3. Managing patients with HIV drug resistance can be incredibly challenging. The best way to deal with resistance is to prevent its development in the first place.

4. Some patients may have primary infection with drug-resistant virus. In such cases, patients need to be reassured that the presence of drug resistance is not their fault and that there is a good chance of successfully treating their infection given the wealth of potent agents to choose from in a variety of antiretroviral classes.

THE COST OF POOR ADHERENCE AND DRUG RESISTANCE

It is very clear that adherence to antiretroviral therapy is a key determinant of how well patients will respond to treatment. Indeed, a recent prospective study showed that patients with less than 95% adherence to antiretroviral therapy had a 2.80-fold higher risk of mortality (95% confidence interval [CI]: 2.27-3.46; P < .001) than patients with higher levels of adherence.[3] These findings stress the importance of deferring treatment initiation (unless urgently indicated) until a patient has been fully informed about the significance of strict adherence and has demonstrated both willingness and motivation to start treatment.

The human cost of using inactive HIV treatment, which can result from poor adherence and/or from the development of antiretroviral resistance, can be high for some patients. At the recent Conference on Retroviruses and Opportunistic Infections (CROI) in early 2008, Steven Deeks and colleagues presented data compiled before widespread availability of the newest antiretroviral classes (i.e., CCR5 antagonists and integrase inhibitors).[4] They showed that a lower CD4+ cell count, a higher viral load, and a history of AIDS at the time of failure on second-line therapy independently increased the risk of mortality:

• Compared with a CD4+ cell count above 200 cells/mm³, a CD4+ cell count of 50-200 cells/mm³ increased the risk of death by 81% (relative hazard [RH]: 1.81; 95% CI: 1.55-2.11; P < .001), while a CD4+ cell count less than 50 cells/mm³ more than quadrupled a patient’s risk of death (RH: 4.24; 95% CI: 3.54-5.09; P < .001).

• Compared with a viral load below 10,000 copies/mL, an HIV-1 RNA level of 10,000-100,000 copies/mL increased the risk of death by 25% (RH: 1.25; 95% CI: 1.07-1.47; P < .01), while a viral load above 100,000 copies/mL nearly doubled the risk of death (HR: 1.93; 95% CI: 1.61-2.31; P < .001).

• Having a clinical history of AIDS increased the risk of mortality by 29% (HR: 1.29; 95% CI: 1.13-1.48; P < .001).

Based on these findings, the study investigators urged clinicians to promptly address second virologic failure in patients, particularly those with the high-risk disease characteristics detailed above.

HEALTH LITERACY AND ADHERENCE

Educating patients about the value of adherence and the importance of avoiding drug resistance is more difficult than it may seem at first blush. A recent report from the Institute of Medicine revealed that 90 million people, or nearly half of all American adults, have difficulty obtaining, processing, and understanding basic health information in order to make informed and appropriate decisions about their health—a concept known as health literacy.[5] Prior studies have shown that HIV-infected individuals with low health literacy possess a poor working knowledge of their disease and its management.[6,7]

Although results are mixed, deficits in health literacy may have a direct impact on adherence among HIV-infected individuals. In a recently published observational study, HIV-infected patients with low heath literacy, defined as a reading level of health-related words at grade 6 or below, were 2.12 times (95% CI: 1.93-2.32) more likely to be nonadherent to their antiretroviral regimen than patients with adequate literacy.[8] These effects were seen independent of race. An earlier study also identified low literacy as a significant risk factor for poor adherence to antiretroviral therapy, increasing the risk 3.3-fold (95% CI: 1.3-8.7; P < .001).[9] However, this study demonstrated that the relationship between low health literacy and poor adherence was mediated by self-efficacy, which refers to an individual’s perceived ability to carry out a set of behaviors – in this case, behaviors related to the care of their disease. Individuals who perceived themselves as having low medication self-efficacy were 7.4 times (95% CI: 2.7-12.5) as likely to be poorly adherent to their medication compared with those with high perceived self-efficacy. These findings suggest that comprehensive interventions focusing on adherence that extend beyond simply providing knowledge may be needed to address self-efficacy among patients across all literacy levels.

In a large survey conducted by Timothy Hogan and Carole Palmer of a diverse nationwide sample of HIV-infected individuals, 35% of respondents reported that they were not provided with enough information on how to consistently take and adhere to their medications.[10] Hogan noted that these findings were consistent with those of other researchers who have determined that many HIV-infected individuals feel that they are not provided with adequate information about their antiretroviral medications and related side effects.[11] Hogan and others view adherence as an information-intensive activity and feel that arming patients with explicit information about the treatment experience may promote adherence.

