JAIDS Journal of Acquired Immune Deficiency Syndromes:
Response to Antiretroviral Therapy in HIV-Infected Ugandan Children Exposed and Not Exposed to Single-Dose Nevirapine at Birth
Musoke, Philippa M MBChB*†; Barlow-Mosha, Linda MD, MPH*; Bagenda, Danstan PhD*‡; Mudiope, Peter MBChB, MSc*; Mubiru, Michael*; Ajuna, Patrick MBChB*; Tumwine, James K MBChB, PhD†; Fowler, Mary Glenn MD, MPH§
From the *Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda; †Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda; ‡School of Public Health, College of Health Sciences, Kampala, Uganda; and §Department of Pathology, Faculty of Medicine, Johns Hopkins University, Baltimore, MD.
Received for publication January 28, 2009; accepted June 17, 2009.
Presented in part at the 15th Conference on Retroviruses and Opportunistic Infections, February 2008, Boston, MA.
Supported by Elizabeth Glazer Paediatric AIDS Foundation, International Leadership Award, 2003.
Correspondence to: Philippa Musoke, MBChB, MUJHU Research Collaboration, Box 23491, Kampala, Uganda (e-mail: firstname.lastname@example.org).
Objective: To compare the response to a nevirapine (NVP)-based highly active antiretroviral therapy (HAART) in HIV-infected Ugandan children, exposed and nonexposed to single-dose NVP (sd NVP) at birth.
Methods: HIV-infected study children were initiated on stavudine/lamivudine/NVP as a fixed dose combination. CD4 cell percent and HIV-1 RNA were documented at baseline, 12, 24, 36, and 48 weeks post-initiation of HAART.
Results: Ninety-two children were enrolled in the study, 44 in the sd NVP-exposed and 48 in the nonexposed cohort. The median age at enrollment was 1.7 years [interquartile range (IQR) 1.2-2.4] and 7.8 years (IQR 5.9-9.2) in the sd NVP-exposed and nonexposed cohorts, respectively (P < 0.001). At baseline and week 48 post-HAART, the median CD4 cell percentages were 14% and 33% for the NVP-exposed group and 8% and 22.5% in the nonexposed group (P < 0.0001). The median (IQR) viral load at baseline was 650,568 (359,979-2,086,613) RNA copies/mL and 239,027 (105,904-494,813) RNA copies/mL in the NVP-exposed and nonexposed cohorts, respectively. After 48 weeks of HAART, 76% of the NVP-exposed and 80% of the nonexposed children had a median viral load of <400 copies/mL (P = 0.74).
Conclusions: Both HIV-infected Ugandan older infants and children that were exposed and not exposed to sd NVP at birth had favorable treatment outcomes on NVP-containing HAART.
Approximately 2.1 million children are living with HIV infection worldwide, and the number continues to rise with over 400,000 new infections in the last year.1 Ninety percent of these children reside in sub-Saharan Africa with over 1500 babies infected daily. Without access to antiretroviral therapy, infected children from resource-limited settings have an unacceptably high mortality with 50% dying by 2 years of age.2,3 Over the last 5 years, access to free antiretroviral therapy in developing countries has increased significantly with over 1 million individuals on highly active antiretroviral therapy (HAART), but regrettably less than 10% on antiretroviral treatment are children.4 Before the scale-up of antiretroviral therapy in resource-limited settings, many developing countries had implemented Prevention of Mother to Child HIV Transmission (PMTCT) programs using the single-dose nevirapine (sd NVP) regimen.5,6 Therefore, a significant proportion of African children who become infected despite antiretroviral prophylaxis for PMTCT will have been exposed to sd NVP at birth. Multiple studies have documented the emergence of resistant mutations to NVP in both women and infants exposed to sd NVP during the peripartum period7-10; followed by subsequent waning using standard genotypic resistance testing. These high levels of viral resistance to NVP raise concerns about the effectiveness of a subsequent NVP-containing HAART regimen in women and children exposed to sd NVP.
