Steven Y. Hong

Pharmacy Adherence Measures to Assess Adherence to Antiretroviral Therapy: Review of the Literature and Implications for Treatment Monitoring

Prescription or pill-based methods for estimating adherence to antiretroviral therapy (ART), pharmacy adherence measures (PAMs), are objective estimates calculated from routinely collected pharmacy data. We conducted a literature review to evaluate PAMs, including their association with virological and other clinical outcomes, their efficacy compared with other adherence measures, and factors to consider when selecting a PAM to monitor adherence. PAMs were classified into 3 categories: medication possession ratio (MPR), pill count (PC), and pill pick-up (PPU). Data exist to recommend PAMs over self-reported adherence. PAMs consistently predicted patient outcomes, but additional studies are needed to determine the most predictive PAM parameters. Current evidence suggests that shorter duration of adherence assessment (≤ 6 months) and use of PAMs to predict future outcomes may be less accurate. PAMs which incorporate the number of days for which ART was prescribed without the counting of remnant pills, are reasonable minimum-resource methods to assess adherence to ART.

HIV Treatment Adherence, Drug Resistance, Virologic Failure: Evolving Concepts

Poor adherence to combined antiretroviral therapy (cART) has been shown to be a major determinant of virologic failure, emergence of drug resistant virus, disease progression, hospitalizations, mortality, and health care costs. While high adherence levels can be achieved in both resource-rich and resource-limited settings following initiation of cART, long-term adherence remains a challenge regardless of available resources. Barriers to optimal adherence may originate from individual (biological, socio-cultural, behavioral), pharmacological, and societal factors. Although patients and providers should continuously strive for maximum adherence to cART, there is accumulating evidence that each class of antiretroviral therapy has specific adherence-drug resistance relationship characteristics allowing certain regimens more flexibility than others. There is not a universally accepted measure for cART adherence, since each method has distinct advantages and disadvantages including cost, complexity, accuracy, precision, intrusiveness and bias. Development of a real-time cART adherence monitoring tool will enable the development of novel, pre-emptive adherence-improving strategies. The application of these strategies may ultimately prove to be the most cost-effective method to reduce morbidity and mortality for the individual and decrease the likelihood of HIV transmission and emergence of resistance in the community.

Update on World Health Organization HIV drug resistance prevention and assessment strategy: 2004-2011

The HIV drug resistance (HIVDR) prevention and assessment strategy, developed by the World Health Organization (WHO) in partnership with HIVResNet, includes monitoring of HIVDR early warning indicators, surveys to assess acquired and transmitted HIVDR, and development of an accredited HIVDR genotyping laboratory network to support survey implementation in resource-limited settings. As of June 2011, 52 countries had implemented at least 1 element of the strategy, and 27 laboratories had been accredited. As access to antiretrovirals expands under the WHO/Joint United Nations Programme on HIV/AIDS Treatment 2.0 initiative, it is essential to strengthen HIVDR surveillance efforts in the face of increasing concern about HIVDR emergence and transmission.

HIV Drug Resistance Early Warning Indicators in Cohorts of Individuals Starting Antiretroviral Therapy Between 2004 and 2009: World Health Organization Global Report From 50 Countries

The World Health Organization developed a set of human immunodeficiency virus drug resistance (HIVDR) early warning indicators (EWIs) to assess antiretroviral therapy clinic and program factors associated with HIVDR. EWIs are monitored by abstracting data routinely recorded in clinical records, and the results enable clinics and program managers to identify problems that should be addressed to minimize preventable emergence of HIVDR in clinic populations. As of June 2011, 50 countries monitored EWIs, covering 131 686 patients initiating antiretroviral treatment between 2004 and 2009 at 2107 clinics. HIVDR prevention is associated with patient care (appropriate prescribing and patient monitoring), patient behavior (adherence), and clinic/program management efforts to reduce treatment interruptions (follow up, retention on first-line ART, procurement and supply management of antiretroviral drugs). EWIs measure these factors and the results have been used to optimize patient and population treatment outcomes.

