In sub-Saharan Africa, recent results from the scaling-up of HAART programmes are very encouraging. Indeed, despite the circulation of non-B HIV-1 subtypes, the survival and immuno-virological response to HAART appeared to be comparable to those observed in developed countries where subtype B is predominant [1–6]. However, most of these African studies have been conducted among HIV-1-infected adults. There were few such reports for children [7,8]. Further, with the exception of the Senegalese adult cohort , these studies demonstrated only the short-term (from 12 to 24 months) effectiveness of HAART. Furthermore, experiences in developed countries showed that HAART monitoring became more difficult with time, especially in paediatric populations (higher frequency of ‘blips’, as well as virological failure, compared with adult populations) [10,11].
We have previously demonstrated the short-term effectiveness of HAART among 78 children recruited in the ANRS 1244/1278 Children's cohort (Abidjan, Côte d'Ivoire), mainly infected with CRF02_AG strains, and treated with HAART . Here, we report the longer-term effectiveness of HAART in this observational cohort.
Patients and methods
The study population consisted of 78 HIV-1-infected children enrolled in the ANRS 1244/1278 Children's cohort from October 2000. The children were treated with HAART and followed to September 2004. This study was approved by the national Ethics Committee on AIDS, and written consent was obtained from the childrens' parents or caregivers. The criteria for eligibility for HAART were having AIDS stage C infection or a CD4 T cell percentage (CD4%) < 15%. Initial HAART consisted of two nucleoside reverse transcriptase inhibitors with either nelfinavir (NFV: 90 mg/kg daily; doses taken two or three times a day as 250 mg pills or 50 mg powder for oral suspension) or efavirenz (EFV: 15 mg/kg daily; taken once daily as 200 mg capsules or 600 mg pills).
At baseline, each child underwent a clinical and psychological evaluation and a chest radiograph. Clinical evaluations were carried out every quarter during the follow-up period. Children were also seen for any intercurrent diseases if necessary. All diseases and health-related events during the follow-up were recorded on a standardized form. Consultations at the outpatients clinic and the day-hospital, treatments and tests were free of charge.
Both immunological and virological measurements were performed at baseline and every 6 months thereafter. The CD4% was measured by flow cytometry (FACScan, Becton Dickinson, Aalst-Erembodegem, Belgium). Plasma HIV-1 RNA levels were initially determined using the Versant HIV-1 RNA version 3.0 assay (Bayer Diagnostics, East Walpole, Massachusetts, USA). The detection threshold of this assay was 250 copies/ml (i.e., 2.4 log10 copies/ml) using 0.2 ml plasma. From April 2003, HIV-1 RNA viral load was determined using a real-time reverse transcriptase polymerase chain reaction targeted the long terminal repeat of HIV-1. The detection threshold of this assay was 300 copies/ml (i.e., 2.5 log10 copies/ml) using 0.2 ml plasma .
For the comparison of immunological and virological responses to HAART with either NFV or EFV, CD4% and HIV-1 RNA viral load were first assessed by performing time-point specific analysis. Both were subjected to as-treated (censoring was applied at the time of death or discontinuation of the primary treatment regimen) and intention-to-treat (no censoring) analysis. Second, a longitudinal data analysis was performed using a random-effects model in order to take into account repeated measures at various times in the same child . Covariance structure was defined by random intercept and slope plus a measurement error. Fixed explanatory variables were drug and AIDS stage; time-dependent variables were HIV-1 RNA levels at baseline, CD4% at baseline and age. Multivariate mixed models were performed using the procedure MIXED in SAS version 9.1 (SAS Institute, Cary, North Carolina, USA).
Among the 78 HAART-treated children, 34 were girls (43.6%). The median age at initiation of treatment was 6.5 years (range, 0.7–15.2). The follow up was for a median of 36 months [interquartile range (IQR), 30–42]. Sixty-four (> 80%) children had been followed for at least 30 months. Four children were lost to follow up. Initial HAART regimens consisted of two nucleoside reverse transcriptase inhibitors with either a protease inhibitor (NFV; in 61 children) or a non-nucleoside reverse transcriptase inhibitor (EFV; in 17 children). During follow-up, 10 children changed their primary NFV-based regimens as follows: nine had to switch to an EFV-based regimen [median time of switch, 33 months (IQR, 16.5–36)], and one to a boosted protease inhibitor (Kaletra)-based regimen. Reasons for changing therapy included drug toxicity in six and treatment failure in four. At baseline, 76 children had pre-HAART values for both CD4% and HIV-1 RNA viral load: the median CD4% was 7.5% (IQR, 2.1–11.1) and the median HIV-1 RNA was 5.37 log10 copies/ml (IQR, 5.07–5.99).