Most developing countries, including those from sub-Saharan, have used NVP as the nonnucleoside reverse transcriptase inhibitor (NNRTI) in both adults and children initiating HAART. Therefore, NVP has been incorporated into both PMTCT and antiretroviral treatment (ART) programs. Several studies among women who received sd NVP and then began NVP-based HAART treatment suggest that there is little impact on treatment success if the woman begins HAART >6-12 months after the single-dose exposure, whereas virologic suppression is reduced among a subset of those women who require treatment within the first year after delivery.11-13 There is, however, limited data on the effectiveness of NVP-based HAART in HIV-infected children exposed to sd NVP at birth. The aim of this study was to determine the immunologic and virologic response to a NVP-containing HAART regimen in HIV-infected Ugandan children, exposed and not exposed to sd NVP at birth.
Study Setting and Population
Between October 2004 and June 2006, HIV-infected children aged 6 months to 13 years attending the Mulago Hospital Paediatric HIV clinic and the Makerere University-Johns University Research Collaboration (MUJHU) Research clinic in Kampala, Uganda, were referred for study screening. HIV-infected children who were eligible for antiretroviral therapy according to the World Health Organization (WHO) antiretroviral therapy guidelines for Resource Limited Settings, 2002,14 fulfilled the study inclusion criteria and whose parents/caretakers consented to have their child participate in the study, were enrolled consecutively. Before enrollment, all the children underwent the standard MUJHU clinic screening visits required to initiate HAART. These included adherence counseling, clinical and psychosocial assessments, and a home visit. Parents/caretakers provided informed consent for their children to enroll in the study and initiate HAART. Families whose children did not fulfill the study inclusion criteria had their children initiated on HAART through the general ART program at MUJHU or the pediatric HIV treatment program of the Mulago Hospital.
Study Design and Procedures
We conducted an observational cohort study of HIV-infected Ugandan children who were either exposed to sd NVP at birth in cohort 1 or not exposed to sd NVP for cohort 2. The enrollment criterion for the study was similar to that for the children initiating HAART in the MUJHU ART program and reported elsewhere by Mosha et al.15 The inclusion criteria was as follows: confirmed HIV infection by HIV rapid tests (Determine and Unigold in series) or 2 positive HIV-1 DNA polymerase chain reaction (PCR) tests (Roche Amplicor; Roche Diagnostics, Indianapolis, IN) for those children under 18 months of age; WHO clinical stage III (2003) and or CD4 cell % <20% or <15% in those younger than 1 year and older than 1 year, respectively; care taker willing to provide informed consent, prior adherence to clinic visits and antiretroviral drug naive except for PMTCT. Laboratory exclusion criteria included hemoglobin ≤7.0 g/dL, platelet count ≤49,000/mm3, absolute neutrophil count < 250/mm3, and alanine transferase/aspartate transferase ≥ 5 × upper limit of normal, and serum creatinine >1.7 mg/dL. Additional exclusion criteria included known hypersensitivity to diazepam or NVP, malignancy, or on current cytotoxic chemotherapy. The study was approved by the Makerere University, Faculty of Medicine Research and Ethics Committee and Uganda National Council for Science and Technology. Informed consent was obtained from parents/caretakers before study-specific procedures were performed.
In February 2006, the protocol was amended to allow for enrollment of younger infants, between the ages 6 and 12 months; a weight of less than 10 kg and initiation of syrup formulations for those children weighing <10 kg. The protocol was amended because most of the children who were screened for the NVP-exposed arm were either less than 12 months of age and or weighed <10 kg. Before the amendment, these children were not eligible for the fixed-dose combination (FDC) and were thus excluded from the study. The documentation of exposure to sd NVP was confirmed by several methods: examining antenatal records for those who attended the Mulago PMTCT program, previous study records for those children who participated in perinatal prevention trials, and maternal verbal reports including specific detailed questions to confirm exposure to sd NVP at birth. Most of the children from the nonexposed cohort were born before the start of the Mulago PMTCT program and therefore did not have access to sd NVP for PMTCT.
