Antiretroviral Adherence and Pharmacokinetics: Review of Their Roles in Sustained Virologic Suppression

Abstract

High levels of adherence to antiretrovirals are important to prevent the development of genotypic resistance and achieve virologic suppression. Although the decreased complexity of regimens is associated with improved adherence, there is little evidence that adherence is better with once-daily dosing regimens compared to twice-daily regimens. The relationship between adherence, resistance, and virologic suppression is different for different classes of antiretrovirals. Boosted protease inhibitor (PI)-based regimens are preferred to unboosted PI-based regimens for patients with poor adherence. With PI-based regimens, the pharmacologic consequence of a single missed dose is greater with a once-daily regimen than with a twice-daily regimen (e.g., once-daily versus twice-daily lopinavir/ritonavir). Although resistance is a concern for patients taking non-nucleoside reverse transcriptase inhibitor-based regimens with imperfect adherence, virologic suppression can be achieved with less than 95% adherence. It is important for clinicians to address adherence problems in their patients and to tailor individual regimens based on treatment history, genotype resistance, side effect profile, drug interactions, pharmacokinetics, schedule preferences, and perceived adherence.

Introduction

T he interplay between adherence, pharmacokinetics, and genotypic resistance on the likelihood of virologic suppression has been extensively studied. However, the optimal antiretroviral regimen for maximizing long-term clinical benefit is still debated. Multiple studies have found that the level of adherence is directly correlated with the likelihood of virologic suppression.^1
–3 An early study found that adherence greater than 95% was required to achieve sustained virologic suppression. However, this study was conducted during an era of unboosted protease inhibitor (PI)-based regimens.¹ Ritonavir-boosted PI regimens take advantage of the pharmacokinetic enhancement and allow for a simpler dosing schedule and lower pill burden. This is a lofty goal, because adherence rates in the clinic range widely, from 53% to 93%.^2,4 The large variation in adherence rates observed between various cohorts and studies is due to differences in patient populations and the definition of adherence. For example, a 53% adherence rate was based on the percentages of doses taken in 1 week by patients with a history of active intravenous drug use using a Medication Event Monitoring System (MEMS) caps.² On the other hand, an exceptional adherence rate of 93% was measured by self-report in patients who took more than 95% of their doses in the previous 4 weeks.⁴ In general, self-report adherence rates are higher than MEMS caps objective measurements, but they are both well correlated with the likelihood of virologic suppression.^2,5 Similarly, pill count was closely correlated with self-report and MEMS caps.⁶ There is a strong relationship between viral suppression and all independent measures of adherence.^2,5,6

Simplification of Antiretroviral Regimens

Once- and twice-daily regimens

The complexity of regimens has a negative impact on adherence.^4,7 In a cross-sectional evaluation of the Swiss HIV cohort study, nonadherence, defined as taking fewer than 95% of doses in the last 4 weeks, was more likely in a nonboosted PI regimen (odds ratio [OR] 1.70), a boosted PI regimen (OR 1.98), or a triple nucleoside regimen (OR 2.03) compared with a non-nucleoside reverse transcriptase inhibitor (NNRTI).⁴ Other factors that may decrease adherence rates to highly active antiretroviral therapy (HAART) include younger age, high pill burden, depression, lack of social support, and self-reported side effects.^4,7 A population-based cohort study also found that mean adherence decreases significantly over time, from 79% within the first 6 months of starting HAART to 72% within the 24- to 30-month period (p < 0.01).⁸ As expected, patients with incomplete adherence over time are 3.13 times more likely to die than are those with high-level adherence (≥95%). Patients treated with an NNRTI-based regimen and boosted PI-based regimen are 3.61 and 3.25 times more likely to die compared with those with high-level adherence.⁸ Various adherence programs have been implemented in HIV clinics to improve patients' adherence, but only interventions targeting practical medication management skills delivered over 12 weeks or more were associated with improved adherence outcomes.⁹ A pillbox organizer is a cost-effective way to improve adherence and has been shown to improve adherence by 4%; moreover, it has been associated with a 15% higher probability of virologic suppression.¹⁰ Another approach that has been proposed to improve adherence rates is the simplification of HAART regimens to once-daily administration.¹¹ However, it is unclear if adherence is improved with once-daily HAART regimens compared with more frequent dosing.¹² The adherence rate is generally inversely proportional to the frequency of drug administration, but it does not substantially decrease until patients are asked to take a drug 4 times a day.¹³ With other therapy, such as antiepileptic drugs, the adherence rate is 87% with once-daily dosing, 81% with twice-daily dosing, 77% with drugs taken three times a day, and 39% with drugs taken four times a day (using the MEMS device).¹³ A questionnaire study assessed patient perceptions of several different HAART regimens, including those given once daily, and their impact on adherence. Although once-daily dosing was preferred, there was no significant difference on the perceived likelihood of adherence between once- and twice-daily regimens as long as the pill burden in the twice-daily group was simple (2–3 pills per administration) and food and morning/bedtime restrictions were limited.¹² When several prospective studies evaluated the efficacy of simplification from a twice-daily to a once-daily regimen in virologically suppressed patients, simplification did not have a clinical benefit.^14
–16