Nine (11.5%) children died during follow-up. All deaths but one occurred among severely immunosupressed children who already had AIDS at inclusion and were observed within the first year after enrollment. Overall, the survival probabilities were 0.88 [95% confidence interval (CI), 0.79–0.94] and 0.86 (95% CI, 0.77–0.92) at 36 and 42 months, respectively. No significant difference was observed in terms of mortality between children receiving a NFV-based regimen and those receiving an EFV-regimen (log rank test, P = 0.38).
Figure 1 shows the median change in CD4% and plasma HIV-1 RNA over time. Overall, at 30, 36 and 42 months after the start of HAART, the median values for CD4% reached 22.8% (+15.3% from baseline median), 23.1% (+15.6%) and 24.8% (+17.3%), respectively. When stratifying by the HAART regimen, the immune recovery was significantly higher in children receiving a NFV-containing regimen than in those receiving an EFV-containing regimen, in whom a decrease of CD4% was observed at month 36. This was not found at the time points before or after month 36.
The median HIV-1 RNA viral load values at 30, 36 and 42 months of follow-up decreased to 3.17 log10 copies/ml (−2.2 from baseline value), 3.08 log10 copies/ml (−2.29) and 2.64 log10 copies/ml (−2.73), respectively. The suppression of detectable HIV-1 RNA viral load was achieved in 40.0% (95% CI, 27.0–54.1), 46.5% (95% CI, 31.2–62.3), and 45.0% (95% CI, 23.1–68.5) of children, respectively, at 30, 36 and 42 months of follow-up. No significant difference was observed in terms of virological response according to the HAART regimen. Very similar CD4% and HIV-1 RNA kinetics were obtained in an intention-to-treat analysis (data not shown). At month 30, about 80% of children with virological success (< 300 copies/ml) showed CD4% values > 20% whereas about 65% with HIV-1 RNA levels > 4.0 log10 copies/ml exhibited CD4% values < 20%. Similar proportions were obtained at month 36 and 42.
Finally, by using a random-effects model for longitudinal data adjusted on age, AIDS stage, as well as HIV-1 RNA viral load and CD4% values obtained at baseline, no significant difference was observed in terms of immunological and virological responses according to the HAART regimen (containing NFV or EFV) (Fisher test: P = 0.51 for CD4% and P = 0.31 for HIV-1 RNA viral load).
This study described the long-term survival as well as immunological and virological responses to HAART in one of the rare paediatric cohorts documented in Africa. Overall, after 42 months of treatment, these HAART-treated children exhibited a low mortality rate, very comparable to that reported in the Senegalese adult cohort . A good immune recovery and a sustained viral suppression were also obtained.
The proportion of children with suppressed HIV-1 RNA viral load remained stable (about 50.0%) throughout the entire follow-up period, whatever the HAART regimen. Despite these encouraging results, the virological efficacy in our cohort was slightly lower to that generally observed among HAART-treated children from developed countries and Thailand [11,14–16]. For instance, in the Netherlands, Scherpbier et al.  reported viral response rates of 58% and 54% after 3 and 5 years of HAART, respectively. In Thailand, after 72 weeks of HAART, 76% of children had HIV RNA < 50 copies/ml . In fact, such differences are quite difficult to interpret and may be related to differences in populations studied, study design, regimens received by children (including dosage) and adherence . The higher virological failure in our study might also be explained by other factors such as a low CD4 cell count at baseline, initial physicians' inexperience in HAART management and the small number of available alternative drugs for children in Côte d'Ivoire. Indeed, from 2000 to late 2002, only four nucleoside reverse transcriptase inhibitors (zidovudine, lamivudine, didanosine and stavudine) and one protease inhibitor (NFV) were available for children in Ivory Coast. EFV was only introduced in Ivory Coast in 2003.
Overall, the immunological reconstitution in our cohort was similar to that reported in other paediatric cohorts [11,14–16]. After an initial increase until month 18, the CD4% remained stable throughout the follow-up period. In the mixed model, the long-term immunological benefit appeared similar in children who received a regimen including EFV as in those who received a NFV-based regimen. However, the small number of children in the subset receiving an EFV-based regimen has limited the ‘statistical power’ of our study. Therefore, these results are not to be extrapolated to a population basis and reflect only our field experience.
