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How much has adherence changed with newer antiretroviral regimens?

Is poor antiretroviral adherence a worry of the past? With six once-daily single-tablet regimens available, almost as many two-pill combinations in hand, and once-monthly injected antiretroviral maintenance in phase 3 trials, (1,2) will problems taking antiretrovirals evaporate?

Not likely. For starters, four of the six single-tablet regimens must be taken with food, one (Atripla) must be taken on an empty stomach, and only one (Triumeq) can be taken with or without food--a tally leaving plenty of room for incorrect dosing. And if once-monthly or every-2-months injected antiretrovirals get licensed, no one knows how regularly people will get their shots outside clinical trials. For example, a study of a quarter-million US women taking contraceptives found stopping injected agents within 3 months much more likely than stopping oral pills. (3)

Just forgetting to take antiretrovirals remains the leading cause of faulty adherence among adults and adolescents, (4) and people can just forget a once-daily tablet as easily as a twice-daily dose. With almost everyone starting antiretroviral therapy (ART) feeling better as a result, factors related to better health may assume greater importance as reasons for imperfect adherence: being away from home, (4) changing one's daily routine, (4,5) being busy. (5)

But of course the more convenient, less toxic regimens that surged to the fore in the past decade inevitably improved adherence, as the next section of this article makes clear. Still, the clinical threats of wavering adherence--viral rebound, resistance, disease progression, death--remain a cautionary tale clinicians should be sure their patients understand, as the final section of this article details. The remaining articles in this issue attempt to spell out the major reasons for poor adherence (page 21), offer clear advice on adherence assessment (page 36), and explain which adherence strategies work (page 41). Almost all research cited in these reviews appeared within the past 10 years; even so, a caveat deserves stressing: Older studies reflect adherence to more toxic and cumbersome regimens, including those featuring lopinavir/ritonavir, efavirenz, tenofovir disoproxil fumarate (TDF), and other even more compromising agents. So adherence in a 2017 report does not mean what it meant in a 2007 report.

Adherence improving with newer regimens

Five large cohort studies in the North America and Europe chart improving adherence over the past two decades, (6-10) with study years ranging from to 1996-2009 (6) to 2006-2013 (10) (Table 1). A study of 682 drug injectors in Vancouver, Canada determined that adherence of at least 95% during the first year of treatment, based on pharmacy refill records, climbed steadily from 19.3% in 1996 to 65.9% in 2009. (6) Linear regression analysis linked every year after 1996 with 8% higher odds of good adherence (adjusted odds ratio [aOR] 1.08, 95% confidence interval [CI] 1.03 to 1.13, P < 0.001).

At London's Royal Free HIV Clinic, a study of 2060 HIV patients tracked for a median of 4.5 years from 1999-2002 through 2007-2008 used generalized estimating equation models to determine that chances of better than 95% adherence improved 2% every year (aOR 1.02, 95% CI 1.01 to 1.04, P = 0.0053). (7) A US study of 1215 men who have sex with men (MSM) in the Multicenter AIDS Cohort Study (MACS) and 337 drug injectors in the AIDS Linked to the Intravenous Experience (ALIVE) cohort figured that at least 95% self-reported adherence in the last 4 days rose from 84% to 90% in MACS and from 87% to 92% in ALIVE from 2001 through 2011. (8) Every 2 years average adherence improved 11% in MACS and 14% in ALIVE.

Swiss HIV Cohort Study (SHCS) investigators tracked self-reported adherence from 2003 through 2009 in 6709 cohort members. (9) Through a median follow-up of 4.5 years, the proportion reporting no doses missed in the last 4 weeks climbed from 70% in 2003 to 83% in 2009. In the US Women's Interagency HIV Study (WIHS), the rate of 95% or better self-reported adherence improved from 78% in 2006 to 85% in 2013 (P < 0.001). (10) Increased use of single-tablet regimens (from 7% in 2006 to 27% in 2013) accounted for much of the improved adherence (adjusted risk ratio [aRR] 1.05, 95% CI 1.03 to 1.08), and single-tablet therapy raised chances of virologic suppression (aRR 1.06, 95% CI 1.01 to 1.11).

The consistency of these five studies reassures that no single HIV risk group, gender group, or nationality explains improving adherence in recent years. (6-10) The studies include drug injectors, (6,8) men who have sex with men, (7-9) heterosexual men, (6-9) and women (100% of the WIHS study (10) and 22% to 36% of other cohorts that include women). There were 682 people from Canada, 2060 from Britain, 3279 from the United States, and 6709 from Switzerland.

