Protease Inhibitor Combinations Work Best With at Least 95% On-Time Pill Taking

November 2015

Antiretroviral combinations including a protease inhibitor (like Prezista or Reyataz) made viral loads undetectable more often when people took their pills on time at least 95% of the time than when they took their pills less often.1 Viral load control rates did not differ significantly in people taking a combination including a nonnucleoside (like Edurant, Intelence, or Sustiva) if their pill-taking on-time record lay between 90% and 94% or at 95% or greater. That does not mean people taking a nonnucleoside can skip doses, but it suggests HIV control suffers less if someone mistakenly misses a nonnucleoside dose than if someone misses a protease inhibitor dose.

Adherence is the term health professionals use to describe how faithfully people take pills prescribed by their provider. The goal is to take every pill on time every day, exactly as your provider instructs. But sometimes people forget to take one or more pills, and sometimes they miss a dose when they run out of pills or leave home and forget to take their pills with them.

The main goal of antiretroviral therapy is to reach and maintain an undetectable viral load. Researchers and HIV providers want to know how often an undetectable viral load becomes detectable when people miss one or more doses of their antiretrovirals for any reason. Undetectability rates vary from one antiretroviral combination to another when someone misses a dose because different antiretrovirals stay in the body for different periods. An antiretroviral that stays in the body for a longer time after a dose will keep the viral load undetectable longer after a missed dose.

Rates at which antiretroviral-treated people reach and keep an undetectable viral load increased greatly over the past 10 years. One reason for this increase is better pill-taking adherence by people with HIV. Adherence improved as antiretroviral combinations became easier to take, required fewer pills, and caused fewer side effects. Researchers working with a large HIV-positive U.S. veterans group conducted this study to determine adherence levels needed to keep viral loads undetectable with the newest antiretroviral combinations in use today.


How the Study Worked

This analysis involved HIV-positive veterans who were part of the ongoing Veterans Aging Cohort Study Virtual Cohort (VACS-VC) at some point between October 2000 and September 2010. Researchers checked Veterans Affairs records for medical and laboratory details and to see which antiretroviral combinations these veterans took. The investigators classified combinations as (1) single pill versus multiple pills and (2) once daily versus twice daily. They assessed three major types of antiretroviral combination -- those including a nonnucleoside, those including a protease inhibitor, and those including an integrase inhibitor (the newest type of antiretroviral, including Isentress, Tivicay, and Vitekta).

The researchers checked Veterans Affairs pharmacy records to determine when veterans filled prescriptions for their antiretrovirals. The investigators defined adherence as the number of days a person had antiretrovirals available during 1 year divided by total days between the first and last antiretroviral prescription refill in a year. They defined "minimum needed adherence" as the adherence level at which chances of having an undetectable viral load did not differ significantly from the chance of having an undetectable viral load with at least 95% adherence (that is, at least 95% as defined in the previous sentence).

The researchers recorded changes in rates of adherence, undetectable viral load, type of antiretroviral combination, and antiretroviral dosing (once or twice daily) over time for each veteran. They used accepted statistical methods to determine changes in adherence over time and the impact of adherence on reaching an undetectable viral load. This type of analysis accounts for the potential impact of several factors that may influence adherence and undetectable viral load, such as race, alcohol abuse, drug abuse, major depression, number of antiretrovirals taken, and CD4 count.

The main aim of the study was to determine "minimum needed adherence" for antiretroviral combinations used from 2006 onward.

What the Study Found

The study involved 21,865 HIV-positive veterans taking antiretrovirals, 98% of them men, 46.5% black, 41.6% white, and 7.6% Hispanic. When veterans entered the study, they averaged 46 years in age.

From 2001 through 2010, use of multi-pill protease inhibitor combinations fell from 65% to 43%, and use of multi-pill nonnucleoside combinations dropped from 33% to 16%. From 2006 onward, use of single-pill combinations rose from 1% to 29% and use of integrase inhibitors (the newest type of antiretroviral) rose from 0% to 11%. Atripla, which contains the nonnucleoside Sustiva, was the only single-pill combination these veterans took during the study period. Starting in 2006 veterans taking a single-pill combination had better adherence than those taking two or more pills and those taking antiretrovirals twice daily.

The proportion of veterans with 95% adherence or better rose slightly from 37% in 2001 to 42% in 2010. Statistical analysis determined that the overall adherence rate rose 8% each year, rose 13% every 2 years, and rose 16% from 2001-2005 to 2006-2011 (Figure 1). This analysis accounted for the impact of several factors on adherence, so the researchers can be confident that the increasing adherence was not affected by those factors -- age, race, alcohol abuse, drug abuse, major depression, or time since antiretroviral therapy began.

