Secondary Logo

Journal Logo

Epidemiology and Prevention

Adherence and HIV RNA Suppression in the Current Era of Highly Active Antiretroviral Therapy

Viswanathan, Shilpa MS, PhD*; Justice, Amy C. MD, PhD†,‡; Alexander, G. Caleb MD, MS*; Brown, Todd T. MD, PhD*,§; Gandhi, Neel R. MD‖,¶,#; McNicholl, Ian R. PharmD, FCCP, BCPS, AAHIVP**; Rimland, David MD#,††; Rodriguez-Barradas, Maria C. MD‡‡,§§; Jacobson, Lisa P. ScD*

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1, 2015 - Volume 69 - Issue 4 - p 493-498
doi: 10.1097/QAI.0000000000000643

Abstract

INTRODUCTION

Over the past decade, the proportion of individuals on highly active antiretroviral therapy (HAART) who achieve HIV RNA suppression has increased dramatically.1 This success has been attributed to improved medication adherence because of decreased HAART toxicity, fixed-dose combination pills, and simplified dosing strategies.2,3

With improved second-generation formulations of nonnucleoside reverse transcriptase inhibitors (NNRTIs) (eg, rilpivirine, etravirine), protease inhibitors (PIs) (eg, darunavir, atazanavir), and newer classes like integrase strand transfer inhibitors (INSTIs) (eg, raltegravir), levels of adherence as those required with early HAART regimens (ie, ≥95%)4,5 may not be needed for maximal treatment effectiveness. A better understanding of the levels of adherence needed for effective treatment in the current era of HAART could further inform clinical care and also alleviate provider concerns about prescribing HAART to patients with barriers to adherence at early stages of HIV infection (eg, high-risk behaviors, sociodemographics, and comorbidities).6

We sought to determine whether adherence to HAART and HIV RNA suppression have changed over time and estimate the minimum optimal adherence level for HIV RNA suppression by HAART regimen type using data from a large, population-based cohort study.

METHODS

Source Population

The analysis used longitudinal pharmacy refill data collected prospectively from HIV-positive persons on HAART and followed in the Veterans Aging Cohort Study Virtual Cohort from October 1, 2000 to September 30, 2010. Details of the Veterans Aging Cohort Study Virtual Cohort have been previously described.7 Laboratory and clinical data and outpatient prescriptions for each subject were obtained by linking Immunology Case Registry and Pharmacy Benefits Management Registry records, respectively.8 HAART was defined using the Department of Health and Human Services (DHHS) guidelines.9 Only person-years in which HAART was used for at least 180 days in the year were included.

For each person-year, we used the regimen most frequently refilled to classify HAART as NNRTI-based, PI-based (including users of PIs, and both NNRTIs and PIs), INSTI-based, or 3 nucleoside reverse transcriptase inhibitors containing abacavir or tenofovir. We classified regimens as being single versus multi-pill and whether administered once-daily versus twice-daily.

Outcomes and Exposures

Because HIV RNA levels were determined using assays with varying detection limits,8 we used values of <400 copies per milliliter as nondetectable viral load and used the last HIV RNA test of the year for analyses. Sustained suppression was examined among those with multiple viral load measurements in a year and was defined as having undetectable levels following their first measurement if suppressed.

We calculated adherence to HAART using the medication possession ratio defined by Steiner and Prochanska,10 which measures the duration of time the patient had the medications available, relative to the total number of days between refills. This was calculated for each person-year that contained at least 1 refill as follows:

We excluded stockpilers (20.2% of study population), defined as person-years with a refill frequency exceeding the scheduled dosing interval by more than 5%, because the Steiner algorithm was not validated in this subgroup.8,11

Potential confounders of viral load suppression and adherence included sociodemographic, behavioral, disease, and treatment characteristics. Fixed characteristics included race, smoking, and geographical location obtained at the first time seen after October 1, 2000 (baseline). Time-varying factors for each year included alcohol abuse, drug abuse, and major depression obtained using the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes recorded at 1 inpatient visit and 2 outpatient visits, the number of antiretrovirals used, number of days in possession of HAART regimens, regimen type, time since first HAART initiation, and mean CD4 cell count.

Statistical Methods

We graphically depicted temporal trends of adherence, suppression, regimen type, and dosing frequency from 2001 to 2010. The change in adherence over time was determined using linear mixed-effects models with adherence percent as outcome, accounting for repeated measures over time, and adjusting for confounders. In sensitivity analysis, we restricted the entire population to (1) those who were in follow-up after January 1, 2009 (ie, including those starting before or after 2009, but in follow-up between 2009 and 2010) to avoid a biased temporal trend because of earlier attrition of those with worse outcomes from low adherence and (2) person-years on the first HAART regimen because switching regimens may not be random and may result from lower adherence and drug resistance.

