Int J STD AIDS 2008;19:866-867
doi:10.1258/ijsa.2008.008075
© 2008 Royal Society of Medicine Press
Use of darunavir and enfuvirtide in a pregnant woman
O Sued MD MSc * ,
J Lattner MD 
,
A Gun Bioch *,
P Patterson MD *,
L Abusamra MD *,
C Cesar MD *,
V Fink MD *,
A Krolewiecki MD * and
P Cahn MD PhD *
* Fundación Huèsped, Area de Investigaciones Clinicas, CP1202 Buenos Aires;
Hospital Fernández, Servicio de Infectologia, CP1425 Buenos Aires, Argentina
Correspondence to: Dr Omar Sued, Fundación Huésped, Pasaje Angel Peluffo 3932, C1202AAB, Buenos Aires, Argentina Email: omar.sued{at}huesped.org.ar
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Summary
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A 41-year-old pregnant woman with multiple virological failures
started darunavir, enfuvirtide, zidovudine and lamivudine at
week 28 of pregnancy. During week 38, the patient had a viral
load <400 copies/mL and a CD4 count of 180 cells/mm
3 (13%).
The child was found to be in good health, with negative HIV-polymerase
chain reactions at birth, at two and at six months.
Key Words: darunavir • TMC114 • pregnancy
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INTRODUCTION
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In patients with triple class failure, a new antiretroviral
(ARV) regimen should include at least two new drugs, if possible
including a new class.
1
In pregnant women, suppression of HIV RNA to undetectable levels is desirable before the delivery in order to reduce the risk of perinatal HIV transmission. Management of pregnant women harbouring multidrug HIV-resistant strains is a complex challenge in daily practice, and occasionally requires the prescription of new ARV drugs for which there is limited experience regarding safety or efficacy.
Here, we report a case of a pregnant female with multidrug-resistant HIV who received a darunavir (DRV)–enfuvirtide (T2O)-based highly active antiretroviral therapy (HAART) during pregnancy.
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CASE REPORT
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The patient was a 41-year-old infected woman who had been diagnosed
with tuberculous lymphadenitis in 1999, and was tested positive
at that time for hepatitis C virus (HCV) and HIV. She started
ARV therapy in 1999 with zidovudine (ZDV)–(3TC) lamivudine–IDV
with suboptimal adherence and failure documented in the year
2000. Subsequently, she failed another three ARVs regimens.
In July 2006, she was referred to our centre to be evaluated
for a salvage regimen. During admission she was receiving atazanavir
boosted with ritonavir (ATV/r)–tenofovir (TDF)–3TC
since 2003. Laboratory results showed GOT 43 U/L, GPT 35 U/L,
total bilirubin 38 mmol/L (attributable to ATV), a negative
pregnancy test, HCV-polymerase chain reaction (PCR)-positive,
CD4 122 cells/mm
3 and viral load (VL) 2910 copies/mL. The genotype
(Virco
® TYPE, Mechelen, Belgium) showed multiple resistance
mutations predicting resistance to emtricitabine (FTC), nevirapine
(NVP), fosamprenavir (F-APV), and atazanavir (ATV); minimal
response to lamivudine (RTC), abacavir (ABC), tenofovir (TDF),
indinavir (IDV), nelfinavir (NFV), saquinavir (SQV), amprenavir
(APV), lopinavir (LPV) and tipranavir (TPV); reduced response
to zidovudine (ZBV), didanosine (ddI), and stavudine (d4T);
and sensitivity to efavirenz (EFV) and darunavir (DRV). When
genotypic data were available, the pregnancy was confirmed.
She was instructed to discontinue ARVs, waiting until week 28
and then to start DRV/r–T20–ZDV–3TC. Frequent
visits, ongoing training and support were provided during the
first three months of therapy with T20. The patient presented
no tolerability complaints, except for painfulness subcutaneous
nodules due to T20. Within 45 days of ARV therapy, VL was <400
copies/mL and her CD4 count was 180 cells/mm
3 (13%). At week
38, a caesarean section was performed. She received the last
ARV dose two hours before surgery, and conventional intravenous
ZDV during the procedure. Maternal samples taken at weeks 34
and 36 showed adequate darunavir trough concentrations (3010
and 3470 ng/mL, respectively).
