The ultimate goal of HIV care and treatment is to improve the duration and quality of life of persons with HIV. These goals are met through suppression of HIV RNA and restoration of immune function, which in turn decrease morbidity and mortality.^1–4 Viral suppression has population level benefits as well, in that persons who are virally suppressed have effectively no risk of sexually transmitting HIV to uninfected partners.⁵ To become and remain virologically suppressed, persons with HIV must be adherent to appropriate antiretroviral therapy (ART) throughout their lifetime. Although adherence is important to the outcomes of therapy, patients face multiple barriers to consistent adherence including lack of access, treatment fatigue, stigma, and comorbid conditions.^6,7

Given patients’ adherence barriers, potential history of nonadherence to therapy, and lifelong need for treatment, having a better understanding of what ART adherence level is necessary for viral suppression is valuable for clinicians when determining optimal antiretroviral (ARV) regimens for patients. Researchers have frequently set a benchmark for adherence at ≥95%. This threshold is mostly derived from a study conducted between 1997 and 1999, of persons on unboosted protease inhibitor therapy, which found that persons with adherence levels ≥95% (measured using a microelectronic monitoring system) had less virologic failure and increased CD4 lymphocyte count when compared with persons with adherence <95%.⁸ Other early studies showed similar results.^9,10 Although 95% has long been considered the gold standard of adherence to ART, a lower adherence level of ≥90% has been set by the Pharmacy Quality Alliance.¹¹ Given the enhanced pharmacokinetic profiles of newer ARV medications, even the lower adherence level of ≥90% may not be necessary to achieve HIV viral suppression.¹² As such, we used data from a national demonstration project to estimate the minimum adherence level required for HIV viral suppression.

Of the 765 participants, 570 had ≥1 HIV viral load test result with a corresponding PDC value and were, therefore, eligible for the analysis. More than half of these individuals were aged ≥50 years (53%), non-black or of unknown race/ ethnicity (59%), men (78%), and nonprivately insured (85%) (Table 1). Each person’s record contributed a median of 4 viral load test results (interquartile range [IQR]: 2–6) to the analysis. More than half (67%) of the 2427 viral load test results, included in the analysis, coincided with a PDC ≥90% in the previous 365 days and most (90%) were <200 copies/mL. The primary regimen types were: INSTI-based (31%), “all other” (30%), NNRTI-based (21%), and PI-based (18%) (Table 1).

After adjusting for demographic factors, within-person correlation, and ARV regimen type, we found that the odds of viral suppression did not differ significantly between persons with adherence levels between 80% and <85% or 85% to <90% and those with the Pharmacy Quality Alliance recommended adherence level of ≥90%. In addition, the overall estimated adherence level necessary to achieve viral suppression in 90% of HIV viral load tests was 82% and varied by regimen type; 90% of viral load tests associated with INSTI-based and NNRTI-based regimens were virally suppressed at adherence levels of 75% and 78%, respectively. These results indicate that the adherence level necessary to reach viral suppression may be lower than previously believed and may be more in line with the 80% adherence threshold often applied for other chronic diseases (eg, hypertension, hypercholesterolemia).¹⁶

Previous studies on the adherence threshold required for viral suppression are heterogeneous and often differ in the outcome of interest (eg, HIV RNA level of <50, <200, or <400 copies/mL), the adherence measure (eg, self-report, pill counts, medication possession ratios, and proportion of days covered), and the threshold for failure (eg, 10% or 20% of persons not suppressed) which makes comparisons between this and other studies somewhat difficult.^17–22 However, our finding of no significant difference in the adjusted odds of viral suppression with adherence between 80% and <85% or 85% to <90% and ≥90% is consistent with like studies.^17–23 For example, a meta-analysis of 43 studies which evaluated adherence thresholds and virologic outcomes, found no significant difference in the pooled odds of virologic failure at adherence levels of ≥95% or ≥98%–100% and adherence levels of ≥80%–90%.²¹ Similarly, using adherence self-report from a cohort study of men who have sex with men, Viswanathan et al¹⁷ found that ≥80% of persons were virally suppressed (<50 copies/mL) at adherence levels between 80% and 84%.

