Competing priorities: ART adherence presents the health care community with a spectrum of challenges

A diverse array of issues, some of which are contradictory, surrounds the study of adherence to antiretroviral therapy among patients with HIV/AIDS.

Patients in resource-limited settings in sub-Saharan Africa, who may face a battle with structural barriers preventing them from accessing care, often have near perfect adherence rates, according to several experts. In contrast, a higher percentage of patients in resource-rich Western countries struggle to take doses.

Steven Johnson, MD, professor of medicine in the division of infectious diseases at the school of medicine at the University of Colorado in Denver, said although an increasing number of patients with HIV now have access to ART, adherence is an issue.

“A report from UNAIDS estimated that 42% of the 9.5 million patients with HIV in low- and middle-income countries had access to antiretroviral therapy in 2008,” Johnson told Infectious Disease News. “Since access to therapy is still not universal and the prevalence of HIV infection in many of these countries is high, mortality from untreated HIV infection is still quite common. So, apart from cultural differences in the approach to medications, people living in low- and middle-income countries may simply be more motivated to adhere to therapy because the therapy is so scarce and the number of treatment options are fewer.”

Contrary to many people’s expectations, research continues to demonstrate that populations in sub-Saharan Africa have higher rates of ART adherence than many resource-rich Western countries.

Social capital

Elizabeth Connick, MD, associate professor of medicine at the University of Colorado in Denver, director of the University of Colorado Center for AIDS and member of the Infectious Disease News Editorial Board, offered an explanation for this phenomenon. “In Africa, the perception is that these drugs are life savers,” she said. “They perceive the medicines as precious, a perception that has largely worn off in other parts of the world, where ART has been available for longer periods of time.”

A key to this notion is a concept known as social capital. Research by Norma Ware, PhD, associate professor in the department of psychiatry and the department of global health and social medicine at Harvard Medical School, has demonstrated social capital in action. Results of studies by Ware and colleagues showed that treatment partners, family members, friends and health care providers give assistance to patients in times of serious need.

Ware’s findings also stress the value of making expectations for adherence known to the patient. The patient is then effectively bound to fulfill the social responsibility of taking medications. Patients who continue to adhere to medications can then count on help from caretakers when needs arise in the future. This give-and-take system helps patients find ways of overcoming economic obstacles to treatment. Adherence becomes a priority. Patients in these circumstances may borrow or even beg for money for transportation to the clinic, make difficult choices to allocate resources for treatment and go without minor luxuries or even essential items, Ware said.

“The norms of social responsibility and reciprocity that help to explain the amount and quality of help people get with adherence are also core elements in African society and culture,” Ware told Infectious Disease News. “They enable people to survive in settings of poverty.”

David Bangsberg, MD, director of the Center for Global Health at Massachusetts General Hospital and Harvard Medical School, said social networks and social responsibility play an important role in adherence.

“There is a striking interdependent social network in these communities which certainly contributes to the culture of social responsibility surrounding ART,” Bangsberg told Infectious Disease News

. “But beyond that, bedbound people draw valuable resources, including time and energy spent by members of the community. Those members of the community want bedbound people to get better. One sick person makes the whole community weak.”

Bangsberg said that this simple process of taking turns drives the culture of adherence. “Once you get strong, you give back,” he said.

Moving west

Mills and colleagues conducted a random-effects meta-analysis of studies conducted among mixed populations in North America and Africa. Thirty-one studies involving 17,573 patients from North America and 27 studies involving 12,116 patients from 12 African countries were examined.

Pooled analysis indicated a pooled estimate of 55% of populations in North America achieved adequate levels of adherence, compared with adequate adherence levels met by 77% of the populations in the African countries studied.

Connick discussed a few possible explanations for this dichotomy. “The perception that ART is precious is less prevalent in the United States largely because potent ART has been widely available for more than 10 years,” she said. “Also, HIV/AIDS is no longer perceived as a death sentence in the United States, which contributes to unsafe sex and poor adherence levels. We need to figure out a way to foster that sense of the preciousness of ART in this country.”

Connick also expressed more fundamental concerns with American culture. “There is a broader problem with our health care system and the way we perceive illness,” she said. “Many have that attitude that, ‘it does not matter if I get sick, just give me a pill.’ This undermines the prevention message.”

Mental health in the United States

Edward M. Gardner, MD, assistant professor of medicine in the division of infectious diseases at the University of Colorado in Denver, said mental health issues often have an effect on a patient’s adherence to medication regimens. Gardner cited findings from a study conducted by Horberg and colleagues, which indicated that depression may significantly decrease ART adherence and HIV viral control. Those findings also indicate that depressed patients with HIV who are compliant with selective serotonin reuptake inhibitors may be more likely to adhere to ART and have improved viral outcomes.

