How Much Adherence Is Enough Adherence?

Have newer generation drugs changed the rules about HIV adherence?

Photo Credit: Justin Sullivan/Getty Images

Drug adherence remains a key component to successfully treating and managing HIV infection. Unlike chronic medication used to treat illnesses such as heart disease or diabetes—which require as little as 70% adherence to achieve the clinical goals—antiretroviral therapy (or ART) requires near-perfect adherence to sustain viral suppression and prevent the premature development of drug resistance.

But given that we now have a newer, improved generation of antiretroviral drugs, are the rules necessarily the same?

The 95% Adherence Mantra

HIV treatment guidelines traditionally dictate that patients need to maintain greater than 95% adherence in order to ensure sustained viral suppression. For a once-daily drug regimen, that translates roughly to 14 days of occasional, missed doses over the course of a year.  

However, some have begun to argue that the "95% mantra" is based on data collected in the late 1990s, when drug regimens were more complex and drugs had far shorter half-lives. While there are few who would rightly proclaim 85% or even 90% as the "new" adherence standard, many believe that the need to berate or stigmatize patients for being less than perfect is nowhere near as imperative as it was 10 years ago.

Still, there are plenty who believe that lowering the adherence threshold (or even suggesting a change) is a mistake, allowing for levels of slippage that will only increase over time.

There is evidence to support this argument.

According to data prepared by the U.S. Centers for Disease Control and Prevention (CDC), roughly 30% of Americans on ART are unable to achieve viral suppression. Most agree that suboptimal adherence plays a key role in this, while other studies suggests that adherence traditionally declines after the first "honeymoon" month following the initiation of ART.

However, there is enough evidence to support that newer generation drugs are far more "forgiving" insofar as resistance is concerned, particularly "boosted" drugs able to sustain greater plasma drug concentrations over longer periods of time.

But is the evidence enough to call for a relaxation of adherence practices? Even with the better, more effective antiretroviral medications, are we truly at that stage yet?

Weighing the Evidence

Protease inhibitors (PIs) are a prime example of advances in modern ART. Today, PIs are almost universally "boosted"—meaning they are co-administered with a secondary drug able to extend the serum half-life of the PI.  A meta-analysis of five major studies suggests that newer generation boosted PIs—like Prezista (darunavir)—may, in fact, only require 81% adherence in order to achieve viral suppression.

By contrast, older boosted PIs like Kaletra (lopinavir + ritonavir) are shown to be less effective when adherence drops below 95%, with one study suggesting that only 53% of patients are able to attain undetectable viral loads below this adherence level.

Research is far less clear about the impact of adherence on other classes of antiretrovirals.  While some studies have shown that non-nucleoside reverse transcriptase inhibitors (NNRTI) drugs like Sustiva (efavirenz) may need only 80% to 90% adherence when used in combination with a boosted PI, others argue that high levels of adherence are still required due to the likely potential for resistance and cross resistance to other NNRTI drugs. Similarly, the CPCRA FIRST Study found that rates of resistance among nucleoside reverse transcriptase inhibitor (NRTI) drugs like Retrovir (AZT, zidovudine) increase in direct correlation with decreases in drug adherence.

There are currently few studies available to assess the relationship between adherence and newer generation drug like Intelence (etravirine) or even the popular nucleotide analogue, Viread (tenofovir). Similarly, of the integrase inhibitors approved for use, only one small study of Isentress (ratelgravir) suggests that adherence levels of 90% may be acceptable.

Should Missing One (or Several) Doses Concern Me?

Missing an occasional dose or failing to take a dose on time is something that happens to everyone on chronic medication. For the most part, this shouldn’t cause undue concern. However, the longer or more frequently these lapses occur, the less able the drugs are to maintain undetectable viral suppression.

One study conducted by the National Institute of Infectious Diseases in Rome showed that gaps in therapy of just two days during the course of a month resulted in a five-fold increase in the incidences of detectable viral activity. Supporting research in 2013 has shown that even sustained, "near-detectable" viral loads (between 50 and 199 copies/mL) can result in a 400% greater risk of virologic failure.

Similarly, research from the Côte de Nacre University Hospital in France demonstrated that longer gaps in ART increased the likelihood of treatment failure, with interruption of 15 days conferring to a 50% probability of viral rebound.

