Let me briefly share with you another type of information that you may find of interest and we can discuss at your next visit.

In this city/county, we have access to studies that help us answer specific health questions for youth who are living with HIV. For example, there are studies designed to find ways to help teens stay healthy or take their medications. There are also studies to help us gain a better understanding of how (the bodies of) young people respond to certain HIV medications. These studies are called clinical trials, and they may take from few to several visits. Some of those studies are designed to give us more information about how people handle HIV medications, the best doses to use, the best ways to take them, how these medicines relate to other medicines, how teens avoid infections, etc. The participation in these studies is voluntary and the person can decide to stop being part of the study at any time. Researchers closely check for any symptoms or concerns related to being part of the study and are available to respond to any questions. I will give you some information about it (Title IV brochure) and next time, if you are interested, we can discuss it further.

The perception of patient and family regarding research is important when talking to a youth about research. For immigrant youth and families, it is important to assess their familiarity and experience with the health care system and with clinical trials and research. In addition, the provider should be able to offer information about cultural competency in clinical trials. For example, is the informed consent language for a specific clinical trial written in the patient's native language? Are there any providers who can communicate in the patient's language?

References

1. Branson BM, Handsfield HH, Lampe MA, et al. U.S. Centers for Disease Control and Prevention. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006 Sep 22;55(RR-14):1-17.
2. Ridley CR. Imperatives for ethnic and cultural relevance in psychology training programs. Prof Psychol Res Pr. 1985;16(5):611-622.
3. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Smedley BD, Stith AY, Nelson AR, eds. Washington: National Academies Press; 2003.
4. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. July 29, 2008. 1-134.
5. Ryan C, Futterman D. Lesbian and Gay Youth. New York: Columbia University Press; 1998.
6. Machtinger EL, Bangsberg DR. Adherence to HIV Antiretroviral Therapy. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF Center for HIV Information; May 2005.
7. Chesney MA. The elusive gold standard. Future perspectives for HIV adherence assessment and intervention. J Acquir Immune Defic Syndr. 2006 Dec 1;43 Suppl 1:S149-55.
8. Meichenbaum D, Turk DC. Facilitating treatment adherence: A practitioner's guidebook. New York, NY: Plenum Press. 1987.
9. Viani RM, Peralta L, Aldrovandi G, et al. Adolescent Medicine Trials Network for HIV/AIDS Interventions. Prevalence of primary HIV-1 drug resistance among recently infected adolescents: a multicenter adolescent medicine trials network for HIV/AIDS interventions study. J Infect Dis. 2006 Dec 1;194(11):1505-9.
10. Murphy, DA, Durako SJ, Moscicki AB, et al. Adolescent Medicine HIV/AIDS Research Network. No change in health risk behaviors over time among HIV infected adolescents in care: role of psychological distress. J Adolesc Health. 2001 Sep;29(3 Suppl):57-63.
11. Personal communication with Bret J. Rudy, MD, Associate Division Chief, Craig Dalsimer Division of Adolescent Medicine, Children's Hospital of Philadelphia.
12. Sbarbaro JA. The patient-physician relationship: compliance revisited. Ann Allergy. 1990 Apr;64(4):325-31.
13. Murphy DA, Wilson CM, Durako SJ, et al. Adolescent Medicine HIV/AIDS Research Network. Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA. AIDS Care. 2001 Feb;13(1):27-40.
14. Rogers AS, Miller S, Murphy DA, et al. TREAT Project Team. The TREAT (Therapeutic Regimens Enhancing Adherence in Teens) program: theory and preliminary results. J Adolesc Health. 2001 Sep;29(3 Suppl):30-8.
15. Hawkins T. Appearance-related side effects of HIV-1 treatment. AIDS Patient Care and STDs; 2006;20:6-18.

ARV Treatment and Adherence: Resources

For Providers

Adherence

• Adherence to Antiretroviral Therapy. In Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. November 3, 2008; 92-94.
• Adherence and HIV/AIDS. HRSA CARE ACTION. May 2005.
• Adherence to Antiretroviral Therapy for Children, Youth and Families. Gross, E. François-Xavier Bagnoud Center of the University of Medicine and Dentistry of New Jersey. 2004. This self-study module outlines issues pertinent to adherence to antiretroviral therapy (ART) in children and youth, and suggests intervention strategies that may be of help in supporting children, youth and families.
• Adherence to HIV Treatment Regimens: Recommendations for Best Practices. Jani, AA, Ed. American Public Health Association. June 2004.

Clinical Management

• Adolescent HIV Care Protocol From: Ryan C, Futterman D. Lesbian and Gay Youth. New York: Columbia University Press; 1998. [Table 14.3].
• Clinical Manual for Management of the HIV-Infected Adult, 2006 Edition. Coffey S, ed. AIDS Education & Training Centers; 2006.
• Treatments for HIV & AIDS (Available in English and Spanish).
• Database of Antiretroviral Drug Interactions. HIV InSite website. Interactive database.
• Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Panel on Antiretroviral Guidelines for Adult and Adolescents. Department of Health and Human Services. November 3, 2008; 1-113.
• Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. July 29, 2008; 1-134.
• HIV Classification: CDC and WHO Staging Systems. In: Clinical Manual for Management of the HIV-Infected Adult. Coffey, S, Ed. 2006.
• Medication Teaching Guide. Northwest AIDS Education and Training Center. March 2008.

Clinical Trials

• Adolescent Trials Network for HIV/AIDS Interventions. Federally funded research network. Site includes resources and publications.
• AIDS Clinical Trials Information Service (ACTIS). Federal portal for HIV/AIDS information, including a clinical trials database.
• ClinicalTrials.Gov Resources. Fact sheets about clinical trial participation from federal clearninghouse.

For Patients

• Adherence. Margolese S. The Well Project. July 2003. Article from website by and for HIV-infected women.
• Adherence Strategies That Can Work for You. Cichocki M. About.com HIV/AIDS Guide.
  • General Adherence Information. About.com resource listing.
• Adhering To My HIV Treatment Regimen. Fact sheet providing practical tips for adhering to HIV treatment regimens. AIDSInfo.nih.gov. Also available in Spanish.
• AIDS InfoNet. HIV treatment, medication, and disease fact sheets. Material written to be easy to understand, and all fact sheets are available in English and Spanish.
• e-pill. Online store selling products to improve adherence (pill boxes, alarms).
• HIV and Its Treatment: What You Should Know. Fact sheet series with an overview of HIV infection and treatment beneficial for individuals recently diagnosed with HIV infection or who are considering starting HIV treatment. Includes information on testing, medications, treatment adherence, pregnancy, and prevention. From aidsinfo.nih.gov. Also available en español.
• Making MEDS Work for You. Lerner-Weiss N, Burr C. François-Xavier Bagnoud Center, University of Medicine and Dentistry of New Jersey. Booklet for young people with HIV infection who have decided to begin antiretroviral therapy. Written with the ongoing input of an advisory group of experts in HIV care and young people living with HIV, the booklet discusses how antiretroviral medicines work in the body and makes suggestions about successfully managing medication schedules. 2005.