Patients with depression who were not being treated with antidepressants had significantly decreased odds of achieving ≥90% adherence to ART. Patients who had compliance rates of 80% to depression medications had rates of ART adherence and viral control that were statistically similar to patients with HIV who were taking ART but who were not depressed.

“Depressed people often focus on depression,” Gardner said. “ART adherence becomes secondary, if that. This creates a whole set of competing priorities in their lives that is extremely challenging.”

Gardner said that adherence to medications for chronic illness is a learned behavior, and that it is not something people know how to do instinctively. “Because of the competition for focus, depression impacts the way people learn how to take medications every day,” he said.

Some experts said that it may be necessary to treat depression before beginning ART. Many researchers also said the same strategy could be effective for another mental health disorder affecting a significant proportion of patients with HIV/AIDS in the United States — substance abuse.

Substance abuse

Mellins and colleagues examined the rates of ART adherence among 1,138 patients with HIV who had been diagnosed with psychiatric and substance abuse disorders.

Results indicated that among the 62% of the patients who had been prescribed ART at baseline, 45% reported skipping medications in the last three days.

The researchers observed associations between non-adherence and a detectable viral load (P<.01).

Current drug and alcohol abuse, increased psychological distress, less attendance at medical appointments, non-adherence to psychological medications and lower rates of self-reported spirituality were associated with non-adherence to ART.

“Substance abuse also creates competition for the time and attention of the individual,” Gardner said. “Controlled substances may impact thoughts, priorities and decision-making capacities of people who use them. This reduces your ability to organize your life.”

Gardner said that the combination of substance abuse and a disorganized life lead to other contributing factors to the epidemic, such as homelessness and incarceration. “These factors and situations are the hallmarks of an unstructured life, and ART adherence depends greatly on structure,” he said.

Injection drug use

Gardner said that data demonstrate that people who handle addiction improve adherence. Substance abuse treatment provides the opportunity to get people with HIV into a more structured life. Given that injection drug use can lead to primary transmission of the infection and a host of competing priorities, programs to treat injection drug users are essential to curbing the epidemic and maintaining ART adherence.

“Methadone clinics can be a great site for administering ART,” he said. “In that setting, we can actually watch patients swallow doses.”

In 2005, WHO added methadone and buprenorphine to the WHO Model List of Essential Medicines for opioid addiction treatment. However, in Eastern Europe and many parts of Asia, where HIV/AIDS is largely driven by injection drug use, opioid substitution programs remain limited or non-existent.

WHO data indicate that limited inroads to substitution programs have been made in Belarus, Ukraine, Lithuania, Kyrgyzstan, Georgia and Uzbekistan, but that such programs have yet to enroll patients. Opioid substitution therapy remains illegal in the Russian Federation.

Although China has instituted a number of clinics to treat injection drug users, such clinics have barely opened in the Indian subcontinent, and methadone and buprenorphine remain illegal in Malaysia.

Roux and colleagues evaluated whether receiving take-home methadone and buprenorphine could lead to better ART adherence. Data for 276 patients in France were collected from out-patient hospital visits. The results indicated that patients who reported not using injection drugs or opioid substitutes had comparable levels of adherence to patients who ceased injection during opioid substitution treatment.

Compared with patients who abstained from drugs, patients who reported injecting opioid substitutes had a two fold risk for nonadherence, and patients who reported injecting other drugs had a three fold risk for non-adherence (P<.01 linear trend).

The researchers wrote that access to and effectiveness of opioid substitution programs could increase adherence levels in patients with HIV who are injection drug users.

Clinician perspective

Connick said that a challenging aspect of treating patients with a chronic condition is determining what will motivate them to adhere to medications. The language and attitude employed by the physician can influence whether the patient adheres or not.

“We see all kinds of patients, and while there are indicators of who may be adherent and who may not, it is impossible to make predictions,” Connick said. “Education and intelligence are not necessarily related to whether a person will adhere or not. As a physician, you have to be careful not to assume that patients who seem intelligent, or who have high levels of education and who understand a good bit of the science behind adherence, will take their medications.”

Johnson said that most patients in care understand the importance of adherence, even if they are seen only every three to six months. “These patients seem to manage their infection quite well,” he said. “However, a small subset of the patients in our clinic either does not understand the importance of adherence or have barriers that limit their ability to take medications.”

Connick said that it is the duty of the clinician to understand these barriers. “You need to deliver messages to your patients that will motivate them to adhere to their medications,” she said. “Each patient has a ‘hook,’ and it is up to us to find it.”

