Chapter V
Adherence To HIV Therapies

Laura W. Cheever, MD

I. Introduction  TOP

Adherence to HIV therapies is critical if patients are to achieve and maintain undetectable viral loads and avoid preventable opportunistic infections. Initial clinical trials of highly active antiretroviral therapy (HAART) demonstrated that 80–90% of patients receiving protease inhibitor therapy could achieve viral loads <400 copies/mL (Gulick, 1997). However, currently in real-world clinical practice only 50% of patients achieve this goal (Lucas, 1999). The primary reason is nonadherence with therapy. Adherence with medications in any chronic disease is a challenge for most patients. As a general rule, only 50% of patients with chronic illnesses maintain “good adherence” (taking >80% of medication doses) over time. Patients with HIV infection have similar rates of adherence. Unfortunately in this infection, “good adherence” is not good enough, and the consequences of nonadherence are severe. Nonadherence with antiretroviral therapy is strongly associated with HIV disease progression and mortality (Hoggs, 2002).

This chapter addresses the important issues regarding adherence with HIV medications. Beyond this specific issue, there are other aspects of adherence with medical care, including adherence with recommendations for laboratory monitoring for toxicity and clinical response and adherence with appointment keeping, that are also critical factors in successful HIV treatment.

II. The Unforgiving Nature of HIV and the Medications to Treat It  TOP

Adherence with medications is critical in HIV infections for several reasons involving both the nature of the virus and the drugs to combat it. First, the virus has a very high replication and mutation rate. If drug doses are intermittently missed, the virus quickly begins to replicate. In the presence of low levels of drug, viral mutations that confer drug resistance will thrive. Second, the most potent drugs, both protease inhibitors and nonnucleoside reverse transcriptase inhibitors, have broad class resistance. That is, when resistance to one drug in the class occurs, often resistance has developed to many other drugs in that class. Thus, nonadherence to one regimen can result in virus resistant to many antiretrovirals.

Finally, a patient needs to have near-perfect adherence, as shown in Figure 5-1, to achieve the undetectable viral load necessary to prevent the development of resistant virus (Paterson, 2000). For most chronic diseases, 80% adherence is considered “good adherence.” However, only 49% of patients achieved undetectable viral load with this level of adherence.

Figure 5-1; Adherence Rates Predict Viral Load Responses

Source: Adapted from Paterson, 2000. Modified with permission from American College of Physicians.

Thus, in HIV infection, patients must have exceptionally high levels of adherence to therapy to prevent the emergence of resistant virus. Additionally, unlike other chronic diseases, such as hypertension, if HIV-infected patients are nonadherent, even for a few weeks, they may severely limit their future treatment options because of broad class resistance.

III. Predictors of Adherence  TOP

Adherence is a complex behavior. In analyzing predictors of adherence, it is important to consider factors related to the patient, the treatment regimen, the doctor-patient relationship, and the system of medical care. Several patient-related factors are consistently predictive of adherence or nonadherence among HIV-infected individuals. Depression and active substance abuse (including alcohol, cocaine, or heroin) correlate with nonadherence, whereas the patient’s belief that they can both make HIV medication regimens fit into their life and be adherent with the regimen is predictive of adherence (Table 5-1, Cheever, 1999). In addition, one of the best predictors of adherence is adherence with previous therapy.

In most chronic diseases, demographic characteristics, such as sex, race, income, education, and age, are not predictive of adherence (Haynes, 1979). However, in the initial studies of these factors of HIV-infected patients, the data are inconclusive. In the HIV Cost and Services Utilization Study, a national probability sample survey, the investigators found that women, African Americans, Hispanics, younger adults, and patients with higher CD4 counts reported lower rates of adherence (Wenger, 1999). Other studies report conflicting results, and the relationship between these demographic variables and adherence needs further exploration.

In terms of the treatment regimen, side effects are a major cause of nonadherence (Heath, 2002). Adherence decreases as the number of doses per day, pills, or medications increase. Likewise, medications with food restrictions are harder to take as directed. Length of time on therapy also impacts medication adherence. Adherence tends to wane over time, which is a compelling reason to delay therapy until the risk of progression to AIDS is significant. Pharmacy and social work counseling of patients whenever HAART is initiated or the regimen is changed can be helpful in ensuring that patients understand dosing and side effects and can assist in developing strategies to avoid missing doses.

The doctor-patient relationship is also an important variable in adherence and should not be overlooked. Several studies have shown that patients who trust their doctor are more likely to adhere to therapy, including studies among HIV-infected patients (Altice, 2001). Most medical providers believe that they can predict which patient will be able to adhere to a medical regimen. However, studies have repeatedly shown that physicians, nurse practitioners, and nurses cannot predict with reliability which patients will adhere to therapy (Paterson, 2000). Table 5-2 lists the most common reason patients say they miss their medication (Chesney, 1997; Eldred, 1998). These reasons vary significantly from the reasons that providers cite as reasons their patients miss doses (Gallant, 1998).