Population-based Monitoring of Hiv Drug Resistance in Namibia With Early Warning Indicators

Introduction:HIV drug resistance (HIVDR) testing is not routinely available in many resource-limited settings, therefore, antiretroviral therapy (ART) program and site factors known to be associated with HIVDR should be monitored to optimize the quality of patient care and minimize the emergence of preventable HIVDR. Methods:In 2009, Namibia selected 5 World Health Organization Early Warning Indicators (EWIs) and piloted abstraction at 9 ART sites: “ART prescribing practices, patients lost to follow-up at 12 months, patient retention on first-line ART at 12 months, on-time antiretroviral drug pick-up, and antiretroviral drug-supply continuity”. Results:Records supported monitoring of 3 of 5 selected EWIs. Nine of 9 (100%) sites met the target of 100% initiated on appropriate first-line regimens. Eight of 9 (89%) sites met the target of ≤20% lost to follow-up, although 20.8% of ART starters (range: 4.6%-44.6%) had a period of absence without documented ART coverage of 2.3 months (range: 1.5-3.9 months). Six of 9 (67%) sites met the target of 0% switched to a second-line regimen. Conclusions:EWI monitoring directly resulted in public health action which will optimize the quality of care, specifically the strengthening of ART record systems permitting monitoring of 5 EWIs in future years and protocols for improved ART patient defaulter tracing.

Medication Possession Ratio Associated with Short-Term Virologic Response in Individuals Initiating Antiretroviral Therapy in Namibia

The visual-analogue scale (VAS), Likert item (rating scale), pills identification test (PIT), and medication possession ratio (MPR) provide estimates of antiretroviral therapy (ART) adherence which correlate with HIV viral suppression. These simple adherence measures are inexpensive and easy to administer; however, require validation and adjustment prior to implementation. The objective of this study was to define the optimal adherence assessment measure in Namibia to identify patients at risk for sub-optimal adherence and poor virologic response 6 months after ART initiation. We conducted a cross-sectional survey in HIV-infected adults receiving ART for 6–12 months prior to the adherence assessment. Adherence measures included 30-day VAS, 30-day Likert item, self-reported treatment interruptions, PIT, and MPR. Association of adherence measures with 6-month HIV-1 RNA level was assessed using two thresholds (1000 copies/mL and 5000 copies/mL). Adherence was assessed in 236 patients, mean age 37.3 years, 54% female. Mean adherence was 98.1% by 30-day VAS, 84.7% by 30-day Likert item, 97.0% by self-reported treatment interruptions, 90.6% by PIT, and 98.8% by MPR. Agreement between adherence measures was poor using kappa statistic. 76% had HIV-1 RNA <1000 copies/ml, and 88% had HIV-1 RNA <5000 copies/ml. MPR (continuous) was associated with viral suppression <5000 copies/ml (p = 0.036). MPR <75% was associated with virologic failure at ≥5000 copies/ml with OR 3.89 (1.24, 12.21), p = 0.013. Adherence was high with all measures. Only MPR, was associated with short-term virologic response, suggesting its cross-culturally utility for early identification of patients at high risk for virologic failure.

Effects of physical tracing on estimates of loss to follow-up, mortality and retention in low and middle income country antiretroviral therapy programs: a systematic review.

Background A large proportion of patients receiving antiretroviral therapy (ART) in low and middle income countries (LMICs) have unknown treatment outcomes and are classified as lost to follow-up (LTFU). Physical tracing of patients classified as LTFU is common; however, effects of tracing on outcomes remains unclear. The objective of this systematic review is to compare estimates of LTFU, mortality and retention in LMIC in cohorts of patients with and without physical tracing. Methods and Findings We systematically identified studies in LMIC programmatic settings using MEDLINE (2003–2011) and HIV conference abstracts (2009–2011). Studies reporting the proportion LTFU 12-months after ART initiation were included. Tracing activities were determined from manuscripts or by contacting study authors. Studies were classified as “tracing studies” if physical tracing was available for the majority of patients. Summary estimates from the 2 groups of studies (tracing and non-tracing) for LTFU, mortality, stop of ART, transfers out, and retention on ART were determined. 261 papers and 616 abstracts were identified of which 39 studies comprising 54 separate cohorts (n = 187,666) met inclusion criteria. Of those, physical tracing was available for 46% of cohorts. Treatment programs with physical tracing activities had lower estimated LTFU (7.6% vs. 15.1%; p<.001), higher estimated mortality (10.5% vs. 6.6%; p = .006), higher retention on ART (80.0 vs. 75.8%; p = .04) and higher retention at the original site (80.0% vs. 72.9%; p = .02). Conclusions Knowledge of patient tracing is critical when interpreting program outcomes of LTFU, mortality and retention. The reduction of the proportion LTFU in tracing studies was only partially explained by re-classification of unknown outcomes. These data suggest that tracing may lead to increased re-engagement of patients in care, rather than just improved classification of unknown outcomes.

Household food insecurity associated with antiretroviral therapy adherence among HIV-infected patients in Windhoek Namibia.

