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Hospital-Based Directly Observed Therapy for HIV-Infected Children and Adolescents to Assess Adherence to Antiretroviral Medications

Pediatric and Adolescent HIV Program, Section of Infectious Diseases, Department of Pediatrics, University of Chicago, Chicago, Illinois

	ABSTRACT

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BACKGROUND. The introduction of highly active antiretroviral therapy for HIV led to significant declines in HIV-associated morbidity and mortality in children. Nonadherence to antiretroviral therapy is the leading cause of treatment failure in HIV-infected patients. The ability to recognize nonadherence is suboptimal, and differentiating it from other causes of inadequate viral suppression may be difficult.

OBJECTIVES. The purpose of this work was to examine the efficacy of hospital-based directly observed therapy in assessing adherence to antiretroviral medications in HIV-infected children and adolescents suspected of nonadherence and failing other interventions.

METHODS. The medical charts of all HIV-infected patients admitted to the University of Chicago Comer Children's Hospital for directly observed therapy from July 2004 to June 2006 were reviewed. Patients were hospitalized for 7 days. Data collected included demographics, clinical and immune class category, previous and current antiretroviral medications, viral resistance tests, HIV-1 RNA viral load, and CD4⁺ T-cell number and percentage before and after directly observed therapy.

RESULTS. There were 9 perinatally infected patients with a total of 13 admissions. The median age was 13 years, and 8 had been treated with multiple antiretroviral regimens. Three common patterns of changes in the viral load over time were observed. In the first, the viral load dropped at the end of the directly observed therapy period and stayed low thereafter. In the second, the drop in the viral load seen at the end of the period was not sustained. In the third, there was no change in the viral load during or after the directly observed therapy period. Compared with the viral load at admission, the viral load at the end of directly observed therapy was lower in 8 patients with a mean ± SD decrease of 0.8 ± 0.55 log₁₀ copies per mL.

CONCLUSIONS. Short, hospital-based directly observed therapy was helpful in confirming nonadherence to antiretroviral medications, therefore impacting future therapeutic decisions in HIV-infected children and adolescents. Short, hospital-based directly observed therapy should be considered in patients with poor virological control for whom outpatient interventions have failed.

Key Words: HIV • adherence • directly observed therapy • children • adolescents

Abbreviations: HAART—highly active antiretroviral therapy • DOT—directly observed therapy • VL—viral load

Various reports have documented that highly active antiretroviral therapy (HAART) can inhibit HIV replication and result in significant declines in HIV-associated morbidity and mortality in children and adults.^1,2 Inadequate suppression of viral replication by HAART can result from poor adherence to therapy, low potency of the antiretroviral regimen, viral resistance to antiretroviral medications, and pharmacokinetic interactions causing inadequate drug delivery.³

Nonadherence is the leading cause of HAART failure in suppressing viral replication.^3–5 It is essential to achieve 95% adherence to the HAART regimen to suppress viral replication and avoid the emergence of resistance.⁶ HAART, therefore, requires an especially high level of adherence for an indefinite time period to achieve optimal viral suppression.

The problem of nonadherence is significant in the pediatric population because of a lack of liquid formulations for some drugs, the often-required large volume of medications, the extremely poor palatability of some medications, and the dependence of the child on a caregiver to administer the drugs. The caregiver is often also HIV infected, thus further complicating the psychosocial conditions. Nondisclosure of the diagnosis of HIV to the child or family members can further complicate therapy and increase nonadherence. Adolescent patients present even more challenges, given the unique developmental, psychosocial, and lifestyle issues implicit in adolescence.^4,7

In a child or adolescent not responding to HAART, nonadherence should be a major consideration. However, the ability to recognize nonadherence is suboptimal, and differentiating nonadherence from other causes of inadequate viral suppression may be difficult, especially in heavily drug-experienced patients with a multidrug resistant virus. Interventions to encourage adherence include patient education and counseling, behavioral contracts, pill boxes, electronic pill monitors, simplified drug regimens, gastrostomy tube placement, reminder calls, home health nurse visits, and directly observed therapy (DOT).^7–10

DOT is a direct method to measure adherence and is considered to be the most accurate.⁷ The principle of DOT has its roots in the treatment of tuberculosis, for which DOT programs have dramatically improved cure rates.¹¹ Studies with DOT in HIV-infected patients included mainly community-based interventions for marginalized populations, such as adults with drug abuse and HIV-infected inmates being released from prisons.^12,13 Hospital-based DOT for HIV-infected children and adolescents has been rarely reported.^9,14,15 These studies, however, provide evidence for the potential to substantially decrease the HIV viral load (VL) in a short hospital stay.

