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AIDS Care Vol. 22, No.

7, July 2010, 843850

Impact of maternal HAART on the prevention of mother-to-child transmission of HIV: results of an 18-month follow-up study in Ouagadougou, Burkina Faso
Seni Kouandaa*, Halima Tougria, Mireille Cisseb, Jacques Simporec, Virginio Pietrad, a a Boukare Doulougou , Gautier Ouedraogo , Charlemagne Marie Ouedraogoe, Robert Soudree and Blaise Sondoa
Public health, IRSS, Rue 29.09 porte 35, Ouagadougou 03 BP 7192, Burkina Faso; bUNICEF, Ouagadougou, Burkina Faso; CERBA, Ouagadougou, Burkina Faso; dCMA, Nanoro, Burkina Faso; eUFR/SDS, Universite de Ouagadougou, Ouagadougou, Burkina Faso
c a

(Received 6 July 2009; final version received 19 November 2009) Mother-to-child transmission remains the main cause of global pediatric HIV infections, especially in subSaharan Africa. Many interventions based on single-dose antiretroviral therapy have been implemented to reduce the mother-to-child transmission of HIV. In resource-limited settings, highly active antiretroviral therapy (HAART) has only been recommended for HIV-infected pregnant women requiring treatment for their own health. Here, we assessed the efficacy over 18 months of maternal HAART versus peripartum short-course antiretroviral therapy (SCART) regimens for the prevention of mother-to-child transmission (PMTCT) of HIV. We conducted a retrospective cohort study of patients from two medical centers in Ouagadougou, Burkina Faso. The PMTCT files and registers from 1 January 2003 to 31 December 2006 were obtained from routine data collected at these sites. The main assessment criterion was the rate of HIV-1 positivity in children born to HIVpositive mothers as measured with HIV-1 rapid tests at 18 months. A total of 586 pregnant HIV-1-infected women in PMTCT programs were selected. Among these women, 260 were undergoing HAART and 326 received single-dose nevirapine (91.3%) or single-dose zidovudine (8.7%) at delivery. HIV-1 serological tests were performed on 454 children at 18 months old. The rate of HIV-1 vertical transmission was 0% (0/195) in the HAART group and 4.6% (12/259) in the single-dose monotherapy group (P B0.01). Eight infants in the HAART cohort and 30 in the SCART cohort were breastfed; three in the SCART group were HIV-positive. A total of 62 children died, 19 in the HAART group and 43 in the single-dose monotherapy group. Our study confirms that HAART for mothers effectively reduces the risk of infant HIV infection while preserving the breastfeeding option for mothers.

Keywords: HIV/AIDS; PMTCT; HAART; SCART

Mother-to-child transmission remains the main cause of global pediatric HIV infections, especially in subSaharan Africa, where 90% of the 2.0 million infected children live. It is estimated that more than 90% of children living with HIV acquired the virus during pregnancy, birth, or breastfeeding (UNAIDS, 2008). In resource-rich settings, perinatal transmission rate of 2% or less are achieved through the combination of antiretroviral therapy, obstetrical interventions, and avoidance of breastfeeding (Cooper et al., 2002; Dorenbaum et al., 2002). Shorter, more deliverable antiretroviral regimens have likewise proven effective in resource-limited settings. These include short-course zidovudine (ZDV; Dabis et al., 1999; Shaffer, 1999; Wiktor, Ekpini, & Karon, 1999) or zidovudine and lamivudine (ZDV/3TC) therapy (Petra Study Team, 2002) given to the mother in late pregnancy, or single-dose nevirapine (SD NVP; Guay,
*Corresponding author. Email: skouanda@irss.bf
ISSN 0954-0121 print/ISSN 1360-0451 online # 2010 Taylor & Francis DOI: 10.1080/09540120903499204 http://www.informaworld.com

