Published online September 10, 2007
PEDIATRICS Vol. 120 No. 4 October 2007, pp. e856-e861 (doi:10.1542/peds.2006-1122)
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ARTICLE

Efficacy of Highly Active Antiretroviral Therapy in HIV-1–Infected Children in Kenya

Rinn Song, MDa, Justine Jelagat, MBChBb, Doris Dzombo, RCOb, Marietta Mwalimu, RNb, Kishorchandra Mandaliya, MBChBb, Khadija Shikely, MBChBb and Shaffiq Essajee, MDb,c

a Departments of Pediatrics
c Pediatric Infectious Diseases, New York University, New York, New York
b Family Care Clinic, Coast Province General Hospital, Mombasa, Kenya


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Few studies have investigated the efficacy of antiretroviral therapy among HIV-infected children in resource-poor settings. This observational, retrospective analysis describes the clinical, immunologic, and virologic effects of highly active antiretroviral therapy in treatment-naive, HIV-infected children in Mombasa, Kenya. In keeping with a public health approach, all children were treated by using a simplified, nationally approved, triple-drug regimen.

METHODS. Clinical data and stored plasma samples from 29 children who were followed prospectively between April 2003 and October 2004 were analyzed. All children received generic formulations of nevirapine, zidovudine, and lamivudine and were evaluated at baseline and at 3, 6, 9, 12, and 15 months. At each visit, weight and CD4 lymphocyte counts were measured and plasma samples were stored for analysis. HIV RNA load was determined retrospectively at baseline and 9 months after initiation of therapy.

RESULTS. The mean age of the children was 8.5 years (range: 2–16 years). At baseline, the mean CD4 count (±SD) was 182.3 x 106 cells per µL (±145.6). On treatment, CD4 counts increased step-wise by a mean of 187 x 106 cells per µL at 3 months, 293 cells per µL at 6 months, 308 cells per µL at 9 months, 334 cells per µL at 12 months, and 363 cells per µL at 15 months. The mean plasma viral load decreased from a baseline level of 622 712 to 35369 copies per mL, and at 9 months was undetectable in 55% of the patients. Mean z scores for weight for age increased from a baseline of –1.61 to –1.12 at 12 months into therapy.

CONCLUSIONS. A public health approach using 1 treatment regimen in generic form showed excellent efficacy among treatment-naive, HIV-infected children in a resource-limited country. Clinical and immunologic improvement occurred in all patients, but 9 months after the start of therapy, only 55% of the children had an undetectable viral load.

Key Words: HIV-1 • AIDS • HAART • African children • Kenya

Abbreviations: WHO—World Health Organization • ART—antiretroviral therapy • HAART—highly active antiretroviral therapy • CDC—Centers for Disease Control and Prevention

During the past 20 years, the global impact of the HIV epidemic on children around the world has been devastating. According to the Joint United Nations Programme on HIV and AIDS, ~2.2 million children were living with HIV at the end of 2004, with >80% of these children in sub-Saharan Africa.1 In Kenya, the number of HIV-infected children at the end of 2003 was estimated to be 100000, and the number of newly infected children per year may be as high as 25000.2 However, as in many African countries, most of the infected children in Kenya either have not received a diagnosis or do not receive adequate treatment after diagnosis. Despite current endeavors to improve the delivery of antiretroviral drugs to resource-constrained countries, the World Health Organization (WHO) estimates that only 3% to 4% of HIV-infected African children who require immediate treatment are actually receiving it.3 Without antiretroviral treatment, mortality in HIV-infected African children approaches 60% by 2 years of age and 75% before age 5.4–6 This has had a marked impact on overall child mortality in Kenya. The infant mortality rate among Kenyan children was recently estimated to be 77 per 1000, an increase from 50 per 1000 in the pre-AIDS era.7,8 Mortality in children who are younger than 5 years has also increased from 110 to 115 per 1000.7,8

Although the clinical efficacy of highly active antiretroviral therapy (HAART) in children has been well documented in industrialized countries,9–13 there are few data from the African continent. The first report by Fassinou et al14 from Cote d'Ivoire noted a 72.8% probability of survival after 24 months of treatment in children with a CD4 cell percentage <5% at baseline and 97.8% survival in children with a CD4 cell percentage >5%. In total, 50% of the children achieved an undetectable viral load after an average of 756 days of HAART. The incidence of pneumonia and acute diarrhea was significantly lower during the treatment period, and weight-for-age z[r] scores improved significantly during the treatment period. Overall, HAART was well accepted and tolerated by most of the children in this study.14