After enrollment into the study and initiation of HAART, the children attended routine visits at 2 and 4 weeks and then every 4 weeks for the first 48 weeks. For the study, the children had clinical and laboratory monitoring done at baseline, 12, 24, 36, and 48 weeks after HAART initiation. Laboratory monitoring included complete blood count, CD4 cell count (absolute and percent), chemistries (aspartate transferase and alanine transferase), and HIV-1 RNA PCR. The pharmacy provided ART drug refills on a monthly basis as recommended by the Uganda Ministry of Health HIV treatment program. Toxicity monitoring (chemistries) was done at 2 weeks after initiation of antiretroviral therapy and subsequently when clinically indicated.
Antiretroviral Therapy-Eligibility and Regimen
Consistent with the WHO and national antiretroviral therapy guidelines, study children initiated treatment with 2 nucleoside reverse transcriptase inhibitors and a nonnucleoside reverse transcriptase inhibitor (NNRTI).14,16 Despite enrollment over a 2-year period (2004-2006), to remain consistent with the original inclusion criteria and maintain a homogeneous group at entry only those children eligible for ART according to the 2002 WHO guidelines were enrolled into the study. Those children who were screened and fulfilled the criteria for ART according to revised WHO ART treatment guidelines were enrolled in the ART program. All the children were ART naive and the ART regimen included the first-line Uganda MOH regimen; stavudine (d4T), lamivudine (3TC), and NVP were prescribed as a FDC Triomune (Cipla d4T 30 mg/40 mg, 3TC 150 mg, and NVP 200 mg). The dose was prescribed according to the children's weight using specific dosing weight bands as shown in Table 1. These dosing weight bands were developed before the 2006 WHO dosing weight bands.17
After the protocol amendment, infants <10 kg were initiated on syrup formulations of the same antiretroviral drugs in the FDC. When the children's weight was equal to 10 kg they were switched to the FDC and dosed according to the study dosing weight bands. Tablets were precut using a pill cutter in the clinic pharmacy and dispensed to the patients in labeled plastic medicine containers. FDC tablets were dispensed as whole, half, or quarter but subsequently dispensing of quarter tablet was discontinued. In January 2007, in response to the NVP FDC pharmacokinetics study from Zambia and Malawi, the children on quarter tablet were switched to half tablet of the FDC.18 Plasma was stored for later NVP pharmacokinetics in a substudy of 20 children on the FDC. Those children who developed side effects in particular NVP skin rash were switched to Efavirenz or Abacavir, terminated from the study, and transferred to the ART program. None of the study children were switched to a second line treatment regimen during the 48 weeks of follow-up.
All laboratory tests were performed in the MUJHU Research Collaboration laboratory in Kampala, Uganda. This laboratory conforms to US Clinical Laboratory Improvement Act of 1988 regulations for the assays used in this study and participated in proficiency testing programs for these assays. The MUJHU Core Lab is also a College of Pathologist certified laboratory. The CD4 cell counts and CD4 cell percentage were measured using a fluorescence-activated cell sorting instrument (Becton-Dickinson, San Jose, CA). Quantitative HIV-1 RNA PCR testing was done using the Roche HIV-1 Amplicor MONITOR assay v1.5 kit (Roche Diagnostics, Indianapolis, IN) on plasma separated from whole blood and frozen at −70°C within 24 hours of collection.
Descriptive statistics are presented including means, standard deviations, medians, and interquartile ranges. Statistical comparisons of means and medians are based on the 2-sided evaluation of the Student t test and the Wilcoxon signed rank sum test. Proportions of different baseline characteristics of the children and P values are also provided. Weight and height z-scores of these children with respect to the British Growth-based Reference Population 1990 of children of similar age and sex were computed.
