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Nine-Study Review Raises No Lopinavir Efficacy or Safety Concerns in Pregnancy
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Third International Workshop on HIV and Women, January 14-15, 2013, Toronto
Mark Mascolini
Systematic review of nine studies involving 2675 pregnant women found that standard-dose lopinavir/ritonavir controlled HIV replication and limited HIV transmission well, despite prior reports of low levels of the protease inhibitors in the third trimester [1]. The analysis raised no grave safety concerns with lopinavir/ritonavir, and fewer than 2% of pregnant women stopped lopinavir/ritonavir in studies that reported that outcome.
US Perinatal Guidelines list lopinavir/ritonavir as a preferred regimen for pregnant women. Pharmacokinetic studies found lower lopinavir plasma concentrations in the third trimester with a dose of 400/100 mg twice daily [2]. But such studies are not designed or powered to assess clinical outcomes, and lower lopinavir concentrations do not seem to affect maternal clinical outcomes or rates of mother-to-child transmission.
To get a better fix on maternal outcomes, transmission rates, and lopinavir/ritonavir safety during pregnancy, Abbott Laboratories investigators conducted a systematic review of electronic databases and HIV conferences for studies published or presented through May 31, 2012. They selected studies of lopinavir/ritonavir during pregnancy that reported maternal and infant outcomes as primary objectives.
The investigators identified 13 publications or presentations involving nine studies that included 2675 pregnant women treated with lopinavir/ritonavir: 1618 women took 800/200 mg of lopinavir/ritonavir daily, 70 took a higher dose, and 987 took an unreported dose.
More than 80% of women (range 64% to 97%) reached an undetectable viral load as defined by the study in which they participated. The 64% response rate (with a 300-copy lower detection cutoff) came in the three-country African Kesho Bora trial. The one study that evaluated both standard and high-dose lopinavir/ritonavir found no significant difference in the proportion of women with a viral load at or above 1000 copies/mL.
Eight studies reported vertical transmission measured at times ranging from birth to 18 months after delivery. Transmission rates ranged from 0% to 2.8%. In the single trial comparing standard and high doses of lopinavir/ritonavir, 1 of 162 women (0.6%) taking the standard dose and none of 69 women taking the high dose transmitted HIV to their infant.
Preterm delivery rates in seven studies ranged from 8.7% to 25.0%, low birth weight rates from 11.5% to 20.3%, and stillbirth rates from 1.0% to 4.8%.
In four studies involving 1011 women that reported maternal serious adverse events, rates ranged from 0 to 36%. Two studies involving 687 women reported types of adverse events: infectious diseases in 34 of 412 women (8%) and obstetric pathologies in 8 of 275 women (3%) were the most frequent.
In three studies of 914 women grade 3 or 4 laboratory events affected 7 of 164 women (4.3%) in one study, 18 of 405 (4.4%) in the second, and 32 of 273 (1.2%) in the third. The most common lab abnormalities were anemia in 12 of 275 (4%), increased cholesterol in 5 of 162 women (3%), decreased hemoglobin in 10 of 377 (3%), and increased bilirubin in 1 of 68 (1.5%).
Two studies involving 697 women reported treatment discontinuations in 7 of 412 women (1.7%) and 1 of 285 women (0.4%), but neither study noted reasons for discontinuations.
"Despite decreases in lopinavir/ritonavir plasma exposure during the third trimester," the Abbott team concluded, "maternal plasma HIV-1 RNA levels and rates of mother-to-child transmission in this review were consistent with or below those observed with alternative antiretroviral regimens." They noted that high-dose lopinavir/ritonavir evaluated in one study did not yield efficacy, safety, or transmission results much different from those seen with standard dosing.
References
1. Pasley M, Martinez M, Stubbs R, D'Amico R, Hermes A, Nilius A. Systematic review of the safety and efficacy of lopinavir/ritonavir-based antiretroviral therapy in pregnant women. Third International Workshop on HIV and Women, January 14-15, 2013, Toronto. Abstract O_15.
2. Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS. 2006;20:1931-1939.
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