In Canada and other high-income countries much progress has been made in reducing the risk of HIV transmission from mother to child over the past several decades. According to the Canadian Perinatal HIV Surveillance Program, mother to child transmission of HIV is extremely rare in Canada today.
A key part of reducing this risk is to significantly reduce the amount of HIV (the viral load) in the mother’s blood as early as possible in the course of pregnancy so that it becomes as low as possible and stays that way. This is why potent combination anti-HIV therapy (commonly called ART) plays an essential role in helping to reduce the spread of HIV from mother to child. By using a series of steps outlined below, the risk of mother-to-child HIV transmission can be reduced to less than 1%:
- counselling with a doctor about pregnancy planning
- HIV testing and counselling before pregnancy
- the use of ART during pregnancy so that the mother’s viral load is less than 50 copies/ml
- regular visits to a clinic for care and advice during pregnancy
- the use of intravenous AZT and, if medically necessary, sometimes the use of additional medicines for the mother during the birthing process as recommended by Canadian guidelines
- giving birth via Caesarean section (if medically necessary)
- giving the newborn a short course of anti-HIV medicines for further protection
- using formula and not breastfeeding, as HIV can be spread via breast milk
- not pre-chewing food for the baby when solids are introduced. Adults who have both HIV and oral infections can inadvertently cause a small amount of blood to leak and be present in the food that they chew. This blood can contain HIV, and if the pre-chewed food is fed to the infant, it could transmit HIV.
According to doctors in the U.S., “Despite massive public health efforts…[the spread of HIV from mother to child] still occurs, often among women who [seek] care late in pregnancy with a high viral load due to drug resistance issues, [not taking ART every day as directed], or late entry into HIV care.”
In cases when a pregnant woman has a high HIV viral load close to when she is due to give birth, doctors and nurses have few options to minimize the risk of infection for the infant:
- planning surgery to deliver the baby (a Caesarean section, or C-section)
- considering changing the mother’s ART so that the viral load can decrease
Enter integrase inhibitors
Integrase inhibitors are a class of anti-HIV medicines that when used as part of ART can quickly reduce viral load compared to ART that does not contain integrase inhibitors. Examples of integrase inhibitors are as follows:
- raltegravir (Isentress)
- dolutegravir (Tivicay and in Triumeq)
- elvitegravir (Stribild and in Genvoya)
Doctors at 11 major hospital-based clinics across the U.S. reviewed data collected from pregnant HIV-positive women, comparing their use of ART that did or did not contain integrase inhibitors. The doctors found that regimens containing integrase inhibitors could reduce viral loads by tenfold (one log) in as short as one week. In contrast, regimens that did not contain integrase inhibitors took longer—between three to six weeks—to have a similar effect on viral load.
The study doctors therefore underscore the potential of integrase inhibitor–based ART to play an important role in reducing viral loads in women who seek care late in the course of their pregnancy.
Study details
The doctors reviewed data from each clinic’s database. This data was collected between July 2009 and July 2015. In total, data from 101 HIV-positive pregnant women were reviewed.
Their average profile upon entering the study was as follows:
- age – 27 years
- months pregnant – seven
- proportion not taking ART – 76%
- lowest CD4+ count during pregnancy – 276 cells/mm3
- initial HIV viral load – 16,000 copies/mL
- proportion with an AIDS diagnosis – 43%
- hepatitis B virus co-infection – 5%
- hepatitis C virus co-infection – 10%
- engaged in substance use – 19%
- diagnosed with depression and/or other mental health conditions – 28%
Results—Starting ART
Among the 101 HIV-positive pregnant women, 76% were not taking ART at the start of the study. However, once in the study, some of the regimens used were as follows:
- integrase inhibitor and two nukes (nucleoside analogues)
- integrase inhibitor and two nukes and a boosted protease inhibitor (this latter concept is explained later)
Among the 24% of women who were taking ART at the beginning of the study, most were taking a regimen based on a boosted protease inhibitor. Use of the class of drugs called protease inhibitors today requires that they be taken with a small dose of another drug, either ritonavir (Norvir) or cobicistat. These two drugs cause the level of a protease inhibitor to rise and remain elevated, allowing for once-daily dosing. Commonly used boosted protease inhibitors in HIV-positive pregnant women in high-income countries today include the following:
- darunavir (Prezista)
- atazanavir (Reyataz)
- lopinavir + ritonavir (Kaletra)
In addition to their boosted protease inhibitor, these women also took two nukes.
Other women took the fixed-dose combination sold as Complera, which contains the following medicines:
- rilpivirine + tenofovir + FTC
Changes to treatment
During the course of the study, 18 women changed their regimens entirely. In most cases, the women changed to a regimen based on an integrase inhibitor.
In the case of seven other women, all added an integrase inhibitor (raltegravir or dolutegravir) to intensify the anti-HIV activity of their existing regimen.
At and after birth
The average time between either initiation of ART or intensification of ART and giving birth was two months.
Most (85%) of the women who began or changed ART during the study had their viral load fall at least tenfold (one log), according to the last blood test that was performed before they gave birth. In only 35% of participants in this study were viral loads less than 40 copies/mL (the lower limit at which viral loads could be accurately counted) before the women gave birth.
There were no reports of abnormal blood tests or complications in the women caused by ART. There were very few apparent birth defects. As this study was small and not designed to assess potential birth defects, we cannot be certain about the cause of such defects.
One baby was diagnosed with HIV infection using tests that sought and identified HIV’s genetic material in the baby’s blood after birth. The baby’s mother was diagnosed with HIV during pregnancy. She also suffered from depression. Her initial regimen was Kaletra + AZT + 3TC, which was initiated when she was already 31 weeks pregnant. Just prior to initiating ART, her viral load was about 22,000 copies/mL. Her next viral load test, done when she was 37 weeks pregnant, was 2,171 copies/mL. She also had an active genital herpes virus infection. At 37 weeks doctors performed a C-section to deliver the baby. However, they think that the baby was infected earlier in the course of pregnancy.