However, it should be noted that the studied regimens of an NNRTI plus didanosine and tenofovir or an NNRTI plus zidovudine, abacavir, and lamivudine once-daily are not recommended by the Department of Health and Human Services.¹⁷ In patients with sustained virologic suppression, simplification to once-daily unboosted atazanavir from more frequently administered PI regimens resulted in less virologic rebound compared to those who continued to receive comparator PIs (7% versus 16%; p = 0.004).¹¹ The higher proportion of sustained virologic suppression with once-daily atazanavir was only observed when patients were switched from unboosted PI regimens with known inferior pharmacokinetic properties (i.e., nelfinavir, indinavir, and saquinavir).

The convenience of a once-daily PI-based-regimen is appealing, but the pharmacologic consequence of a missed dose is greater with a once-daily compared with a twice-daily regimen. Furthermore, the likelihood of missing a single dose in a once-daily regimen is higher than missing two or three consecutive doses in a twice-a-day regimen.¹⁸ Although total drug exposure (area under the curve) is similar between once- and twice-daily boosted PI regimens, the trough concentrations are lower and more variable with once-daily regimens. For example, trough concentrations for soft-gel capsule lopinavir/ritonavir 800 mg/200 mg once daily and lopinavir/ritonavir 400/100 mg twice daily is 3.22 μg/mL (SD ± 2.07) and 6.56 (SD ± 3.71), respectively (p < 0.05).¹⁹ Another disadvantage of once-daily lopinavir administration is a higher rate of moderate to severe diarrhea (5% versus 16%; p = 0.036). This led to a higher rate of discontinuation in the once-daily group, but it is unclear if the same rates of gastrointestinal intolerance would have occurred with the newer tablet formulation. No differences in virologic responses between the once- and twice-daily regimens were observed in these PI-naive patients through 48 weeks; 70% and 64%, respectively, achieved an HIV-1 RNA level less than 50 copies per milliliter.¹⁹ The potential advantage to once-daily dosing is the ability to have a directly observed therapy (DOT) program, but this benefit should be weighed against factors such as baseline viral load, pharmacokinetics, and genotypic resistance. In a three-arm, open-label, 48-week study, antiretroviral therapy (ART)-naive patients were stratified by screening RNA greater than 100,000 copies per milliliter to receive in a 2:2:1 ratio lopinavir/ritonavir 400/100 mg twice daily, lopinavir/ritonavir 800/200 mg once daily self-administered, and lopinavir/ritonavir 800/200 mg DOT. Patients in the DOT group came to clinic Monday through Friday (weeks 0 to 24) but received self-administered once-daily lopinavir/ritonavir after week 24. Visit compliance was 86% in the DOT group. The probability of sustained virologic response through week 24 was higher for the DOT arm than for the once daily self-administered arm (91% versus 84%), but as expected, the rate of virologic suppression was not significantly different when the DOT intervention was stopped. Overall, the result of twice- versus once-daily lopinavir/ritonavir did not differ significantly; however, in the HIV stratum of HIV RNA greater than 100,000 copies per milliliter, sustained virologic suppression was significantly higher in the lopinavir/ritonavir twice-daily arm than in the lopinavir/ritonavir once-daily arm (89% versus 76%, p = 0.038).²⁰

In another randomized, controlled trial, no significance difference in virologic suppression was observed between directly administered antiretroviral therapy (DAART), intensive adherence case management (IACM) intervention, and standard of care.²¹ Undetectable viral load at 6 months between the DAART, IACM, and standard-of-care groups were 54%, 60%, and 54%, respectively. During the course of this study, all patients could receive one-on-one adherence counseling from providers, in addition to the DOT 5 days per week (DAART group) and weekly adherence counseling with a case manager (IACM group). Adherence counseling support received in the standard-of-care group may have been the reason for the lack of a clinically significant difference in virologic response between the three groups. Implementing DOT programs for all patients may be too costly but may be beneficial to a targeted group of patients with risk factors for nonadherence. Similar to studies in adult patients, virologic suppression is associated with self-reported adherence in pediatrics and adolescents. The adherence rates in adolescent cohorts are low, with only 41% reporting good adherence and 28% reporting taking all of their prescribed antiretrovirals in the previous month.^22,23 The most common reasons given for nonadherence to HAART are simply forgot, did not have medication with them, and change in daily routine.²³ In another observation study, having too many pills to take was the most commonly reported reason for missing medication.²⁴ In an analysis of Pediatric AIDS Clinical Trials Group studies involving 2088 children and adolescents, child and provider characteristics were examined to determine the relationship between self-reported medication adherence to health, demographics, and psychosocial issues. In a multivariate analysis, factors such as older children, female gender, stressful life events, and diagnosis of depression were associated with nonadherence.²⁵ In younger children (ages 3–13), poor parent–child communication, caregiver stress, and less social disclosure of HIV status to others were psychosocial and family factors that were significantly associated with poor adherence.²⁶ Based on these findings, it is important to tailor an antiretroviral regimen that will fit the busy lifestyle of an adolescent in addition to supporting the family environment to optimize adherence.

