Abstract
Antiretroviral medications are becoming available for HIV-infected children in resource-limited settings. Maryknoll, an international Catholic charity, provided directly observed antiretroviral therapy to HIV-infected children in Phnom Penh, Cambodia. Child care workers administered generic antiretroviral drugs twice daily to children, ensuring adherence.
Treatment began with 117 late-stage HIV-infected children; 22 died of AIDS during the first 6 months. The rest were treated for at least 6 months and showed CD4 count increases comparable to those achieved in US and European children. Staffing cost for this program was approximately US $5 per child per month, or 15% more than the price of the medications. Drug toxicities were uncommon and easily managed.
Directly observed antiretroviral therapy appears to be a promising, low-cost strategy for ensuring adherent treatment for HIV-infected children in a resource-limited setting.
Fewer than 10% of the 660000 children worldwide who are HIV infected and in need of antiretroviral treatment receive such treatment.1 Cambodia continues to have one of the highest rates of HIV infection in Asia, with a national prevalence of 1.9%.2 It is estimated that between 3800 and 12000 Cambodian children younger than 16 years were living with HIV as of 2003.3 Recently, in the wake of dramatic price reductions, highly active antiretroviral therapy (HAART) has become available to a limited number of Cambodian children who are HIV infected, and Cambodian pediatricians are receiving training in the use of HAART. As of 2004, approximately 4200 adults and 314 children were receiving antiretroviral therapy in Cambodia.2 The Ministry of Health of Cambodia declared a national target of having 1500 children on antiretroviral therapy by 2005.2
Although community-based treatment models for children with HIV infection will be indispensable for worldwide antiretroviral therapy scale-up, the feasibility of such programs remains largely untested. Adequate adherence to antiretroviral medications is crucial for successful treatment.4–6 Ensuring medication adherence is a particular problem for children who are HIV infected, because they must be given often-unpalatable liquid medications by diverse caregivers. One approach to optimizing medication adherence in children is directly observed treatment.7
THE MARYKNOLL LITTLE SPROUTS PROGRAM
The Little Sprouts program of Maryknoll, an international Catholic charitable organization, has provided directly observed treatment with HAART to orphans who are HIV positive in Phnom Penh since June 2002.8 It is the first program in Cambodia to treat children with HIV infection using directly observed treatment. The Little Sprouts program maintains group homes for children who are HIV positive and whose parents have died of AIDS. The program also has a home-based care program for orphans who live with extended family. Children receive their antiretroviral medications from a child care worker who observes the ingestion of medication twice daily.
A series of didactic training sessions are given by the Little Sprouts program manager to new child care workers, who also participate in fieldwork with veteran workers or the program manager. Medication adherence is recorded and verified during twice weekly meetings between child care workers and project managers. Each child care worker is responsible for approximately 10 children. All child care workers have cell phones and are encouraged to call the project manager directly when problems arise, such as missed doses.
In addition to the child care worker, a case manager is assigned to each child; the case manager visits the child and family twice per week to monitor general health and well-being. If health concerns arise, the child is taken to the Little Sprouts clinic for evaluation by a physician. There are well-child checks every 3 months with the same Little Sprouts doctor.
KEY FINDINGS.
Orphaned children who died of AIDS-related illness within 6 months of beginning antiretroviral treatment appeared to have very-late-stage HIV disease.
Cambodian children who received directly observed treatment with HAART for at least 6 months showed substantial improvements in CD4 counts and percentages similar to those seen in other cohorts of children who received HAART without directly observed treatment.
Children in the program showed significant and sustained improvement in nutritional status.
Toxicities of antiretroviral drugs were uncommon and easily managed.
Directly observed treatment of HAART to orphaned children appears to be a feasible and inexpensive way to ensure medication adherence in a resource-limited setting.
During the evaluation, children rarely changed households. In 1 case, a family moved because of a house fire, but medical care was continued. In instances when the child was not in the household at the time the child care worker arrived, the decision to leave a single dose of HAART for the family to administer was made on a case-by-case basis. For all cases in which a child was not present, after administering medication to the rest of their patients, child care workers returned to either give the child HAART or verify that the family had given the child the medication. Missed HAART doses occurred, but were rare. During the evaluation, fewer than 1% of all scheduled doses were missed.
Children were monitored for possible drug toxicities and for change in CD4 levels. Other observations included weight, hemoglobin, common illnesses, and mortality. Each child received daily multivitamin supplementation, nutritious food, nutritional monitoring, and general medical care as a part of the program.
All children in the Little Sprouts program who were HIV infected underwent baseline basic blood tests, including complete blood count, level of the liver enzyme alanine transaminase (ALT), absolute CD4 count, and percentage of lymphocytes that were CD4 cells (CD4 percentage). Children whose CD4 counts were below 15% were started on HAART. CD4 measurements were routinely repeated every 6 months. The Little Sprouts program did not provide antiretroviral medicine to adult caregivers—the adults were helped by other programs.