In a similar vein, the Adherence and Efficacy of Protease Inhibitor Therapy (AEPIT) trials studied the impact of dose timing errors on viral activity. According to the research, patients who allowed up to three hours leeway on either side of their usual dosing time had 300% greater viral activity than those who had taken their medication on time.

So What Does This Mean for Me?

There is little doubt that newer generation drugs are easier to use and tolerate, offering greater "forgiveness" should a patient miss the odd dose.  And while we are clearly moving toward longer-acting drugs requiring less frequent dosing, the jury is still out as to whether this foreshadows an actual change in the adherence recommendations.

Ultimately, ART is based on a combination of antiretroviral agents, each with different half-lives and pharmokinetics. Some of the regimens have smaller margins for errors; others greater. From a practical standpoint, it would be counterproductive to change the adherence goalpost with every treatment regimen.

Instead, issues of adherence should be met with greater tolerance from treaters and less anxiety from patients afraid to admit their shortcomings. If anything, it calls for greater patient-provider interaction, with specific aims and interventions to ensure optimal, real-life adherence. These should include:

  • Proactive assessment of adherence barriers prior to ART initiation (e.g., work schedule, children, disclosure, isolation, etc.)
     
  • On-going evaluation and collaboration to address any new or existing problems (including treatment side effects, family troubles, emotional issues, etc.)
     
  • Simplification of treatment regimen, where indicated.
     
  • Addressing alterable factors associated with poor adherence (e.g., substance abuse, depression, homelessness, etc.)
     
  • The use of adherence devices (e.g., medication organizers, reminder devices) or adherence support systems.

In short, it is more productive to address adherence not so much in terms of "How much is enough?," but rather as a means to identify the tools to ensure that ART is a functional, stress-free part of a person’s everyday routine.

If this can be achieved, then the question of "how much" may fall away entirely.

Sources:

Gross, R.; Bilker, W.; Friedman, H.; et al. "Effects of adherence to newly initiated antiretroviral therapy on plasma viral load." AIDS. November 9, 2001; 15:2109-2117.

Kobin, A. and Sheth, N. "Levels of Adherence Required for Virological Suppression among Newer Antiretroviral Medication." The Annals of Phamacology. 2011; 45(3):372-379.

Paterson, D.; Swindells, S.; Mohr, J.; et al. "Adherence to protease inhibitor therapy and outcomes in patients with HIV infection." Annals of Internal Medicine. July 4, 2000;133(1):21-30.

Shuter, J.; Sarlo, J.; Kanmaz, T.; et al. "HIV-infected patients receiving lopinavir-ritonavir-based antiretroviral therapy achieve high rates of virological suppression despite adherence rates less than 95%." Journal of Acquired Immune Deficiency Syndrome. May 1, 2007;45(1):4-8.

Martin, M.; Del Cacho, E.; Codina, C.; et al. "Relationship between adherence level, type of antiretroviral regimen, and plasma HIV type 1 RNA viral load: a prospective cohort study." AIDS Research Human Retroviruses. October 2008; 24(10):1263-1268.

MacArthur, R.; Novak, R.; Peng, G.; et al. "A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial." Lancet. December 16, 2006; 368(9553):2125-2135.

Mena, A.; Blanco, F.; Cordoba, M; et al. "A pilot study assessing raltegravir QD versus BID in HIV patients included in a simplification trial." Presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Francisco, California; September 12-15, 2009.

Laprise, C.; de Pokomandy, A.; Baril, J.; et al. "Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation." Clinical Infectious Diseases. November 2013; 57(10):1489-96.

Ammassari, A.; Trotta, M.; Zaccarelli, M.; et al. "Impact of different types of adherence behaviours and of cART characteristics on plasma HIV-1 RNA detection under the lower limit of quantification at real-time assay." Presented at the 12th European AIDS Conference. Cologne, Germany; November 11-14, 2009.

Parienti, J.; Das-Douglas, M.; Massari, V.; et al. "Not all missed doses are the same: sustained NNRTI treatment interruptions predict HIV rebound at low-to-moderate adherence levels." PLoS|ONE. July 30, 2008; 3(7):e2783.

Continue Reading