AIDS:
23 October 2010 - Volume 24 - Issue 16 - p 2481–2488
doi: 10.1097/QAD.0b013e32833e1659
Clinical Science
Maternal and nenonatal tenofovir and emtricitabine to prevent vertical transmission of HIV-1: tolerance and resistance
The TEmAA ANRS 12109 Study Group
Author Information
*The members of the TEmAA ANRS 12109 Study Group are listed in the Acknowledgements section.
Received 10 June, 2010
Revised 8 July, 2010
Accepted 9 July, 2010
Correspondence to Elise Arrivé, DMD, PhD, INSERM U897, Université Victor Segalen Bordeaux 2, 33076 Bordeaux Cedex, France. Tel: +33 5 57 57 48 10; fax: +33 5 57 57 56 30; e-mail: elise.arrive@isped.u-bordeaux2.fr
Abstract
Objective: Viral resistance occurs with a high frequency after single-dose nevirapine. We aimed to evaluate the tolerance and resistance profiles of a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) given to HIV-1-infected delivering women and their newborns.
Design: An open-label phase I/II trial in Cambodia, Côte d'Ivoire and South Africa.
Methods: HIV-1-infected pregnant women received zidovudine from the enrollment until the beginning of labor, when single-dose nevirapine and two tablets of TDF/FTC were given. One daily tablet of TDF/FTC was then administered for 7 days postpartum. All infants received single-dose nevirapine with single-dose TDF (13 mg/kg) and single-dose FTC (2 mg/kg) and 1 week of zidovudine. Mothers and infants were followed for 2 months. Serious adverse events, kinetic of maternal plasma HIV-1 RNA, pediatric HIV infection and genotypic resistance and viral subtype were assessed.
Results: Thirty-six HIV-1-infected pregnant women were enrolled: median age 28 years (interquartile range: 26–31 years), median CD4 cell count 462 cells/μl (interquartile range: 376–632) and median HIV-1 RNA 3.7 log10 copies/ml (interquartile range: 2.95–4.11). Two infants had clinical serious adverse events, including one who died (neonatal sepsis). One transient grade 3 neutropenia and two grade 3/4 hyperbilirubinemia were also reported in neonates. One HIV pediatric in-utero infection was diagnosed (2.8%; 95% confidence interval 0–15.4%). Genotypic viral resistance to nevirapine was detected in one mother out of 34 (2.9%) at one month postpartum, but was also detectable at enrollment.
Conclusion: The combination of TDF/FTC to delivering women and their neonates appears well tolerated and to minimize the occurrence of nevirapine viral resistance.
Introduction
The WHO reports an increasing number of countries having shifted away from providing single-dose nevirapine (NVP) only, for the prevention of mother-to-child transmission of HIV (PMTCT), toward the use of more complex and efficacious antiretroviral drug regimens [1]. However, single-dose NVP is often still the corner stone of the PMTCT programs described in many recent reports from low-income countries[2–7]. Evidence is growing about the deleterious effect of viral resistance induced by single-dose NVP on the response to subsequent nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral treatment [8–11]. Preventing the occurrence of viral resistance to NNRTIs is possible with the addition of intrapartum/postpartum short-course antiretroviral regimens and different strategies have been successfully evaluated [12–15]. Among these, adding a single intrapartum dose of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) to single-dose NVP has been shown to reduce the occurrence of viral resistance to NNRTIs without any additional PMTCT effect in a Zambian trial [12,16,17]. Given the long half-life of NVP [18], we hypothesized that NNRTI resistance could be prevented to a large extent in mothers by combining intrapartum and postpartum TDF/FTC and, in the newborns infected despite the intervention, by adding neonatal TDF/FTC to the neonatal NVP. The TEmAA ANRS 12109 trial was, thus, designed with the objectives of studying the pharmacokinetic properties of TDF and FTC in delivering women and their newborns, evaluating the tolerance and the risk of peripartum mother-to-child transmission (MTCT) as well as the risk of acquisition of viral resistance and its evolving pattern. In the first step of the study, the tolerance of and viral response obtained with a TDF/FTC combination given to HIV-1-infected pregnant women during labor and for 1 week postpartum was shown to be good [19]. We then administered this drug combination to neonates, in addition to single-dose NVP, which was already assessed in similar conditions [18].