Missoke, & Fleming, 1999; Jackson, Musoke, & Fleming, 2003) given to the mother at labor onset, followed by NVP/ZDV prophylaxis for the newborn (Taha, Kumwenda, & Gibbons, 2003). Most recently, the combination of short-course maternal ZDV or single-dose ZDV/3TC with NVP have appeared to act in synergy to reduce transmission to B2% in nonbreastfeeding settings and to 69% in breastfeeding settings when compared to short-course antenatal ZDV or ZDV/3TC, or peripartum SD NVP alone (Lallemant et al., 2004; Leroy, Sakarovitch, & Viho, 2007). In resource-limited settings, up to 40% of children born to HIV-infected mothers have become infected by the end of the breastfeeding period (which may last up to 18 months). But breastfeeding is not discouraged in developing countries because of the highmortality associated with formula-feeding (Atashili,

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S. Kouanda et al. Due to the duration of the study, the tests that were used varied with time (Determine , Genie-II , Bioline , . . .). For mothers whose serology status was known before pregnancy, the same procedures were used to confirm and document HIV status. Determination of the childs serology status At the Saint Camille Center, RT-PCR was used two six and 18 months after birth to determine the serology status of the children. Briefly, HIV-1 RNA was extracted using the QIAamp Viral RNA Mini Kit (50) from QIAagen. For extraction of RNA, lysis of leucocytes was followed by separation and purification of nucleic acids and then elution of nucleic acids into 60 ml RNase-free water. Retrotranscription and amplification were carried out using HIV-1 RNA directly. The primer set for the detection of the viral RNA (DIAtech) and Taq Polymerase (DIAtech) were used in accordance with the manufacturers protocol. Amplified products were visualized under ultraviolet light after electrophoresis in a 3% agarose gel containing ethidium bromide for one hour at 120 V. At the Pissy Medical Center, PCR was unavailable at twosix months after birth, so infected children were identified at 9 and 18 months by rapid tests. A child was considered infected by HIV after two positive results through PCR and a positive result at 18 months. Statistical analysis Data were processed using Epi Info 6.04, French version, then analyzed with SPSS software version 12 (SPSS Inc., Chicago, IL, USA). Common statistics (mean, standard deviation, and proportions) were used for the analysis of our results. In order to compare sociodemographic, clinical, and immunological variables among the two groups of women, the x2 test was used. The significance threshold was set at 0.05. Results Our sample was made up of 586 HIV-1 positive women; 66.9% of them were tested during the pregnancy. Figure 1 shows that 55.6% of women (326/ 586) were on monotherapy and 44.4% (260/586) were on tritherapy. Women receiving short-course antiretroviral therapy (SCART) and highly active antiretroviral therapy (HAART) Table 1 summarizes the type of antiretroviral therapy the women received. Among women on antiretroviral

Kalilani, Sejsaria, & Sickbert-Bennett, 2008). Given the benefits of breastfeeding or the practical need to breastfeed, a variety of interventions directed to the mother, child, or both has been used to find an effective manner to interrupt transmission. WHO guidelines for the prevention of mother-tochild transmission (PMTCT) recommend the use of highly active antiretroviral therapy (HAART) for pregnant women in need of antiretroviral therapy for their own health (WHO, 2006), but few studies have been conducted to assess the impact of maternal HAART on postnatal transmission (Marrazi et al., 2006; Simpore et al., 2007; Tonwe-Gold et al., 2007). We assessed the 18-month efficacy of maternal HAART versus peripartum short-course antiretroviral therapy (SCART) regimens for PMTCT. Materials and methods Study design and participants This retrospective cohort study was conducted in Saint Camille Medical Center and Pissy Medical Center in Ouagadougou, Burkina Faso. The studied population consisted of women who attended these medical centers and tested seropositive for HIV either prior to or during pregnancy. Two groups of women were included in this study. The first group consisted of pregnant women testing HIV-positive before or during pregnancy and who continue to receive HAART. The second group consisted of pregnant women testing HIV-positive during the course of pregnancy and who received a NVP or AZT single dose as prophylactic treatment. HIV-positive women infected with HIV-2 or with both HIV-1 and HIV-2 strains were excluded from the study. We began by compiling a list of all women on SCART and HAART from clinical files at each medical center from 1 January 2003, to 31 December 2006. These women were then followed during delivery and at the testing of the newborn babies at 26, 9, and 18 months. We collected information from the follow-up registers and clinical files of seropositive women and their children. Any missing information was completed by analyzing registers from the maternity hospital or the referring facilities for the women. Laboratory procedures Determination of the mothers serology status To determine the status of mothers whose serology status was unknown, two rapid tests were used to identify anti-HIV-1 and anti-HIV-2 antibodies. A third test was carried out whenever there was a discrepancy between the results of the first two tests.

