Dr. Kalichman ranks among the leading experts on antiretroviral adherence and psychological aspects of HIV infection. Besides being Principal Investigator in Psychological Sciences at the University of Connecticut, he directs the Southeast HIV and AIDS Research and Evaluation (SHARE) Project in Atlanta and pursues HIV research in South Africa in collaboration with the Medical Research Council. The author of more than 300 peer-reviewed articles, Dr. Kalichman has also written and edited five books on HIV infection, most recently Denying AIDS: Conspiracy Theories, Pseudoscience, and Human Tragedy. He is current editor of the monthly journal AIDS and Behavior. Dr. Kalichman received the 2005 Distinguished Scientist Award from the Society of Behavioral Medicine.
Mark Mascolini: With widening use of tolerable once-daily regimens, has antiretroviral adherence become less of a problem?
Seth Kalichman: Yes, for most people adherence is certainly much easier than it used to be, primarily because of the simplicity of the drug regimens -- most people are taking only one or two pills a day -- and because toxicity is much less frequent. So certainly adherence is easier for most people.
Adherence used to be very difficult for almost everyone being treated with antiretrovirals. Then, as the medications improved, grew simpler, and became less toxic, more-resourced patients who have the capacity to adhere certainly began having an easier time. But there's a substantial patient population that continues to struggle with adherence, and we have to target this select group for added support.
Key Indicators in Assessing Need for Adherence Support
MM: How should clinicians determine whether a person otherwise ready for antiretroviral therapy will be adherent?
SK: That's a real challenge for many clinicians. Our view is that patients shouldn't be denied antiretroviral therapy because they may have adherence challenges. We believe the burden lies on the clinician to provide adherence support to all patients, depending on how much support they need.
To estimate how much support a patient needs, clinicians should look for key indicators of potential nonadherence. For example, depression is a very good indicator that a patient may have difficulty adhering and will require support. Any kind of substance use -- including and maybe especially alcohol use -- is another good indicator of adherence problems down the road. And indicators of poverty are a potential warning of poor adherence. So patients who have mental health or substance use problems or are living in poverty are people who are going to be facing the most adherence challenges and will often require adherence support.
Clinicians can try to assess patients' organizational skills or their ability to store and maintain their medications in an organized way and have a daily routine. Another indicator may be how well connected into care a patient is in the first place. But those factors may be less important than issues of mental health, substance use, and poverty. Those are the things clinicians should be looking for to see what kind of adherence support the patient is going to need.
MM: When antiretroviral-naive patients run a high risk of poor adherence because of problems like substance use, should clinicians defer antiretroviral therapy until they take steps to remedy the obstacles?
SK: That's a philosophy of clinical practice question that may not have a right or wrong answer. I believe there's a consensus emerging -- and it's certainly the view of our research team -- that antiretroviral therapy should not be deferred because of challenges to adherence until those challenges are resolved. There are interventions that can be done to support patients. And often patients with nonadherence risk factors turn out to be quite adherent. An awful lot of our study participants who actively use alcohol or drugs, or who are significantly depressed, nonetheless have good antiretroviral adherence.
It's not a one-to-one relationship. Those adherence predictors are just that -- they're just predictors, not determinants. Researchers often use those words interchangeably and that's a big mistake. Something that's a determinant is definite to happen. Something that's a predictor or a correlate raises the odds of it happening, but it isn't a perfect relationship.
Alcohol and drug use do not determine nonadherence, but they're pretty good predictors. They tell you that patients with substance use problems, for example, may require some adherence support. Of course we always want to move patients toward stopping substance use, but the predictor and the outcome are absolutely not a one-to-one relationship: patients with substance use problems can adhere and do adhere quite well. So we do not advocate deferring antiretroviral therapy for anyone unless they refuse therapy.
Gauging Adherence After Treatment Begins
MM: Once a person starts antiretroviral therapy, how should clinicians assess adherence?
SK: This is a significant issue. Clinicians I work with will often determine adherence based on viral load. When people have a suppressed viral load, you can pretty much assume that they're adhering to their medications. But when their viral load starts to creep up, that may indicate the patient is not adhering well and risks developing resistance. But by relying on viral load as the indicator of adherence, clinicians will intervene when it's too late. What you want to do is monitor adherence and make adjustments in adherence before the viral load begins rebounding and resistant virus emerges. So this is the challenge to clinicians -- detecting nonadherence early, before viral load starts creeping up.
Clinicians in tune with this thinking usually rely on patient self-report, and there are good, evidence-based self-report questions that clinicians can ask (Table 1).¹ But clinicians often aren't aware of validated self-report measures. And these validated self-report measures are good, but they're not great. Patients may not provide a valid self-report for a variety of reasons, such as saying what they think their clinicians want to hear. And often patients are simply unaware of their own nonadherence. What we're asking patients to do in self-reporting adherence is to remember something that they forgot or to report something that they're intentionally not doing.