In conclusion, this study demonstrates the durability of both clinical and biological response to HAART in African children. As in western countries, HAART prolongs survival of HIV-1-infected children. In our cohort, approximately half the children had undetectable HIV-1 RNA levels throughout the whole follow up period, and CD4% values recovered and remained stable as well. In Africa and other resource-limited settings, large-scale studies assessing the effectiveness of HAART in the long term are further required to demonstrate definitively the feasibility of these life treatments.
We would like to thank the children and parents who agreed to participate in the children's programme. Special thanks to Alphonse Kpozehouen and Roselyne Vallo for statistical support.
Sponsorship: This study was supported by the French Agence Nationale de Recherches sur le SIDA (ANRS).
1. Laurent C, Diakhate N, Gueye NFN, Toure MA, Sow PS, Faye MA, et al
. The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. AIDS 2002; 16:1363–1370.
2. Seyler C, Anglaret X, Dokoury-Dogbo N, Messou E, Toure S, Danel C, et al
. Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Coke d'Ivoire. Antivir Ther 2003; 8:385–393.
3. Djomand G, Roels T, Ellerbrock T, Hanson D, Diomande F, Monga B, et al
. Virologic and immunologic outcomes and programmatic challenges of an antiretroviral treatment pilot project in Abidjan, Côte d'Ivoire. AIDS 2003; 17(Suppl 3):S5–S15.
4. Auvert B, Males S, Puren A, Taljaard D, Carael M, Williams B. Can highly active antiretroviral therapy reduce the spread of HIV? A study in a township of South Africa. J Acquir Immune Defic Syndr 2004; 36:613–621.
5. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoue N, Bourgeois A, Calmy A, et al
. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet 2004; 364:29–34.
6. Coetzee D, Hildebrand K, Boulle A, Maartens G, Louis F, Labatala V, et al
. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS 2004; 18:887–895.
7. Fassinou P, Elenga N, Rouet F, Laguide R, Kouakoussui KA, Timite M, et al
. Highly active antiretroviral therapies among HIV-1 infected children in Abidjan, Côte d'Ivoire. AIDS 2004; 18:1905–1913.
8. Eley B. Addressing the paediatric HIV epidemic: a perspective from the Western Cape region of South Africa. Trans R Soc Trop Med Hyg 2006; 100:19–23.
9. Laurent C, Ngom Gueye NF, Ndour CT, Gueye PM, Diouf M, Diakhate N, et al
. Long-term benefits of highly active antiretroviral therapy in Senegalese HIV-1-infected adults. J Acquir Immune Defic Syndr 2005; 38:14–17.
10. van Rossum AM, Fraaij PL, de Groot R. Efficacy of highly active antiretroviral therapy in HIV-1 infected children. Lanc Infect Dis 2002; 2:93–102.
11. Fraaij PL, Verweel G, van Rossum AM, van Lochem EG, Schutten M, Weemaes CM, et al
. Sustained viral suppression and immune recovery in HIV type 1-infected children after 4 years of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:604–608.
12. Rouet F, Ekouevi DK, Chaix ML, Burgard M, Inwoley A, Tony TD, et al
. Transfer and evaluation of an automated, low-cost real-time reverse transcription-PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a west African resource-limited setting. J Clin Microbiol 2005; 43:2709–2717.
13. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982; 38:963–974.
14. Resino S, Bellon JM, Ramos JT, Resino R, Urbindo MD, Mellado MJ, et al
. Impact of highly active antiretroviral therapy on CD4(+) T cells and viral load of children with AIDS: a population-based study. AIDS Res Hum Retrovirus 2004; 20:927–931.
15. Scherpbier HJ, Bekker V, van Leth F, Jurriaans S, Lange JMA, Kuijpers TW. Long-term experience with combination antiretroviral therapy that contains nelfinavir for up to 7 years in a pediatric cohort. Pediatrics 2006; 117:E528–E536.
16. Puthanakit T, Oberdorfer A, Akarathum N, Kanjanavanit S, Wannarit P, Sirisanthana T, 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.
17. Arrivé E, Anaky MF, Wemin ML, Rouet F, Salamon R, Msellati P, et al
. Assessment of adherence to highly active antiretroviral therapy in a cohort of African human immunodeficiency virus-infected children in Abidjan, Côte d'Ivoire. J Acquir Immune Defic Syndr 2005; 40:498–500.