Abstract
Adequate antiretroviral therapy is essential for HIV-positive pregnant women to prevent mother-to-child transmission. We report a small case series of five women receiving raltegravir as part of their antiretroviral regimen during pregnancy.
Introduction
The risk of mother-to-child transmission of HIV has been dramatically reduced since the use of combination antiretroviral therapy (ART) and is strongly correlated to maternal viral load in late pregnancy.1,2 Specific issues such as late-presenting pregnant HIV-infected women remain a clinical challenge. Raltegravir (RGV) is the first integrase inhibitor to become available and pregnancy data are scarce.3–5 In animal studies no treatment-related effects on embryonic/fetal survival or fetal weights were observed. However, treatment-related increases in the incidence of supernumerary ribs as compared with controls were seen in rats. 6 Nevertheless, the rapid viral load decrease under RGV-containing ART regimens offers a promising new strategy. Also, recent data suggest high placental transfer with a potential preloading effect for the neonate. 4 A retrospective analysis of five cases within the Austrian Cohort Study was undertaken.
Case Series
All women were RGV-naïve and received RGV in addition to at least two other antiretroviral drugs. Patient characteristics are shown in Table 1: the median age was 39 years (range 24–39) with a known HIV positivity for 0–11 years. The number of previous ART regimens ranged from 0 to 5. Indications for RGV included presentation during late pregnancy (cases 1 and 5) for which therapy was initiated without delay in the same week after pregnancy was established. However for case 1, the HIV diagnosis was prior to this pregnancy and was made during a first pregnancy in 2008, where the patient interrupted ART after delivery, she represented at week 34 during this second pregnancy. One patient (case 4) had been on ART for two years before conception and her HIV viral load remained undetectable until week 24 of pregnancy. Between weeks 24–34 of pregnancy, this patient interrupted her medication due to an acute psychological stress disorder. On her next visit, viral load rebound was detected and she was admitted as an inpatient for therapy reinitiation and psychiatric care. The remaining two cases had persistent low-level viraemia (cases 2 and 3). The median length of exposure to RGV was 23 days (17–46 days) before Caesarean delivery. For the very late presenting pregnant women, a massive viral load reduction was achieved, while both cases of persistent low viraemia became undetectable at delivery. Subjective tolerability of ART at time of RGV use was good. In one case an intermittent elevation of liver transaminases (twice above the normal range) was observed during the first two weeks after starting ART and this resolved spontaneously. None of the five infants was HIV-infected and all are doing well. For one infant (case 4) a plagiocephaly was diagnosed, which was successfully treated with a plagiocephaly helmet – a causal relationship with RGV use is unlikely. The prevalence of plagiocephaly in the general population is around one in 300 children. 7 This patient received ART as an inpatient, therefore Caesarean delivery was accomplished within three hours of premature rupture of membranes (week 37). In another case, Caesarean delivery was performed due to premature labour (week 35 + 5).
Patient characteristics of five women receiving raltegravir as part of their antiretroviral regimen during pregnancy
ART = antiretroviral therapy; RGV = raltegravir
Medical care of pregnancy in HIV-infected women has become easier with the availability of numerous drugs in developed countries. Specific circumstances such as late presentation, multidrug-resistant viruses or poor adherence still require careful case-by-case management beyond routine perinatal guidelines. With the release of new drugs such as enfuvirtide, darunavir or RGV, new options have emerged but experience regarding efficacy and safety is limited. RGV is the first-in-class oral integrase inhibitor and prevents insertion of HIV DNA into human DNA genome, thus blocking HIV replication. Its efficacy and tolerability were shown in both BENCHMRK studies for treatment-experienced patients with optimized background therapy. 8 The main side-effects are minor and include diarrhoea, nausea and headache. It has been classified in pregnancy category C by the Food and Drug Administration. In our case series the rationale for RGV use was not based on genotypic resistance testing, as alternative therapeutic options could have been considered. For two patients (cases 2 and 3) the fear of viral rebound led to the inclusion of RGV, despite the fact that no difference in vertical transmission among women with plasma viral load levels <400 or <50 copies/mL has been shown. 2 The remaining three patients had typically high viral loads and rapid viral load suppression was desirable.
The role of accurate and early HIV diagnosis in pregnancy remains a key issue and routine antenatal screening in Austria has finally been implemented in January 2010. Cohort analyses demonstrate that ART prior to conception is associated with the lowest HIV transmission rates.1,2 Complicated HIV pregnancy settings need specific and novel strategies with adequate antiretroviral drugs while minimizing eventual maternal and fetal toxicity. The importance of viral load as marker for the time-point for initiation of ART is growing. 9 There is new evidence for the role of rapid and sustained control of plasma HIV RNA level for prevention of residual vertical transmission as seen for women harbouring a HIV viral load <500 copies/ mL at delivery. 10 Overall, such cases showed a significantly higher baseline viral load that decreased more slowly than in control subjects (non-transmitters with viral load <500 copies/mL at delivery), reflecting again the necessity of rapid and effective viral load reduction in pregnancy. However, the small number of patients presented precludes firm conclusions. RGV is proposed here as a potent new option, due to its virological potency and favourable tolerability profile. However, further clinical assessment of its safety profile is needed.