We report our experience with hospital-based DOT for HIV-infected children and adolescents cared for by the Pediatric and Adolescent HIV Program at the University of Chicago Comer Children's Hospital. Since 1990, HIV-infected and exposed infants, as well as HIV-infected children and adolescents, have been cared for by the program; some have been followed for >10 years. We currently care for 73 HIV-infected patients ranging in age from 1 to 23 years and 37 HIV-exposed infants. We used a short hospital-based DOT in 9 patients as an intensive strategy to ensure adherence, differentiate nonadherence from viral drug resistance, look for and address social problems, and evaluate for toxicities of treatment. The objective of this retrospective analysis is to show that hospital-based DOT is an effective approach for managing suboptimal response to HAART in the HIV-infected pediatric and adolescent population.

	METHODS

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Subjects
The medical charts of all of the HIV-infected children and adolescents admitted to the University of Chicago Comer Children's Hospital for DOT from July 2004 (the starting date for our inpatient-based DOT policy) until June 2006 were reviewed retrospectively. Data collected from each patient's record included date of birth, ethnicity, gender, diagnosis date of HIV infection, mode of infection, Centers for Disease Control and Prevention clinical and immune class category, number of previous HAART regimens, current HAART medications, previous interventions to enhance adherence to the medication regimen, viral resistance test results, dates of hospitalization, HIV-1 RNA VL and CD4⁺ T-cell number and percentage before and after DOT, and changes in HAART regimen made after DOT. Data about significant events during DOT, such as drug-related adverse events, missed or late medication administration, and psychosocial issues were also collected. HIV-1 RNA VL was measured by reverse transcription-polymerase chain reaction with a detection range of 400 to 750000 copies per mL with the standard procedure or 50 to 100000 copies per mL with the ultrasensitive procedure (Roche Amplicor 1.5; Roche, Branchburg, NJ). All of the data were entered into a Microsoft Access program (Microsoft, Redmond, WA). The study was reviewed and approved by the University of Chicago Institutional Review Board.

Patients hospitalized for DOT were suspected of nonadherence with the treatment regimen. In most cases, each of the following 4 criteria were met: (1) evidence of treatment failure as indicated by a more than threefold (>0.5 log₁₀) increase in HIV-1 RNA levels in 2 consecutive laboratory evaluations; (2) caregiver or patient's insistence that adherence to HAART is complete; (3) viral genotype and/or phenotype tests indicating viral susceptibility to the patient's antiretroviral regimen (partial susceptibility in heavily drug-experienced patients); and (4) no decrease in HIV-1 RNA level after intensified clinic visit schedule and intensive education about the importance of adherence, including health education group meetings, telephone call reminders, and home visits.

The virological parameter of treatment failure was chosen based on the "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection"¹⁶ and on the observation that HIV-1 VL can fluctuate in the range of 0.5 to 0.7 log₁₀ copies per mL in patients receiving stable therapy or no treatment for HIV.¹⁷ We hypothesized that patients nonadherent to antiretroviral therapy will demonstrate significant decrease in the HIV-1 VL after a week of hospital-based DOT.

DOT
The decision to use DOT was made based on the criteria mentioned above. The patient was informed about DOT during a clinic visit. DOT was then scheduled to take place between 2 and 4 weeks after the last clinic visit. In the DOT protocol, the patient was hospitalized for a 7-day period on a general pediatric ward at the University of Chicago Comer Children's Hospital. The University of Chicago Comer Children's Hospital is a 155-bed tertiary care hospital on Chicago's south side. During the hospital stay, patients and caregivers received education from physicians, nurses, nutrition specialists, and social workers from the HIV program. Under direct observation of the nursing staff, patients were administered exactly the same HAART regimen as prescribed at home. Timing of administration was similar to the home schedule of the patient. The CD4⁺ T-cell number and percentage and VL were measured before DOT and at the last day of the hospital stay. The laboratory results of DOT, as reflected in the VL and other parameters, were discussed with the patient or caregiver at the next clinic visit after DOT.