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586 HIV-positive women

260 under HAART


three deaths 12 abortions 19 lost to followup

326 under SCART

Three lost to followup 330 babies delivered, including five sets of twins and one set of triplets Five stillborn

235 babies delivered, including nine sets of twins

Seven stillborn

228 live newborns

325 live newborns 66 not tested - 43 deaths - 21 lost to followup - two transferred

33 not tested -19 deaths -14 lost to followup 195 infants tested 259 infants tested

00 HIV+

195 HIV

12 HIV+

247 HIV

Figure 1. Results of highly active antiretroviral therapy (HAART) versus short-course antiretroviral therapy (SCART) in the prevention of mother-to-child transmission.

monoprophylatic treatment used as SCART (n 0326), 302 received NVP (92.6%) and 24 received AZT (7.4%). Women on HAART (n 0260) received the therapeutic combinations D4T'3TC'NVP (50%), AZT'3TC'NVP (44.2%), and 2INTI'1IP (5.8%). Among women on HAART, 154 (59.2%) women had

Table 1. Distribution of women according to antiretroviral treatment. Treatment SCART HAART n (%) 326 (55.6) 260 (44.4) ARV n (%)

received the treatment before pregnancy and 106 (41.8%) during the course of pregnancy. At birth, 460 children (83.2%) received a single dose of 2 mg/kg NVP and 71 children (12.8%) received AZT at 4 mg/kg/day bid for seven days. Twenty of the children (4%) were identified as not being on antiretroviral prophylactic treatment. Among these, 11 were born to mothers on HAART and nine to mothers on monoprophylaxis. Sociodemographic characteristics of admitted women The two groups had similar sociodemographic characteristics except that women on HAART were older (Table 2). Among women who received SCART, 26.3% (85/323) were aged 1524; this age bracket made up 10.3% (26/260) of those who received HAART (PB0.001). More married women received

NVP 302 (92.6) AZT 24 (7.4) AZT'3TC'NVP 115 (44.2) D4T'3TC'NVP 130 (50.0) 2INTI'1IP 15 (5.8)

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Table 3. Clinical and immunological status of women under SCART versus HAART. SCART, n (%) Stage WHO Stage I Stage II Stage III'IV CD4 (per mm3) B200 200500 500 HAART, n (%) P

Table 2. Sociodemographic characteristics of women participating in the study. Characteristics Age (years) 1524 2534 ]35 Marital status Divorced Widowed Single Married Education No education Primary only Secondary only Higher education Employment Housewives Employees Retailers Students Others SCART, n (%) HAART, n (%) P

85 (26.3) 201 (62.2) 37 (11.5) 4 16 48 254 (1.2) (5.0) (14.9) (78.9)

26 (10.3) 180 (68.8) 54 (20.9) 5 18 40 194 (1.9) (7.0) (15.6) (75.5)

B0.001

187 (64.0) 72 (24.7) 33 (11.3) 29 (9.7) 185 (61.7) 86 (28.6)

52 (23.0) 122 (54.0) 52 (23.0) 123 (51.0) 98 (40.7) 20 (8.3)

B0.001

NS

B0.0001

100 (34.0) 85 (28.9) 102 (34.7) 7 (2.4)

58 (26.1) 68 (30.6) 88 (39.6) 8 (3.6)

NS

252 36 9 3 22

(78.3) (11.2) (2.8) (0.9) (6.8)