Adoption and impact of once-daily and single-tablet combos

The surging adherence rates cataloged over recent across countries and risk groups (6-10) reflect the ever-improving convenience, tolerability, and activity of newer antiretrovirals. Several individual studies and meta-analyses confirm the intuitive ideas that once-daily regimens are easier to take than twice-daily combinations, and that single-tablet regimens have an adherence advantage over multitablet medleys.

A 2009 meta-analysis compared adherence with once- versus twice-daily regimens in 11 randomized controlled trials involving 3029 participants. (11) All studies used pills counts or electronic MEMS pill bottle caps to measure adherence, defined as total number of doses taken over total doses prescribed. Adherence proved significantly better with once-daily regimens in the overall analysis (+2.9%, 95% CI 1.0% to 4.8%, P < 0.003) and in 11 sensitivity analyses, each of which removed one study.

A more recent meta-analysis scrutinized 19 randomized controlled trials published through March 2013 involving 6312 adults. (12) In both once- and twice-daily groups, taking more pills daily predicted lower adherence (P = 0.0014) and worse virologic suppression (P < 0.0001). Adherence measured by pill count or MEMS again proved slightly but significantly higher with once-a-day dosing (weighted mean difference +2.55%, 95% CI 1.23% to 3.87%, P = 0.002). Adherence decreased less over time with once-daily regimens than twice-daily regimens.

Meta-analysis of 21 studies presented up to March 2013 and involving 27,230 people compared regimens containing fixed-dose agents combining two or three antiretrovirals with regimens containing no fixed-dose agents. (13) In six randomized trials, random effects meta-analysis determined that fixed-dose agents conferred a 10% higher chance of adherence as defined in the original study (nonsignificant at relative risk [RR] 1.10, 95% CI 0.98 to 1.22). In observational studies, chances of adherence were significantly higher with fixed-dose antiretrovirals (RR 1.17, 95% CI 1.07 to 1.28). Virologic suppression tended to be better with fixed-dose drugs in randomized trials (RR 1.04, 95% CI 0.99 to 1.10) and observational studies (RR 1.07, 95% CI 0.97 to 1.18).

Analysis of 7381 US Medicaid patients from 11 states in care between 2005 and 2009 compared adherence measured by medication possession ratio in people taking a once-daily single-tablet regimen versus those taking two or more antiretroviral pills daily. (14) Almost half of study participants (46%) in this low-income group were women. One quarter of participants taking a single-tablet regimen (25.3%) compared with 17.4% taking multiple pills had at least 95% adherence (P < 0.0001). The hospital admission rate proved significantly lower in the single-tablet group than in the multitablet group (21% versus 24.4%, P = 0.003). Multivariate Poisson regression analysis linked single-tablet regimens to a 15% lower chance of hospital admission (incidence rate ratio 0.8457, P < 0.001). Total monthly healthcare costs averaged $2959 in the single-tablet group versus $3544 in the multitablet group (P < 0.001). A more recent study of 2174 South Carolina Medicaid recipients used multivariate regression models to confirm greater adherence and a lower hospital admission risk (hazard ratio 0.71, 95% CI 0.59 to 0.86) with single-tablet antiretroviral regimens than with multiple-tablet combinations. (15)

A study of 327 women in the US WIHS cohort determined that self-reported 95% adherence to a single-tablet regimen did not differ between the luteal phase of menstruation and the follicular phase--a finding allaying concern that changing cognition, mood, and premenstrual symptoms in the luteal phase imperil adherence. (16) But adjusted analyses showed that suboptimal adherence was more likely in women with 12 or fewer years of education (aOR 3.55, 95% CI 1.04 to 12.2, P = 0.04) and in those with more CESD-determined depressive symptoms (aOR 2.60, 95% CI 1.15 to 5.90, P = 0.02).

Despite this strong evidence of better adherence and fewer hospital admissions with single-tablet regimens, some people taking a suppressive two-pill once-daily regimen may prefer to stick with that treatment rather than switching to a single-tablet combination. That conclusion emerged from a Swiss study of 84 people taking fixed-dose TDF/emtricitabine plus efavirenz who switched to the 3-in-1 combination of these antiretrovirals. (17) Six of the 88 people (7%) opted to return to their two-pill regimen, while efavirenz blood levels rose and a score estimating perception of treatment necessity fell significantly after the switch. Although self-reported adherence did not change after patients traded two pills daily for one, the researchers suggest that the waning treatment-necessity score and higher risk of efavirenz side effects could eventually dim adherence with the one-tablet regimen.

