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Expert Analysis: Insights for International Clinicians on New Data From CROI 2020

Josep M. Llibre, MD, PhD
Laura Waters, FRCP, MD
Released: April 21, 2020

Adherence With Modern ARVs

Plenary: Practical Approaches for Adherence With Modern ARVs

Laura Waters, MD:
Building upon our discussion of care engagement, I will summarize an excellent symposium talk given by Dr. Castillo-Mancilla[40] on ART adherence. This is a clinically and financially important issue: Suboptimal adherence to medication—not just to ART—is one of the drivers behind prescription drug–related morbidity and mortality, which was estimated to cost US $528.4 billion in 2016 in the United States.[41] Whereas suboptimal adherence had greater ramifications with earlier ARVs, the development of modern ART regimens has enabled PWH to achieve virologic suppression with good, rather than perfect, adherence.

Research is underway to assess the individual and public health consequences of “good enough” adherence that, while able to achieve consistent virologic suppression as measured at clinic visits, may still be associated with higher levels of inflammation and immune activation.[40] Dr. Castillo-Mancilla reviewed interesting data on treatment interruption and suboptimal adherence indicating that the re-emergence of inflammation precedes the re-emergence of viremia.[42-44] These observations suggest that even though patients could maintain undetectable viremia with “good enough” adherence, they may nonetheless be at risk for long-term comorbidities associated with inflammation.

Plenary: Methods for Measuring Adherence

Laura Waters, MD:
Much of Dr. Castillo-Mancilla’s talk focused on emerging strategies for measuring adherence. Analyses of PrEP adherence, in particular, have illustrated that there can be large discrepancies between self-report vs pill count vs measures of ARV concentrations in plasma or dried blood spots (DBS).[45-47]

The gold standard for quantifying adherence is directly observed therapy, but that is generally not an option for oral ARVs. As long-acting injectables—which are directly observed, of course—are introduced into the clinic, I anticipate that we will learn even more about the relationship between adherence and clinical outcomes.

One method discussed was real-time electronic adherence monitoring, which involves a small pillbox that sends a signal when the dispenser is opened; if you have not opened your pillbox, you receive a text reminder. Several years ago, I trialed one of these pillboxes, which I filled with jellybeans. Unfortunately, I found it highly irritating to have a little plastic box telling me what to do and my adherence to the jellybeans went down.

A more advanced approach to measuring adherence involves digital pills, which are pills covered with a biosensor in the capsule. Once swallowed, the sensor sends a signal as gastric acid breaks down the capsule. Digital pills may improve on the electronic pillboxes because they actually measure ingestion of the medication, not just whether the container was opened. Although I found the concept of digital pills fascinating, I have reservations about their potential cost.

Plenary: Recent vs Cumulative Adherence Measures

Laura Waters, MD:
Dr. Castillo-Mancilla also addressed determining adherence by measuring drug levels in plasma, DBS, urine, peripheral blood mononuclear cells, and hair, and how these compare in terms of the past adherence time frame that they are able to capture.

We only do a limited number of these assays in our clinic because, generally speaking, patients improve adherence when you tell them that you will be measuring drug levels. However, data suggest that by measuring tenofovir diphosphate (TFV-DP) levels in DBS from PWH with undetectable viremia, which captures cumulative exposure over approximately 8 weeks or more, it is possible to predict future viremia.[48,49] Those with lower TFV-DP levels in DBS, which suggested intermittent or suboptimal adherence, were more likely to experience future viremia. These findings imply that rather than measuring drugs levels after failure has occurred, we could instead monitor drug levels to determine when we need to be counseling more intensively to minimize the risk for future virologic failure.

The talk also touched on how we can measure TFV in urine, which captures exposure in the past 1-7 days, including a highly sensitive and specific point-of-care urine test that identifies dosing within the last 24-48 hours.[50,51]

Plenary: Clinical Implications

Laura Waters, MD:
The key takeaway from this talk was that if we can better measure adherence, we can better counsel patients.[40] PWH with high adherence who have undetectable viremia should simply continue what they are doing. PWH with low adherence who have undetectable viremia should be targeted for counseling. PWH with good adherence but detectable viremia should be screened for resistance. Finally, PWH with low adherence who have detectable viremia should receive clinical care aimed at addressing adherence issues and identifying barriers. Again, we could perhaps use some of these newer tools to measure adherence and identify PWH in need of counseling and care.

Josep M. Llibre, MD, PhD:
Dr. Waters, what are your thoughts on the potential role of long-acting CAB and RPV in PWH with adherence issues? Will this approach be beneficial in this group or will it be risky because this combination has a long pharmacokinetic tail and, if patients fail to attend for the injections, they could select for resistance and indeed potentially transmit the resistance in the community?

Laura Waters, MD:
My answer depends on which PWH with adherence issues we are considering. Broadly speaking, we can divide PWH with low adherence into 2 groups. The first group comprises those who do not come to clinic, miss appointments, and usually only arrive in the clinic for an emergency prescription. For these patients, I do not think long-acting injectables are the best approach because if they miss their injectable appointments, they will be at risk of developing resistance.

The second group comprise those who attend clinic regularly and collect their medications, yet have unexplained viremia. Sometimes you learn that these patients have untaken medications at home and that there were barriers in place to actually taking the medications they collected. For these people who engage in care but do not take their pills, I consider long-acting injectables to be the ideal solution. Obviously, these groups are the extremes; there will be many people who fall somewhere in the middle.

Provided by USF Health, in partnership with Clinical Care Options, LLC

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This activity is supported by educational grants from
Gilead Sciences
ViiV Healthcare

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