172 45 18 8 17

(66.1) (17.3) (6.9) (3.1) (6.5)

NS

(219/260) of women on tritherapy (PB0.001). There was no significant difference between the two groups of women in delivery mode. The majority of women in both groups chose formula-feeding over breastfeeding: 75.8% (246/325) on monotherapy and 88.6% (202/228) on tritherapy. Of those who breastfed (n0 105), the mean duration of breastfeeding was 492 months in the SCART group and 593 months in the HAART group (P0NS). During the first HIV testing, 38 of 105 infants were still breastfed. Among them, eight had mothers on HAART (n026) and 30 on SCART (n079). At 9 and 18 months, no infants were breastfed. Evaluation of prevention of mother-to-child transmission (PMTCT) of HIV Table 4 shows the distribution of children tested by PCR twosix months after delivery at Saint Camille Medical Center. The rate of mother-to-child transmission of HIV-1 was 6.2% (10/162) among women on SCART and 0% (0/156) among those on HAART
Table 4. Prevention of mother-to-child transmission: postnatal transmission of HIV for children with mothers under SCART versus HAART. SCART, n (%) HAART, n (%) P

SCART (79%) than HAART (75.5%) (P 0NS); 34% (100/294) of women on SCART and 26.1% (58/222) on HAART did not have formal education (P 0NS), and more women on SCART (78.3%) than on HAART (66.1%) were housewives (P 0NS). Clinical and immunological status of admitted women On admission, women on SCART were better off, clinically and immunologically, than those on HAART; 64% (87/292) of women on monotherapy versus 23% (52/226) of women on tritherapy were at Clinical stage 1 of the WHO classification for HIV/ AIDS (PB0.001). At the immunological level, 9.7% (29/300) of women on monotherapy and 51% (123/ 241) of women on tritherapy had B200 CD4 cells/ mm3 (PB0.001; Table 3). Pregnancy monitoring More women on HAART (69.6%) than on SCART (36.4%) had at least three antenatal visits. Among women on SCART, three (0.9%) dropped out of the study before delivery, and among those on HAART, 19 (7.3%) dropped out of the study (Figure 1). Twelve women on HAART and no women on SCART had abortions. Viable deliveries were seen in 97.5% (318/326) of women on monotherapy and 84.2%

Children tested at twosix months Positive 10 (6.2) 0.0 (0.0) Negative 152 (93.8) 156 (100.0) Children tested at nine months Positive 6 (7.1) Negative 78 (92.8) Children tested at 18 months Positive 12 (4.6) Negative 218 (94.7) Overall transmission Positive 12 (4.6) Negative 247 (94.4) 2 (7.1) 26 (100.0) 0 (0.0) 155 (100.0) 0 (0.0) 195 (100.0)

B0.001

NS

B0.01

B0.01

AIDS Care (P B0.001). Among breastfed infants, three in the SCART group were HIV-positive. Of children tested at nine months at the Medical Center of Pissy only with the rapid test, 7.1% (6/84) of children with mothers receiving SCART were HIV-positive versus 7.1% (2/28) of children with mothers on HAART (P 0NS). At 18 months, the transmission rate was 5.2% (12/ 230) and 0% (0/155), respectively, among children born to mothers on SCART and among children born to mothers on HAART (PB0.01). Among children whose tests were positive at nine months, two of two HIV' children whose mothers were on HAART and four of six HIV' children whose mothers were on SCART became negative at 18 months. Taking into consideration children tested with PCR between two and six months and/or with rapid tests at 18 months, the overall rate of transmission was 4.6% (12/259) among the group of children born to mothers on SCART and 0% (0/195) among children whose mothers were on HAART (PB0.01). However, the causes and HIV status of 33 children in the HAART cohort (19 children who died and 14 that were lost-to-follow-up) could not be determined. The rate of transmission was 3.6% (7/195) among formula-fed children and 7.8% (5/64) among breastfed children for mothers on monotherapy (P=NS). Change in childrens weight from birth to 12 months Children born to mothers on SCART gained more weight on average than children born to mothers on HAART for up to six months. After six months, there was no longer any significant difference between the weights of children born to mothers on HAART or on SCART (Table 5). Among breastfed children, there was no significant difference between the average weight of children whose mothers were on tritherapy and that of children whose mothers were on monotherapy. Among women who bottle-fed their children, the average weight of children whose mothers were on

