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Supplements Addressing Adherence Challenges Associated With Antiretroviral Therapy: Focus on Noninfectious Diarr

The Importance of Treatment Adherence in HIV

Kenneth L. Schaecher, MD, FACP, CPC
Treatment adherence is generally regarded as an important factor in achieving optimal outcomes across many disease states; in the treatment of HIV, poor adherence to treatment has the potential to impact outcomes on multiple levels. Poor adherence to antiretroviral therapy (ART) is associated with less effective viral suppression, which risks the immediate health of the patient, but also risks creating permanent treatment resistance to that particular agent or group of agents within a given combination therapy regimen. This may have downstream effects on treatment costs as well as therapeutic options. The causes of poor adherence to ART are extremely diverse, and include complexity of therapeutic regimens (eg, pill burden and dosing frequency), treatment side effects, poor health literacy, poor patient-physician relationship, and limited access to ART as a result of formulary restrictions or copayment costs. Treatment approaches, such as the use of fixed-dose combinations of ART agents to reduce dosing complexity, as well as educational interventions, such as medication therapy management initiatives, have been shown to improve adherence to therapy in HIV. It is important that all members of the healthcare team address potential barriers to adherence in order to achieve viral suppression and optimize outcomes in patients with HIV.

Am J Manag Care. 2013;19(12 suppl):S231-S237
Introduction: The Consequences of Poor Adherence in HIV

In addition to the primary objective of reducing the risk of morbidity and mortality, the secondary goal of treatment for HIV is viral suppression. Numerous effective therapeutic agents for viral suppression in HIV have been developed. Their efficacy, however, requires that patients with HIV be adherent to their prescribed regimens. Effective use of antiretroviral agents requires not only good adherence to therapy on the part of patients but sustained adherence over time (persistence) if viral suppression is to be successful.1 For HIV therapeutic regimens in which an unboosted protease inhibitor is a component, there exists a substantial risk of failed viral suppression with treatment adherence less than 95%.2

High levels of treatment adherence in HIV have been shown to predict better viral suppression outcomes, whereas poor treatment adherence in HIV is associated not only with less effective viral suppression but also with drug resistance and reduced survival.3,4 The Figure3 shows the relationship between levels of adherence to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and viral suppression in an observational cohort study involving 2821 adults infected with HIV. The differences in effect on viral suppression of 80% to 89% versus 100% adherence, and even 90% to 99% versus 100% adherence, are notable.

Different classes of antiretroviral therapy (ART) are associated with different thresholds of adherence needed to achieve viral suppression and avoid resistance mutations. Each class of agents has a unique relationship between adherence rates and these 2 key outcome variables. For example, highly active antiretroviral therapy (HAART) based around an NNRTI needs a very high level of adherence to limit the risk of resistance mutations. A study by Maggiolo et al found a 4.9% risk of resistance mutations in patients receiving NNRTI-based HAART who dropped below a 75% rate of treatment adherence, while patients treated with HAART with an unboosted protease inhibitor (PI) as its backbone had a very low mutation risk at that level of adherence. Boosted PIs were associated with a mutation risk between unboosted PIs and NNRTIs at the same adherence rate. By comparison, the risk of viral rebound after the cessation of an unboosted PI HAART regime was approximately 5-fold the viral rebound risk observed with an NNRTI-based HAART, while a boosted PI HAART regime had a rebound risk approximately two-thirds greater than NNRTI.5 The data on integrase inhibitors is much more limited at present, and it remains uncertain where these agents sit on the HAART spectrum with regard to adherence requirements.

In the United States, the rate of adherence to HIV therapy is generally low. A meta-analysis of adherence studies—the durations of which ranged from a few days to 1 year—observed a rate of 55% who “achieved adherence” among a pooled group of 17,573 patients. The definition of “achieving adherence” in the studies ranged from above 80% adherence to 100% adherence. By comparison, in sub-Saharan Africa, the pooled adherence rate in studies comprising 12,116 patients was 77%.6

The causes of poor adherence in HIV treatment are extremely varied (Table 1),7 including patient challenges related to age, health literacy, psychosocial and neurocognitive issues, and substance abuse, among other factors. Adherence is also impacted by medication-related barriers, such as complexity of regimens and treatment side effects; and healthcare system challenges, such as drug costs and coverage issues, can also reduce the likelihood of a patient taking his or her medications as appropriate. The purpose of this article is to review the nature and impact of several key adherence-related factors in HIV.

