de lamorce dune antirtrovirothrapie prophylactique associative ( arpa ) contenant du raltgravir ( ral ) sur la charge virale ( cv ) du vih chez les femmes enceintes do nt la suppression de la cv est leve ou sous - optimale en fin de grossesse .
les chercheurs ont extrait le dossier des femmes enceintes infectes par le vih qui avaient amorc une arap contenant du ral aprs 28 semaines de grossesse dans deux centres hospitaliers universitaires entre 2007 et 2013 .
onze femmes infectes ont entrepris un traitement de ral  une mdiane de 35,7 semaines de grossesse ( plage de 31,1  38,0 semaines ) .
les indications pour entreprendre le ral taient une prsentation tardive au suivi de grossesse ( n=4 ) et une suppression sous - optimale de la cv en raison dun mauvais respect du traitement ou dune rsistance virale ( n=7 ) .
la cv moyenne au dbut du traitement au ral tait de 73 959 copies / ml ( plage de moins de 40 copies / ml  523 975 copies / ml ) .
les patientes ont pris du ral pendant une mdiane de 20 jours ( plage de un  71 jours ) .
la diminution moyenne de la cv entre le dbut du ral et laccouchement tait de 1,93 log ,  lexception dune patiente qui na reu quune dose de ral et dune patiente do nt la cv ntait pas dcelable au moment dentreprendre le ral .
au bout de huit jours de ral , 50 % des femmes prsentaient une cv infrieure  1 000 copies / ml ( le seuil pour recommander une csarienne afin de rduire le risque de transmission prinatale ) .
la prsente tude fournit des donnes provisoires pour soutenir lutilisation darpa contenant du ral afin dacclrer la rduction de la cv du vih-1 chez les femmes qui prsentaient une cv leve ou une suppression sous - optimale de leur cv pendant la grossesse , ainsi que pour rduire le risque de transmission prinatale du vih tout en vitant une csarienne .
a retrospective review of two canadian hiv perinatal databases ( those of the oak tree clinic at bc woman s hospital , vancouver , british columbia , and of the grossesse avec maladie infectieuse clinic at sainte - justine hospital , montreal , quebec ) was conducted to identify hiv - infected pregnant women who initiated treatment with ral ( 400 mg twice per day orally ) after 28 weeks gestation .
data collected between 2007 , the year when ral became available , and december 2013 were reviewed .
each patient s chart was then retrospectively abstracted for data including ral indication , tolerance and timing of exposure .
the standard of care in both clinics included treatment of hiv - infected pregnant women with cart regardless of baseline cd4 cell - count and hiv-1 vl , as well as assessment of the women s clinical , virological and immunological status every four weeks .
infants were evaluated at least at birth , two weeks of age , one month of age and then every three to four months until 18 months of age .
hiv - negative status in infants was defined presumptively by at least two negative hiv rna polymerase chain reaction test results before four months of age , and confirmed by the absence of hiv-1 antibody at 18 months of age .
maternal and neonatal adverse reactions were systematically addressed according to who criteria ( 27 ) , with specific attention devoted to hematological and hepatic complications .
hiv-1 vl was measured either using the ultrasensitive amplicor hiv-1 monitor test or cobas taqman hiv-1 test , v1.0 ( roche molecular systems inc , usa ) for cases in vancouver , and the abott realtime hiv-1 assay ( abbott molecular inc , usa ) for cases in montreal .
the study was approved by the institutional review board of each centre . a descriptive analysis of population characteristics
a nonparametric survival analysis was then conducted to compute the time to achieve a vl < 50 copies / ml and < 1000 copies / ml , respectively .
the statistical analysis was performed using r version 2.11.1 ( r core team , 2013 ) .
a descriptive analysis of population characteristics was performed . because of the non - normal distribution , median and range are reported .
a nonparametric survival analysis was then conducted to compute the time to achieve a vl < 50 copies / ml and < 1000 copies / ml , respectively .
the statistical analysis was performed using r version 2.11.1 ( r core team , 2013 ) .
a total of 11 women who initiated ral during the third trimester of their pregnancies were identified .
three women ( cases 3 , 5 and 7 ) had a new diagnosis of hiv during the current pregnancy .
the median gestational age at their first clinic visit was 24 weeks ( range seven to 35 weeks ) .
the median duration of consistent cart received was 42 days ( range seven to 202 days ) .
indications for ral were late presentation in pregnancy ( n=4 ) and suboptimal vl reduction secondary to poor adherence or viral resistance ( n=7 ) .
all patients received ral in combination with at least two other active antiretroviral agents , started at a median gestational age of 35.7 weeks ( range 31.1 to 38.0 weeks ) .
exposure duration was a median of 20 days ( range one to 71 days ) .