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SCART was significantly higher than that of children whose mothers were on HAART, for up to six months. Child deaths during the follow-up period A total of 62 children (11.2%) died before the determination of their serology status, among which 8% (19/228) were born to mothers on HAART and 13% (43/325) were born to mothers on SCART (P 0 NS). Among the deceased children, 10.5% (47/448) were bottle-fed and 14.3% (15/105) were breastfed (P 0NS). The causes of death in these children were not well documented. Discussion Our study was a retrospective cohort study based on data gathered routinely rather than data obtained from planned clinical tests, which are generally considered more definitive. This analysis therefore has some limitations because some of the files had incomplete or lack of biological data (CD4 counts and viral load). The data we considered for our study included the global transmission rate as well as transmission at twosix months and at 18 months after birth. No change in serology status at 18 months was seen among the children tested earlier with PCR. In contrast, two children born to mothers on tritherapy who tested positive at nine months became negative at 18 months. The earlier test probably gave a false positive due to the presence of maternal antibodies in the child. The HIV transmission rate from mother to child was 4.6% among children with mothers on SCART and 0% among those born to mothers on tritherapy. Previously, researchers have found residual transmission rates of 6.8% (in Brazil), 8.8% (in South Africa), and 10% (in Ukraine) (Coetzee et al., 2005; Fernandez, Araujo, & Medina-Acosta, 2005; Malyuta, Newell, Ostergren, Thorne, & Zhilka, 2006), based on retrospective studies of the assessment of the efficiency of PMTCT obtained with routine utilization of

Table 5. Evolution of the weight (grams) of children participating in the study according to the mothers treatment. SCART Age (months) 0 2 4 6 9 12 n 305 204 172 144 157 130 Mean9SD (g) 28439508 48339886 61319942 68599991 788491084 953491520 n 210 151 132 110 104 88 HAART Mean9SD (g) 27499532 45829850 58149930 654891000 762991011 936091235 P 0.04 B0.01 B0.01 B0.05 NS NS

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S. Kouanda et al. occurrence of resistant strains that emerge due to the utilization of monotherapy for PMTCT. In 2006, Nadembega reported the occurrence of HIV mutant ` strains due to the use of antiretrovirals in Burkina Faso (Nadembega et al., 2006). Women on SCART had well-functioning immune systems compared with women on tritherapy. But, they were registered during the last antenatal visit, in contrast to the women on tritherapy, who benefited from monitoring from the start. Consistent with the differences in immune status, 1.5% of children born to women on monotherapy and 2.9% to women on tritherapy were stillborn. These events are not considered to be related to the antiretroviral therapy received by the women; the mothers immunological status and advanced clinical stage are factors previously associated with poor pregnancy outcomes (Tuomala et al., 2002). For mothers on monotherapy, the rate of transmission was higher among breastfed children than those to formula-fed (NS). Simpore et al. (2006) also noted that the transmission was high among breastfed children. In contrast, among women on tritherapy, the transmission rate was nil whatever the feeding method used by the woman was. In fact, viremia is particularly high in breast milk at the beginning of breastfeeding (colostrum), but preliminary studies have shown that the viral load in colostrum among seropositive women treated with NVP decreases from 100,000 copies/mL to less than 10,000 copies/mL during the first three days after delivery (Musumeci et al., 2007; Simpore et al., 2007). It is therefore advisable to avoid breastfeeding for the first three days following delivery (Musumeci et al., 2007). Children born to mothers on monotherapy had higher weights than those born to mothers on tritherapy between birth and six months. This can be explained by the fact that the women on tritherapy had worse clinical and immunological profiles than those on monotherapy. The effect of combination antiretroviral therapy itself on birth outcomes is controversial: Tuomala et al. (2002) reported that combination antiretroviral therapy courses were associated with neither premature birth nor low birth weight, whereas Ekouevi et al. (2008) observed an association between antiretroviral therapy and low birth weight (Ekouevi et al., 2008; Tuomala et al., 2002). The death rate was not different among children whose mothers were on tritherapy (13%) and those whose mothers were on monotherapy (8%), although the rates were higher than the overall rate of infant mortality of 5% in infants between one and 12 months of age in Burkina Faso (Institut National des Statistiques et de la Demographie & ORC Macro, 2003). However, these rates are consistent with those