We defined the minimum optimal adherence as the level of adherence at which the odds of suppression were not statistically different from that observed among those with ≥95% adherence. To focus on newer HAART regimens, we restricted this analysis to data from 2006 onward and used logistic regression with viral load suppression as the outcome and adherence percent as the primary exposure controlling for repeated measures over time and adjusting for confounders. Because characteristics informing prescribing patterns may affect adherence and HIV RNA suppression, we adjusted for this possible confounding by indication using propensity scores to weight the repeated-measures logistic regression model. The propensity score for using an NNRTI-based regimen was determined by logistic regression, which included age, race, geographical location, time since first HAART initiation, and CD4 count, HIV RNA suppression, drug abuse, alcohol abuse, and major depression diagnosis lagged to the previous year. Using the propensity score, weights were generated as the average treatment effect for the treated (ATT) and included in the repeated-measures logistic regression model as a covariate.

In sensitivity analyses, we varied the restriction on the number of days on HAART in the year to 270 and 330 days. All analyses were performed using SAS 9.2 (SAS Institute, Inc., Cary, NC) and STATA 12.1 (StataCorp. 2011, Stata Statistical Software, College Station, TX); P < 0.05 was used to define statistical significance.

RESULTS

Study Population Characteristics

A total of 21,865 HAART users contributed 82,217 person-years between October 1, 2000 and September 30, 2010. At baseline, the mean age was 45.7 (standard deviation: 9.9) years; 98% were male, and 46.5%, 41.6%, and 7.6% were black, white, and Hispanic, respectively (Table 1). Almost 60% were current smokers, 47% used Veterans Affairs (VA) facilities in the South, 23.3% in the Northeast, and less than 20% in the Midwest and West, respectively. Unadjusted, those with ≥95% adherence were older, less likely to have abused alcohol or drugs, and had higher CD4 cell counts compared to those with lower adherence during follow-up.

T1-17
TABLE 1:
Characteristics of Study Population (2001–2010)

The use of PI-based and NNRTI-based multi-pill regimens declined between 2001 and 2010 from 65% to 43% and from 33% to 16%, respectively (see Figure S1, Supplemental Digital Content, https://links.lww.com/QAI/A671). Single-pill regimen use and INSTI-based regimen use increased steeply since 2006 from 1% to 29% and from 0% to 11% respectively, in 2010. All the participants on single-pill regimens were using efavirenz (EFV)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC).

Adherence

The proportion of HAART users with ≥95% adherence increased marginally from 37% in 2001 to 42% in 2010 (Fig. 1). More users of NNRTI-based regimens were ≥95% adherent than users of PI-based regimens. Up to 2006, multi-pill regimens were associated with significantly better adherence if taken once-daily versus twice-daily (see Figure S2, Supplemental Digital Content, https://links.lww.com/QAI/A671). From 2006 onward, users of single-pill regimens had better adherence than those using regimens composed of multiple pills and doses. After accounting for within-person correlation, there was a 13% increase in the adherence every 2 years on average (see Table S1, Supplemental Digital Content, https://links.lww.com/QAI/A671).

F1-17
FIGURE 1:
Distribution of ≥95% adherence over time (2001–2010). The proportion of person-years with ≥95% adherence. The HAART regimens can be identified as blue line for NNRTI-based regimens, red line for PI-based regimen, and green line for INSTI-based regimen. The HAART regimen is the most frequently refilled regimen for each person-year. INSTI-based regimen use is 2008–2010. NNRTI-based regimen includes single-pill and multi-pill regimens; 82,217 person-years were used for this analysis.

HIV RNA Suppression

Among those with <95% adherence, the proportion suppressed increased over time from 38% in 2001 to 84% in 2010 (Ptrend < 0.001) (Fig. 2A) and did not appreciably differ when restricted to persons who were in follow-up after 2009 or on their first HAART regimen. This increase in viral suppression was observed even among those with 75%–79% adherence (Fig. 2B). Across all years, HAART users had an average of 3 HIV RNA tests per year, and the proportion with sustained viral load increased over time from 77.5% in 2001 to 92.0% in 2010. This trend occurred across regimen types but at different levels (see Figure S3, Supplemental Digital Content, https://links.lww.com/QAI/A671).