So evaluating adherence in the treated patient remains a real challenge for clinicians. We've been working on trying to use pill counts done over the telephone with patients. The goal is to have patients count their pills and monitor their pill taking over the course of time. In our research we use that technique routinely. We've been trying to make that a clinical tool, but it isn't something clinicians are doing right now.
We also have to remember that patients face structural challenges to adherence. Specifically, AIDS Drug Assistance Program (ADAP) reauthorization is a huge challenge for some patients, simply because the case management system may not do those reauthorizations early enough. So some patients bump up against reauthorization deadlines and face a lapse in their antiretroviral therapy, which is a very bad thing.
Which Antiretroviral Adherence Interventions Work?
MM: Is there an antiretroviral adherence strategy that has proved both simple and effective and that clinicians can put into use with most patients?
SK: Sometimes a simple thing can make a huge difference. In our behavioral interventions, we routinely use pill organizers for patients. It's remarkable how few patients are trained in organizing their pills and maintaining their medications. Very carefully statistically controlled retrospective analyses show that just providing a patient with a cheap weekly pill box can improve adherence dramatically.²˒³
Sometimes clinicians will just give patients pill boxes, but very brief instructions on how the pill box can assist the patient can make a big difference. For example, patients who have adherence challenges may not only forget to take their medications, they may forget they did take them. They can double-dose on a day because they forgot they took the medication once. When that happens, their pills will run out before the end of their prescription. And of course double-dosing can increase toxicity. A pill box really remedies that problem because if you forget you took your medications, you can go back and look at the pill box and see that you actually did take them today. Pill box organizers are a very powerful tool that is actually quite simple.
In our interventions we don't just hand people pill boxes. We embed pill-box skills building in relatively brief phone calls that a case manager or adherence nurse can handle. Doing that provides a broader conversation about challenges that patients may be experiencing and then addresses those challenges one by one in a problem-solving way. We think our adherence counseling, delivered over the phone, is quite easy and simple. Counseling by phone reduces cost and gives adherence nurses, case managers, counselors, and sometimes peer advocates a tool that is easy to administer.
In the clinic itself, a clinician can assess adherence challenges and try to address them in a problem-solving way. To ask the right questions, clinicians can use validated tools to gauge adherence. Maybe the best set of questions out there is one developed by Ira Wilson at Brown University (Table 1).1 Dr. Wilson's three questions are validated and get you the best self-report, which I think is still limited because of factors we already discussed. After a validated assessment, clinicians can provide patients with simple tools like pill boxes and pocket dose-carriers. For many patients, that's going to be enough. However, some patients are going to require a lot more assistance, and there are demonstrated effective and validated brief interventions that can be delivered over the phone to those select patients . [The CDC plans to post the phone-delivered adherence intervention that Dr. Kalichman discusses around the time this issue of RITA becomes available]
MM: If a patient shows evidence of poor adherence, how does a clinician decide whether to implement one of these supportive strategies or to switch to another regimen that might be easier for the patient?
SK: When clinicians see viral load start creeping up, they genotype the virus to see if it is still sensitive to the regimen; if not, they switch regimens. That's standard of care. What I don't think is standard of care in a lot of settings is assessing adherence and heading off the viral load rebound. In this case you wouldn't have to genotype the virus because it is still suppressed, but you would look for adherence indicators by self-report or assess predictors like depression or substance use. Reviewing these indicators of potential or actual nonadherence would suggest intervening with an adherence strategy before viral load goes up.
Unless a patient is not tolerating a regimen well -- which is also a good predictor of nonadherence -- I don't think clinicians switch regimens based on adherence. They try to improve adherence. Regimens are typically switched when there's an indicator of resistance.
Adherence Mistakes and Misperceptions
MM: What are the biggest mistakes HIV clinicians make regarding adherence?
SK: As we've already discussed, relying on viral load to predict adherence is a mistake because by the time viral load is going up, resistance can be developing and it's too late. I do think that's something that needs to be remedied in clinical practice.
Another example of faulty thinking about adherence in the clinic is that an adherence intervention is going to be labor-intensive, difficult to implement, and expensive. And that's just not true. Every patient does not require an adherence intervention. In the developing world the World Health Organization has established a standard for differential adherence care: On the one hand there are patients who are doing well, taking a regimen that's working for them, with HIV suppressed for 6 months and with no indicators of nonadherence. Those patients can continue routine care.
On the other hand, there are patients who have indicators of nonadherence or who are late picking up their antiretrovirals or who report specific indicators of nonadherence in response to validated questions (Table 1). Those patients require adherence intervention. But that assistance is not necessarily burdensome or expensive -- and it can be delivered by adherence intervention professionals.
MM: Can busy HIV clinics make time to conduct adherence interventions?
SK: HIV care clinics can develop the capacity to implement adherence interventions. We work in a very high-quality clinic in the middle of Georgia, which is a very under-resourced part of the country. You don't think of the middle of Georgia as a place that would have a state-of-the-science multifaceted infectious disease clinic like those in Atlanta, for example, where you have world-class comprehensive HIV care. But Macon, Georgia does too. In this poor setting the clinic has an adherence nurse, a community nurse, case managers, and peer advocates. Any one or all of those providers can deliver a brief, weekly or biweekly 15- to 30-minute adherence counseling session by phone to those patients who need it.