The primary endpoint for this analysis is sustained achievement of viral load <400 copies/mL and the analyses presented with reference to this endpoint are Kaplan-Meier estimates of conditional probabilities of achieving the endpoint through 48 weeks after initiation of HAART. Differences between K-M curves are assessed for statistical significance using the log-rank test. In addition, Cox regression analyses adjusting for, and indicating the hazard associated with the various baseline characteristics measured are presented. Graphs indicating the average trends of major virologic and immunologic measures taken are illustrated means and 95% confidence interval bars. All P values are evaluated for statistical significance at the 0.05 2-sided alpha-significance level. All analyses were performed using STATA version 10.0 (STATA Corp, 2003, Stata Statistical Software, Release 8, College Station, TX; StataCorp LP).
Characteristics of Study Population
A total of 148 HIV-infected children were screened, and 92 fulfilled study inclusion criteria and were enrolled into the study. Five children did not have complete data for the analysis because 2 died, at 3 and 44 weeks after HAART initiation, and 3 developed a mild rash within the first 2 weeks of HAART initiation and were terminated from the study. Baseline demographic data were available for all 92 children but only 90 children had baseline HIV RNAs. Eighty-nine children (43 in cohort 1 and 46 in cohort 2) were included in the final analysis, having completed 48 weeks of antiretroviral therapy (Fig. 1). The median duration of follow-up for all children was 72 weeks (range 48-96 weeks) with the children enrolled at the beginning of the study, mainly from the nonexposed group, completing 96 weeks of follow-up (49/92.53%). However, for this analysis we only included time points up to 48 weeks where both cohorts had similar and complete data. Ninety-seven percent (89/92) of all study children completed the 48 weeks of follow-up on HAART. One of the children who died had data available up to 44 weeks when they were censored.
The NVP-exposed cohort was significantly younger than the NVP-unexposed cohort (median 1.7 vs 7.8 years, P < 0.001, Table 2). At baseline, the NVP-exposed group had more advanced HIV disease (WHO stage III 54% vs 2%) than the non-NVP exposed cohort based on both virologic and clinical assessment (Table 2). However, as expected, the NVP-exposed group, which was younger, had higher baseline CD4 cell percents (14% vs 8.5%) compared with the relatively older NVP nonexposed group. The 2 groups were similarly severely stunted in terms of height z-scores and demonstrated moderate wasting at baseline. Other baseline demographic and laboratory characteristics are listed in Table 2.
Adherence to ART based on caretaker report and bottle returns was similar in the 2 cohorts (>95%), however, those children who initiated HAART on syrup formulations tended to have poorer adherence (80%) during the time on syrups (data not shown).
Antiretroviral Treatment Outcomes
At weeks 12, 24, and 48, the proportion of HIV-infected children with <400 copies/mL (virologic treatment success) in those children exposed to sd NVP was 61% (26/43), 81% (34/42), and 75% (33/44), respectively. In those children not exposed to sd NVP, virologic success occurred in 64% (29/45), 76% (34/45), and 80% (35/44), at the same time points (log-rank test P value = 0.8 through 48 weeks; Fig. 2). Despite the differences and variation in baseline viral load measurements between and within the 2 cohorts, the majority of children from both cohorts had a significant decline in HIV-1 RNA, reaching <400 copies/mL as early as 12 weeks after initiation of HAART. By 48 weeks after HAART initiation, over 75% of both cohorts had <400 copies/mL. The graphic representation of the average (geometric mean) virologic response of both cohorts of children over time is presented in Figure 3. At week 48, there were 20 children with detectable viral load, 11 in the exposed and 9 in the nonexposed cohorts. Four of these children had <2000 copies/mL, 7 children had >50,000 copies/mL. None of the study children required second line ART during the 48 weeks of follow-up. In multivariate analysis, none of the baseline factors including sd NVP exposure, viral load, CD4 percent, age, height-for-age z-score (HAZ), and weight-for-age z-score (WAZ), sex, and WHO stage had an effect on the outcome of virologic treatment success (viral load < 400 RNA copies/mL; Table 3).