Health literacy is not restricted to the individual patient; it is also influenced by the skills and expectations of healthcare providers.⁵ Debra L. Roter, DrPH, Professor of Medicine, Johns Hopkins Bloomberg School of Medicine, said it well: “If you can’t convey information in a conversational manner so that anybody can understand it, then you’re not doing a good job…That’s the objective that we have to move toward, to turn back the responsibility and the definition of doing a good job to one that includes plain speak and ordinary conversations in the delivery of medical care.”[12] Although simple tools and language can enable healthcare providers to communicate with patients about treatment adherence and HIV drug resistance in comfortable and familiar terms, the “plain speak” used will likely need to be adapted to each individual patient depending on their age, race, gender, sexual orientation, and other characteristics. Indeed, another facet of health literacy, aside from education, involves cultural and social factors that pertain to each individual.[5]

Clinicians today are under growing pressure to see patients ever more quickly and efficiently. Even though this pressure may pose a barrier to provider-patient communication, employing some sort of educational intervention makes sense to anyone who understands the importance of adherence in improving clinical outcomes in HIV-infected patients. Better patient outcomes justify allocating sufficient resources for such thorough provider-patient discussions and make education on the topics of resistance and adherence a high priority.

COMMUNICATING ABOUT DRUG RESISTANCE AND ADHERENCE

Limited health literacy may be a widespread barrier to the management of HIV infection, but this barrier is potentially modifiable. The development of communication strategies that span all literacy levels or that target low-literacy individuals at risk of poor treatment adherence has the potential to promote better adherence to therapy and reduce the risk for the development of drug resistance. Although framing the information in simplistic terms may not be entirely scientifically precise, easily understandable information—be it in the form of brochures, posters, pamphlets, illustrations, and so forth—has the potential to put HIV into context for patients and provide a base level of understanding.

Some examples from various sources of simple messages about HIV drug resistance written for patients at various reading levels include the following:

• “When drug resistance occurs, the drug—or combination of drugs—loses its ability to block the germ from reproducing. Over time, the treatment can stop working completely. It is important to prevent germs from reproducing during treatment to prevent drug resistance from occurring.”[13]

• “The basic HIV virus is called wild type. HIV drug resistance happens when the wild type HIV ‘changes’ enough to allow HIV to make copies of itself even though you are taking anti-HIV drugs.”[14]

• “Resistance tests are not available everywhere. They are expensive. However, they are becoming more common, faster, and cheaper. The tests aren’t good at detecting ‘minority’ mutations (less than 20% of the virus population). Also, they work better when the viral load is higher. If your viral load is very low, the tests might not work. Tests usually cannot be run if the patient’s viral load is less than 500 to 1,000 copies per mL.”[15]

• “Mutations are dangerous because they can build up and take away the power to control HIV from more and more drugs” (see Figure 1).[16]

As mentioned earlier, the best way to manage antiretroviral resistance is to prevent its development in the first place. To achieve this, healthcare providers need to discuss the potential consequences of nonadherence to patients initiating first-line therapy. Communicating this information to asymptomatic patients with early infection is particularly important, because many of these individuals may not yet be experiencing any untoward consequences of infection and may not yet fully appreciate the gravity of taking all their medications even when they feel well. Even though several recent studies have clearly demonstrated the benefits of initiating early treatment in patients (Figure 2),[17-19] engaging patients in discussions of adherence and drug resistance before treatment initiation can help clinicians decide whether patients are emotionally ready to make the commitment to therapy.

Patients who present to their physicians already infected with drug-resistant virus need to be reassured that the presence of drug resistance is not their fault. Moreover, it is important to make it clear that drug resistance is not an all-or-none phenomenon; various degrees and levels of resistance exist. The current availability of a large number of antiretrovirals in several different drug classes—availability that continues to grow —will enable providers and patients, in the vast majority of cases, to design a potent first-line regimen even if a patient harbors resistance to a particular drug or drug class. The information provided by resistance testing is essential to achieving this goal.

PROVIDER-PATIENT COLLABORATION TO PROMOTE ADHERENCE

Achieving treatment adherence and avoiding the development of antiretroviral resistance should be viewed as a collaborative effort between patients and providers. There are several potential pitfalls that can undermine a patient’s best intentions to take their therapy, including problems related to the complexity of the regimen, side effects, mental health, and illicit drug use. By identifying these and other problems early on and addressing them accordingly, physicians can assist patients in achieving treatment success. To facilitate this process, providers should encourage patients to be communicative and to act as co-managers of their care.