Data Analysis
For statistical analysis, 5 periods of time around the DOT hospitalization were chosen. These include the pre-DOT clinic visit to day 1 of the DOT period, day 1 of DOT to last day of the DOT period, day 1 of the DOT to the first clinic visit after the DOT period, day 1 of the DOT to the 6-month post-DOT follow-up period, and the pre-DOT clinic visit to the 6-month post-DOT follow-up period. These periods were chosen to examine immediate and sustained effects of DOT. Paired t tests were used to compare changes in VL, CD4⁺ T-cell count, and CD4⁺ T-cell percentage over each period of time. The log₁₀ transformation of the VL data was taken before analysis. Nonparametric Wilcoxon signed-rank tests were also used, but because the conclusions were similar, only the results from the paired t tests are reported. A P < .05 was considered statistically significant. For analysis purposes, VL listed as less than the lower limit of detection was assigned a value 1 less than that amount, and VL greater than the upper limit of detection was assigned a value 1 greater than that amount (ie, HIV-1 RNA values reported as <50 copies per mL were changed to 49 copies per mL, and values >750000 copies per mL were reported as 750001 copies per mL). In patients with multiple DOT visits, only the first visit was used in analysis. In addition, if a subject did not have a visit at 6 months after DOT, the nearest follow-up visit after 6 months was used for calculations. All of the statistical analyses were performed using Stata 9 (Stata Corp, College Station, TX).

	RESULTS

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Description of Study Population and Clinical Data
A total of 13 admissions of 9 patients occurred during the study period. Three patients were admitted more than once (2 or 3 times). In 1 patient, the hospitalization was shortened because of a substantial decrease in VL value drawn on day 1 of the DOT compared with previous values. All of the patients were perinatally infected and were black. There were 7 girls and 2 boys, and the median age was 13 years (range: 7–17 years). In 6 of the 9 patients, the primary caretaker was an HIV-infected mother. Three patients had gastrostomy tubes in place. Patient characteristics are shown in Table 1. All of the patients had received antiretroviral therapy since the diagnosis of HIV. At the time of DOT, 6 patients were being treated with HAART and 3 with mega-HAART. Except for 1, all of the patients were treated with multiple antiretroviral therapy regimens in the past. Five of 7 patients, in whom HIV resistance testing was performed, experienced triple-class resistance mutations. Therapeutic data are shown in Table 2.

Three common patterns of changes in the log₁₀ VL over time were seen and are depicted in Fig 1. In the first (Fig 1A), the patient experienced a rapid decline in VL observed at the end of the DOT period. In this case, nonadherence was confirmed and relayed to the patient and caregiver together with emphasis on the good results achieved by the patient when the medications were actually taken. The decrease in VL was maintained after the patient was discharged and followed in clinic. This improvement was long-standing in some patients (patient 4 has a response lasting >24 months). The second pattern of response seen (Fig 1B) was similar to the first in the hospital phase, with a marked decrease of VL, but not sustained in the home environment (patient 5, 7, and 9), necessitating reemphasizing the importance of adherence and identifying specific reasons for being nonadherent. The third pattern was seen in patients in whom the VL failed to improve with DOT (Fig 1C). In these patients, hospitalization was helpful in recognizing the limitation of current medications (patient 3), and future outpatient strategies included changing the medications to a different regimen or adding medications to the existing regimen based on resistance testing. In another subgroup of patients (patients 5 and 6), a substantial decrease in VL was found at the beginning of DOT as compared with pre-DOT results (Table 2 and Fig 1B). This result suggested previous nonadherence and was available even before the completion of the DOT hospitalization.

View larger version (7K): [in this window] [in a new window]   FIGURE 1 Three typical patterns of HIV VL detected over time among HIV-infected patients receiving DOT. HIV VL was measured as RNA log10 copies per mL. Pre indicates pre-DOT clinic visit; Day 1, first day of DOT hospitalization; Post, last day of DOT hospitalization; Follow-up 1, first post-DOT clinic follow-up; 6 mo, 6-month post-DOT clinic follow-up.