Compared with baseline, there was a significant and brisk increase in CD4 cell percent in both cohorts. The average trend of CD4 cell percent and absolute CD4 cell count response over 48 weeks for the 2 cohorts are presented in Figure 4A and 4B. In the NVP-exposed cohort, the mean baseline CD4 cell percent was 14% and there was a brisk and robust mean response in CD4 cell percent of 20 percentage points at week 48 on HAART. In the non-NVP exposed cohort, the mean baseline CD4 percent was 8% with a mean CD4 cell percentage increase of 19% percentage points at 48 weeks. When the average baseline CD4 cell percent response was categorized into <10%, 10%-15%, and >15%, the mean CD4 cell percent in the NVP-exposed children was 29.8% (7.4) in the <10% group and 34.8% (6.4) in the >15% category at week 48. In the non-NVP exposed cohort, who were older, the mean CD4 cell percent was 22% (7.4) in the <10% group and 33.2% (4.7) in the >15% category.
Three children required a change in antiretroviral regimen because of a mild skin rash. Because the study regimen was in a FDC, the children with a rash required replacement of study drug and therefore termination from the study. There were 2 deaths during the 48-week study follow-up but none were related to study ART. One child who was severely immunosuppressed at baseline (CD4 cell count 0.5%) and died 2 weeks after enrollment from severe pneumonia and the other death at 44 weeks was due to HIV nephropathy.
The majority of HIV-infected women from developing countries still receive only sd NVP for PMTCT. WHO and national guidelines recommend combining NVP with other antiretroviral drugs to improve the effectiveness of the PMTCT ART intervention. In addition, NVP remains the most widely used NNRTI in first-line HAART regimens for children in sub-Saharan Africa.19 Therefore, it is critical to document the effectiveness of an NVP-based ART regimen in infants and children exposed to perinatal NVP. Our study documented a significant and robust response to an NVP-containing HAART regimen in children older than 6 months who were exposed and not exposed to sd NVP at birth. Over 70% of the children from both cohorts had <400 copies/mL after 48 weeks on HAART and the majority achieved <400 copies/mL by week 12. Using multivariate analysis, none of the baseline characteristics including sd NVP exposure, age, CD4 cell percent, sex, WHO clinical stage, and viral load were significantly associated with the virologic treatment success outcome. The high treatment success rate in this study is probably related to the intense counseling support, FDC antiretroviral therapy with subsequent high adherence rates. This virologic treatment success noted in our study is similar to the other early pediatric ART program in Mulago, Uganda, where virologic failure occurred in 26% of the children after 6 months of HAART.20
Our findings are consistent with previous adult data including women from the randomized Botswana MASHI (“milk”) trial, where later initiation (beyond 6 months) of an NVP-containing HAART regimen did not have a significant impact on virologic response in NVP-exposed women when compared with those women who were not exposed.11,12 In addition, Chi et al report brisk and similar CD4 cell responses among 6740 Zambian women exposed and not exposed to sd NVP when they initiated an NVP-based HAART regimen greater than 6 months after sd NVP exposure.13 In contrast, although the numbers are quite small, 15 children from the MASHI trial who were exposed to sd NVP and then initiated an NVP-based HAART regimen within 6 months after birth, experienced extremely high virologic failure rates.11 This difference in virologic treatment success between our study and the children in the MASHI trial may be explained by the following: significantly younger age at time of HAART initiation (<6 months) when resistance mutations are still more likely to be observed, small numbers in the MASHI trial, and the different HIV subtypes. Subtype C found in southern Africa has been reported to have higher levels of NVP resistance mutations emerge after sd NVP exposure.8,21 Subtypes A and D are the predominant subtypes in Uganda and are the most likely subtypes in our study children.22
At the time of HAART initiation, all the study children in this Ugandan study were over 6 months of age, with 5 and 10 children between 6-12 months and 12-18 months of age, respectively. In the younger age category, 3 of the 5 children in the NVP-exposed cohort achieved virologic treatment success by week 48. The virologic failure noted in 2 infants may be related to the higher viral load at baseline, possible persistence of NVP resistance mutations, and the use of syrup formulations which may also contribute to less than optimum adherence.23 In the 12-18 months age group, 9 of the 12 children in the NVP-exposed cohort achieved virologic treatment success by the same time point and this is consistent with the fading of NVP-resistant mutations using standard genotypic testing technologies. One would have anticipated that children with a higher baseline viral load and previous exposure to sd NVP would have higher virologic failure rates, but the NVP-exposed children with a median viral load of 650,568 copies/mL compared with 239,027 copies/mL for the NVP-unexposed cohort also had a similarly robust virologic response.
