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ICAAC 2013: Raltegravir Appears Safe for Mothers and Babies During Pregnancy

Antiretroviral regimens containing the HIV integrase inhibitor raltegravir (Isentress) were shown to be safe and effective for HIV positive pregnant women and did not cause birth defects in their infants, researchers reported at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) this month in Denver.

Effective antiretroviral therapy (ART) during pregnancy can suppress viral load, improve the health of HIV positive pregnant women, and dramatically reduce the likelihood of mother-to-child transmission. Current treatment guidelines recommend that all pregnant women should start combination ART by the second trimester, regardless of CD4 T-cell count.

But drugs taken during gestation -- especially during the first trimester when fetal organs are forming -- present a potential risk of adverse events including pregnancy complications, premature birth, and congenital abnormalities in infants.

Vincent Jeantils from Jean Verdier Hospital in Bondy, France, presented findings from a study of outcomes among pregnant women treated with raltegravir. While the pregnancy safety of older drugs such as zidovudine (AZT; Retrovir) and nevirapine (Viramune) is well-established, newer antiretrovirals like raltegravir may offer better-tolerated alternatives.

Determining safety of new drugs during pregnancy is particularly urgent for women who need these drugs due to extensive resistance, those who are already on these drugs when they become pregnant, and those who are found to be HIV positive late in pregnancy and must bring down their viral load rapidly before delivery, Jeantils noted as background.

This analysis, begun in 2008, included 31 pregnant women at a single centre near Paris. Most (80%) were black, including many African immigrants, and the median age was 31 years (range 18-44 years); 3women were coinfected with hepatitis B and 2 with hepatitis C.

The median duration of ART use before pregnancy was about 6 months, but half were antiretroviral treatment-naive. At the time of raltegravir initiation the median CD4 count was 442 cells/mm³ and the median HIV viral load was approximately 17,700 copies/mL.

The women underwent monthly obstetrical exams, fetal ultrasound scans, CD4 and HIV RNA viral load monitoring, and tests to assess liver, kidney, blood cell, and metabolic toxicities. After birth, babies' weight, height, and Apgar scores were measured, and PCR HIV DNA testing was done at birth and at 1, 3, and 6 months of age to determine HIV infection status.

Only 5 of the women (16%) had started raltegravir before pregnancy and stayed on the drug. The rest began taking raltegravir during pregnancy, 3 during the second trimester and 23 during the third trimester. The median duration of raltegravir use was 71 days. In addition to raltegravir, about 60% also took protease inhibitors and nearly 40% used tenofovir/emtricitabine (Truvada).

There were 5 women who switched to raltegravir due to side effects of their current ART regimen (all related to protease inhibitor) and 19 who did so due to poor adherence. In addition, 2 women tested HIV positive during late pregnancy (at 28 and 34 weeks) and needed to suppress viral load quickly.

All but 1 of the women received intravenous zidovudine during labor and delivery -- an element of an older standard-of-care that most experts no longer consider necessary if an HIV positive woman is on effective combination ART with undetectable viral load. Approximately two-thirds of participants underwent caesarean sections for various reasons -- half elective and half emergency -- including 2 planned procedures due to viral load still being detectable.

Results

• Raltegravir was generally safe and well-tolerated with no notable adverse events.
• Antiviral efficacy in the pregnant women was similar to that seen in the general population.
• The median duration of gestation was 38 weeks.
• By the time of delivery, most women (81%) had undetectable HIV RNA according to the most recent test; median viral load had fallen to 41 copies/mL, with levels ranging from 45-641 copies/mL among those with detectable virus.
• There were 32 live births, including a set of twins; median infant weight was 3100 g, median height was 48 cm, and median Apgar score was 9.6 -- all within normal ranges.
• No birth defects or biological abnormalities were observed in any of the babies in this study.
• After delivery the infants were started on a course of prophylactic antiretrovirals (mostly zidovudine alone, with 4 receiving dual and 5 receiving triple therapy).
• No adverse events were observed among the infants and 93% had undetectable HIV RNA at 6 months.
• Pharmacokinetic testing in a subset of participants revealed median raltegravir levels of 169 ng/mL in mothers' plasma, 127 ng/dL in amniotic fluid, and 198 ng/mL in umbilical cord blood, with a cord-to-maternal blood ratio of 3.48.

In this study "a regimen containing raltegravir in pregnancy seems safe for the mothers and the neonates," the researchers concluded. They added that the safety of a raltegravir-containing regimen, together with its rapid antiretroviral activity, absence of embryonic or fetal toxicity in animal studies, and high placental transfer "offers a promising new strategy."

Raltegravir penetrates well into cerebral-spinal fluid, semen and cervical-vaginal fluid, the researchers noted. Therapeutic concentrations in infants are maintained for several days after delivery. As raltegravir rapidly lowers viral load and its good placental transfer allows for "pre-loading" of the baby, they suggested it may be an effective new option if HIV infection is discovered late in pregnancy.

Jeantils noted that to date the Antiretroviral Pregnancy Registry has received 3 reports of congenital defects among 119 infants exposed to raltegravir during the first trimester and 6 defects among 109 exposures during the second or third trimesters.

He explained that children will be followed through 6 years, if possible, to look at long-term outcomes. So far the longest duration of follow-up is 5 years, and no adverse outcomes related to prenatal raltegravir exposure have been observed.

9/22/13

Reference

V Jeantils, H Messaouden and L Carbillon. Pregnancy and a regimen containing raltegravir: a pilot study on the Materno Foetal Safety. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-1463.