The system of care can affect adherence to a medication regimen. Situations that facilitate patients’ access to medication, in terms of refill requests, reminders to refill medication, and mechanisms to obtain medications when gaps in medication insurance occur, can significantly affect a patient’s ability to adhere. Similarly, systems that help patients overcome barriers to seeking medical care, including problems with transportation, childcare, and paying for services, also assist in the patient’s adherence efforts. Finally, patient education is a critical part of improving adherence. Within the system of care, personnel and resources need to be dedicated to this important endeavor.

IV. Adherence in Special Populations  TOP

A. INCARCERATED PATIENTS

Incarcerated patients have unique challenges to medication adherence. Medical regulations vary significantly among correctional systems, and these regulations influence patients’ medication adherence. Correctional institutions may provide directly observed therapy of each dose of medication, which may result in excellent medication adherence. On the other hand, lockdowns and other security concerns supercede medical concerns and may result in missed doses. In correctional systems where HIV-infected inmates are identified and called by name to receive medications, many patients forego treatment rather than risk disclosure of their HIV infection. Additionally, the incarceration process itself provides many opportunities for potential disruption in access to medications. Most patients do not immediately access their antiretroviral medication on entry to the system or at times of transfer within the system. When patients are discharged from the penal system, they are provided with a limited supply of medication; often patients run out of medication before they can establish medical care in their communities, resulting in nonadherence with their regimen.

B. HOMELESS PATIENTS

It is often assumed that homeless patients face insurmountable barriers to adherence with medications. Certainly, homelessness itself creates many challenges to adherence. Additionally, many homeless patients have mental illness or substance abuse that may further contribute to nonadherence. However, homeless patients can be successful in taking HAART. In a study of homeless and marginally housed patients from San Francisco, 38% of the 32 homeless patients taking protease inhibitors had high levels of adherence (Bangsberg, 2000). However, the group appears to be highly selected since only 34 of 153 patients in this marginally housed cohort were prescribed HAART.

C. CHILDREN AND ADOLESCENTS

Young children are dependent on the adults around them for their medication adherence. As with many HIV-infected adults, HIV-infected children may be in tenuous social situations due to poverty and unstable housing, in addition to illness among their parents. Many children are unable or unwilling to swallow unpalatable medication or pills, making dosing administration take hours each day. In one study, gastric tubes were placed in children who had extreme problems with taking medication. These children subsequently showed improvement in adherence, viral load, time necessary to administer doses, and interpersonal relationships with the persons administering the medication (Shingadia, 2000). Adolescents who have not disclosed their HIV status may miss doses because of lack of a private place to take their medication. Furthermore, adolescence is a time of testing limits and feelings of invulnerability, both of which may contribute to the likelihood of nonadherence.

V. Measuring Adherence  TOP

There are many methods to measure adherence including electronic devices, pill counts, and drug assays. However, in clinical practice, the most efficient method to measure adherence is simply to ask the patient (Icovicks, 1997). It is critical to ask over time as patients’ adherence will vary, for example, in response to re-initiation of substance abuse.

When asked in a nonjudgmental way, most patients (80% in several studies) are truthful about their medication taking (Sackett, 1976). To get the most reliable information, patients should be given permission to have missed doses, asked in a nonjudgmental way, and given a specific time frame. For example, “Everyone misses doses some of the time. In the last 2 weeks, how many doses have you missed?”

Computer assisted self-interviewing (CASI) technology is increasingly used to assess adherence and improves the reliability of patient self report (Turner, 1998, Bangsberg, 2002). The technology is also used to simultaneously collect information on side effects and high risk behaviors that might be missed in a less structured format of a patient-clinician interaction.

Pharmacy records can also give important information regarding adherence when available to the clinical staff. Serum drug level tests are now commercially available. These are most useful when patients professing adherence are not responding well to therapy; however, low drug levels may also be due to poor absorption or drug-drug interactions as well as to nonadherence.

VI. Improving Adherence  TOP

Given the importance of adherence in HIV infection and the relatively low rates of adherence in any chronic disease, it is of utmost importance to support efforts to increase patient adherence. Many interventions have been shown to increase adherence with pill taking in chronic disease. However, most interventions only have a modest effect on adherence. Those that work best are multifaceted (working on more than one aspect of the pill taking behavior) and repetitive (having the intervention reapplied over time) (McDonald 2002, Roter, 1998). With antiretroviral medication, it is critical to start the intervention before nonadherence, and viral resistance, have occurred.