F2-17
FIGURE 2:
A, Proportion suppressed among those with <95% adherence (2001–2010). The proportion of person-years suppressing HIV RNA among those with <95% adherence: blue line for all persons, red line for persons who were in follow-up after 2009, and green line for persons on their first HAART regimen. B, Proportion suppressed among those with <95% adherence (2001–2010). The proportion of person-years suppressing HIV RNA among those with <95% adherence by levels of adherence between 75% and 95% divided into 4 groups: blue line for 75%–79%, red line for 80%–84%, green line for 85%–89%, and purple line for 90%–94%.

Minimum Optimal Adherence

Overall, HIV RNA suppression for persons with 90%–94% adherence did not differ from those with ≥95% adherence [odds ratios (ORs): 1.05 (0.91–1.21)] (see Table S2, Supplemental Digital Content, https://links.lww.com/QAI/A671). However, the proportion suppressed among users of an NNRTI-based regimen was higher at all adherence levels compared to that among users of PI-based and INSTI-based regimens (Fig. 3). The significant (P < 0.05) difference in the minimum optimal adherence by regimen type persisted even after adjusting for the propensity for using NNRTIs, and therefore, we used stratified analyses to identify treatment-specific cutoffs. Users of PI-based regimens were less likely to suppress virus if <95% adherent compared to ≥95% adherent [eg, 90%–94% adherence, OR: 0.88 (0.77–0.99)] (Fig. 4). Conversely, among NNRTI users, the odds of HIV RNA suppression at adherence levels as low as 85% did not significantly differ compared to that with ≥95% adherence [OR: multi-pill users: 0.82 (0.64–1.04), single-pill users: 0.88 (0.69–1.11)]. There were no differences in the proportions virally suppressed in NNRTI users with 90%–94% adherence compared to ≥95% adherence [OR: 1.10 (0.89–1.36)].

F3-17
FIGURE 3:
Proportion suppressed by adherence category (2006–2010). The proportion suppressing HIV RNA by levels of adherence in the current HAART era. The HAART regimens can be identified as green line for NNRTI-based single pill, light blue line for NNRTI-based multi-pill, red line for PI-based regimen, purple line for INSTI-based regimen, and black line for all persons. The HAART regimen is the most frequently refilled regimen for each person-year. INSTI-based regimen use is 2008–2010.
F4-17
FIGURE 4:
ORs and 95% confidence interval (CI) of HIV RNA suppression by adherence category (2006–2010). The dots in the forest plot represent the OR estimates, and the bars represent the 95% CI. The ORs come from a repeated-measures logistic regression model with viral load suppression as outcome and adherence levels as exposure, adjusted for age, race, alcohol abuse, major depression, drug abuse, geographical location, and time since first HAART initiation. The size of the dots represents the sample size of the exposure category. The HAART regimens can be identified as green triangle for PI-based regimen, red square for NNRTI-based single-pill regimen, and blue diamond for NNRTI-based multi-pill regimen. The HAART regimen is the most frequently refilled regimen for each person-year. INSTI-based regimen use is 2008–2010; 48,308 person-years were used for this analysis.

Sensitivity analyses by varying the number of days on HAART inclusion criterion and restricting to the first HAART regimen did not alter our results appreciably (see Figure S4, Table S3, Supplemental Digital Content, https://links.lww.com/QAI/A671).

DISCUSSION

In this population of HIV-infected treated persons seeking care at a Veterans Health Administration Center, adherence and viral load suppression improved between 2001 and 2010, concomitant with use of newer HAART regimens. The proportion suppressed increased over time even among those with less than perfect adherence. More of those using NNRTI-based regimens had adherence ≥95%, and also a higher proportion suppressed at lower levels of adherence compared to those using other regimens.

The utilization of newer HAART regimens in this study population is similar to that in other HIV-infected populations.12 Single-pill use began in 2006 and rose to almost 30% in 2010. The higher adherence observed with the use of single-pill regimens conforms with studies contrasting the ease of use of single-pill regimens and once-daily formulations with multi-dose regimens12–17 and also with studies of medication use in the general population.18 Lower toxicity profiles may also have contributed to improved adherence to newer drugs. Our estimation was restricted to those who were on HAART for at least 180 days in the year. Given that the complement comprised persons who just started HAART and the poorest adherers, that is, those who discontinued treatment, their inclusion would serve to dampen the estimate of high adherence. However, because the proportion of HAART users with less than 180 days on HAART decreased over time (data not shown), our finding of improved adherence over time is conservative.