Emergence of resistant mutations, commonly K103 and Y181 in women and infants after sd NVP exposure, is well described.8-10 This is then followed by fading of these mutations over time, with reemergence of wild-type virus and may explain the limited impact of sd NVP exposure on virologic treatment success on those infants initiating ART after 6 months.9,24,25 Despite documentation that the NVP-resistant mutations fade with time, there is still concern that low levels of the mutations may remain archived and that, with longer exposure to NVP in a HAART regimen, there would be reemergence of the NVP-resistant mutations and subsequent virologic failure.9,25 In our study with 48 weeks of follow-up, there was no evidence of increasing virologic failure in the sd NVP-exposed cohort. One explanation for this finding was that there may be little archiving of resistant mutations which is consistent with a 12-month follow up virologic study by Flys et al.9 Alternatively, the virologic success noted in the NVP-exposed cohort could be explained by the short-term effectiveness of dual therapy, thereby contributing to initial virologic success in the first 48 weeks of therapy.26 The dual therapy would include d4T and 3TC because the NVP in the triple HAART regimen would be ineffective in the presence of NVP resistant mutations that could emerge after sd NVP exposure. However, with reemergence of resistant mutations after chronic exposure to NVP and waning effectiveness of dual therapy, one might then expect to see higher virologic failure rates in the exposed cohort. Because of fewer exposed children followed into the second year on therapy we could not disprove or prove this theoretical concern in our study.
The immunological response of children from both cohorts was significant with the highest mean increase in CD4 cell percent occurring between baseline and week 12 (9.1 exposed and 6.8 nonexposed). This finding is consistent with other reports of children initiating ART in sub-Saharan Africa.20,27-29 The older children in the nonexposed cohort had a lower median baseline CD4 count (8% vs 14%) and their response to HAART peaked at a lower median level when compared with the younger children (27.8 vs 37.1). A slower and modest rise in CD4 cell count in severely immunocompromised children has been reported elsewhere.30 It is believed that younger children even though severely immunocompromised tend to have a brisk CD4 cell response due to an active thymus and the ability to rapidly generate new memory T cells.31 Similar to other reports, young children from our study with low CD4 cell percents had a brisk response to ART and at the 24-weeks time point the median CD4 cell percent was 18%.32 In those children over 6 years, the mean absolute CD4 cell count increased by >300 cells in the first 24 weeks of HAART regardless of cohort.
Because Triomune is a FDC, inadequate serum drug levels of NVP when the tablet is broken in half have been reported.15 However, Puthanakit et al33 reported adequate drug levels of NVP when tablets were broken in half and dispensed to children in Thailand. The adult FDCs are not the most appropriate for children but where there are no pediatric formulations they provide a simple, cheaper, and feasible option for treating infected children in RLS. Currently, WHO has approved pediatric FDC, Pedimmune and pharmacokinetic data are available from Zambia.34 Therefore, there is an urgent need to increase access to pediatric FDCs so as to improve adherence and delivery of HAART for children in RLS.