The child was found to be in good health, with an Apgar score of nine and 10 at one and five minutes, respectively. Immediately after birth, the newborn was started on boosted ZDV for four weeks. This medication was clinically well-tolerated and three HIV-1-PCR for HIV (at birth, at two and six months) were negative.
After delivery the mother continued the same regimen with good adherence, tolerability and efficacy as shown by a sustained suppressed VL and CD4 recovery at nine months of follow-up (Figure 1).
This report is the first one describing the use of darunavir
during pregnancy. Enfuvirtide has seldom been used in pregnant
women and there are only four cases reported in the literature.
In one of these cases enfuvirtide was successfully used with
tipranavir. In other case, the use of enfuvirtide did not prevent
the perinatal transmission despite viral suppression below 50
copies/mL in the mother.
2–5 Enfuvirtide does not cross
the placenta and the authors hypothesized that ineffective concentrations
of enfuvirtide in the genital tract might have resulted in failure
to prevent HIV transmission.
3
Darunavir was approved by the Food and Drug Administration (FDA) in June 2006 as part of combination HAART therapy for use in treatment – experienced patients with HIV-1 strains resistant to more than one protease inhibitor (PI). The approved dosage of darunavir is 600 mg in combination with ritonavir 100 mg twice daily taken with food. As illustrated in the previous studies, DRV/r can result in substantial antiviral efficacy and immunological benefit with good tolerance in experienced patients, showing better efficacy than LPV/r.6–9 Darunavir is in FDA Pregnancy Category B; no embryotoxicity or teratogenicity in mice, rats or rabbits were observed with this drug.10
No controlled studies using darunavir included pregnant women. Owing to the scarce information regarding safety in pregnant women, the selection of the HAART regimen in our case was taken after careful evaluation of the risk and benefits for the mother and the child. The goal of the treatment was to achieve an undetectable VL as soon as possible before labour and delivery, which can be expected to occur using these two new drugs. Although genotypic analysis showed resistant mutations associated with ZDV and 3TC; these drugs were added because they demonstrated efficacy during pregnancy, and the potential effect on fitness, respectively. Efficacy and safety of this regimen was good and resulted in the prevention of mother-to-child transmission.
Trough levels of darunavir were adequate in this patient. Population pharmacokinetic data in non-pregnant patients showed geometric mean concentrations of ±1151 ng/mL of darunavir,10 suggesting that no dose adjustment might be required, in opposition to other PIs showing significant changes in the plasma concentration during pregnancy.11
We report the first case of darunavir use during pregnancy, with satisfactory outcomes for both mother and newborn. Further pharmacokinetic, efficacy and tolerability data need to be collected in order to confirm that this drug can be included as a new option for pregnant women with triple class failure.
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ACKNOWLEDGEMENTS
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We thank Elvira Heyartz from Janssen Cilag, Argentina for her
help in providing darunavir, to Caroline Feys and Vanitha Sekar
from Tibotec Belgium for darunavir bioanalytical assays, to
Horacio Beylis for the critical reading of the manuscript, and
to the patient for her time.
(Accepted April 16, 2008)
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REFERENCES
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- DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents – December 1, 2007. See [http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf] (last checked 15 January 2008)
- Brennan-Benson P, Pakianathan M, Rice P, et al. Enfurvirtide prevents vertical transmission of multidrug-resistant HIV-1 in pregnancy but does not cross the placenta. AIDS 2006;20:297–9[Medline]
- Cohan D, Feakins C, Wara D, et al. Perinatal transmission of multidrug-resistant HIV-1 despite viral suppression on an enfuvirtide-based treatment regimen. AIDS 2005;19:989–90[Medline]
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- Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 2007;369:1169–78[Medline]
- Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 2007;370:49–58[Medline]
- Fenton C, Perry CM. Darunavir: in the treatment of HIV-1 infection. Drugs 2007;67:2791–801[Medline]
- Molina JM, Hill A. Darunavir (TMC114): a new HIV-1 protease inhibitor. Exp Opin Pharmacother 2007;8:1951–64[Medline]
- Tibotec, Inc. PREZISTA (darunavir) Tablets: Full Prescribing Information. See [http://www.prezista.com/docs/us_package_insert.pdf] (last checked 15 January 2008)
- Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS 2006;20:1931–9[Medline]
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Summary
INTRODUCTION