Relationship Between Adherence and Resistance for Different Antiretroviral Regimens

PI-based regimens

Boosted PI-based regimens are generally favored by clinicians when treating patients at high risk for nonadherence. When boosted lopinavir was compared to unboosted nelfinavir in a prospective clinical trial, the development of resistance was more common in nelfinavir-treated patients regardless of adherence level. Nelfinavir resistance was observed in 20% of patients with an 85%–90% level of adherence, whereas no resistance to boosted lopinavir was observed with the same degree of adherence. Virologic efficacy was directly correlated with the level of adherence in both groups, but an adherence rate of at least 72% was sufficient in lopinavir/ritonavir-treated patients, whereas greater than 83% was needed for nelfinavir-treated patients to obtain a greater than 50% probability of never having a detectable viral load.²⁷ Similarly, another observational study found that virologic suppression with a lopinavir/ritonavir-based regimen was achieved with a mean adherence rate of 73%.²⁸ This is not a surprising finding, since an unboosted PI barely achieves the desired trough concentrations associated with good virologic suppression (Table 1).^29
–31 Although adherence remains a crucial factor in maximizing viral suppression, this study suggests that a boosted lopinavir regimen offers a higher level of “forgiveness.” Unlike unboosted PIs with a low pharmacokinetic barrier to resistance or NNRTIs (e.g., nevirapine and efavirenz) with a low genetic barrier to resistance, all boosted PI regimens offer a pharmacokinetic advantage as well as a high genetic barrier to resistance. Similar to lopinavir, genotypic resistance to other boosted PIs is uncommon in treated antiretroviral-naive patients experiencing virologic failure. In a 48-week open-label study, fos-amprenavir/ritonavir (1400 mg/200 mg once daily) or nelfinavir (1250 mg twice daily) both combined with abacavir/lamivudine were compared in ART-naive patients. There was no emergence of PI resistance in the fos-amprenavir/ritonavir treatment group, versus 50% emergence resistance in the nelfinavir treatment group (p < 0.001). There was also less NRTI resistance in the fos-amprenavir/ritonavir group compared with the nelfinavir group (13% versus 69%; p < 0.001).³²

Table 1.

Effect of Ritonavir Boosting on the Minimum Drug Concentration (C_min) of Selected Protease Inhibitors

Expected C_min	C_min associated with virologic suppression
ATV 400 mg once daily: 0.27 μg/mL (95% CI, 0.21–0.51)	0.15 μg/mL^20,28,29
ATV/r 300/100 mg once daily: 0.86 μg/mL (95% CI, 0.58–1.53)
FPV 1400 mg twice daily: 0.35 μg/mL (95% CI, 0.27–0.46)	0.4 μg/mL^21,29,30
FPV/r 700/100 mg twice daily: 2.12 μg/mL (95% CI, 1.77–2.54)
IDV 800 mg every 8 hours: 0.127 μg/mL (95% CI, 0.098, 0.17)	0.1 μg/mL³¹
IDV/r 800/100 mg twice daily: 1.396 μg/mL (95% CI, 0.99, 1.99)

CI, confidence interval; ATV, atazanavir; ATV/r, atazanavir/ritonavir; FPV, fos-amprenavir; FPV/r, fos-amprenavir/ritonavir; IDV, indinavir; IDV/r indinavir/ritonavir.