AZT or NVP. Prospective studies conducted in 2003 in Cameroon and in 2006 in Burkina Faso on seropositive women receiving NVP reported residual transmission rates of 10.6% and 10.4%, respectively (Ayouba, Tene, Cunin, & Foupouapouognigni, 2003; Simpore et al., 2006). Most of these studies were conducted during the early phases of PMTCT in resource-limited countries, when antiretroviral therapy was not accessible to everybody, so even women eligible for tritherapy were treated with monotherapy (Simpore et al., 2006). Other studies have compared the efficacy of utilizing both therapeutic treatments, one with shortcourse NVP or AZT, the other with tritherapy. Simpore et al. (2007) reported a transmission rate of 2.8% at six months among children born to mothers on monotherapy and of 0% among children born to mothers on tritherapy in 2007. In Cote dIvoire, a transmission rate of 3.1% at four weeks was seen among children whose mothers were on SCART, as compared to 1% among those whose mothers were on tritherapy; at 12 months, the transmission rate was 7.5% among the children born to mothers on SCART; and 3.3% among the children born to mothers on tritherapy (Tonwe-Gold et al., 2007). A similar study conducted in Cote dIvoire showed a PMTCT rate of 16.1% at 12 months among mothers having received SCART and 2.3% among those on tritherapy (Ekouevi et al., 2008). In the USA, a study on PMTCT showed a transmission rate of 1.2% among women on tritherapy who did not breastfeed their children. In Europe, mother-to-child transmission decreased from 15.5% in 1994 to 5.1% in 19971998 and then to 0.99% in 20012002, thanks to increasing use of tritherapy (European Collaborative Study Group, 2005). Our results prove the efficacy of tritherapy in the PMTCT of the virus. Tritherapy, which has mainly been aimed at protecting the mothers health, has proven very profitable to the child as well. In fact, the risk of HIV-related morbidity, mortality, and transmission is higher among pregnant women at an advanced clinical stage (Garcia et al., 1999). The reduction of the viral load and the increase in the CD4 cell count brought about by the administration of antiretroviral therapy both improves the mothers health and considerably reduces mother-to-child transmission of HIV. It is therefore important that pregnant women eligible for antiretroviral therapy use it for their own health as well as for PMTCT, as recommended by the WHO in recent guidelines (WHO, 2005). Additionally, the systematic use of tritherapy could contribute to a reduction in expenditures for breast-milk substitutes (formula). Moreover, the use of tritherapy would reduce the

AIDS Care reported by Tonwe-Gold et al. (2007) of 10% among children in Cote dIvoire whose mothers were on tritherapy and 6% among those whose mothers were on SCART. In the course of an evaluation of the PMTCT program in Benin, Adeothy-Koumakpa et al. (2004) reported 10% mortality among children aged 312 months. The most frequent causes of death reported by Adeothy-Koumakpa et al. (2004) were gastroenteritis and respiratory ailments. Conclusion The debate about the use of SCART versus HAART has long been perceived in terms of cost efficiency. However, due to a considerable decrease in their costs, increasing access to antiretroviral treatments is now possible, and the treatment strategies recommended for developing countries should increasingly rise to the same standard as those of developed countries. Acknowledgements
The authors thank the PMTCT teams of Saint Camille Medical Center, Pissy Medical Center, and Doctors without Borders (MSF).

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