In addition to being easier to administer, newer HAART formulations do not necessitate consistently high levels of adherence for viral load suppression as required by older HAART formulations.2,16 Second-generation drugs have enhanced pharmacokinetic profiles, lower toxicities, and lower resistance rates and lead to sustained viral load suppression.2,19,20 Our finding of a higher proportion sustaining viral load suppression in the latter era compared to the earlier era is consonant with the improved effectiveness of the newer drugs. Although a relatively new formulation, INSTI-based regimens had a lower proportion suppressed over time compared to other regimens. This maybe attributed to the fact that this was the first-line regimen for less than 1% of the study population; their initial use was therefore predominantly as a salvage regimen for patients with failed previous regimens, who were, as a consequence, more prone to virologic failure.

Our data suggest that adherence levels lower than 95% maybe sufficient for viral load suppression in populations using newer NNRTI formulations. Although based on relatively imprecise estimates (ie, wide confidence intervals), 85%–89% adherence on NNRTI-based regimens maybe sufficient for viral load suppression; 82.2% of this group suppressed virus compared to 84.6% of those with ≥95% adherence. The inference of effective treatment with less than perfect adherence concurs with the literature, suggesting that on the basis of pharmacy refill data, chronically ill patients using 80% of their medications are generally categorized as being adherent to their treatment.21 Although being 85% adherent to HAART maybe sufficient for optimal virologic outcomes in a population, we would like for this message to be interpreted with caution at the individual level. Several non-HAART–related barriers, such as treatment access, behavioral factors, and comorbidities, may lead to suboptimal adherence, resistance, and treatment failure.3 Providers must continue to encourage patients to achieve perfect adherence, but comprehensive adherence improvement strategies maybe administered on a case-by-case basis.22

There were limitations in our study. We calculated adherence using pharmacy refill records, making the assumption that the medications were used as dispensed. Although pharmacy refill records have the disadvantage that they may misrepresent adherence,3 they are not associated with recall error and social desirability bias as with other adherence measures like self-report and pill count.3 Although our findings are generalizable because of the large sample size with a widespread geographical distribution in the United States, extrapolating our findings to women is limited because our population was predominantly male. The population had a higher CD4 count on average and a higher proportion suppressed while on HAART than some other studies,23 and this may indicate different medication choices in this population. The generalizability of our findings is also limited because of the population being insured through the VA, indicating good access to care. The internal validity of our study is, however, boosted by this very fact because 98% of the participants do not refill their prescriptions outside the VA.24 Resistance data were not available, and hence, we do not know if PI-based regimens were used preferentially among patients with known resistance or known poor adherence.

Despite the limitations, our study had several strengths. More than 20,000 HAART users were followed up for >10 years, allowing us to reliably examine trends in adherence and viral load suppression and determine the minimum adherence cutoff by HAART regimen type after controlling for potential confounding by indication. Our findings regarding NNRTI-based regimens having relatively better adherence and virologic outcomes will enrich research on adherence in the current era by focusing attention to very low adherers. These data also serve as a guide for providers treating HIV-infected persons.

An integral component of the treatment of HIV like other chronic illnesses is adherence. With newer HAART regimens, adherence is easier, and high adherence levels are not required for viral load suppression. Providers should not let concerns regarding barriers to adherence hinder the prescription of newer HAART regimens at early stages of the disease.25 A recent report by the Institute of Medicine on HIV treatment and quality of care states that “improving access to, and consistent use of medicines by HIV-infected individuals would decrease their risk of transmitting the virus to others.”26 Efforts must be made to maximize the prescription and use of single-pill regimens. Future work should focus on the use of other approved single-pill regimens and newer drugs now included as recommended regimens in more recent guidelines and their use in populations with poor access to and retention in care.