	DISCUSSION

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We made the decision to hospitalize patients for the duration of 1 week. This duration was chosen to make the DOT period as short and effective as possible. The Pediatric AIDS Clinical Trials Group 381 Study has shown a significant drop in HIV-1 VL in infected adolescents receiving HAART after as short as 1 week of therapy.¹⁸ Gigliotti et al¹⁴ demonstrated, in a small study of HIV-infected children who were heavily drug experienced, significant drops in VL occurring after 4 to 8 days of DOT. Similar results were reported by Roberts et al⁹ in another small DOT study involving children. We also considered that 7 days of hospitalization provides enough time for both patient and medical staff to get acquainted with the new environment and the concept of DOT, as well as to address, by a multidisciplinary approach, some of the problems that HIV-infected children and adolescents have. Within this short hospitalization period, we indeed found a statistically significant decline in HIV VL of patients.

Nonadherence to medication is a major problem in the care of pediatric and particularly adolescent patients infected with HIV. Differentiating between nonadherence to medications and resistance of the virus to HAART as the cause of virological and immunologic failure is problematic, especially in heavily drug-experienced patients in whom interpreting results of resistance testing is difficult, and remaining therapeutic options are limited. The complexity of associated social problems, some of them unique to the HIV-infected population (Table 1), makes assessment of adherence even more difficult. Particularly in these scenarios, DOT can provide valuable information.

Our management was different for each of the 3 patterns of response that we have seen. In the majority of patients we observed a rapid decline in VL at the end of the DOT period. In these cases, nonadherence was confirmed. Relaying the results to the patient and caregiver together with emphasis on the good results achieved by the patient when the medications were actually taken is an important part of assuring adherence. In patients who maintained the response after the hospitalization, it is prudent both to continuously reinforce the importance of taking medications and assess at the same time for reemergence of nonadherence. Patients who responded initially but had a relapse in the VL after the hospitalization are complex and challenging case subjects who raise the ongoing issues of nonadherence, viral resistance, or both. Therefore, maximizing adherence through the use of DOT will provide valuable information about the ability of a current HAART regimen to suppress viral replication. Addressing specific issues (frequently encountered while the patient is hospitalized for DOT), such as medication-associated toxicities, body image problems, domestic disruption, and depression, can help convince the patients to take their medications. In our adolescent patients, we intensified the clinic visit schedule and created specific adherence group meetings. The meetings included adherence topics discussions and problem solving combined with social activities and provision of small incentives and electronic reminder devices. In 3 patients, we used a subsequent DOT hospitalization to confirm nonadherence and to address multiple associated problems. Two of our patients in this group were adolescent sisters who had admitted, only after the second DOT, to not taking the medications because of gastrointestinal adverse events. Unfortunately, all of the methods that we used to increase adherence in their case have failed, thus demonstrating the complexity of the situation. A statistically significant sustained decrease in the VL in our study population was not observed, probably because of this subgroup of patients. The last pattern was seen in patients in whom the VL failed to improve with DOT. In these patients, hospitalization was helpful both in ruling out nonadherence as the major factor of virological failure and in recognizing the limitation of the current HAART regimen. Future outpatient strategies included changing the medications to a different regimen or adding medications to the existing regimen based on resistance testing. Thus, all 3 types of patients benefited from DOT. In a subgroup of patients, a substantial decrease in VL was evident at the beginning of DOT as compared with pre-DOT results, confirming the "white-coat adherence."⁷ In this phenomenon, patients are improving their medication-taking behavior in the few days before the appointment with the health care provider. We did not encounter this improvement before routine clinic follow-up, thus emphasizing the importance of inpatient DOT in changing both the medication-taking habits of patients and the routine of doctor-patient encounters.

Hospital-based DOT also had other advantages for patients in providing a multidisciplinary approach toward problems encountered while the patient was in the hospital. For example, body image issues associated with a gastrostomy tube in a young adolescent girl were explored, and after a written contract was created between the patient and caregivers, the gastrostomy tube was removed while the patient maintained her weight and medication taking. Addressing medication-associated adverse effects, discussing sexual behavior, providing nutrition advice, and consulting specialists about various medical problems were also accomplished during hospitalization. We have found that the DOT stay provided a relaxed, unhurried atmosphere in which problems could be discussed and addressed, unlike the often-limited time devoted to patients in a busy clinic.