the median gestational age at delivery was 38.7 weeks ; one patient ( case 9 ) delivered at 35 weeks in a context of spontaneous preterm labor . at the time of delivery ,
nine women had a hiv vl < 1000 copies / ml , of which seven were < 50 copies / ml . figure 1 summarizes the typical vl evolution after ral initiation . among the 11 women , three had a vaginal delivery , three had a caesarean section for obstetrical indications and five had a caesarean section to further decrease the risk of hiv perinatal transmission .
three of these caesarean sections could have been avoided ( ie , the vl was below threshold of 1000 copies / ml ) if the hiv vl had been known at the time of the delivery .
there were no cases of hiv perinatal transmission observed in the in utero - exposed infants .
one infant ( case 11 ) presented a transient symptomatic cardiac arrhythmia at birth , as well as unilateral hydronephrosis and skin abnormalities ( nevus , four nipples ) , which were not prenatally diagnosed .
the following two cases were excluded from subsequent analysis : 
 one woman ( case 3 ) had an undetectable vl at ral initiation . she was initially started with a combination regimen with zidovudine , lamivudine and ritonavir - boosted lopinavir at 28 weeks and four days . however , she had adherence issues in a context of a newly diagnosed hiv infection in pregnancy with hepatitis c coinfection and substance use .
the woman was admitted for directly observed therapy and ral was started at 33 weeks to rapidly suppress her vl . at the time of ral initiation , the last available vl result ( measured two weeks previously ) was 1762 copies / ml , and the woman reported poor adherence to her cart regimen during this time period . retrospectively , it was determined that at the time of ral initiation , her vl was undetectable ; however , because of concerns surrounding adherence and risk of resistance rise , ral was pursued .
the woman discharged herself from hospital for three days at approximately 35 weeks gestation but returned with a positive urine cocaine screen .
she had a vaginal delivery at 38 weeks and five days gestation with a confirmed undetectable vl.one woman ( case 10 ) received only one dose of ral .
her pregnancy had been complicated by poor adherence and intolerance to cart . at 37 weeks gestation , she was admitted for supervised cart , and her vl was found to be 232,245 copies / ml .
as soon as this result was known , ral was added to her regimen to attempt a rapid and maximal suppression of the hiv vl before delivery . however , 3 h after receiving the first dose of ral the woman experienced spontaneous rupture of membranes and went into active labour .
she was initially started with a combination regimen with zidovudine , lamivudine and ritonavir - boosted lopinavir at 28 weeks and four days .
however , she had adherence issues in a context of a newly diagnosed hiv infection in pregnancy with hepatitis c coinfection and substance use .
the woman was admitted for directly observed therapy and ral was started at 33 weeks to rapidly suppress her vl . at the time of ral initiation , the last available vl result ( measured two weeks previously ) was 1762 copies / ml , and the woman reported poor adherence to her cart regimen during this time period . retrospectively , it was determined that at the time of ral initiation , her vl was undetectable ; however , because of concerns surrounding adherence and risk of resistance rise , ral was pursued .
the woman discharged herself from hospital for three days at approximately 35 weeks gestation but returned with a positive urine cocaine screen .
she had a vaginal delivery at 38 weeks and five days gestation with a confirmed undetectable vl .
her pregnancy had been complicated by poor adherence and intolerance to cart . at 37 weeks gestation , she was admitted for supervised cart , and her vl was found to be 232,245 copies / ml .
as soon as this result was known , ral was added to her regimen to attempt a rapid and maximal suppression of the hiv vl before delivery . however , 3 h after receiving the first dose of ral the woman experienced spontaneous rupture of membranes and went into active labour . in the remaining nine women ,
median vl at ral initiation was 88,707 copies / ml ( range 246 to 523,975 copies / ml ; mean 73,959 copies / ml ) .
the mean decline of vl from time of ral initiation to delivery was 1.93 log10 copies / ml ( 95% ci 1.32 to 2.53 log10 copies / ml ) ( figure 1 ) .
in the four women who received < 2 weeks of ral , the mean vl decrease was 1.82 log10 copies / ml .
in the four women who had an initial vl > 4 log10 copies / ml , the mean decrease was 2.65 log10 copies / ml . after eight days on ral , 50% of the women achieved a vl < 1000 copies / ml ( figure 2 ) .
similarly , 50% of the women achieved a vl < 50 copies / ml after 26 days on ral .
an asymptomatic elevation of liver enzyme levels ( 11- and fivefold the upper limit of normal of alanine aminotransferase and aspartate aminotransferase , respectively ) was noted in a woman for whom ral was added to a combination of zidovudine , lamivudine and ritonavir - boosted lopinavir because of late presentation .
the elevation of liver enzyme levels was first observed after five days on ral , without signs of preeclampsia or cholestasis . the status regarding hepatitis a , b and c infections was confirmed to be negative .
in our experience , adding ral to a cart regimen was useful in rapidly reducing hiv-1 vl to prevent perinatal transmission in women who have high vl or suboptimal suppression late in pregnancy . our findings are consistent with previously published cases of ral use late in pregnancy , which are summarized in table 2 ( 8,1518,2022,2426,28 ) . among these ,
only one case of perinatal transmission has been reported ( 8) ; the clinical presentation in that case suggested in utero hiv transmission .