The Influence of Dosing and Formulations on Adherence

As with many diseases requiring complex treatment regimens, adherence to therapy in HIV is strongly affected by how difficult it is to follow the prescribed treatment. Pill burden— the number of pills a patient needs to take in a given period—is one important factor in the relationship between dosing and adherence in HIV, and the medical literature shows significantly greater rates of adherence when the pill burden is low.8

The influence of pill burden on adherence and outcomes was observed in a study published in 2012 by Sax et al, in which 7073 commercially insured HIV-infected patients (selected from the LifeLink database) were evaluated for adherence and risk of hospitalization, with medication possession ratio (MPR) being used to measure adherence. The study subjects were stratified into 3 groups: those taking 3 plus pills per day (60.8%), 2 pills per day (5.8%), or 1 pill per day (33.4%). A treatment adherence rate of 95% or higher was observed in approximately 47% of patients taking 1 pill a day versus 41% in patients taking 2 pills a day versus 34% taking 3 pills or more a day (P = .019 for 1 pill vs 2 pills; P <.001 for 1 pill vs ≥3 pills). After logistic regression analysis, hospitalization risk was found to be significantly lower for patients taking 1 pill a day versus those taking 2 or 3 plus pills a day (P = .003), although there was no difference in risk between the 2 pills and 3 plus pills groups.9

Dosing frequency can also play a significant role in treatment adherence for HIV, as evidenced by the NOCTE study, a 48-week randomized controlled trial in which 87 patients received the same HAART either in a once-nightly or twice-daily dosing schedule. Persistence—which, along with proper execution of a prescribed regimen, is one of the 2 components of adherence—was the main driver of adherence in the study, with 81% of those dosing once nightly persisting with treatment for the full 48 weeks compared with 62% of those dosing twice daily. At the end of the trial period, patients in the once-nightly dosing group were significantly more likely to have been adherent compared with patients in the twice-daily dosing group (P = .03).10

Because ART regimens commonly involve taking multiple drugs at the same time, fixed-dose ART combinations (FDCs), which combine 2 or more drugs in a single formulation, have been developed to increase the likelihood of treatment adherence. The emergence of generic versions of some antiretroviral drugs has, however, caused some third-party payers to consider disallowing FDCs when a generic equivalent is available, in order to lower treatment costs.

A cost-utility study sought to evaluate the validity of this approach by comparing cost and utility scores of 70 patients with HIV/AIDS receiving ART as an FDC regimen with a matched group of 70 patients with HIV/AIDS receiving ART as separate pills. Mean annual costs were $15,766 for patients receiving FDC compared with $11,895 in the separate-pill group. Utility, measured by the SF-6D health instrument, was higher in the FDC group, but not significantly so. However, the incremental cost-utility ratio was shown to favor the FDC regimen above the $40,000 threshold.11

An additional benefit of FDCs for the personal health of patients, as well as for public health, is that these formulations limit the possibility of selective noncompliance, or covert monotherapy, which can increase the risk of drug resistance.12

ART-Related Adverse Events

ART is associated with a number of adverse events (AEs) that may negatively impact adherence to therapy. The association between adherence and specific AEs was the subject of a recently published meta-analysis of studies of adherence to ART in adults with HIV. The authors identified 19 studies from which pooled odds ratios for the risk of reduced adherence with specific AEs were derived. Among those AEs associated with statistically significant reduced adherence were anxiety, confusion, nausea, fatigue, taste disturbances, and loss of appetite (Table 2).13

These results are consistent with a French survey that examined factors contributing to nonadherence in 1010 patients with HIV who were treated with HAART for up to 10 years (follow-up period range: 12-120 months). Nonadherence was strictly defined as taking less than 100% of prescribed HAART medications in the 4 weeks prior to the survey. Adherence behavior was determined via a questionnaire that sought to identify nonadherent behaviors, including skipping a dose, altering the dosing schedule at least once, and taking all of a day’s medications at once instead of at planned intervals. The authors observed that a higher number of self-reported treatment side effects (from a list that included diarrhea, nausea, stomach pain, headache, change in taste, skin itching, muscle pain, heartburn, sore mouth, vomiting, fever, kidney stones, and fatigue) was one factor contributing to nonadherence. Other factors associated with reduced adherence were younger age, daily ART dosing 3 or more times per day, depressive symptoms, alcohol consumption, and poor partner support.14

Of those ART-related AEs that contribute to poor adherence, gastrointestinal AEs may, ultimately, be the most consequential. According to a recently published study in which 1096 patients with HIV were retrospectively followed up to determine those factors most likely to cause discontinuation of treatment (which may be regarded as a form of total treatment nonadherence), gastrointestinal AEs were the primary culprit, accounting for nearly 29% of all discontinuations due to AEs.15

Healthcare System Factors Impacting Adherence to Treatment

Osterberg and Blaschke have described a series of related interactions between patients, physicians, and the healthcare system that have a negative influence on treatment adherence. On the patient side, several common types of barriers to adherence prevail, including gaps in knowledge about: a) the disease, b) the rationale for a given treatment, and c) how that treatment should be implemented. These areas of poor understanding combine patient limitations and, perhaps, insufficient guidance and education from providers and/or the healthcare system in which the patient is a participant. The complexity of a treatment regimen—as prescribed by a provider—is also a potentially serious barrier to adherence that should be addressed by patient and provider. Forgetfulness is the most common patient factor leading to poor adherence, while personal or emotional issues can also affect adherence.16

Providers may unintentionally influence adherence due to limited familiarity with drug costs and/or limited knowledge of insurance coverage and formularies. A physician may select a treatment regimen optimized for a given patient based on clinical trial data and personal clinical knowledge without taking into account patient cost and access to treatment, factors which may ultimately influence patient adherence.16

 
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