A recent qualitative study conducted focus groups with HIV-infected individuals to identify which factors they felt influenced their ability to adhere to antiretroviral therapy.[20] The most influential factor affecting treatment adherence was regimen effectiveness, followed closely by pill burden (Figure 3). It is important for clinicians to bear this latter factor in mind when designing an antiretroviral regimen for patients, because they may have some flexibility in minimizing the number of pills that must be taken per day and/or in simplifying the food/fasting requirements of the overall regimen. Table 1 provides a brief summary of food/fasting requirements of currently approved antiretrovirals. The third most influential factor affecting treatment adherence that was identified in the qualitative study was the occurrence of side effects. Minimal side effects positively influenced adherence, whereas certain detrimental side effects negatively influenced adherence. Patients reported that the most detrimental side effects influencing their adherence included neuropathy, lipodystrophy, diarrhea, and nausea.

It should be noted that this is just one of numerous studies assessing patients’ perceived barriers to treatment adherence. Other large, well-conducted studies have attained a different ranking of factors—for example, with side effects being more important and pill count less so with regard to their effects on adherence. These differences emphasize the variability in perceived barriers for any given patient and stress the need for good provider-patient communication to identify those factors that are of greatest concern to each individual patient.

A team from Kaiser Permanente analyzed data from almost 3400 HIV-infected patients nationwide who initiated treatment with a new regimen between 2000 and 2003 to determine the effect of mental health on adherence to treatment and disease progression.[21] The investigators found that almost half of the study participants (42%) had depression during the 12-month period of analysis. Individuals with untreated depression were less likely to take their HIV medications (odds ratio of ³ 90% adherence: 0.81; 95% CI: 0.70-0.98; P = .03) and had a worse virologic response to treatment (odds ratio of HIV-1 RNA < 500 copies/mL: 0.77; 95% CI: 0.62-0.95; P = .02) compared with patients who were not depressed. However, when depressed patients took prescribed antidepressants (selective serotonin reuptake inhibitors), they had the same health outcomes as patients who were not depressed. The simple message delivered by lead author Michael A. Horberg, MD, Director of HIV/AIDS for Kaiser Permanente, was that “HIV and depression often go hand in hand. If you are HIV-infected, you should be screened regularly for depression, and if you are depressed, and you are going to go on HAART, it’s very worthwhile to treat your depression.”

Past or current illicit drug use among HIV-infected individuals is common, and studies have shown that this factor can influence HIV treatment outcomes. For example, one study reported that current methamphetamine use increased viral load by decreasing the effectiveness of antiretroviral therapy, whereas past amphetamine use had no effect on the effectiveness of therapy at suppressing viral load.[22] In a broader study, an analysis of cross-sectional data from roughly 1200 HIV-infected individuals and 300 HIV-uninfected controls in the United States found that 86% of HIV-infected individuals had ever used drugs compared with 67% of controls (P < .0001), and 28% of HIV-infected individuals reported current drug use compared with 18% of controls (P = .0001).[23] Treatment effects according to the type of drug used were varied. Whereas current and past cocaine use and current heroin use were associated with a lower probability of undetectable viral load (odds ratios: 0.43, 0.65, and 0.19, respectively), past heroin use appeared to have no effect on viral load (odds ratio: 1.12) and past amphetamine use was actually associated with a higher likelihood of undetectable viral load (odds ratio: 1.86). The investigators of this study stressed that understanding a patient’s specific drug-use history is important for optimal patient management given the differential effects of various drugs and their timing of use on HIV treatment outcomes.

SUMMARY: KEY POINTS

• Avoiding the development of antiretroviral resistance is a key factor in the success of HIV treatment.

• It is essential that both providers and patients understand the importance of resistance, resistance testing, and proper treatment adherence.

• Treatment adherence can be influenced by patient-related variables (e.g., social and cultural beliefs, substance use, mental health), provider-related variables (e.g., provision of adherence counseling, management of toxicity), and regimen-related variables (e.g., adverse events, pill burden, dosing frequency, dosing restrictions).

• Health professionals are obligated to educate HIV-infected patients in their care about antiretroviral resistance and adherence; this is not an optional task.