Connick added that different strategies work for different people. She said that some patients like having pill boxes, whereas others simply require periodic reminders. People who have low levels of education or intelligence may be put off by detailed scientific explanations of mechanisms underlying drug resistance, whereas some sophisticated patients may be compelled to adhere by such conversations. Some patients are responsive to praise because they care deeply what their physician thinks; other patients may not care. Some patients respond to more negative stimuli such as stories of the consequences of developing multidrug-resistant HIV as a result of poor adherence. Connick said underlying mental health and substance abuse issues may be present but may not be immediately evident upon initiation of treatment. “You cannot assume anything about your patients,” she said.

“The bottom line is we want our patients’ viral loads to be undetectable,” Connick said. “It is our obligation to do all we can to make a person healthy, and if that means sitting down and convincing the patient, by whatever means necessary, to take their medications, then we must do it.”

Delivering the message

Ware said that no matter what the setting, whether it is resource-rich or resource-limited, good results have been obtained through “simple, accurate messages.”

Bangsberg encouraged a return to the basic science of collecting evidence. “We need to find out more specifically why some people do not take their medications, why other people do well, and how this impacts the individuals and the epidemiology of the disease,” he said. “This, in turn, needs to inform our interventions.”

Ware said that such research can lead to programs that are in tune with the targeted populations. “Research and guidelines can help us understand what works, but we also have to give local populations the latitude to be creative with the interventions they implement,” she said.

Connick said clinics should develop interactive media for patients to view and work with while waiting to be seen. “None of us discuss it enough,” she said. “We need to find ways to get the message across using available technology whenever possible.”

Simoni and colleagues attempted to determine the effect of such interventions as peer support and pager messaging on adherence rates. The findings indicate that peer intervention was associated with greater levels of self-reported adherence immediately after intervention. However, follow-up results at six and nine months indicated that neither adherence levels nor positive biological outcomes were maintained.

Associations between pager intervention and sustained improved biological outcomes were observed. However, patients receiving pager messages did not have higher adherence rates. Despite these mixed results, most clinicians said technology remains an untapped resource that could improve ART adherence rates.

Gardner said a range of sources should deliver the message of adherence. “The message needs to come from a system of people influencing the patient,” he said. “It should get out at every level, from the health care partner, to the nurse, the provider, the pharmacist, the social worker, the psychiatrist. Repetition is critical.”

Ongoing challenges

Most experts said the biggest challenge associated with ART adherence is that patients with HIV will be required to take medications for the rest of their lives.

Gardner said that a culture of adherence must be maintained. “No matter how you look at it, adherence tends to decline over time,” he said. “Even the most adherent patients slow down. You cannot stop talking to patients about adherence six months into treatment because they are doing well.”

Despite this, evidence is beginning to grow that a rigorous drive for 100% adherence may not be necessary. Research conducted by Rosenblum and colleagues indicates that the risk of virologic failure for adherence greater than 50% declines as the duration of continuous suppression increases. The researchers wrote that high adherence is necessary to maximize the probability of lasting viral suppression, but that once suppression has been maintained for a prolonged period, the range of adherence capable of sustaining that suppression increases.

When the researchers compared the probability of virologic failure after one month with the probability of failure after 12 months of continuous suppression, the difference in risk was 0.47 at 50% to 74% adherence, 0.29 at 75% to 89% adherence and 0.36 at 90% to 100% adherence.

“The conventional thinking before was that the percentage of doses taken was most important,” Bangsberg said. “But now we are seeing evidence that patterns may also be important and not just percent and number of doses taken. The relationship between adherence and viral suppression changes over time.”

Johnson said that the science behind the development of resistance is sufficient motivation to maintain the message of adherence. “If the virus is not replicating, it cannot generate resistant mutants,” he said. “Different ART regimens vary based on propensity to lead to resistance based on their mechanism of action, potency, pharmacokinetics and side effect profile.”

In the end, though, challenges will remain.

“We are talking about decades of treatment,” Bangsberg said. “This is a marathon rather than a sprint.”–by Rob Volansky

What is the relationship between adherence to care and adherence to ART?

For more information:

• Horberg MA et al. J Acquir Immune Defic Syndr. 2008;47:384-398.
• Mellins CA et al. AIDS Care. 2009;2:168-177.
• Mills EJ et al. JAMA. 2006;296:679-688.
• Rosenblum M et al. Plos One. 2009;Vol 4, e7196:1-6.
• Roux P et al. Addiction. 2008;103:1828-1836.
• Simoni JM et al. J Acquir Immune Defic Syndr. 2009;52:499-506.
• Ware NC et al. Plos Med. 2009;Vol 6, e1000011:39-46.