The objective of our retrospective analysis was to describe the clinical, immunologic, and virologic effects of HAART in a population of African children who were followed at a busy clinical center where all children are treated with the same first-line regimen. This type of standardized public health approach is in contrast to the more individualized approach to treatment that is practiced in industrialized countries.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Site and Patients
Study patients were treated at the Family Care Clinic at Coast Province General Hospital (Mombasa, Kenya). Coast Province General Hospital is Mombasa's largest government hospital, and the Family Care Clinic has been in operation since 2001 and is supported by Keep a Child Alive, New York University and the Kenyan Ministry of Health. The clinic provides free care and treatment services to HIV-infected children and families and is based on the principles of provider continuity, community involvement, and free comprehensive care. Services offered include mother and child social groups, adherence support, and nutritional therapy for children with low weight for age. For encouragement of regular follow-up visits, caregivers are offered transport reimbursement for scheduled clinic appointments. The clinic is supported by a specialized HIV laboratory that offers HIV serologic testing, CD4 and CD8 immune monitoring, and DNA polymerase chain reaction.

All HIV-1–infected children who were included in this analysis were consecutively enrolled from a cohort of vertically infected children between April 2003 and October 2004. Patients were selected for treatment on the basis of the Kenyan national criteria for eligibility for antiretroviral therapy (ART): confirmed HIV-1 seropositive status in children who are older than 18 months and either advanced clinical disease (stage 3 or 4 according to WHO classification) or severe immune suppression (CD4 percentage or age-adjusted CD4 count ≤15%). In accordance with national recommendations, patients who had treatment contraindications (inability to adhere to the treatment regimen, severe anemia, liver enzymes elevated more than 5 times the upper limit of normal, concurrent treatment for active tuberculosis disease, or concurrent severe acute illness) were not initiated on treatment until resolution of the contraindication.

Procedures
All patients received the same triple therapy of generic drugs: nevirapine (120 mg/m2 twice daily), zidovudine (180 mg/m2 twice daily), and lamivudine (4 mg/kg twice daily). Most of the children received syrups, although older children were treated with adult tablets or capsules. Patients were seen at enrollment and then followed prospectively for routine care every 3 months. At each routine visit, an interval history was obtained and patients were given a physical examination including anthropometric measurements. In addition to these routine follow-up visits, patients were seen 2 weeks and 4 weeks after initiation of therapy for toxicity check and came to the clinic to collect medications each month. Adherence messages were reinforced at each patient contact.

Blood sampling was performed in accordance with the published Centers for Disease Control and Prevention (CDC) guidelines at baseline and at 3, 6, 9, 12, and 15 months after initiation of therapy.15 CD4 counts were assayed using the BD FACSCOUNT (Becton Dickinson Immunocytometry Systems, San Jose, CA) instrument in the Family Care Clinic laboratory, which participates in an National Institutes of Health–approved quality assurance program. Patients were classified into immune categories using the 1994 revised guidelines by the CDC.16 At each time point, samples of blood were processed within 6 hours of collection, and the plasma fraction was separated at 4°C and stored at –86°C. For the retrospective analysis, 1-mL aliquots of plasma were shipped while still frozen to a commercial laboratory for viral load measurements using the Roche (Basel, Switzerland) Amplicor V.1.5 assay. Viral load determinations were performed on the baseline and 9-month specimens.