PROGRAM EVALUATION AND RESULTS
A retrospective record review was conducted for all children enrolled in the Maryknoll Little Sprouts program in Phnom Penh between August 2002 and October 2004 (Figure 1 ▶). The study population included children aged 1 to 18 years who had documented HIV infection measured by an HIV antibody test and were living in an orphanage or with families in the community.
FIGURE 1—
Flowchart of children receiving directly observed treatment with HAART from the Maryknoll Little Sprouts program: Phnom Penh, Cambodia, August 2002 to October 2004.
Medical records of all children started on directly observed treatment with HAART were reviewed. The 95 children who received at least 6 months of twice-daily directly observed treatment with HAART and had both baseline and at least 1 subsequent CD4 count measurement were included in the analyses. CD4 measurements were repeated after a mean of 6.2 ±0.7, 12.3 ±0.2, and 18.8 ±0.9 months of directly observed treatment with HAART. Sixty-eight of the children received 12 or more months of treatment, and 33 received approximately 18 months of directly observed treatment with HAART. Mean age at treatment initiation was 5.5 years (SD = 2.5 years), with a range of 1 to 13 years. The group comprised 54 boys and 41 girls. Thirty-three orphans were living in group homes, and 62 were living in family settings.
DRUG REGIMEN, TOXICITIES, AND MORTALITY
Children received a HAART regimen of nevirapine (NVP) or efavirenz (EFV) plus stavudine and lamivudine (all antiretroviral drugs used were manufactured by Government Pharmaceutical Organization, Bangkok, Thailand). Children younger than 3 years or weighing less than 10 kg were started on an NVP-based regimen. Drugs were given in accordance with World Health Organization dosing guidelines. Liquid formulations of NVP, lamivudine, and stavudine were given to children who did not meet appropriate weight criteria to receive tablets or capsules or who could not swallow pills. Fifty-nine children were started on an NVP-based regimen, and 36 were started on an EFV-based regimen. Five children who were receiving concomitant tuberculosis treatment were treated with EFV.
There were no deaths attributable to antiretroviral drug toxicities. Four children developed NVP skin rashes, which were easily managed by switching to EFV. Five children started on NVP switched to EFV because of elevated liver enzymes after beginning treatment. One patient switched from NVP to EFV because of treatment failure on NVP (defined as no significant rise in CD4 count after 6 months).
Twenty-two patients, all of whom completed less than 6 months of HAART, died from AIDS-related illness; they were not included in the analysis of CD4 cell changes because follow-up CD4 measurements were not available. Baseline CD4 measurements were available for 8 of the 22 children who died before receiving 6 months of antiretrovial treatment. Baseline CD4 counts (mean of 53 cells/mm3) and percentages (mean of 1.98%) were significantly lower (P < .01) than those for the surviving children (255 cells/mm3 and 6.84%, respectively). Although these CD4 cell data are incomplete for the children who died, they suggest that mortality may have been attributable to later-stage disease at initiation of antiretroviral treatment. One child who received 15 months of directly observed treatment with HAART died of chronic cryptosporidial diarrhea.
OUTCOMES AND COSTS
Before receiving directly observed treatment with HAART, children were significantly underweight. Average weight-for-age z scores were calculated for children who received 6 or more months of treatment using Epi-Info version 3.3.2 (Centers for Disease Control and Prevention, Atlanta, Ga). An increase in weight-for-age z scores with directly observed treatment with HAART was seen over time, as shown in Table 1 ▶.
TABLE 1—
Mean CD4 Counts and Percentages in Children Receiving Directly Observed Treatment With HAART: Phnom Penh, Cambodia, August 2002 to October 2004
| Timetable of Treatment and Number of Patients | Mean CD4 Count (SD) | Mean CD4 Percentage (SD) | Mean Weight-for-Age z Score (SD) |
| Baseline, n = 95 | 255 (282) | 6.84 (6.82) | −3.8 (2.9) |
| 6 months, n = 95 | 656 (406)a | 16.73 (7.75)a | −2.7 (2.5)a |
| 12 months, n = 68 | 854 (431)a | 21.73 (7.45)a | −2.4 (1.8)a |
| 18 months, n = 33 | 992 (417)a | 23.40 ( 6.20)a | −2.2 (1.5)a |
Note. HAART = highly active antiretroviral therapy.
aSignificantly higher than baseline by paired t test (P < .001).
Improvements in mean absolute CD4 count and CD4 percentages in the cohort are shown in Table 1 ▶. The mean absolute CD4 count increased from 255 cells/mm3 at baseline to 656 after 6 months of directly observed treatment with HAART, 854 after 12 months, and 992 after 18 months. These improvements in T-cell immunity compare favorably with those reported in other cohorts of children in both the developed and the developing world, none of which used directly observed treatment.6,9–12
The relatively low cost of employing trained child care workers in Cambodia to administer daily HAART made it feasible to ensure nearly 100% medication adherence in the children enrolled in the Maryknoll program. The additional cost of personnel plus training to provide directly observed treatment to children in this program was estimated to be US $5 per child per month or $60 per child per year. This represents an additional 15% cost for directly observed treatment beyond the cost of HAART medications. It is hoped that directly observed treatment with HAART will result in long-term cost savings by optimizing medication adherence and postponing the development of drug resistance and treatment failure, which necessitate switching to more expensive second-line regimens.