In 2 of our patients (patients 2 and 9 in the third DOT), we have used hospitalization for a specific medical problem (chronic suppurative otitis media for intravenous antibiotics or evaluation of a chronic cough) as an opportunity for DOT. In these circumstances, with the patient being only mildly ill, expected to stay for 7 days, and able to take the medications on time, the DOT protocol (if needed) could be initiated. Not every hospitalization event is suitable for DOT because of the nature and severity of illness, changes in absorption of medications, or problems with the correct timing of medication administration. However, in a well-chosen setting, using the hospitalization also for DOT can be advantageous. In both of our patients, the VL measured at the end of the hospital stay was significantly lower.

CD4⁺ T-cell count and percentage are independent predictors of disease progression and mortality in HIV-infected children.¹⁹ Response to HAART is slower with regard to CD4⁺ T-cell counts and percentage as evidenced in previous studies.^20,21 We did not observe significant changes in our study population immediately after the DOT period, but there was a trend toward increased CD4⁺ T-cell percentage from day 1 of DOT to the 6-month follow-up. It is possible that, with a larger cohort of patients, we could demonstrate a significant increase in CD4⁺ T-cell number and percentage and, therefore, provide a benefit in survival.

Our study is limited by a relatively small sample size, the lack of cost-effectiveness analysis, and by its retrospective design. However, given the high frequency of nonadherence to medications in the pediatric and adolescent HIV-infected population and the importance of adherence for longevity, implementing accurate assessment and improvement of adherence is crucial. We have found short, hospital-based DOT as such. Although DOT is a time-honored method, there are only a handful of reports of hospital-based DOT for HIV-infected children and adolescents. Our report is unique; we have used a tertiary care hospital and a uniform protocol of a 7-day DOT for a population of mainly adolescents. This differs from Parsons et al,¹⁵ who used DOT in a chronic care facility with a variable length (24–79 days) of stay, or Gigliotti et al,¹⁴ who used a hospital stay of 4 to 8 days or an HIV summer camp in a small group of children. Another report published recently by Roberts et al⁹ describes a 4-day DOT as part of a stepwise interventional approach consisting of home health nurse referral, DOT, and submission of a neglect report in cases of nonadherence. This report involved a small population of young children and focused mainly on nonadherence to medications by the caregivers as medical neglect. Assessing the effect of DOT on VL in this article is difficult, because the VL measurements were done before the actual hospitalization and at the end of the hospital stay combining, therefore, the "white-coat adherence" and DOT effects.

Hospital-based DOT necessitates preparations before implementation of the protocol. In the pre-DOT clinic visit, conveying to the DOT candidates that the hospital stay is not a punishment but is intended to help with medication taking and quality of life is important. Education of the nursing personnel about their unique duties of supervision of medication taking and strict adherence to timing of administration is crucial. The hospital pharmacy should be contacted to ensure the supply of the exact medications that the patient is taking at home in a timely manner. For example, a problem may be encountered with hospital formulary of combination pills, such as Trizivir (contains abacavir, lamivudine, and zidovudine). Residents should be educated about the DOT concept and about the complexity of problems associated with the HIV-infected population. Also important is the coordination of the multidisciplinary team for using most effectively the hospital stay for purposes of education and counseling.

We propose that a short, hospital-based DOT be considered in appropriate HIV-infected pediatric and adolescent patients suspected of nonadherence, because DOT seems to be an effective method for the assessment and encouragement of medication taking in complex cases.

	ACKNOWLEDGMENTS

 
We thank Drs Surabhi Vora and Kenneth Alexander at the University of Chicago for critical review of the article.

	FOOTNOTES

 
Accepted Nov 2, 2006.

Address correspondence to Daniel Glikman, MD, Section of Pediatric Infectious Diseases, Wyler Pavilion, 5841 S Maryland Ave, MC 6054, Chicago, IL 60637. E-mail: dglikman{at}peds.bsd.uchicago.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

Ms Mangat's current affiliation is Department of Pediatrics, Section of Infectious Diseases, University of Illinois at Chicago, Chicago, IL.

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Glikman, D. Articles by Marcinak, J. F. Search for Related Content PubMed PubMed Citation Articles by Glikman, D. Articles by Marcinak, J. F. Related Collections Infectious Disease & Immunity

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