CATIE News

30 March 2016 

Canadian researchers review the use of raltegravir in pregnancy

As mentioned in the previous CATIE News report, there are several steps that can be taken to help reduce the risk of HIV transmission from mother to child. A key part of this risk reduction is the use of potent combination anti-HIV therapy (commonly called ART) by HIV-positive women during pregnancy. ART helps to lower the amount of HIV (viral load) in the pregnant mother’s blood so that ideally it falls to less than 50 copies/mL and stays low, particularly at the time that she gives birth.

It takes time for HIV treatment to lower one’s viral load, and this span of time can vary depending on the regimen used as well as the mother’s viral load when ART is initiated.

In clinical trials, regimens based on the class of HIV drugs called integrase inhibitors tend to lower viral loads faster than regimens that do not include these drugs.

Integrase inhibitors

The following integrase inhibitors are licensed in Canada and other high-income countries:

  • dolutegravir (Tivicay and in Triumeq)
  • elvitegravir (in Genvoya and Stribild)
  • raltegravir (Isentress)

The leading HIV treatment guidelines in the U.S. (which are a model for guidelines in the rest of the world) are produced under the aegis of the U.S. Federal Ministry of Health called the Department of Health and Human Services (DHHS). In 2015 these guidelines for the first time recommended an integrase inhibitor, raltegravir, as a preferred option as part of a regimen used during the initial treatment of HIV in pregnant women. It is therefore likely that interest in this drug by doctors caring for HIV-positive pregnant women will increase.

Canadian researchers recently conducted an extensive review of published articles and conference reports on raltegravir. Focusing on the drug’s use in pregnancy, they found data on 278 HIV-positive women and their infants. According to the researchers, “…raltegravir appears safe and effective in preventing mother-to-child transmission in late pregnancy…”

Furthermore, thanks to raltegravir-based regimens, the reviewers found that “…most women were able to [give birth] with [very low] viral loads.” In general, the drug was “well tolerated” and no consistent pattern of general adverse effects was reported.

Review results

The research team scoured publication and conference databases and amassed data on 278 HIV-positive women and their offspring.

The majority (almost 70%) of these cases had their details reported as part of a review of a series of cases or in individual reports. The remainder of the cases reviewed came from studies.

Most of the women were from high-income countries in North America or Western Europe.

Doctors chose to use raltegravir for the following reasons:

  • It caused a rapid reduction in viral load.
  • It intensified the anti-HIV activity of an existing regimen.
  • It had activity against strains of HIV that were resistant to some other drugs.

Reducing the risk of transmission

When raltegravir was being developed in phase III clinical trials nearly a decade ago, the priority at that time was to assess its efficacy against HIV that had become resistant to other therapies.  At that time, raltegravir was not formally tested for its ability to reduce the risk of mother-to-child transmission. Therefore, robust conclusions about its effectiveness in this regard cannot be drawn from this review (clinical trials are underway to assess raltegravir’s effectiveness in pregnant women). However, there were only two cases in which the researchers said that “the infants tested positive [for HIV] after birth and it was clear that the mother [had used raltegravir].”

In the first of these cases, the data were incomplete and no information was available about the mother’s viral load before starting raltegravir or at birth. In the second case, researchers suspect that HIV infection of the fetus occurred before the mother initiated therapy with a raltegravir-based regimen. The baby was born with a rash and other symptoms suggestive of acute HIV infection and tested positive for HIV’s genetic material one week after birth.

Side effects—in mothers

In performing their review, the researchers found that possible side effects were not always reported. In part, this may be due to the general tolerability of raltegravir. In 61 cases, the doctors noted that there were no side effects experienced by the mother.

According to the reviewers, “the only consistently reported maternal adverse effect was a reversible and [temporary] increase in liver [enzyme levels in the blood].”

The researchers noted that in HIV-positive adults who are not pregnant and who have used raltegravir, about 3% develop elevated levels of the liver enzymes AST and/or ALT in their blood. This problem resolves when raltegravir is discontinued.

Side effects—in infants

According to the reviewers, “most infants were born without adverse outcomes.” Furthermore, even when adverse effects occurred, the researchers found that “there was no consistency among type or severity” associated with them. Thus, they did not appear to be related to the use of raltegravir.

The reviewers also made this statement:

“Our review of the prospective clinical studies, case reports and case series did not reveal any potential newborn safety issues.” However, due to the relatively small numbers of cases reviewed, researchers cannot be certain of raltegravir’s safety for infants whose mothers used the drug. Such information will come from clinical trials underway (more about those later).

Suppressing HIV

A key part of reducing the risk of HIV transmission from mother to child is to reduce the mother’s viral load. Regimens that contain integrase inhibitors can do this relatively quickly. In their review, the Canadian researchers found that the fastest rate of viral load decline with a raltegravir-based regimen was 1.2 log in about seven days. They noted that the ability to take raltegravir every day exactly as prescribed may be a factor in the rate and amount of decline in viral load. For instance, in one report, healthcare workers observed the ART-taking habits of three HIV-positive pregnant women. In all three cases, viral loads declined substantially—by 2 logs.

Raltegravir—changes in pregnancy

Pregnancy causes temporary and complex changes to the body. In addition to the obvious increase in weight, pregnancy can increase inflammation and alter the activity of enzymes that process drugs. It is therefore important to conduct studies that assess the level of critical medicines at different stages of pregnancy.

Two studies have found that the concentration of raltegravir decreases during the course of pregnancy. It was lowest during the final trimester of pregnancy. Despite this finding, the Canadian researchers asserted that most women in their review had an undetectable viral load when they gave birth and mother-to-child transmission was not detected.

They noted that current HIV treatment guidelines do not see the need for assessing the level of raltegravir in the blood of pregnant women except in “high-risk clinical scenarios such as persistently detectable viral load at [the 36th week of pregnancy].”

The research that is needed

In the history of HIV treatment, integrase inhibitors are relatively new and evaluating their safety and effectiveness during pregnancy was not part of the initial studies of these drugs. However, there are at least three studies underway in France, Brazil, the U.S., Argentina and Thailand that are evaluating a raltegravir-based regimen in HIV-positive pregnant women. When these studies are completed in several years, the resulting data will provide important additional information about the safety and effectiveness of raltegravir in pregnancy.

The present review provides a timely and helpful analysis for doctors, nurses and pharmacists when counselling HIV-positive pregnant women.

Resources

Society of Obstetricians and Gynaecologists of Canada

Canadian HIV Pregnancy Planning Guidelines

Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States – U.S. Department of Health and Human Services

Information for Women who are Diagnosed with HIV during Pregnancy – Women’s College Hospital

Pregnancy Planning Information for HIV+ Women and Their Partners – Women’s College Hospital

Information for HIV+ New Moms – Women’s College Hospital

Pregnancy Planning Information for HIV+ Men and Their Partners – Women’s College Hospital

American Academy of Pediatrics issues statement on infant feeding and HIV transmission ­– CATIE News

Prevention of vertical HIV transmission and management of the HIV-exposed infant in Canada in 2014 – Canadian Paediatric and Perinatal AIDS Research Group

—Sean R. Hosein

REFERENCE:

Maliakkal A, Walmsley S, Tseng A, et al. A review of the efficacy, safety and pharmacokinetics of raltegravir in pregnancy. Journal of Acquired Immune Deficiency Syndromes. 2016; in press.