• Patients who understand the importance of avoiding drug resistance will likely be motivated to properly adhere to therapy and engage in conversations with their healthcare providers on issues pertaining to their care (e.g., regarding the choice of antiretroviral regimens).

• There are many sources of information about adherence and drug resistance, including physicians, other members of the healthcare team, printed materials, and web sites, among others.

References

1.      US Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1. Accessed February 24, 2008.

2.      Gallant JE. Strategies for long-term success in the treatment of HIV infection. JAMA. 2000;283(10):1329-1334.

3.      Wood E, Hogg RS, Yip B, Moore D, Harrigan PR, Montaner JS. Impact of baseline viral load and adherence on survival of HIV-infected adults with baseline CD4 cell counts > or = 200 cells/microl. AIDS. 2006;20(8):1117-1123.

4.      Deeks S, North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the IeDEA. Trends in second virologic failure and predictors of subsequent mortality among ART-experienced patients: North American experience. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 41.

5.      Institute of Medicine. Health Literacy: A Prescription to End Confusion. Washington, DC: National Academies Press, 2004.

6.      Kalichman SC, Benotsch E, Suarez T, Catz S, Miller J, Rompa D. Health literacy and health-related knowledge among persons living with HIV/AIDS. Am J Prev Med. 2000;18(4):325-331.

7.      Wolf MS, Davis TC, Arozullah A, et al. Relation between literacy and HIV treatment knowledge among patients on HAART regimens. AIDS Care. 2005;17(7):863-873.

8.      Osborn CY, Paasche-Orlow MK, Davis TC, Wolf MS. Health literacy: an overlooked factor in understanding HIV health disparities. Am J Prev Med. 2007;33(5):374-378.

9.      Wolf MS, Davis TC, Osborn CY, Skripkauskas S, Bennett CL, Makoul G. Literacy, self-efficacy, and HIV medication adherence. Patient Educ Couns. 2007;65(2):253-260.

10.  Hogan TP, Palmer CL. Information preferences and practices among people living with HIV/AIDS: results from a nationwide survey. J Med Libr Assoc. 2005;93(4):431-439.

11.  Reynolds NR. The problem of antiretroviral adherence: a self-regulatory model for intervention. AIDS Care. 2003;15(1):117-124.

12.  Easley Allen C, Kindig DA, Parker RM, Roter DL. Assuring Quality Care for People With Limited Health Literacy. Available at: www.medscape.com/viewarticle/569200. Accessed February 24, 2008.

13.  AIDS Community Research Initiative of America. HIV Drug Resistance and Resistance Testing. Available at: http://www.acria.org/treatment/treatment_edu_drug_resist.html. Accessed February 24, 2008.

14.  Visionary Health Concepts. Are You Experienced? HIV and You. Available at: http://www.freehivinfo.com/pdfs/AYE_2008_Update.pdf.  Accessed February 24, 2008.

15.  AIDS InfoNet. Fact Sheet Number 126: HIV Resistance Testing. Available at: http://www.aidsinfonet.org/factsheets/en/pdfs/126.pdf.  Accessed February 24, 2008.

16.  Visionary Health Concepts. Blocking the Mutant Invasion. Available at: www.freehivinfo.com/pdfs/BTMI_English_2007.pdf. Accessed February 24, 2008.

17.  Jaén A, Esteve A, Miró JM, et al. Determinants of HIV progression and assessment of the optimal time to initiate highly active antiretroviral therapy: PISCIS Cohort (Spain). J Acquir Immune Defic Syndr. 2008;47(2):212-220.

18.  Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44(3):441-446.

19.  Marin B, Thiébaut R, Rondeau V, et al. Association between CD4 and HIV RNA with non AIDS-related causes of death in the era of combination antiretroviral therapy (cART). Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB019.

20.  Beusterien KM, Davis EA, Flood R, Howard K, Jordan J. HIV patient insight on adhering to medication: a qualitative analysis. AIDS Care. 2008;20(2):251-259.

21.  Horberg MA, Silverberg MJ, Hurley LB, et al. Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients. J Acquir Immune Defic Syndr. 2007;

22.  Ellis RJ, Childers ME, Cherner M, et al. Increased human immunodeficiency virus loads in active methamphetamine users are explained by reduced effectiveness of antiretroviral therapy. J Infect Dis. 2003;188:1820-1826.

23.  Cofrancesco J Jr, Scherzer R, Tien PC, et al. Illicit drug use and HIV treatment outcomes in a US cohort. AIDS. 2008;22(3):357-365.