It's a mistake to wait until the 3-month routine viral load check and prescription refill to assess adherence. That's insufficient for patients who need assistance. It probably is sufficient for 65% of the patients at that clinic. But one third of those patients really need some support. And that support doesn't require an office visit. I think the billing for telemedicine is being worked out so that Ryan White can reimburse for those services. And if those services are not being reimbursed, certainly that needs to be addressed.
At the Macon clinic we're working with an infectious disease doctor, Harold Katner, at Mercer University, and our collaboration focuses on telemedicine-based adherence interventions. A 15- to 30-minute phone call every 2 weeks has demonstrated efficacy. These interventions are not hypothetical; they're not just ideas. The National Institutes of Health has funded multiple studies demonstrating the effectiveness of relatively brief phone counseling for medication adherence. And the CDC has deemed this an effective intervention and lists it among their medication adherence evidence-based behavioral interventions.⁴ [The CDC plans to post this phone-delivered adherence intervention around the time this issue of RITA becomes available.]
These brief adherence interventions exist, they're available, people can be trained in them. Even under-resourced clinics in the middle of Georgia and similar settings have providers who can do these interventions. I think it's a mistake for clinicians to think that early adherence detection and intervention are infeasible and expensive. That's just not true.
MM: Are there any adherence issues we haven't addressed that you'd like to emphasize for HIV clinicians?
SK: I should mention one thing that's come up an awful lot in our work, and that's intentional nonadherence. This is a significant problem. We usually think of nonadherence as people forgetting to take their pills. That's often true, but missing an occasional dose is not going to cause major problems with today's antiretroviral regimens. It's the longer gaps in adherence that we should worry about. These gaps can be caused by structural challenges -- things that a person can't readily change -- poverty and transportation issues, for example. Adherence support can really assist people in solving those problems and getting the structural barriers out of the way so they can adhere.
But the problem we don't think about very often is when the patient says, "I'm not going to take these drugs." And they don't necessarily tell their clinician. This can result from mistrust of the medications, but we're finding as many as half of patients who drink alcohol will skip taking their antiretrovirals when they're drinking -- and that may be for days -- because they believe it's toxic to do that.⁵⁻⁷ Sometimes patients who believe it's toxic to mix their medications with alcohol stop drinking, and that's not a bad thing. But people who continue to drink may stop taking their antiretrovirals, and that is a bad thing.
Unless a person has a compromised liver, there's no significant risk to taking antiretrovirals when they're going to be drinking. But some people believe mixing antiretrovirals with alcohol has serious health repercussions because there can be with other medications. We can't mix sleeping pills with drinking; that's pretty hazardous. But not antiretroviral therapy.
We're trying to address the intentional nonadherence frequently seen in people who use alcohol and other drugs. I think intentional nonadherence is like the third spoke in the nonadherence wheel that's often ignored. Instead we pay too much attention to forgetting. I think we can forget about forgetting.⁸ Occasionally forgetting an antiretroviral dose is not going to create a huge clinical problem. We should focus more attention on structural problems like ADAP reauthorization, and we also have to deal with intentional nonadherence, especially nonadherence related to substance use.
References
Wilson IB, Fowler FJ Jr, Cosenza CA, et al. Cognitive and field testing of a new set of medication adherence self-report items for HIV care. AIDS Behav. 2014;18:2349-2358.
Conn VS, Ruppar TM, Chan KC, Dunbar-Jacob J, Pepper GA, De Geest S. Packaging interventions to increase medication adherence: systematic review and meta-analysis. Curr Med Res Opin. 2015;31:145-160.
Conn VS, Ruppar TM, Chase JA, Enriquez M, Cooper PS. Interventions to improve medication adherence in hypertensive patients: systematic review and meta-analysis. Curr Hypertens Rep. 2015;17:94.
Centers for Disease Control and Prevention (CDC). Complete listing of medication adherence evidence-based behavioral interventions.
Pellowski JA, Kalichman SC, Kalichman MO, Cherry C. Alcohol-antiretroviral therapy interactive toxicity beliefs and daily medication adherence and alcohol use among people living with HIV. AIDS Care. 2016;28:963-970.
Kalichman SC, Amaral CM, White D, et al. Alcohol and adherence to antiretroviral medications: interactive toxicity beliefs among people living with HIV. J Assoc Nurses AIDS Care. 2012;23:511-520.
Kalichman SC, Kalichman MO, Cherry C, et al. Intentional medication nonadherence because of interactive toxicity beliefs among HIV-positive active drug users. J Acquir Immune Defic Syndr. 2015;70:503-509.
Kalichman SC, Kalichman MO, Cherry C. Forget about forgetting: structural barriers and severe non-adherence to antiretroviral therapy. AIDS Care. 2017;29:418-422.
[Note from TheBodyPRO.com: This article was originally published by The Center for AIDS Information and Advocacy on in September 2017. We have cross-posted it with their permission.]
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