Objective:Food insecurity is emerging as an important barrier to antiretroviral therapy (ART) adherence. The objective of this study was to determine if food insecurity is associated with poor ART adherence among HIV-positive adults in a resource-limited setting that uses the public health model of delivery. Design:A cross-sectional study using a 1-time questionnaire and routinely collected pharmacy data. Methods:Participants were HIV-infected adults on ART at the public ART clinics in Windhoek, Namibia: Katutura State Hospital, Katutura Health Centre, and Windhoek Central Hospital. Food insecurity was measured by the Household Food Insecurity Access Scale (HFIAS). Adherence was assessed by the pharmacy adherence measure medication possession ratio (MPR). Multivariate regression was used to assess whether food insecurity was associated with ART adherence. Results:Among 390 participants, 7% were food secure, 25% were mildly or moderately food insecure and 67% were severely food insecure. In adjusted analyses, severe household food insecurity was associated with MPR <80% [odds ratio (OR), 3.84; 95% confidence interval (CI): 1.65 to 8.95]. Higher household health care spending (OR, 1.92; 95% CI, 1.02 to 3.57) and longer duration of ART (OR, 0.82; 95% CI: 0.70 to 0.97) were also associated with <80% MPR. Conclusions:Severe household food insecurity is present in more than half of the HIV-positive adults attending a public ART clinic in Windhoek, Namibia and is associated with poor ART adherence as measured by MPR. Ensuring reliable access to food should be an important component of ART delivery in resource-limited settings using the public health model of care.

The global status of HIV drug resistance: Clinical and public-health approaches for detection, treatment and prevention

Antiretroviral therapy (ART) scale-up in resource limited settings (RLS) has been successful, utilizing a standardized population-based approach to ART delivery. An unintended consequence of treatment scale-up is the inevitable emergence of HIV drug resistance (HIV DR) in populations even when patient adherence to ART is optimally supported. HIV DR has the potential to undermine the dramatic gains that ART has had in reducing the morbidity and mortality of HIV-infected patients in RLS. Sustaining and expanding ART coverage in RLS will depend upon the ability of ART programs to deliver ART in a way that minimizes the emergence of HIVDR. Fortunately, current evidence demonstrates that HIVDR in RLS has neither emerged nor been transmitted to the degree that had initially been feared. However, due to a lack of standardized methodologies, HIVDR data from RLS can be difficult to interpret and may not provide the programmatic evidence necessary for public health action. The World Health Organization has developed simple, standardized surveys that generate comparable results to assess acquired and transmitted HIVDR for routine public health implementation in RLS. These HIVDR surveys are designed to be implemented in conjunction with annual monitoring of program and site factors known to create situations favorable to the developments of HIV DR.

HIV Drug Resistance Early Warning Indicators in Namibia with Updated World Health Organization Guidance

Background In response to concerns about the emergence of HIV drug resistance (HIVDR), the World Health Organization (WHO) has developed a comprehensive set of early warning indicators (EWIs) to monitor HIV drug resistance and good programme practice at antiretroviral therapy (ART) sites. Methods In 2012, Namibia utilized the updated WHO EWI guidance and abstracted data from adult and pediatric patients from 50 ART sites for the following EWIs: 1. On-time Pill Pick-up, 2. Retention in Care, 3. Pharmacy Stock-outs, 4. Dispensing Practices, and 5. Virological Suppression. Results Data for EWIs one through four were abstracted and validated. EWI 5 – Virological Suppression was not included due to poor data entry at many sites. On-time Pill Pick-up national estimate was 87.9% (87.2–88.7) of patients picking up pills on time for adults and 90.0% (88.9–90.9) picking up pills on time for pediatrics. Retention in Care national estimate was 82% of patients retained on ART after 12 months for adults and 83% for pediatrics. Pharmacy Stock-outs national estimate was 99% of months without a stock-out for adults and 97% for pediatrics. Dispensing Practices national estimate was 0.01% (0.003–0.064) of patients dispensed mono- or dual-therapy for adults and 0.25% (0.092–0.653) for pediatrics. Conclusions The successful 2012 EWI exercise provides Namibia a solid evidence base, which can be used to make national statements about programmatic functioning and possible HIVDR. This evidence base will serve to contextualize results from Namibias surveys of HIVDR, which involves genotype testing. EWI abstraction has prompted the national program and its counterparts to engage sites in dialogue regarding the need to strengthen adherence and retention of patients on ART. The EWI collection process and EWI results will serve to optimize patient care and support Namibia in making evidence-based recommendations and take action to minimize the emergence of preventable HIVDR.