Although the adjusted odds of suppression were not statistically different between either INSTI-based or NNRTI-based regimens when compared with PI-based regimens, PI-based regimens required a higher adherence level to achieve viral suppression. Although this analysis was not powered to evaluate differences between regimen types, the higher adherence threshold we observed for PI-based regimens, is similar to other studies.^{18,20,22,24,25} However, our analysis did not distinguish between boosted and unboosted PI-based regimens, which might have accounted for some of the threshold differences. Regimens categorized as “all other” had lower adjusted odds of suppression and the highest adherence level necessary for viral suppression. The higher adherence level required for viral suppression with “all other” regimen types is not surprising given that this category includes regimens not considered adequate by treatment guidelines and because this category may represent non-standard or salvage regimens for persons who had previously failed therapy.¹

When examining the study’s “All regimen types” dose-response curve, high proportions of viral load tests were suppressed even with adherence levels around 60%. This result is similar to that of Gordon et al¹⁹ who found a virologic failure rate (defined as 2 consecutive viral loads test results ≥200 copies/mL) for 3 first-line ARV regimens of approximately 20% at adherence levels of roughly 60%. The modest adherence levels necessary for viral suppression, seen in this analysis, is reflective of the improved potency and efficacy of newer ARV medications.¹²

Non-Hispanic black persons, younger persons and women had lower odds of viral suppression even after adjustment for adherence level and regimen category; the reasons for this are unclear. However, achieving viral suppression is dependent on factors additional to adherence such as underlying drug resistance and drug–drug or drug–food interactions, which can affect effectiveness of therapy.^26–28 This analysis was unable to account for these other determinants of viral suppression in any demographic group.

Although we estimate that an overall adherence level of 82% is necessary for viral suppression in 90% of viral load tests, with lower thresholds for INSTI- and NNRTI-based regimens, these results should be used with caution. In addition to the risk of virologic rebound, poor adherence is associated with development of drug resistance (which can potentially reduce future treatment options), systemic inflammation, and higher health care use and costs.^{21,22,29–34} In particular, drug resistance is more common with NNRTI-based regimens in the absence of viral suppression.²⁹ Clinicians’ message to patients should, therefore, remain “every dose every day” and be accompanied by continuous adherence counseling and support.³⁵ These results may be useful when considering patients’ adherence barriers and optimal ARV regimens for these patients. In addition, a PDC of ≥82% may be sufficient to indicate adequate adherence when measuring PDC levels in pharmacy claims or fulfillment data not linked to viral load test results.

The study results should be viewed in light of its limitations. First, the PDC is a proxy for adherence. The PDC measures the amount of time a person has medication available, not actual pill-taking behavior; therefore, adherence was likely overestimated. In addition, the PDC does not measure 2 other important facets of adherence: whether a person takes their medication according to the prescriber’s instruction or on the prescribed schedule. However, using pharmacy fulfillment data to calculate adherence has an advantage over some other methods (eg, self-report, pill counts, and electronic monitoring) that are potentially confounded by social desirability and recall bias or expense.³⁶ For this analysis, accurate PDC measurement required a closed pharmacy system; adherence would be underestimated if persons filled ARV prescriptions outside of the project pharmacy network. This analysis did not take into account the amount of time a person was virally suppressed; therefore, the analysis did not account for the decreased risk of virologic failure after prolonged periods of viral suppression.³⁷ In addition, the analysis did not account for time since treatment initiation. The analysis, therefore, did not account for potentially higher adherence needed to achieve viral suppression in the first year after treatment initiation. Finally, participants in the PCHCM demonstration project represented a convenience sample which limits generalizability.

These data indicate that overall HIV viral suppression can be achieved for 90% of HIV viral load tests with an estimated ART adherence level of 82%, which is similar to that applied to other chronic diseases. The adherence threshold varied by regimen type with both INSTI-based and NNRTI-based regimens achieving viral suppression with even lower adherence levels (75% and 78%, respectively), suggesting that some regimen types may be more forgiving of missed doses than others. These results are reflective of the improved potency and efficacy of newer ARV medications. Although this analysis found an adherence level necessary for viral suppression that was lower than the conventionally reported values of ≥90% or ≥95%, clinicians should be encouraged to continue to advise patients to take all of their medications, as prescribed, to identify and address adherence barriers and to offer continuous adherence support.