In initiating a successful regimen, the most important thing to consider is whether the patient is ready to start antiretroviral therapy. The patient is usually the best judge of when to start therapy as long as she is well informed regarding the rigors of antiretroviral therapy and the consequences of nonadherence. Thus, the bulk of patient education efforts should be made before initiation of therapy. Given that the patient’s “first shot [of antiretrovirals] is the best shot,” most patients benefit in the long run by delaying therapy if they are not ready to start. The urgency of therapy increases as the CD4 count falls and the viral load increases. Many physicians feel pressured by practice guidelines for starting therapy. The best time to start therapy is when the patient is ready.

There are, however, a few “antiretroviral emergencies,” pregnancy being one of them. Clearly, for the pregnant woman, the cost benefit considerations are different, as outlined in Chapter VII on HIV and Reproduction. In the case of pregnant women, the time permitted for the patient to prepare to start therapy may be considerably compressed. Thus, even more intensive educational efforts are needed in this population.

Patient education is clearly important, with high returns on the investment made before starting therapy. Group education generally works better than one-on-one education, probably because of the support and practical peer advice that is shared (Roter, 1998). Many patients resist groups, but many find them beneficial if they can be convinced to go. Specific interventions to improve adherence are outlined in Table 5-3.

Many intervention trials in HIV infection are on-going or completed. The Health Resources and Services Administration funded the evaluation of 14 U.S. based adherence programs. For antiretroviral naïve patients, programs that included readiness training, that is spending time with the patient before the initiation of therapy to prepare them to start, were most effective. For both naïve and experienced patients, programs that included peer support, whether in one-on-one or group sessions, were also highly effective.

VII. Conclusions  TOP

Adherence with medications is critical in HIV infection. Whenever medications are prescribed, special emphasis must be placed on patient readiness and adherence. Many types of interventions can improve adherence, and it is vital that these are employed to give patients the best chance at an optimal response to HIV therapies.

VIII. References  TOP

Altice FL, Mostashari F, Friedland GH. Trust and the acceptance of and adherence to antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;28:47–58.

Bangsberg DR, Bronstone A, Hofmann R. A computer-based assessment detects regimen misunderstandings and nonadherence for patients on HIV antiretroviral therapy. AIDS Care. 2002;14:3–15.

Bangsberg DR, Hecht FM, Charlebois ED, et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS. 2000;14:357–366.

Cheever LW, Wu AW. Medication adherence among HIV infected patients: understanding the complex behavior of taking this complex therapy. Curr Infect Dis Rep. 1999;1:401–407.

Chesney MA. New antiretroviral therapies: adherence challenges and strate-gies. Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada. Evolving HIV Treatments: Advances and the Challenge of Adherence Symposium, 1997.

Eldred LJ, Wu AW, Chaisson RE, et al. Adherence to antiretroviral and pneu-mocystis prophylaxis in HIV disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:117–125.

Gallant JE, Block DS. Adherence to antiretroviral regimens in HIV-infected patients: results of a survey among physicians and patients. J Int Assoc Physicians AIDS Care. 1998;4:32–35.

Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovu-dine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337:734–739.

Haynes RB. Determinants of compliance: the disease and the mechanics of treatment. In: Haynes RB, Sackett DL, eds Compliance in Health Care. Baltimore: Johns Hopkins University Press; 1979:49–62.

Heath KV, Dinger J, O’Shaughnessy MV, Montaner JS, Hogg RS. Intentional nonadherence due to adverse symptoms associated with antiretroviral therapy. J Acquir Immune Defic Syndr. 2002;31:211–217.

Hogg RS, Heath K, Bangsberg D, et al. Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS. 2002;16:1051–1059.

Icovicks J. Behavioral measures. Adherence to New HIV Therapies: a Research Conference. Washington, DC, NIH Office of AIDS Research, 15–18, 1997.

Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions Ann Intern Med. 1999;131:81–87.

McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adher-ence to medication prescriptions: scientific review. JAMA. 2002;288:2868–2879.

Paterson DL, Swindels S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21–30.

Roter DL, Hall JA, Merisca R, et al. Effectiveness of interventions to improve patient compliance: a meta-analysis. Med Care. 1998;36:1138–1161.

Sackett DL, Haynes RB, Gibson ES, et al. Randomized clinical trial of strate-gies for improving medication compliance in primary hypertension. Lancet. 1976;1:1265–1268.

Shingadia D, Viani RM, Yogev R, et al. Gastrostomy tube insertion for improvement of adherence to highly active antiretroviral therapy in pediatric patients with human immunodeficiency virus. Pediatrics. 2000;105:E80.

Turner CF, KU L, Rogers SM, Lindberg LD, Pleck JH, Sonenstein FL. Adoles-cent sexual behavior, drug use, and violence: increased reporting with computer survey technology. Science. 1998;280:867–873.

Wenger N, Gifford A, Liu H, et al. Patient characteristics and attitudes associated with antiretroviral (AR) adherence. Abstract 98: Program and Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago, IL.