Swiss investigators found a higher risk of virologic failure with once- versus twice-daily regimens among cohort members who reported missing one or two doses in the past 4 days. (18) The analysis involved 3150 people starting their first antiretrovirals between 2003 and 2012. Through a median follow-up of 4.7 years, 480 people (15%) had virologic failure (a viral load above 500 copies/mL after being below 50 copies/mL or on treatment for more than 24 weeks). Compared with people who missed no doses, those missing one or two doses of a once-daily combination had a two thirds higher risk of virologic failure (HR 1.67, 95% CI 1.11 to 2.50). But people starting a twice-daily regimen did not risk failure with one or two missed doses more than those with no misses (HR 0.99, 95% CI 0.64 to 1.54).

Clinical consequences of unsteady adherence

As the just-discussed Swiss HIV Cohort Study found,18 missing even one or two doses of a once-daily antiretroviral medley can boost chances of virologic failure. And failure poses a risk of emergent resistance and narrowed antiretroviral options. But worse adherence may have graver and more immediate consequences--including hospital admission and death (Figure 1). As US AIDS care guidelines warn, "adherence is second only to the CD4 cell count as a predictor of progression to AIDS and death." (19)

US researchers used a validated model of HIV disease progression and death to weigh the impact of starting ART at 200, 350, or 500 cells/[mm.sup.3] with adherence ranging from 50% to 100% of prescribed doses taken. (20) The model projected that starting ART at 500 rather than 350 cells/[mm.sup.3] added 3.7 life-years and 3.3 quality-adjusted life-years (QALYs) in people with 100% adherence. Improving adherence from 50% to 80% added up to 2.0 life-years and 1.9 QALYs, while improving adherence from 80% to 100% tacked on up to 4.8 life-years and 4.5 QALYs.

Gauging the impact of adherence on mortality in an epidemiologic study can be difficult, but the Swiss HIV Cohort Study described in the preceding section managed to do so. (18) In this analysis of 3150 people who started their first ART between 2003 and 2012 and had almost 5 years of follow-up, multivariate analysis determined that missing more than two antiretroviral doses in the previous 4 weeks (compared with missing no doses) almost tripled the risk of death (HR 2.89, 95% CI 1.13 to 7.41). In an analysis limited to MSM, missing two doses in the past 4 weeks almost quintupled the risk of death (HR 4.87, 95% CI 2.21 to 10.73). Among MSM 90% to 95% adherence (versus better than 95%) did not significantly affect mortality. But less than 90% adherence more than quadrupled the risk of death (HR 4.45, 95% CI 1.99 to 9.93).

AIDS Clinical Trials Group (ACTG) investigators explored the mortality impact of adherence to first-generation ART in ACTG protocol 362, a study of Mycobacterium avium prophylaxis in 643 people enrolled between October 1997 and April 1999. (21) A generalized estimating equation (GEE) model determined that hard drug use (cocaine, amphetamines, or heroin) doubled the odds of antiretroviral nonadherence (self-reported missed dose in the past 48 hours) (OR 2.14, 95% CI 1.36 to 3.38, P < 0.001). A Cox regression model figured that time-updated nonadherence almost doubled the risk of AIDS progression or death (adjusted HR 1.84, 95% CI 1.15 to 2.94, P = 0.01).

A study of 5177 HIV-positive people using Medicaid in 2008-2009 in 29 states linked poor self-reported adherence to more emergency department visits and longer hospital stays. (22) In a cohort of 50- to 64-year-olds, the researchers used multivariable regression adjusted for race, sex, age, urban residence, and comorbidity to determine the impact of three adherence levels (below 80%, 80% to 89%, and 90% to 94%) compared with optimal adherence (95% or greater). Cohort members with adherence below 80% had a longer hospital stay (regression coefficient 1.24, 95% CI 0.53 to 1.96, P = 0.0007) and 34% higher odds of an emergency department visit (aOR 1.34, 95% CI 1.08 to 1.48, P < 0.0001). But people with adherence of 80% to 89% or 90% to 94% did not differ significantly from the optimal adherence group in emergency visits or hospital duration.

One does not need advanced degrees in pathophysiology and statistics to understand why poor antiretroviral adherence leads to worsening health and sometimes death: Skipping enough doses engenders resistant HIV, which propels rebounds in viral replication and consequent clinical risks. Many studies trace the tie between faulty adherence and detectable or climbing viral load. A 2016 meta-analysis of 43 studies involving 27,905 people in more than 26 countries conflates many of these findings into pooled odds ratios linking suboptimal adherence to virologic failure. (23) While 15 studies took place in North America, 14 occurred in sub-Saharan Africa, 6 in Europe or Australia, 5 in Asia, and 3 in several countries. Most studies (70%) defined optimal adherence at 95% or greater, while the others used cutoffs ranging from 80% to 100%. A randomeffects model determined that optimal adherence compared with suboptimal adherence lowered chances of virologic failure 66% (OR 0.34, 95% CI 0.26 to 0.44). Risk of failure did not differ among three clusters of optimal adherence thresholds (98% to 100%, 95% or greater, 80% to 90%).