IMPLICATIONS
To our knowledge, there are no published reports on outcomes of orphaned children in resource-poor settings receiving directly observed treatment with HAART. Considering that children who are HIV infected will likely need to receive HAART indefinitely and that the cost of second- and third-line regimens will be burdensome in resource-poor settings, it is of particular importance that medication adherence remain optimal to decrease the risk of treatment failure. directly observed treatment with HAART may be especially useful for maintaining medication adherence and thus preventing viral resistance and treatment failure.
The outcomes seen in the children of the Maryknoll Little Sprouts program suggest that directly observed treatment with HAART to children who are HIV infected can be feasible and effective in a resource-poor setting and can employ locally trained personnel at a reasonable cost. The orphaned children in this cohort were started on antiretroviral therapy at a very late stage of disease, and we speculate that better clinical outcomes may be achievable if children can begin directly observed treatment with HAART earlier in the disease course. Further data are needed to evaluate the long-term sustainability of directly observed treatment with HAART programs for children, optimal duration of directly observed treatment, and acceptance by older children, adolescents, and the local community.
Figure 2.
Child receiving directly observed treatment with highly active antiretroviral therapy. Source. Courtesy of John Tucker.
Acknowledgments
This program evaluation was supported by the AIDS International Training and Research Program of the Fogarty International Center of the National Institutes of Health (grant TW00237-04). P. Myung and M. F. Brady were recipients of Foreign Studies Fellowship travel grants from the Brown International Health Institute.
The authors thank the staff of the Maryknoll Little Sprouts program for their cooperation and assistance in making the program evaluation possible.
Human Participant Protection The human subjects review board of Brown University approved the study protocol.
Peer Reviewed
Contributors D. Pugatch and J. Tucker supervised the program evaluation. Data was collected and organized in Phnom Penh by P. Myung and P. Many. P. Myung, D. Pugatch, J. I. Harwell, and M. F. Brady wrote the first draft of the article. D. Pugatch, M. F. Brady, P. Myung, and M. Lurie conducted the data analysis.
References
- 1.World Health Organization. Progress on Global Access to HIV Antiretroviral Therapy: An Update on “3 by 5.” Geneva, Switzerland: World Health Organization; 2005.
- 2.Cambodia: summary country profile for HIV/AIDS treatment scale-up. In: World Health Organization. Progress on Global Access to HIV Antiretroviral Therapy: An Update on “3 by 5.” Geneva, Switzerland: World Organization; 2005, 1–3. Available at: http://www.who.int/entity/hiv/HIVCP_KHM.pdf. Accessed March 8, 2007.
- 3.Cambodia: epidemiological fact sheets on HIV/AIDS and sexually transmitted infections. Available at: http://www.nchads.org/reports.php. Accessed March 30, 2007.
- 4.Chesney MA, Ickovics J, Hecht FM, Sikipa G, Rabkin J. Adherence: a necessity for successful HIV combination therapy. AIDS. 1999;13(Suppl A):S271–S278. [PubMed] [Google Scholar]
- 5.Watson DC, Farley JJ. Efficacy of and adherence to highly active antiretroviral therapy in children infected with human immunodeficiency virus type 1. Pediatr Infect Dis J. 1999; 18: 682–689. [DOI] [PubMed] [Google Scholar]
- 6.Kline MW, Matusa RF, Copaciu L, Calles NR, Kline NE, Schwarzwald HL. Comprehensive pediatric human immunodeficiency virus care and treatment in Constanta, Romania: implementation of a program of highly active antiretroviral therapy in a resource-poor setting. Pediatr Infect Dis J. 2004;23:695–700. [DOI] [PubMed] [Google Scholar]
- 7.Mitty JA, Stone VE, Sands M, Macalino G, Flanigan T. Directly observed therapy for the treatment of people with human immunodeficiency virus infection: a work in progress. Clin Infect Dis. 2002;34:984–990. [DOI] [PubMed] [Google Scholar]
- 8.Fraser B. Getting drugs to HIV-infected children in Cambodia. Lancet. 2005;366:1153–1154. [DOI] [PubMed] [Google Scholar]
- 9.Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. N Engl J Med. 1999;341:1874–1881. [DOI] [PubMed] [Google Scholar]
- 10.Puthanakit T, Oberdorfer A, Akarathum N, et al. Efficacy of highly active antiretroviral therapy in HIV-infected children participating in Thailand’s National Access to Antiretroviral Program. Clin Infect Dis. 2005;41:100–107. [DOI] [PubMed] [Google Scholar]
- 11.Fassinou P, Elenga N, Rouet F, et al. Highly active antiretroviral therapies among HIV-1-infected children in Abidjan, Cote d’Ivoire. AIDS. 2004;18: 1905–1913. [DOI] [PubMed] [Google Scholar]
- 12.van Rossum AM, Fraaij PL, de Groot R. Efficacy of highly active antiretroviral therapy in HIV-1 infected children. Lancet Infect Dis. 2002;2:93–102. [DOI] [PubMed] [Google Scholar]