Statistical Analysis
Continuous variables were expressed as the mean with SD and range. One-way repeated measures analysis of variance test as well as Wilcoxon's rank test were used to compute and evaluate the magnitude of changes in CD4 cell counts, viral RNA, and z scores for weight for age compared with baseline. All analyses were made on the basis of an intention-to-treat approach by using observed data. P < .05 for 2-sided tests was considered to be statistically significant. Virologic success was defined as a plasma HIV RNA level of <50 copies per mL. z scores for weight for age were calculated using the program Nutstat, which is part of Epi Info (CDC, Atlanta, GA, and WHO, Geneva, Switzerland). Data were analyzed with SPSS 13 (SPSS, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Baseline Characteristics of the Patients
From April 2003 to October 2004, 30 HIV-1–infected children who had never previously taken ART were initiated on treatment and followed for 15 months. One child was lost to follow-up after 9 months of treatment because the patient moved to a different city, and this patient was not included in the cohort. Of the remaining 29 children, follow-up data were available from all patients at baseline and 3, 6, and 9 months. At 12 months, 2 patients had no CD4 count available for analysis, and at 15 months, 1 patient's CD4 count was not available. The age (mean ± SD) at initiation of treatment was 8.5 ± 3.4 years). According to the CDC classification, at baseline, 11 children (37.9%) were in immune category 2 (moderate immune suppression) and 18 children (62.1%) were in immune category 3 (severe immune suppression). The mean weight-for-age z score (±SD) at baseline was –1.61 (±1.39). The baseline characteristics of these 29 children are presented in Table 1.


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  		TABLE 1 Baseline Characteristics of the Cohort Before HAART

 
Clinical Outcomes
The weight for age increased during the follow-up period. The mean z score (±SD) for weight for age at baseline was –1.61 (±1.39). At 6 months into therapy, the mean z score increased to –1.19 (±1.11), and at 12 months, it had increased further to –1.12 (±1.09). A 1-way repeated measures analysis of variance was performed and demonstrated a statistically significant increase in weight-for-age z scores over time (P = .04).

No adverse events that warranted discontinuation of or change in therapy were reported during the period. One patient developed tuberculosis while receiving treatment, but the ART was continued and standard antituberculosis drugs that comprised isoniazid, rifampin, and pyrazinamide were initiated with close monitoring of liver function. For the duration of follow-up, none of the participating children had to be hospitalized, and the mortality rate was 0%.

Immunologic and Virologic Outcomes
During follow-up, there was a highly significant step-wise increase in the mean CD4 cell count. For each patient, the mean change in the CD4 cell count was compared with baseline. At 3 months, the CD4 cell count (mean ± SD) had increased by 187 ± 199 x 106/L. The CD4 count increased further by 203 ± 144 x 106/L at 6 months, by 308 ± 210 x 106/L at 9 months, and by 334 ± 365 x 106/L at 12 months. At 15 months into HAART, the CD4 cell count had increased by 363 ± 369 x 106/L compared with baseline. A 1-way repeated measures analysis of variance was conducted to compare mean CD4 counts at baseline with mean CD4 counts at 3, 6, 9, 12, and 15 months into therapy. There was a highly statistically significant increase in CD4 count for the duration of follow-up (P < .0001). In addition, the rate of CD4 cell increase was greater during the first 6 months of the study but then decreased subsequently (Fig 1). This is in keeping with previous reports from developed countries that have shown a bimodal expansion of CD4 cells in both adults and children.17,18


Figure 1
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  		FIGURE 1 Log-transformed CD4 counts from all patients over time.

 
At 9 months into HAART, the reduction (mean ± SD) in the plasma HIV-1 RNA level from baseline was 3.3 ± 0.38 log10 copies per mL, which was highly statistically significant (P < .0001). Plasma HIV-1 RNA levels decreased to <50 copies per mL in 16 children (55.2%), but 11 (37.9%) children had a viral load between 50 and 30000 copies per mL and 2 (6.8%) children had a viral load >30000 copies per mL. These immunologic and virologic data are summarized in Fig 2.


Figure 2
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  		FIGURE 2 Changes in CD4 count and viral load at 3, 6, 9, 12, and 15 months in comparison to baseline.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This observational, retrospective analysis addressed the clinical efficacy of a simplified, standard, triple-drug antiretroviral regimen among HIV-1–infected children in Kenya. The results showed an overall excellent clinical response to HAART. Mean CD4 cell counts improved markedly during the 15 months of the study, with the greatest increase in the first 6 months. These findings are in keeping with data from Thailand19 and a recent report from Kenya that compared treatment outcomes in orphaned and nonorphaned children. Among 279 children who were followed at 9 different clinics in western Kenya, a statistically significant increase in CD4 percentage was observed after treatment initiation with the greatest increase noted during the first 30 weeks on treatment.20

Recent data from a treatment program in South Africa showed a significant difference in survival among children who were on treatment and had advanced disease at baseline. One-year survival in children with WHO stage 4 disease was 77% compared with 96% in children with stages 2 and 3 disease.21 By contrast, a Thai study showed comparable outcomes of therapy, regardless of clinical stage at baseline.22 In our cohort, the majority (62%) of patients had an advanced stage of disease (CDC stage 3) at the start of therapy, but no death or opportunistic infections were observed during the course of treatment. One child developed tuberculosis during the follow-up period, which may have been related to immune reconstitution, but this patient was able to continue ART.