Spuriously high adherence levels indicated by pill counts--called "overadherence" by University of Pennsylvania researchers--correlated with virologic failure in adolescents taking ART. (24) The study involved 300 adolescents who apparently dumped pills before pill counts to mask poor adherence, a practice resulting in the calculation that they took more than 100% of prescribed doses. Defining "overadherence" as greater than 100% adherence on more than one third of pill counts during a year, the researchers identified "overadherence" in 33% of adolescents with virologic failure versus 13% with suppressed viral loads (P = 0.001).

References

(1.) ClinicalTrials.gov. Study to evaluate the efficacy, safety, and tolerability of long-acting intramuscular cabotegravir and rilpivirine for maintenance of virologic suppression following switch from an integrase inhibitor in HIV-1 infected therapy naive participants. ClinicalTrials.gov identifier NCT02938520. https://clinicaltrials.gov/ct2/show/NCT02938520

(2.) ClinicalTrials.gov. Study evaluating the efficacy, safety, and tolerability of switching to long-acting cabotegravir plus long-acting rilpivirine from current antiretroviral regimen in virologically suppressed HIV-1-infected adults. ClinicalTrials.gov identifier NCT02951052. https://clinicaltrials.gov/ct2/show/NCT02951052

(3.) Murphy PA, Brixner D. Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database. Contraception. 2008;77:257-263.

(4.) Shubber Z, Mills EJ, Nachega JB, et al. Patient-reported barriers to adherence to antiretroviral therapy: a systematic review and meta-analysis. PLoS Med. 2016;13:e1002183.

(5.) Chesney MA, Ickovics JR, Chambers DB, et al. Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. AIDS Care. 2000;12:255-266.

(6.) Mann B, Milloy MJ, Kerr T, Zhang R, Montaner J, Wood E. Improved adherence to modern antiretroviral therapy among HIV-infected injecting drug users. HIV Med. 2012;13:596-601.

(7.) Cambiano V, Lampe FC, Rodger AJ, et al. Long-term trends in adherence to antiretroviral therapy from start of HAART. AIDS. 2010;24:1153-1162.

(8.) Viswanathan S, Detels R, Mehta SH, Macatangay BJ, Kirk GD, Jacobson LP. Level of adherence and HIV RNA suppression in the current era of highly active antiretroviral therapy (HAART). AIDS Behav. 2015;19:601-611.

(9.) Glass TR, Battegay M, Cavassini M, et al. Longitudinal analysis of patterns and predictors of changes in self-reported adherence to antiretroviral therapy: Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 2010;54:197-203.

(10.) Hanna DB, Hessol NA, Golub ET, et al. Increase in single-tablet regimen use and associated improvements in adherence-related outcomes in HIV-infected women. J Acquir Immune Defic Syndr. 2014;65:587-596.

(11.) Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better adherence with once-daily antiretroviral regimens: a meta-analysis. Clin Infect Dis. 2009;48:484-488,

(12.) Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials. Clin Infect Dis. 2014;58:1297-1307.

(13.) Ramjan R, Calmy A, Vitoria M, et al. Systematic review and meta-analysis: patient and programme impact of fixed-dose combination antiretroviral therapy. Trop Med Int Health. 2014;19:501-513.

(14.) Cohen CJ, Meyers JL, Davis KL. Association between daily antiretroviral pill burden and treatment adherence, hospitalisation risk, and other healthcare utilisation and costs in a US Medicaid population with HIV. BMJ Open. 2013;3(8).pii:e003028.

(15.) Scott Sutton S, Magagnoli J, Hardin JW. Impact of pill burden on adherence, risk of hospitalization, and viral suppression in patients with HIV infection and AIDS receiving antiretroviral therapy. Pharmacotherapy. 2016;36:385-401.

(16.) Hessol NA, Holman S, Minkoff H, et al. Menstrual cycle phase and single tablet antiretroviral medication adherence in women with HIV. AIDS Care. 2016;28:11-21.

(17.) Rotzinger A, Locatelli I, Bugnon O, et al. Switching from a two-tablet regimen of tenofovir/emtricitabine and efavirenz to a one-tablet regimen may affect patients' perceptions and drug management. HIV Med. 2016;17:390-396.