After the release of the Children with HIV Early Antiretroviral Therapy Response (CHER) data, where delaying initiation of HAART in infancy led to a high mortality, WHO recommends that all HIV-infected infants should initiate HAART regardless of CD4 cell percent.35 Therefore, a large proportion of children under 6 months of age are likely to initiate HAART using a protease inhibitor-based regimen, as recommended by WHO.36 Implementing the current WHO recommendations for universal antiretroviral therapy using a PI-based HAART regimen for all infected infants exposed to sd NVP at birth would eliminate the need for an NVP-containing HAART regimen in these children. However, many countries may not be able to rapidly scale-up use of PI-containing HAART regimens in all sd NVP-exposed infants because of the cost and limited appropriate drug formulations. Our study, however, suggests that successful treatment outcomes using an NNRTI-based HAART regimen may be achieved in sd NVP-exposed HIV-infected infants over 6 months of age, when PIs are not available or affordable.
Limitations of this study are that the children in the 2 cohorts were not randomized to receive sd NVP and therefore the groups could have had baseline differences that may have affected the outcome. Furthermore, the cohorts were significantly different in age, baseline virologic and immunologic indices, and the older children particularly represent longer term survivors. However, this would have placed the NVP-exposed group at a higher risk of virologic failure. Our findings may not be generalizable to other infected children with different subtypes than the predominant ones in Uganda (A and D), because of the rates of selection and fading of resistant mutations to NVP which may vary by subtype.
The strengths of this study include the longitudinal laboratory and clinical data with close monitoring and high rates of follow-up; with 3 monthly CD4 cell counts/percents and HIV-1 RNA measurements for 48 weeks while on HAART. In addition, the 2 cohorts were clearly distinct; the majority of children in the NVP-exposed group had documentation of sd NVP receipt; the majority of children in the nonexposed group were older (PMTCT program had not started) and therefore had not received sd NVP. These data present some of the first reports of the virologic response to an NNRTI regimen in a significant number of children exposed to sd NVP at birth.
This study suggests that HIV-infected children exposed to sd NVP at birth can benefit from an NVP-containing HAART regimen if treatment is initiated more than 6 months after sd NVP exposure. Therefore, NVP-containing HAART regimens which are currently more widely available and affordable in resource-limited settings still have a vital role in the treatment of HIV-infected older infants and children in resource-limited settings.
The authors would like to thank the families and children who participated in the International leadership Award (ILA) study. Their commitment to this important study has advanced our knowledge and understanding of antiretroviral treatment for HIV-infected children from resource limited settings. This study could not have been done without the dedication of the ILA study staff based at MUJHU research collaboration and the support of the Elizabeth Glaser Pediatric AIDS Foundation through the ILA grant. We thank Dr Peter Mugyenyi (JCRC Kampala Uganda) and Prof. Mark Kline (Baylor College of Medicine) for providing consultation to the ILA program and study.
1. UNAIDS/WHO 2008 Report on the Global AIDS Epidemic
. 2008. Available at: www.unaids.org/en/HIV/d
ata. Accessed September 27, 2008.
2. Newell ML, Patel D, Goetghebuer T, et al. CD4 cell response to antiretroviral therapy in children with vertically acquired HIV infection: is it associated with age at initiation? J Infect Dis
3. Obimbo EM, Mbori-Ngachi DA, Ochieng JO, et al. Predictors of early mortality in a cohort of human immunodeficiency virus type 1-infected African children. Pediatr Infect Dis J
5. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet
6. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet
7. Martinson, NA, Ekouevi DK, Dabis F, et al. Transmission rates in consecutive pregnancies exposed to single-dose nevirapine in Soweto, South Africa and Abidjan, Cote d'Ivoire. J Acquir Immune Defic Syndr
8. Eshleman SH, Hoover DR, Chen S, et al. Resistance after single-dose nevirapine prophylaxis emerges in a high proportion of Malawian newborns. AIDS
9. Flys TS, Donnell D, Mwatha A, et al. Persistence of K103N-containing HIV-1 variants after single-dose nevirapine for prevention of HIV-1 mother-to-child transmission. J Infect Dis
10. Jackson JB, Becker-Pergola G, Guay LA, et al. Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission. AIDS
11. Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med
12. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med
13. Chi BH, Sinkala M, Stringer EM, et al. Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine. AIDS
14. WHO. Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Guidelines for a Public Health Approach
. Geneva, Switzerland: World Health Organization; 2002.