Methods
The ANRS 12109 Tenofovir Emtricitabine in Africa and Asia (TEmAA) trial was a phase I/II, multicenter, open-label clinical trial conducted in two sequential steps in Phnom Penh (Cambodia), Abidjan (Côte d'Ivoire) and Soweto (South Africa). Consenting pregnant women tested positive for HIV-1 or HIV-1 and 2, aged 18 years or older, not meeting the criteria for antiretroviral treatment and antiretroviral-naive, were enrolled in the trial. Women who did not meet the enrollment criteria were followed within the national program. The second step, conducted from July 2008 and May 2009, is reported here and maternal and neonatal outcomes were compared with those obtained during the first step. The methods used in this trial have been detailed in a previous publication [19] and the antiretroviral regimens studied in both steps are summarized in Table 1. The main difference between the two steps was the addition of the TDF/FTC neonatal dosing. According to the pharmacokinetic analyses conducted in the first step, the intrapartum dose of TDF/FTC was repeated if labor lasted more than 12 h in this second step [20] and the optimal neonatal dosing of TDF and FTC was calculated [20,21]. As the efficacy of neonatal TDF and FTC alone for PMTCT was not known, neonatal single-dose NVP was also administered. Mothers and infants were followed for 2 months after delivery or birth. The number and type of adverse events, kinetics of maternal plasma HIV-1 viral load and HIV-1 infection status of the infants at 4 weeks of life were assessed. The plasma HIV-1 RNA was quantified using the generic ANRS quantitative real-time PCR in Abidjan and Phnom Penh [22] and Roche Amplicor v1.5 (Roche Molecular Systems Inc., Branchburg, New Jersey, USA) in Soweto[23].
HIV-1 genotypic resistance tests on the reverse transcriptase sequences were performed at 4 weeks postpartum in women and infected children according to the ANRS technique (www.hivfrenchresistance.org) and phylogenetic analyses were conducted to determine the viral subtypes. When a resistance mutation was found at 4 weeks postpartum, genotypic resistance tests were done on samples taken at enrollment and at 2 days postpartum. The laboratories having conducted the resistance tests participated in the annual quality assurance program and no discrepancy was evidenced according to the different subtypes [24].
The protocol was approved by the ethics committee of each participating institution and by the Medical Control Council of South Africa and was registered with http://www.ClinicalTrials.gov (number NCT00334256).
ACCESS, version 2003 (Microsoft Corporation, Redmond, Washington, USA) and SAS, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA) softwares were used for data management and statistical analysis. Descriptive analyses included the calculation of median and interquartile range (IQR) for quantitative variables and frequencies and 95% confidence intervals (CIs) for qualitative variables. Kruskal–Wallis test was used to compare quantitative variables; Yates-corrected chi-squared test or two-sided Fisher's exact test were used to compare qualitative variables. Statistical significance was defined by a P value of 0.05 or less.
Results
Patients' characteristics
Thirty-six HIV-1-infected antiretroviral-naive consenting pregnant women were enrolled in the second step and all of them received the study drugs (nine in Phnom Penh, 15 in Abidjan and 12 in Soweto). The median age was 28 years (IQR: 26–31 years). At baseline, 31 women (86%) had a WHO clinical stage 2, the median CD4 cell count was 459 cells/μl (IQR: 376–632) and seven women (19%) had HIV-1 RNA plasma viral load less than 400 copies/ml. Compared to the first step, the viral load was lower, but the CD4 cell count was not statistically different (Table 2). Women received TDF/FTC 6.2 h in median (IQR: 4.6–7.4) after the beginning of labor. Two women received two additional tablets of TDF/FTC due to prolonged labor. More elective cesarean sections were conducted in the second step than in the first step, because more women were enrolled and delivered in Soweto where cesarean section was the mode of delivery per protocol.
All 36 liveborn babies (median weight 3000 g; IQR: 2700–3225) received the study single doses of TDF and FTC together with single-dose NVP. Five babies were breastfed, all in Abidjan.
One mother–infant pair was lost to follow-up by the 1-month visit in Soweto.
Tolerance
Two biological serious adverse events (SAEs) occurred in mothers (one grade 3 leukopenia and one grade 4 neutropenia.). All these SAEs had resolved by 28 days after delivery. Compared to the first step, the number of SAEs was significantly lower (Table 3).
Anemia (≤9.4 g/dl) was present in three (8.3%) mothers at enrollment, one (2.9%) at the time of first TDF/FTC administration), eight (22.2%) 48 h after delivery and three (8.6%) 7 days after delivery. Neutropenia (≤1500/μl) was recorded in three (8.6%) mothers at the time of first TDF/FTC administration, 1 (2.9%) and six (17.1%) at 7 and 28 days after delivery, respectively.
Two infants, both from Côte d'Ivoire, had clinical grade 4 SAEs (5%) consisting of one infectious event leading to death before the 28-day postnatal visit, and in one acute brain injury at birth of probable obstetrical origin, with prolonged labor after 42 weeks of pregnancy.