NNRTI-based regimens

Resistance is more common to NNRTI- than PI-based regimens. Among patients with a 0%–48% adherence rate, resistance developed in 69% of those treated with an NNRTI-based regimen, versus 23% of those treated with an unboosted PI-based regimen (p = 0.01).³³ An observational study found that virologic suppression can be achieved with adherence of only 53%–73% to NNRTI-based regimens.³⁴ However, in a large cohort study involving 2821 patients, NNRTI-based regimens achieved virologic suppression in only 25% of patients with 50%–60% adherence but increased linearly to 73% with 90%–100% adherence.³⁵ It was observed that a 10% increase in adherence beyond 50% with NNRTI-based regimen increases virologic suppression proportionally by 10%.³⁵

Although it is possible to achieve virologic suppression with less than 95% adherence with NNRTI-based regimens, the risk of developing resistance is concerning. Baseline viral load and imperfect adherence (80%–90% by refill history) have been associated with the development of resistance. ³⁶ Because of the low genetic barrier to resistance, even after one dose of NNRTI, resistance is common.³⁷ Because of the prolonged half-life of the NNRTIs, discontinuing efavirenz or nevirapine before stopping NRTIs has been recommended.¹⁷ However, exactly when to discontinue NNRTIs before taking other antiretrovirals remains to be determined. In a South African study, postnatal nevirapine resistance decreased from 57% to 13%–9% when zidovudine plus lamivudine was given for 4 or 7 days after single-dose nevirapine.³⁸ The staggered discontinuation strategy for efavirenz is further complicated by cytochrome P 2B6 polymorphism, more common among African Americans, which has been associated with therapeutic efavirenz concentrations even 2 weeks after discontinuation.³⁹

Boosted PIs versus NNRTIs

Despite the advantages of a high genetic barrier to resistance and the good pharmacokinetic profile of boosted PI regimens, efavirenz outperformed boosted lopinavir when both were combined with two NRTIs. In a prospective randomized trial, 757 antiretroviral-naive patients were randomized to three regimens: lopinavir/ritonavir + NRTIs, efavirenz + NRTIs, and lopinavir/ritonavir + efavirenz. At a median follow-up of 112 weeks, the time to virologic failure was longer in efavirenz-treated patients (p = 0.006). At 96 weeks, 89% of patients in the efavirenz + two NRTIs arm had viral load less than 50 copies per milliliter, versus 77% in the lopinavir/ritonavir + two NRTIs arm (p = 0.003). The lopinavir/ritonavir + efavirenz arm had similar virologic efficacy compared with efavirenz + two NRTIs (83% versus 89%). There was no difference between the arms in time to first treatment-limiting toxicity; however, triglyceride levels were higher in patients treated with lopinavir/ritonavir +efavirenz. Despite superior virologic response to the efavirenz + two NRTIs regimen, the regimen with lopinavir/ritonavir resulted in a higher increase in CD4 levels (230 versus 287, p = 0.01). In patients with virologic failure, the development of resistance was highest in the lopinavir/ritonavir + efavirenz arm, followed by efavirenz + two NRTIs compared with lopinavir/ritonavir + two NRTIs. Any mutations (excluding minor PI mutations) were observed in 70%, 48%, and 21% in the lopinavir/ritonavir + efavirenz, efavirenz + two NRTIS, and lopinavir/ritonavir + two NRTIs arms, respectively.⁴⁰ Reasons for the superiority of efavirenz-based regimens remain to be determined. The higher HIV inhibitory potential over the dosing interval of efavirenz compared with lopinavir/ritonavir may partially explain the observed difference between the two groups.⁴¹

Conclusions

Although the stringent adherence requirement of greater than 95% with unboosted PI-based regimens may not apply to regimens used in clinical practice (i.e., lopinavir/ritonavir, darunavir/ritonavir, atazanavir/ritonavir, fos-amprenavir/ritonavir, or efavirenz + two NRTIs), it was successful in setting a high adherence standard for our patients. Even with simpler and better tolerated regimens, patient adherence to HAART will continue to be paramount for successful virologic suppression. In treatment-experienced patients who may have low-level resistance or high baseline viral load, the pharmacokinetic benefit of twice-daily boosted PI regimens is essential. In antiretroviral-naive patients, however, the pharmacokinetic advantage must be weighed against patient convenience, pill burden, schedule simplicity, and the consequence of a missed dose with a once-daily regimen. In antiretroviral-naive patients without risk factors for nonadherence (e.g., depression, active intravenous drug use, and/or lack of social support), an NNRTI-based regimen consisting of one pill once a day (i.e., efavirenz/tenofovir/emtricitabine tablet) represents a simple and effective treatment option. In the treatment of patients with risk factors for nonadherence, a boosted PI-based regimen may be preferred over an NNRTI-based regimen. It is important for health care professionals to identify possible risk factors that may lead to nonadherence in individual patients and create a plan that mitigates these risk factors. The optimal regimen must be tailored based on antiretroviral history, genotype resistance, side-effect profile, drug interactions, pharmacokinetics, schedule preferences, and perceived adherence.

Footnotes

Acknowledgments

This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Consultancy: Tibotec–Advisory Board; Honorarium: Boehringer Ingelheim; Other: Boehringer Ingelheim–Pharmacokinetic Grant.

Author Disclosure Statement

No competing financial interests exist.

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