aNorthwick Park Hospital, Harrow, UK
bChelsea and Westminster Hospital, UK
cSt Mary's Hospital, London, UK.
Received 29 August, 2008
Revised 23 October, 2008
Accepted 28 October, 2008
Correspondence to Dr André Furco, Department of Genitourinary and HIV Medicine, Northwick Park Hospital, Watford Road, HA1 3UJ Harrow, Middlesex, UK. E-mail: Andre.Furco@nwlh.nhs.uk
A 38-year-old HIV-1-positive African woman was presented to clinic at 6 weeks of a twin pregnancy. In the past, she had received nucleoside reverse transcripase inhibitors (zidovudine, lamivudine, tenofovir and didanosine), nonnucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) and protease inhibitors (nelfinavir and lopinavir). Her switches in antiretroviral therapy (ART) had been because of virological failure related to poor adherence. Her treatment was tenofovir/emtricitabine (TDF/FTC) and boosted atazanavir. Her viral load was 4660 copies/ml with CD4 cell count of 471 cells/μl.
Therapeutic drug monitoring showed levels in excess for atazanavir. Sequencing of HIV polymerase revealed resistance mutations – reverse transcriptase: D67N, V118I/V, M184V, Y188L, L210W and T215Y; protease inhibitor: L10I, I13V, G16E, K20I, M36I, M46I, I47V, F53L, I54V, D60E, D63T, H69K, I84V and L89M. A phenotypic assay confirmed high-level resistance to almost all licensed antiretroviral drugs. Thus, there was a risk of mother-to-child transmission (MTCT) of multi-class-resistant HIV [multidrug-resistant HIV (MDR-HIV)]. After discussion by a multidisciplinary HIV team, at 25 weeks gestation, she was prescribed darunavir 600 mg twice daily (b.i.d) with ritonavir 100 mg b.i.d, etravirine 200 mg b.i.d (via compassionate release program) and enfuvirtide (T20) 90 mg subcutaneously b.i.d given under direct observation and TDF/FTC (245 mg/200 mg) one tablet q.d. as optimized background therapy. Four weeks later, her viral load was fully suppressed (HIV RNA <50 copies/ml) with CD4 cell count of 356 cells/μl. A pharmacokinetic study of T20, etravirine and darunavir showed maternal plasma levels that were above the expected therapeutic ranges (Table 1).
At 32 weeks gestation, she developed premature contractions and received oxytocin receptor antogonist (atosiban). After spontaneous rupture of membranes at 34 weeks gestation, a caesarean section was performed 3 h after onset of labour. She delivered a healthy baby boy and girl weighing 1.810 and 1.860 kg, respectively. Neither zidovudine nor nevirapine were administered during labour, but she received an extra dose of her current antiretroviral drugs 2.5 h before the caesarean section. At delivery, viral load remained undetectable, and her CD4 cell count was 451 cells/μl. The babies received a postnatal prophylactic antiretroviral drug regimen comprising T20 for 2 days, nevirapine for 1 week and didanosine for 2 weeks. Analysis of cord blood samples from both placentas showed undetectable levels of T20, whereas significant levels of darunavir, ritonavir and etravirine were found (Table 1). At 4 months of age, four HIV-1 DNA polymerase chain reaction tests performed on blood samples from each twin have been negative and no laboratory abnormalities noted.
Adverse events experienced by the mother were mild and included T20 injection site reactions, high fasting triglycerides and anaemia. She developed liver dysfunction at week 4 which peaked at week 8 of therapy (29 and 33 weeks gestation, respectively). All adverse events resolved spontaneously. Serological markers showed that she was hepatitis B immune with negative hepatitis B virus (HBV) DNA and negative for hepatitis A, C, cytomegalovirus (CMV), parvovirus, Q fever and rubella infections. Liver ultrasound was normal.
Use of ART in pregnancy significantly reduces MTCT of HIV . This goal is more challenging in pregnant women with MDR-HIV. Newer antiretroviral drugs lack safety, tolerance and efficacy data in pregnancy. Neonatal MDR-HIV infection poses an even greater problem to treat, as there is no pharmacokinetic data for the newer drugs on infants.
Recent case reports highlighted the efficacy of T20 in preventing MTCT [2–4]. The lack of transplacental crossing renders this drug attractive for use in MDR-HIV-experienced pregnant women with anticipated little or no foetal toxicity . Nevertheless, in one case report, T20-based regimen failed to prevent MTCT, despite an undetectable plasma viral load at delivery suggesting lack of genital tract penetration of such ART .
Unlike T20, placental crossing of darunavir and etravirine is not known. To our knowledge, ours is the first report to show transplacental transfer of darunavir and etravirine in human pregnancy. While raising concerns regarding possible foeto-toxicity, this finding also offers the prospect that these drugs could have prevented HIV infection in babies. Pregnant women have been excluded from all the major clinical trials conducted to date involving the three drugs [7–10]. In animal studies, however, no maternal foetal toxicity was observed for either darunavir or etravirine . The extra dose of antiretroviral drugs given before the delivery may have influenced the cord blood levels, but caused no apparent neonatal toxicity. Clinicians should, where possible, give babies the same ART as the mother's regimen for prophylaxis, and we would advocate caesarean section as preferred mode of delivery in such cases.
In conclusion, we report successful prevention of MTCT in a case of MDR-HIV using a darunavir/etravirine-based regimen with evidence of placental transfer of both drugs.
A.F. is part of multidisciplinary treatment team and wrote the article. B.G., S.N., A.W., W.B., A.P., G.T., D.A., H.L., A.S. and M.K. are part of multidisciplinary treatment team and contributed to the draft of the article.
A special thanks to Ms Margaret Costello, Ms Eileen O'Sullivan and Ms Marthe Le Prevost for their help. We would like to thank Tibotec (Dr Perry Mohamed), Roche Pharmaceuticals (Ms Phillipa Gately) and Delphicdiagnostics (Jon Ventham) for their help with information regarding drug foetal toxicity and support in therapeutic drug monitoring. The authors declare no conflict of interest.
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