Data on tolerability of HAART in African children are limited, but we observed no unexpected adverse events that led to withdrawal or modification of treatment during this relatively short period of follow-up. The majority of patients were on syrup formulations, and this was well tolerated by the patients.

We observed a significant increase in age-adjusted weight among our study population during the follow-up period. Weight-for-age z scores increased from a baseline value of –1.61 to –1.12 at 12 months (P = .04). Low weight for age has been associated with poor survival in African children with HIV,23 but our findings are in contrast to data from a cohort of 80 HIV-infected children in South Africa, in whom analysis of weight-for-age z scores before and after HAART failed to show a statistically significant change.24 This may relate to the fact that children at the Family Care Clinic routinely receive nutritional porridge as part of the package of care services.

After 9 months of therapy, only 55% of children had undetectable HIV-1 RNA levels, and, overall, there was a high degree of discordant virologic and immunologic responses in our study population. The nevirapine dosage that we used was 120 mg/m2 twice daily, which was the WHO-recommended minimum dosage at the time when these patients were enrolled. This recommendation has now been revised in light of data that show subtherapeutic nevirapine levels in children who receive <160 mg/m2 per dose. It is possible that improved outcomes could have been observed with higher dosing of nevirapine, and this question merits additional investigation; however, our virologic outcomes are compatible with reports from other cohorts in developed countries25–27 and with a recent report that pooled data from 8 African countries.28

The main drawbacks to our analysis are the short follow-up period and the relatively small cohort size. Studies in a larger cohort with a longer follow-up period are needed to determine the duration of the clinical, virologic, and immunologic responses and evaluate treatment compliance during a longer period of time. In particular, it is essential to determine how long discordant responses might persist. Recently, a follow-up study was published describing the long-term survival and laboratory responses to HAART among 78 children in the Cote d'Ivoire whose short-term responses were originally reported by Fassinou et al14,29 in 2004. This report showed that both clinical and biological responses were durable. Overall survival probability was 88% at 36 months and 86% at 42 months on treatment. The CD4 percentage increased during the first 18 months and then stabilized, and the proportion of patients with undetectable virus remained stable at ~50%, regardless of the ART regimen.29

Another potential confounder in our study is the age of the patient population. The average age of children who were started on treatment was high at 8.5 years. This is the case for the majority of published reports on treatment outcomes of HIV-infected children in the developing world.14,19,20,28,29 The mortality rates of untreated HIV-infected African children are extremely high, especially within the first 5 years of life.4–6 That the majority of our study patients survived past that age without ART suggests that most of the patients were pediatric slow progressors, which may in part explain the excellent clinical, virologic, and immunologic outcomes of the study. Studies in younger cohorts are essential to understand better the full spectrum of treatment responses in the developing world.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our results demonstrate the feasibility of a public health approach to the treatment of HIV-infected children in a sub-Saharan African country. We were able to show that it is possible to treat African children with generic ART in a public health setting with emphasis on standardized treatment monitoring and close attention to adherence counseling in keeping with recent WHO guidelines.30 In particular, the local health infrastructure was able to support the management and monitoring of the pediatric program. Effective training and supervision of local multidisciplinary staff in conjunction with appropriate laboratory equipment and availability of antiretroviral drugs could produce similar outcomes in other developing countries.


   ACKNOWLEDGMENTS
 
We thank all staff at the Family Care Clinic for dedication and contribution to these data and Keep a Child Alive for ongoing support of our work.


   FOOTNOTES
 
Accepted Feb 7, 2007.

Address correspondence to Rinn Song, MD, Centers for Disease Control and Prevention, International Research and Programs Branch, Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, 1600 Clifton Rd, Ms E-10, Atlanta, GA 30333. E-mail: ggj4{at}cdc.gov

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


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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N. Kumarasamy, K. K. Venkatesh, B. Devaleenol, S. Poongulali, S. N. Mothi, and S. Solomon
Safety, Tolerability and Effectiveness of Generic HAART in HIV-Infected Children in South India
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