REFERENCES

1. Althoff KN, Buchacz K, Hall HI, et al.; North American AIDS Cohort Collaboration on Research and Design. U.S. trends in antiretroviral therapy use, HIV RNA plasma viral loads, and CD4 T-lymphocyte cell counts among HIV-infected persons, 2000 to 2008. Ann Intern Med. 2012;157:325–335.
2. Hughes CA, Robinson L, Tseng A, et al.. New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir. Expert Opin Pharmacother. 2009;10:2445–2466.
3. Kobin BA, Sheth NU. Levels of adherence required for virologic suppression among newer antiretroviral medications. Ann Pharmacother. 2011;45:372–379.
4. Paterson DL, Swindells S, Mohr J, et al.. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21–30.
5. Nelson M, Girard PM, DeMasi R, et al.. Suboptimal adherence to darunavir/ritonavir has minimal effect on efficacy compared with lopinavir/ritonavir in treatment-naïve HIV-infected patients: 96 week ARTEMIS data. J Antimicrob Chemother. 2010;65:1505–1509.
6. Westergaard RP, Ambrose BK, Mehta SH, et al.. Provider and clinic-level correlates of deferring antiretroviral therapy for people who inject drugs: a survey of North American HIV providers. J Int AIDS Soc. 2012;15:10.
7. Fultz SL, Skanderson M, Mole LA, et al.. Development and verification of a “virtual” cohort using the national VA health information system. Med Care. 2006;44(suppl 2):S25–S30.
8. Braithwaite RS, Kozal MJ, Chang CCH, et al.. Adherence, virologic and immunologic outcomes for HIV-infected veterans starting combination antiretroviral therapies. AIDS. 2007;21:1579–1589.
9. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. USA; 2014. Available at: http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed May 2014.
10. Steiner JF, Prochanska AV. The assessment of refill compliance using pharmacy records: methods, validity, and applications. J Clin Epidemiol. 1997;50:105–116.
11. Steiner JF, Kopesell TD, Fihn SD, et al.. A general method of compliance assessment using centralized pharmacy records: description and validation. Med Care. 1988;26:814–823.
12. 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.
13. Cooper V, Horne R, Gellaitry G, et al.. The impact of once-nightly versus twice-daily dosing and baseline beliefs about HAART on adherence to efavirenz-based HAART over 48 weeks: the NOCTE study. J Acquir Immune Defic Syndr. 2010;53:369–377.
14. Gallant JE, DeJesus E, Arribas JR, et al.. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine and efavirenz for HIV. N Eng J Med. 2006;354:251–260.
15. Cooper V, Horne R, Moyle G, et al.; The SWEET Study Group. Simplification with easier emtricitabine and tenofovir (SWEET): results of a 48 week analysis of patients' perceptions of treatment and adherence. Paper presented at: The XVII International AIDS Conference; August 3–8, 2008; Mexico City, Mexico [abstract].
16. Maggiolo F, Airoldi M, Kleinloog HG, et al.. Effect of adherence to HAART on virologic outcome and on the selection of resistance-conferring mutations in NNRTI- or PI-treated patients. HIV Clin Trials. 2007;8:282–292.
17. Nachega JB, Parienti JJ, Uthman OA, et al.. Lower pill burden and once-daily dosing antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials. Clin Infect Dis. 2014;58:1297–1307.
18. Choudhary NK, Fischer MA, Avorn J, et al.. The implications of therapeutic complexity on adherence to cardiovascular medications. Arch Intern Med. 2011;171:814–822.
19. Moline JM, Andrade-Villanueva J, Echevarria J, et al.. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53:323–332.
20. Bangsberg D. Less than 95% adherence to nonnucleoside reverse-transcriptase inhibitor therapy can lead to viral suppression. Clin Infect Dis. 2006;43:939–941.
21. Ho MP, Bryson CL, Rumsfeld JS. Medication adherence: its importance in cardiovascular outcomes. Circulation. 2009;119:3028–3035.
22. Simoni JM, Amico KR, Pearson CR, et al.. Strategies for promoting adherence to antiretroviral therapy: a review of the literature. Curr Infect Dis Rep. 2008;10:515–521.
23. Malta M, Magnanini MMF, Strathdee SA, et al.. Adherence to antiretroviral therapy among HIV-infected drug users: a meta-analysis. AIDS Behav. 2010;14:731–747.
24. Justice AC, Dombrowski E, Conigliaro J, et al.. Veterans Aging Cohort Study (VACS): overview and description. Med Care. 2006;44(suppl 2):S13–S24.
25. Franco RA, Saag MS. When to start antiretroviral therapy: as soon as possible. BMC Med. 2013;11:147.
26. Monitoring HIV Care in the United States. Indicators and Data Systems. Institute of Medicine of the National Academies. USA; 2012. Brief Report. Available at: http://www.iom.edu/∼/media/Files/Report%20Files/2012/Monitoring-HIV-Care-in-the-United-States/MonitoringHIV_rb.pdf. Accessed May 2014.
Keywords:

adherence; current HAART; HIV RNA suppression; Veterans Health Administration Center

Supplemental Digital Content

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.