One grade 3 neutropenia and two grade 3/4 hyperbilirubinemia were also reported, which were not associated with clinical impairment.
Among 34 children followed up at 28 days after delivery, four had grade 1 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation and 11 additional children had grade 1 AST elevation only. Their median blood creatinine was 24.0 μmol/l (IQR: 17.7–26.6): one child had a grade 2 low creatinine clearance (calculated according to the Schwartz formula) and five had grade 1 low creatinine clearance. The median urine β-2 microglobulin was 1.1 mg/l (IQR: 0.2–1.80), including 23 children (67.6%) with a value greater than 0.35 mg/l. However, no difference was observed with regard to creatinine clearance and β-2 microglobulinuria. The number of newborns' SAEs was also significantly lower than that in the first step (Table 3).
Virology
Phylogenetic analysis revealed that 12 women enrolled in the second step of the trial in Abidjan harbored CRF02-AG viral strains, two CRF06 strains and one indeterminate strain. In Phnom Penh, seven women had CRF01-AE strains and two B strains, whereas 11 women from Soweto harbored C viral strains.
Maternal HIV-1 plasma viral load decreased from a median of 3.69 log (IQR: 2.95–4.11) at enrollment to 2.91 log (IQR: 2.6–3.75; −0.78) at 48 h after first TDF/FTC administration and then returned to the initial value at the 28-day postnatal visit (median: 4.07 log; IQR: 3.00–4.74;Table 4).
A viral resistance mutation to NVP (K103N) was detected in one of 34 mothers with available samples at 1 month postpartum. This resistance pattern, found in a South African woman, was already present in mixed populations (K103N/K) at enrollment and at 48 h after first TDF/FTC administration. Thus, among 33 women being tested and with no resistance at baseline, the upper limit of the 95% CI for the resistance rate at 1 month postpartum was 10.6%. No resistance to zidovudine, FTC or TDF was detected in both steps.
One infant out of 34 tested at 4 weeks of life in this second step of the trial had detectable HIV-1 RNA plasma viral load, also detectable at D3, suggesting in-utero HIV infection (2.9%, 95%CI: 0.0–15.4). This infant harbored CRF02-AG strain and had no viral resistance at 1 month postpartum.
Discussion
In this second step of the ANRS 12109 TEmAA trial, the TDF and FTC oral formulations were evaluated for the first time in neonates for PMTCT. The tolerance to the study drugs was good, both in women, receiving two tablets of TDF/FTC during labor and one tablet daily during 7 days postpartum, and also in newborns, exposed in utero and then receiving single doses of TDF and FTC within the first 12 h of life. In addition, no peripartum HIV transmission was reported, and no acquisition of new viral resistance was detected in HIV-infected women or children at 1 month after delivery/birth to either NVP or to TDF and FTC. These findings confirm and update those obtained during the first step of the trial when the study drugs were administered only to the women [19].
There is no pediatric formulation of the truvada combination of TDF/FTC yet, but these two drugs were available separately, allowing for more adequate dosing according to the pharmacokinetics of each drug. The FTC oral solution (10 mg/ml) was licensed in 2008 for use in children aged 0–3 months in the United States [25]. However, the TDF oral suspension (20 mg/ml) used in this trial was an experimental product, as it is not yet licensed for use in children less than 18 years[26]. This product has been evaluated so far in 12 children aged between 2 and 8 years receiving a single dose of 8 mg/kg [26]. Other studies on older children have used tablets, often off-label, either as part of salvage therapy or for children coinfected with hepatitis B [27–29]. Good safety data have also been reported from a small cohort of 15 HIV-infected pregnant women on TDF-based antiretroviral treatment and infant exposed in utero for a median of 127 days [30]. Overall, TDF was well tolerated, and renal and bone toxicities were uncommon and occurred after long-term exposure. In our study, the newborns' exposure to TDF dose was higher than that in the other published studies, though only one dose was given. Therefore, the SAEs that occurred were not expected to be related with TDF use. However, we observed high levels of β-2 microglobulinuria, with 68% of the children experiencing a measurement higher than the usual threshold (0.35 mg/l in children older than 5 years [31]). This was unlikely to be due to neonatal TDF dosing as this abnormality was also recorded in the first step [19]. In addition, it has been shown that normal healthy infants sometimes have high levels of β-2 microglobulinuria and large individual differences have been documented during the first 2 months of life, suggesting renal proximal tubular dysfunction, linked to functional immaturity rather than proximal tubular injury [32]. For instance, the mean value of β-2 microglobulinuria in healthy 1-month-old infants (n = 49) was 0.24 mg/l (95%CI: 0.019–3.108) in a published report [32], corresponding to the ranges in our series.