15. Barlow-Mosha L, Ajuna P, Luttajumwa M, et al. Early effectiveness of triomune in HIV infected children. Proceedings of theIAS Conference on HIV Pathogenesis, Treatment and Prevention, Rio de Janeiro, Brazil, 24-27 July 2005
. Abstract WeOa0103.
16. Katabira ET, Kamya MR, eds. National Antiretroviral
Treatment and Care Guidelines for Adults and Children
. Uganda: WHO, Republic of Uganda, Ministry of Health; 2003.
17. Antiretroviral Therapy of HIV Infection in Infant and Children in Resource-Limited Settings: Towards Universal
Access. Recommendations for a Public Health Approach
. World Health Organization; 2006.
18. Ellis JC, L'homme RF, Ewings FM, et al. Nevirapine concentrations in HIV-infected children treated with divided fixed-dose combination antiretroviral tablets in Malawi and Zambia. Antivir Ther
19. Sutcliffe CG, van Dijk JH, Bolton C, et al. Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa [review]. Lancet Infect Dis
20. Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure among Ugandan children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr
21. Flys TS, Chen S, Jones DC, et al. Quantitative analysis of HIV-1 variants with the K103N resistance mutation after single-dose nevirapine in women with HIV-1 subtypes A, C, and D. J Acquir Immune Defic Syndr
22. Eshleman SH, Becker-Pergola G, Deseyve M, et al. Impact of human immunodeficiency virus type 1 (HIV-1) subtype on women receiving single-dose nevirapine prophylaxis to prevent HIV-1 vertical transmission (HIV network for prevention trials 012 study). J Infect Dis
23. Nabukeera-Barungi N, Kalyesubula I, Kekitiinwa A, et al. Adherence to antiretroviral therapy in children attending Mulago Hospital, Kampala. Ann Trop Paediatr
24. Eshleman SH, Guay LA, Mwatha A, et al. Comparison of nevirapine (NVP) resistance in Ugandan women 7 days vs. 6-8 weeks after single-dose NVP prophylaxis: HIVNET 012. AIDS Res Hum Retroviruses
25. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS
. 2001;15:1951- 1957.
26. Romanelli RM, Pinto JA, Melo LJ, et al. Effectiveness of dual and triple antiretroviral therapy in the treatment of HIV-infected children. J Pediatr
27. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA
. 2007;298:1888- 1899.
28. Song R, Jelagat J, Dzombo D, et al. Efficacy of highly active antiretroviral therapy in HIV-1 infected children in Kenya. Pediatrics
29. Wamalwa DC, Farquhar C, Obimbo EM, et al. Early response to highly active antiretroviral therapy in HIV-1-infected Kenyan children. J Acquir Immune Defic Syndr
30. De Rossi A. Virological and immunological response to antiretroviral therapy in HIV-1 infected children: genotypic and phenotypic assays in monitoring virological failure. New Microbiol
. 2004;27(2 Suppl 1):45-50.
31. Gibb DM, Newberry A, Klein N, et al. Immune repopulation after HAART in previously untreated HIV-1-infected children. Paediatric European Network for Treatment of AIDS (PENTA) Steering Committee. Lancet
32. Walker AS, Doerholt K, Sharland M, et al. Response to highly active antiretroviral therapy varies with age: the UK and Ireland Collaborative HIV Paediatric Study. AIDS
. 2004;18:1915- 1924.
33. 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
34. L'Homme RF, Kabamba D, Ewings FM, et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS
35. Report of the WHO Technical Reference Group, Paediatric HIV/ART Care Guideline Group Meeting
. Geneva, Switzerland: World Health Organization; 2008.
36. Avy V, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med
HIV; children; nevirapine exposure; antiretroviral treatment
© 2009 Lippincott Williams & Wilkins, Inc.
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