Changes in Antiretroviral Pill-Taking Adherence in 21,865 Veterans: 2001 to 2010

Changes in Antiretroviral Pill-Taking Adherence in 21,865 Veterans: 2001 to 2010

Figure 1. From 2001 through 2010, antiretroviral pill-taking adherence rose 8% yearly, 13% every 2 years, and 16% from 2001-2005 to 2006-2011 in a study of 21,865 HIV-positive U.S. veterans.

Among people with less than 95% adherence, the proportion with an undetectable viral load jumped from 38% in 2001 to 84% in 2010. At every adherence level studied, the proportion of veterans with an undetectable viral load was higher in those taking a nonnucleoside combination than in those taking a protease inhibitor combination or an integrase inhibitor combination (although these differences were smaller at the highest adherence levels).

Among all veterans studied, the proportion reaching an undetectable viral load did not differ much between those with 90% to 94% adherence and those with 95% adherence. However, among veterans taking a protease inhibitor combination, those with 90% to 94% adherence versus 95% or better adherence had a 12% lower chance of reaching an undetectable viral load. But among veterans taking a nonnucleoside combination, having 90% to 94% adherence versus 95% or better adherence did not affect chances of reaching an undetectable viral load. That finding with nonnucleosides held true whether veterans were taking a multi-pill nonnucleoside combination or a single-pill nonnucleoside combination.

What the Results Mean for You

This large study of U.S. veterans starting antiretroviral therapy made several interesting findings -- and most of those findings are good news for people with HIV infection. First, the proportion of veterans with less than 95% adherence (on-time pill taking) who reached an undetectable viral load with antiretroviral therapy rose steadily from about 40% in 2001 to almost 85% in 2011. Reaching an undetectable viral load is the main goal of antiretroviral therapy. This finding probably reflects the increasing strength and durability of antiretroviral combinations over the years, which would allow people to miss an occasional dose without hurting their chance of reaching or keeping an undetectable viral load.

It is important to remember, though, that missing too many doses is still risky. When the researchers compared undetectable viral load rates in four adherence groups (90% to 94% adherence, 85% to 89%, 80% to 84%, and 75% to 79%), the undetectable rate was about 10% higher with 90% to 94% adherence than with 75% to 79% adherence all the way from 2001 to 2010.

And worse adherence had an impact in veterans taking an antiretroviral combination including a protease inhibitor. Compared with veterans who had at least 95% adherence with a protease inhibitor combination, those with 90% to 94% adherence (that is, veterans missing only a few more doses over time) had a 12% lower chance of reaching or keeping an undetectable viral load.

Another piece of good news is that adherence improved slowly but steadily over the course of this study (Figure 1). The researchers recorded two factors that help explain this improving adherence: (1) Veterans were switching from twice-a-day combinations to once-a-day combinations, which are easier to remember to take. (2) Veterans were switching from combinations including two or more pills to a combination that puts three antiretrovirals in a single once-daily pill (Atripla*). The study did not explore two other well-known improvements with newer antiretrovirals -- fewer side effects and longer durability (drug levels staying higher longer after each dose).

All of these factors are making it easier for people with HIV to take their antiretrovirals on time, exactly as their HIV provider directs. And everyone should aim for 100% adherence -- taking all antiretrovirals on time every day. Missing a dose every now and then usually does not pose a big threat. But missing a few more doses -- letting adherence slip below 95% -- did pose a risk for veterans taking protease inhibitor combinations in this study. And an even lower adherence rate could pose problems for people taking any type of antiretroviral combination.

Researchers who conducted this study believe their overall findings hold a lesson for HIV providers: They argue that providers should not let concerns about barriers to adherence stop them from prescribing the newest antiretroviral combinations at early stages of HIV infection.

People taking antiretrovirals should never stop taking their antiretroviral pills or deliberately skip doses unless their provider tells them to. If you have trouble taking all your antiretrovirals regularly -- perhaps because you think they're causing side effects -- talk to your HIV provider as soon as you can. If side effects persist, it may be possible to switch to another antiretroviral combination. If the demands of daily living make it hard to take your antiretrovirals on time, you can get help from a social worker or case worker in your provider's office or recommended by your provider. The key is to talk about any problems that come up and work toward a solution. Antiretroviral therapy is helping HIV-positive people live as long as people without HIV. But you have to take your pills.

* Now three other once-daily pills combine three antiretrovirals -- Complera, Stribild, and Triumeq -- and others are on the way.


  1. Viswanathan S, Justice AC, Alexander GC, et al. Adherence and HIV RNA suppression in the current era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;69:493-498.

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This article was provided by The Center for AIDS Information & Advocacy. It is a part of the publication HIV Treatment ALERTS!. Visit CFA's website to find out more about their activities and publications.


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