How Much HIV Drug Adherence Is Enough?

Drug adherence remains a key component to successfully treating HIV. Unlike chronic medications used to treat illnesses such as heart disease or diabetes—which may require as little as 70% adherence to achieve the desired goals—antiretroviral therapy has long required near-perfect adherence to sustain viral suppression, prevent disease progression, and avoid the development of drug resistance.

With the release of the once-monthly or once-every-two-months injectable antiretroviral drug Cabenuva (cabotegravir + rilpivirine) in 2021, the very notion of adherence has been turned on its ear.

Given that we now have a more effective and robust generation of antiretroviral drugs, many have questioned whether the old rules of adherence still apply.

The 95% Adherence Mantra

HIV treatment guidelines have traditionally dictated that people need to maintain greater than 95% adherence to sustain an undetectable viral load. For a daily single-pill drug regimen, that translates roughly to 14 non-consecutive 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 that 85% or even 90% is the "new" adherence standard, there is evidence that the adherence threshold today is nowhere near as slim as it was 10 years ago.

Arguments Against

On one side of the argument, there are those who believe that, rather than lowering the threshold, the focus should be placed on reinforcing optimal adherence.

There is evidence to support this argument, mainly in the form of the HIV care continuum, a public health model that tracks the number of Americans with HIV from diagnosis to achieving and maintaining viral suppression.

Suboptimal adherence has long been known to play a central role in this. Even if adherence is initially good, research suggests that adherence will traditionally slip one to three months after the initiation of treatment. Lowering the threshold may only allow adherence rates to slip even further.

Arguments For

On the flip side, the body of evidence has shown that newer-generation drugs, like integrase inhibitors, are far more "forgiving," meaning that they are able to sustain drug concentrations in the bloodstream even if doses are missed.

Protease inhibitors like Prezista (darunavir) also benefit from newer pharmacokinetic enhancers ("booster drugs") like Tybost (cobicistat) that sustain blood concentrations well beyond the drug's traditional half-life.

This is unlike many antiretrovirals of the past, some of which required a dose every eight hours to prevent the drug from slipping beneath therapeutic levels.

Weighing the Evidence

Generally speaking, the impact of adherence on viral suppression appears to be greater with older-generation antiretroviral drugs than with newer-generation ones. Even so, modern combination antiretroviral therapy often involves drugs from both generations, making an assessment of the threshold all the more difficult to ascertain.

Protease Inhibitors

Protease inhibitors (PIs) are a prime example of this. On the one hand, a meta-analysis published in AIDS Review suggests that newer-generation boosted PIs like Prezista may, in fact, only require 81% adherence to achieve viral suppression.

On the other hand, older boosted PIs like Kaletra (lopinavir + ritonavir) have proven less effective when adherence drops below 95%.

NRTIs and NNRTIs

Research is less clear about the impact of adherence on other classes of antiretrovirals, including early-generation nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).

While some studies have suggested that older NNRTIs like Sustiva (efavirenz) may need only 80% to 90% adherence when used with a boosted PI, others argue that high levels of adherence are still required to prevent the premature development of drug resistance and cross-resistance.

For older NRTIs and NNRTIs, the potential from cross-resistance is significant. Poor adherence to drugs like Viramune (nevirapine) has been known to trigger the rapid onset of resistance to the drug itself and also other drugs in its class, reducing one's future treatment options.

The CPCRA FIRST Study supported these findings, reporting that the rate of drug resistance among users of older NRTIs like AZT (zidovudine) increases in tandem with decreases in drug adherence.

Integrase Inhibitors

As opposed to early-generation drugs like Viramune and AZT, newer-generation integrase inhibitors do not appear to have anywhere near the same concerns. It is for this reason that integrase inhibitors are among the preferred agents today for first-line therapy in the United States and abroad.

In fact, according to CDC research published in 2019, 90% of people on an integrase inhibitor-based regimen were able to achieve an undetectable viral load with only 73% adherence.

A Word From Verywell

There is little doubt that newer-generation antiretroviral drugs are easier to use and offer greater "forgiveness" should you miss the occasional dose. Even so, it doesn't necessarily change the rules about adherence.

In the end, antiretroviral therapy is based on a combination of drugs, each with different half-lives and mechanisms of action. With respect to adherence, some may have smaller margins for error than others. From a practical standpoint, it would be counterproductive to change the adherence goalpost for every treatment regimen.

Instead, the focus should be placed on making adherence a part of your daily routine so that it becomes a habit like brushing your teeth. If adherence is a problem, be honest and let your healthcare provider know.

By working together, you can identify your barriers to adherence, whether they are work schedules, treatment side effects, emotional issues, stigma, substance abuse, or simple forgetfulness. By overcoming these issues, you can live a longer, healthier life and even reduce the risk of passing the virus to others.