(18.) Glass TR, Sterne JA, Schneider MP, et al. Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality. AIDS. 2015;29:2195-2200.

(19.) Health Resources and Services Administration (HRSA). Guide for HIV/AIDS Clinical Care. April 2014. https://www.aidsetc.org/resource/hrsa-guide-hivaids-clinical-care

(20.) Braithwaite RS, Roberts MS, Goetz MB, et al. Do benefits of earlier antiretroviral treatment initiation outweigh harms for individuals at risk for poor adherence? Clin Infect Dis. 2009;48:822-826.

(21.) Cohn SE, Jiang H, McCutchan JA, et al. Association of ongoing drug and alcohol use with non-adherence to antiretroviral therapy and higher risk of AIDS and death: results from ACTG 362. AIDS Care. 2011;23:775-785.

(22.) Abara WE, Adekeye OA, Xu J, Rust G. Adherence to combination antiretroviral treatment and clinical outcomes in a Medicaid sample of older HIV-infected adults. AIDS Care. 2017;29:441-448.

(23.) Bezabhe WM, Chalmers L, Bereznicki LR, Peterson GM. Adherence to antiretroviral therapy and virologic failure: a meta-analysis. Medicine (Baltimore). 2016;95:e3361.

(24.) Okatch H, Beiter K, Eby J, et al. Apparent antiretroviral overadherence by pill count is associated with HIV treatment failure in adolescents. J Acquir Immune Defic Syndr. 2016;72:542-54
Table 1. Improving adherence in large North American
and European cohorts

Author            Group, n, % women     Study years

Mann (6)          Vancouver drug        1996-2009
                  injectors, n = 682,
                  36% W

Cambiano (7)      Royal Free            1999-2002,
                  Hospital, London,     2003-2004,
                  n = 2060, 22% W       2005-2006,
                                        2007-2008

Viswanathan (8)   MACS (n = 1215,       2001-2011
                  0% W) and ALIVE
                  (n = 337, 31% W)
                  cohorts

Glass (9)         SHCS, n = 6709,       2003-2009
                  30% W

Hanna (10)        WIHS, n = 1727,       2006-2013
                  100% W

Author            Adherence measure          Main outcomes

Mann (6)          [greater than or           Rose from 19.3% in 1996
                  equal to] 95% adherence    to 65.9% in 2009; rose
                  (days dispensed/days       8% per year after 1996
                  eligible in first
                  year of ART)

Cambiano (7)      >95% adherence             Rose 2% per year
                  (days dispensed/days
                  covered over 6 months)

Viswanathan (8)   [greater than or           Rose from 84% to 90% in
                  equal to] 95%              MACS and from 87% to
                  self-reported in           92% in ALIVE; every 2
                  last 4 days                years average
                                             adherence rose 11% in
                                             MACS and 14% in ALIVE

Glass (9)         Self-reported 0 missed     Rose from 70% in 2003
                  doses in last 4 weeks      to 83% in 2009

Hanna (10)        [greater than or equal     Rose from 78% in 2006
                  to] 95% self-reported      to 85% in 2013
                  adherence in last
                  6 months

ALIVE, AIDS Linked to the Intravenous Experience; ART, antiretroviral
therapy; MACS, Multicenter AIDS Cohort Study (men who have sex with
men); SHCS, Swiss HIV Cohort Study; WIHS, Women's Interagency HIV
Study.

Figure 1. Data from cohort analyses, clinical trials, and modeling
studies trace links between antiretroviral adherence and mortality.
(ACTG, AIDS Clinical Trials Group; SHCS, Swiss HIV Cohort Study;
images from Servier PowerPoint Image Bank
http://www.servier.com/Powerpoint-image-bank.)

Impact of poor adherence on mortality

Model of HIV disease                Improving adherence from 50% to
progression (20)                      80% adds up to 2 life-years
                                    Improving adherence from 80% to
                                     100% adds up to 4.8 life-years

3ISO in SHCS starting ART           Missing >2 doses in past 4 weeks
2003-2013 (18)                        raises death risk 2.89-fold
                                   IN MSM missing >2 doses in past 4
                                   weeks raises death risk 4.87-fold

643 ACTG participants enrolled      Time-updated nonadherence raises
1997-1999 (21)                    AIDS progression/death risk 1.84-fold
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Title Annotation:Perspectives
Author:Mascolini, Mark
Publication:Research Initiative/Treatment Action!
Article Type:Report
Geographic Code:4E
Date:Sep 22, 2017
Words:3673
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