Focus on dolutegravir
The newest integrase inhibitor is dolutegravir. As it is relatively new compared to raltegravir, doctors are interested in the impact of dolutegravir on pregnancy outcomes—successful prevention of HIV transmission, the overall health of the infant and any possible signals of birth defects. However, in small studies (such as the present one) there is little statistical ability to assess the cause of potential birth defects (which are generally rare).
In the present study, only four women used the following three dolutegravir-based regimens:
- dolutegravir + darunavir (Prezista) + low-dose ritonavir + tenofovir + FTC
- dolutegravir + atazanavir + low-dose ritonavir + tenofovir + FTC
- dolutegravir + tenofovir + FTC
According to the doctors, initiation of ART in these four women occurred late in their final three months of pregnancy. No side effects in the mothers were reported and no babies were born infected with HIV.
At the recent Conference on Retroviruses and Opportunistic Infections (CROI), researchers from the U.S. presented preliminary data on the safety of dolutegravir in pregnant women and their babies. Readers should note that the information we are about to report is preliminary, emerges from an ongoing study, and treatments were not randomly allocated. Therefore, all of these factors make drawing robust conclusions about dolutegravir’s safety difficult. An ongoing trial called IMPAACT 1026s enrolled 21 HIV-positive mothers who were or are using dolutegravir-based regimens. So far data is available on nine infants and four of these have different birth defects. Due to the precautions we have just mentioned, it is not clear if these defects are due to the mother’s exposure to dolutegravir (or other drugs) during pregnancy.
However, what is clear is that much more data about the safety of dolutegravir in pregnancy and on the fetus needs to be collected and analysed. Some of that data may emerge from well-designed studies that are planned or underway, such as dolPHIN1 in Uganda and another study called Aria, which is underway in Canada, the U.S., Argentina, Europe, Mexico, South Africa and Thailand.
Retrospective studies—Caution needed
The design of the present U.S. study on integrase inhibitors is retrospective. That is, doctors reviewed data collected for one purpose and later interpreted it for another purpose. Such study designs can inadvertently lead researchers to draw biased conclusions because of missing data or other factors. Therefore, the findings from retrospective studies are not definitive. However, they are relatively cheap to conduct and are often a useful first step in the process of asking research questions. The findings from a retrospective study can be used to help create a study of a more robust statistical design.
As the present study was relatively small and not randomized, it lacked the statistical ability to analyse the cause of rare events (such as potential birth defects) and could not discriminate between the effectiveness of different integrase inhibitor–based regimens.
However, what the present study does is provide a foundation for designing a future large study of integrase inhibitor–based regimens in pregnant women with HIV.
Issues impacting HIV transmission in pregnancy
In a separate study, doctors in Atlanta, Georgia, performed a review of medical records at a major hospital between 2005 and 2012, They found a series of 27 cases of mother-to-child transmission of HIV. By investigating these cases the doctors found that “24 of 27 transmissions were related to failure in healthcare delivery and uptake.” The doctors noted that specific factors underlying these transmissions very likely included the following factors:
- limited access to pregnancy counselling and care while pregnant
- insufficient HIV testing during pregnancy
- psychological stress
- mental health issues that weakened a woman’s ability to take ART every day exactly as directed, caused a delayed diagnosis of HIV and/or caused late engagement in HIV care
Preventing further transmissions
To prevent further instances of mother-to-child transmission of HIV, the doctors made the following statement:
“Vigilant screening for HIV in pregnancy and resources to support pregnant HIV-infected mothers during pregnancy must be in place to eliminate [mother-to-child transmission of HIV].”
Raltegravir
The U.S doctors encourage other doctors to “be aware of resources and updates to current [HIV treatment guidelines for pregnant women].” Furthermore, the doctors note that the integrase inhibitor raltegravir “is now a preferred agent” for use in combination anti-HIV therapy during pregnancy. So far it is the only integrase inhibitor to have this status conferred upon it by U.S. treatment guidelines.
As raltegravir was the first integrase inhibitor to be approved in high-income countries, doctors have more experience with this integrase inhibitor than they do with the others, including its use in pregnant women. Although it is meant to be taken twice daily, data from clinical trials (as yet unpublished) suggest that a new formulation of this drug under development can be safely taken once a day. However, this new formulation and dosing schedule will need additional study in pregnant women. It is likely that some time in the next two years this new once-daily formulation of raltegravir will become available in Canada and other high-income countries. Our next CATIE News report focuses on research by a Canadian team that has thoroughly assessed information on raltegravir’s safety and effectiveness in pregnant women with HIV.
Acknowledgement
We thank Jason Brophy MD, Children’s Hospital of Eastern Ontario Research Institute, for helpful discussion, research assistance and expert review.
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
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
REFERENCES:
- Rahangdale L, Cates J, Potter J, et al. Integrase inhibitors in late pregnancy and rapid HIV viral load reduction. American Journal of Obstetrics and Gynecology. 2016 Mar;214(3):385.e1-7.
- Mulligan N, Best BM, Capparelli E, et al. Dolutegravir pharmacokinetics in HIV-infected pregnant and postpartum women. Conference on Retroviruses and Opportunistic Infections, February 22 to 25, 2016, Boston, U.S. Abstract 438.
- Camacho-Gonzalez AF, Kingbo MH, Boylan A, et al. Missed opportunities for prevention of mother-to-child transmission in the United States. AIDS. 2015 Jul 31;29(12):1511–-15. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502985/