Kaletra (lopinavir/ritonavir) monotherapy achieves satisfactory levels of virological suppression in pregnant women taking antiretroviral therapy to prevent mother-to-child transmission of HIV, French investigators report in the online edition of Clinical Infectious Diseases.
Eight weeks after starting therapy, 90% of women taking Kaletra monotherapy had a viral load below 200 copies/ml compared to 94% of women taking triple therapy consisting of Kaletra with Combivir (3TC/AZT). Treatment was started during week 26 of pregnancy and none of the women needed HIV therapy for their own health.
Protease inhibitor monotherapy is not recommended for routine antiretroviral treatment. However, the results of this preliminary research suggest that it could be an option for a sub-set of women with a high CD4 cell count, to prevent mother-to-child transmission of HIV.
In industrialised countries, antiretroviral therapy is recommended for all pregnant women with HIV. This is one of the reasons why there is a very low rate of mother-to-child transmission in these countries, where it is typically well below 1%.
A combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and a ritonavir-boosted protease inhibitor is recommended for use during pregnancy. The most widely used combination in Europe and the United States consists of Combivir as the NRTI backbone with the protease inhibitor Kaletra.
However, there is an ongoing debate about the safety of NRTI therapy during pregnancy. NRTIs cross the placenta, and there is some evidence that in utero exposure to AZT can lead to some toxicities, the long-term clinical significance of which are unknown.
Investigators in France therefore evaluated a nucleoside-sparing regimen for the prevention of mother-to-child HIV transmission. They selected Kaletra because the drug is widely used in pregnancy and because monotherapy with the drug has been shown to have potency in non-pregnant adults. Viral resistance is unlikely should monotherapy with the drug fail to suppress viral load. Moreover, Kaletra has a low placental transfer, limiting the risk of in utero toxicities.
The study (ANRS 135 PRIMEVA) involved 105 women living with HIV. All had a viral load below 30,000 copies/ml and a CD4 cell count above 350 cells/mm3. None therefore required HIV therapy for their own health.
The study was open-label and multicentre. Participants were recruited between weeks 20 and 24 of pregnancy. At week 26 they were randomised on a 2:1 basis to start therapy with either Kaletra monotherapy (n=69) or Kaletra with Combivir (n=36), all at standard doses. All the women received intravenous AZT during labour.
Monotherapy was considered to be efficacious if at least 59 women in that arm achieved a viral load below 200 copies/ml after eight weeks of treatment. The authors emphasised that the study was not designed to show the equivalence of monotherapy with triple therapy “as this would require a very large sample size”.
Secondary endpoints included the proportion of women with a viral load below 50 copies/ml at delivery and the safety of therapy.
At screening, the women had a median viral load of approximately 3000 copies/ml and a median CD4 cell count of 525 cells/mm3. Treatment was stopped by two women in the monotherapy arm and by two women in the triple-therapy arm before week eight.
The primary efficacy criterion of the study was achieved. After eight weeks of treatment, 62 women (90%) in the monotherapy arm had a viral load below 200 copies/ml. This compared to 94% of women taking triple-drug therapy, not a statistically significant difference.
At delivery, 93% of women taking monotherapy and 97% of those taking triple-therapy had a viral load below 200 copies/ml. Once again, this difference was not statistically significant.
However, monotherapy was associated with lower rates of viral suppression below 50 copies/ml at delivery than standard treatment (78 vs 97%, p = 0.01).
All the women discontinued therapy after delivery, and four weeks later the women treated with monotherapy had a significantly higher viral load compared to woman taking triple-drug treatment. However, this difference had decreased by week twelve and no resistance was detected in the women taking monotherapy.
Drug concentrations among the women taking monotherapy were within therapeutic ranges.
Adherence rates during the first weeks of therapy were similar between the two arms of the study, with 25% of women taking monotherapy reporting missing doses compared to 14% of women in the triple-drug arm.
Only 1% of women taking monotherapy changed treatment because of toxicities compared to 11% of those treated with a three-drug combination (p = 0.0046).
There was no difference in gestational age, mode of delivery, maternal and infant severe adverse events and serious laboratory abnormalities between the two study arms.
No transmissions occurred in the monotherapy group, but there was one case in the triple therapy group.
“This is the first randomised trial to evaluate a NRTI-sparing strategy of antiretroviral monotherapy during pregnancy in order to prevent mother-to-child transmission of HIV,” write the authors. “We showed that this strategy achieved satisfactory virologic efficacy at 8 weeks of treatment, with 90% of women achieving VL < 200 copies/ml at 34 [weeks of gestation]. Moreover, although the trial was not designed to show equivalence, the proportion was on the same order as with triple therapy.”
They conclude their results “are a step towards the proof of concept that [prevention of mother-to-child-transmission] without NRTI might be an alternative for pregnant immunocompetent women with spontaneously low viral load…the present study may open the way for other novel nucleoside-sparing strategies.”
Tubiana R et al. Lopinavir/ritonavir monotherapy as a nucleoside analogue-sparing strategy to prevent HIV-1 mother-to-child transmission. The ANRS 135 PRIMEVA phase II/III randomized trial. Clin Infect Dis, online edition, 2013.