we were able to confirm the drastic and rapid decrease of hiv vl after ral initiation , and computed a median time to achieve vl < 1000 copies / ml ( eight days ) , information that will be useful in the clinical setting .
moreover , important limitations of the present case series include the absence of data regarding resistance to integrase inhibitors among the women treated , and regarding maternal and neonatal ral plasma concentrations .
published data indicate that , despite a reduction of ral median area under the curve by approximately 50% during pregnancy ( 29 ) , ral readily crosses the placenta and achieves adequate concentrations in the neonate , with mean cord blood - maternal blood drug ratios of 1.5 ( range 0.32 to 9.5 ) ( 15,16,22,28 ) .
else et al ( 30 ) found that ral achieves the highest placental / neonatal concentration among available antiretroviral medications .
explanations for effective placental transfer of ral include its relatively low protein binding and small molecular weight , as well as its favourable ph - dependent lipophilicity , which results in increased amount of ionized drug in the fetal circulation ( 11,22,30,31 ) . a high cord : maternal serum ratio reflects a high placental transfer but also a neonatal accumulation .
the ability of fetuses to metabolize and eliminate ral on their own is likely limited by the immaturity of ugt - glucuronidation pathways ( 22,32 ) .
we observed a 1.82 log10 copies / ml decrease in hiv vl within two weeks of receipt of a ral - containing cart regimen , which is faster than the mean time of approximately five weeks to suppression that is typically observed with traditional cart ( 33 ) .
this finding is consistent with the vl reductions ( 2 log10 copies / ml within 10 to 14 days of receipt of a ral - based regimen ) observed in randomized controlled trials using ral - based regimens ( 1214 ) and in observational studies investigating ral administration late in pregnancy ( 8,15,16,18,21 ) .
the reported case of liver toxicity ( 23 ) is , to our knowledge , the second that has been described with ral use in pregnancy ( 29 ) .
although hepatotoxicity is one of the well - recognized side effects of antiretroviral drugs , it has not been commonly associated with ral therapy , with increase of aspartate aminotransferase and alanine aminotransferase levels > 5 times the upper limit of normal seen in only 5% of exposed individuals ( 31,34 ) .
sufficient data are not yet available to conclude whether the risk of hepatotoxicity is higher in pregnancy .
close follow - up of liver enzyme levels in pregnant women treated with ral would be prudent until more safety data are available .
the infant who was diagnosed with cardiac arrhythmia , unilateral hydronephrosis and skin anomalies had been exposed to ral in utero for 35 days , starting at 36 weeks gestation .
because of this timing , the congenital anomalies are not likely related to ral exposure . however , safety data regarding ral exposure in pregnancy are weak , and it remains a category c drug ( 31 ) .
considering the potential advantages of ral noted above , it remains to be determined whether its ability to rapidly reduce vl in late pregnancy will reduce the need for caesarean delivery and the rate of perinatal transmission for women who present near term with high vl .
this would benefit hiv - infected women , particularly those with low cd4 cell counts , considering the increased risk of postpartum complications related to caesarean delivery ( 35,36 ) .
an important factor to consider , however , is the availability of rapid hiv quantitative test to follow the vl and allow for a safe vaginal delivery .
indeed , in previously published cases of pregnant women treated with ral ( 8,15,16,18,2022,2426 ) as well as in the three cases presented here , vl were retrospectively found to be < 1000 copies / ml after caesarean section was performed to decrease the risk of perinatal transmission .
availability of rapid hiv quantitative polymerase chain reaction would assist the clinician to better decide whether caesarean delivery is indicated , according to their national guidelines ( 4,5 ) .
our findings support the consideration of the use of ral to reduce the risk of perinatal transmission in late - presenting hiv - infected pregnant women and in women with vl rebound near term . however , long - term data are needed to assess the impact of ral use for short - term therapy in the obstetrical setting on the resistance profile . indeed , there is a legitimate concern about the effectiveness of future ral - based regimens .
moreover , current canadian ( 5 ) and united states perinatal guidelines ( 4 ) are permissive but do not advocate for ral use in this setting due to the lack of established data .
the results of two ongoing clinical trials ( nct01854762 and nct01618305 ) will help to assess advantages of ral compared with other antiretrovirals in pregnancy .
further research needs to be performed to understand the role of ral in women with hiv acquisition in pregnancy , who are at even higher risk for perinatal transmission .
 the use of antiretroviral therapy ( art ) has led to a marked reduction in the incidence of perinatal transmission of hiv . with art , 
 it is possible for the viral load to be reduced to undetectable levels during pregnancy . 
 however , some patients ( eg , those with poor adherence or those who acquired hiv during pregnancy ) may still exhibit high viral loads by the third trimester . 
 the purpose of this study was to examine the effect of raltegravir in a combination art regimen in a series of 11 cases in which women presented with high viral loads in the third trimester of pregnancy . 