Resistance to NNRTI can occur not only in women, but also in children infected with HIV despite single-dose, NVP-based PMTCT interventions. The resistance rate varies between 53 and 16% if single-dose NVP is used alone or with additional maternal and/or neonatal antiretroviral [33]. Infants with in-utero HIV infection may be more likely to present NVP viral resistance than those with peripartum or postnatal infection [34,35]. Some studies have shown that prior single-dose NVP exposure was associated with virological failure of NNRTI-based treatment in infants [9,36], even at low level of preexisting NVP resistance [37]. Thus, even if the number of infected infants is expected to be low with already recommended effective PMTCT interventions, alternative strategies without single-dose NVP should be investigated to avoid NVP resistance in these infants. This is particularly true if the neonatal prophylaxis lasts at least 6 months, as the recent WHO guidelines recommend [38], considering the increased risk of resistance that has been already demonstrated with extended NVP prophylaxis [39].
Our study has several limitations. First, the sample size, designed for pharmacokinetic purposes, did not allow for accurate estimates of all outcomes reported here. Second, some laboratory examinations were not conducted routinely at local sites, including urine β-2 microglobulin, and this could have compromised the reliability of the interpretation of the results. Also, a decrease in bone mineral density could not be investigated, though it has been identified as a potential adverse event related to TDF [26]. However, this was not expected to occur after such brief exposure. Third, the protocol follow-up was only 2 months after delivery/birth, so we do not have extended follow-up data as long-term adverse events were unlikely after a single-dose administration. Fourth, the analysis of viral resistance was conducted using sequencing techniques, which could not detect mutant variants present at frequencies lower than 20%. Finally, the state of knowledge at the time the study was conducted did not allow us to exclude the single-dose NVP to infants, but we hope that the pharmacokinetic outcomes coming out from our study will provide evidence soon on the relevance of using the TDF/FTC combination without infant single-dose NVP for PMTCT.
In conclusion, in line with efforts to search for new PMTCT antiretroviral interventions, which can preserve the subsequent treatment options of HIV-infected women and infants, the ANRS 12109 TEmAA trial has explored a simple regimen using TDF and FTC, two drugs likely to soon become the lead combination in first-line antiretroviral regimens for adults in resource-limited settings [40]. It is the first time that these drugs have been used in neonates for PMTCT and our good safety and viral kinetics results are encouraging for further evaluation. In particular, it is possible that a TDF/FTC syrup combination could replace NVP syrup for neonatal use for PMTCT of HIV-1. The pharmacokinetic analyses of the TDF/FTC combination, also administered to the newborns as a single-dose, performed in the second step, will provide further evidence.
If you have Herpes in your whole body such as fever blisters, hsv, or roofing shingles you know what it is like to stay with the pain and discomfort that herpes delivers. I don't need to tell you how awesome it would be to find something that works so well that you no longer need to fear about stress or outbreak,Dr Itua herbal medicine cure my herpes in two weeks of taking it.is genuine and natural herbal medicine it has no side effect, The reason I'm writing this is that I promised Dr Itua I will share his herbal work to the world to see Herpes is no more a big deal.also Dr Itua can as well cure the following diseases...HIV,Hsv 1/2,Hepatitis B,Breast Cancer, Cervical Cancer,Leukuemia Cancer,Lung Cancer,Brain CANCER,Blood Cancer,Prostate Cancer,Diabetes, Men/Woman Infertility, Scoliosis,Fibromyalgia,Fluoroquinolone Toxicity
ResponderEliminarSyndrome Fibrodysplasia Ossificans Progressiva.Fatal Familial Insomnia Facator V Leiden Mutation , Lottery Spell,Copd, Shingles,Fibroid, Fibromyalgia, Liver/Kidney Inflamotry, Epilepsy,Hpv,Weak Erection,Wart Remover,Cold Sore, Coeliac disease,Creutzfeldt–Jakob disease,Cerebral Amyloid Angiopathy, Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Lung disease.Enlarged prostate,Osteoporosis.Alzheimer's disease,
Dementia.Ataxia,Arthritis,Amyotrophic Lateral Sclerosis,Alzheimer's disease,Adrenocortical carcinoma.Asthma,Allergic Asthma. Here His Contact...drituaherbalcenter@gmail.com/ info@drituaherbalcenter.com. Whatsapp Phone.+2348149277976. I paid for his herbal medicine and sent it to me through Courier Service which I pick it urgently and used.