In 2006, the first single-tablet combination regimen was approved for treating HIV infection. Little did we know that one pill-once a day would become the rule, not the exception. The drug Atripla combined three potent drugs for treating HIV: Efavirenz, Emtricitabine (or FTC) and Tenofovir. Efavirenz (Sustiva) was first approved in 1998 and quickly became one of the most widely used HIV drugs. In 2019, we now have at least 10 fixed-dose-combination tablets available for treating HIV. Most contain three drugs, some contain four (three active drugs and a booster) and some contain only two drugs, all combined into one tablet. They are all dosed once a day.
I remember quite vividly when Atripla was approved. Everyone wanted the ease and simplicity of just one pill once a day. But Everyone wasn’t going to get it. Obviously, there were some patients who had become resistant to either efavirenz, or FTC or tenofovir from previous use and so they would not be eligible for the single-pill combination. It would not work well for them. But a whole group of patients would not be able to take Atripla because of safety concerns. Safety concerns for who? We started a discussion about pregnancy in the last article. There’s good news and bad news.
The good news we discussed last time is that HIV medicines can protect an HIV+ mother from infecting her baby, during gestation, delivery and breast-feeding. The bad news is that some medicines can harm babies during development. Because of this, there are many drugs of all types that are not to be given to pregnant women. Drugs that cause harm to a developing fetus are called teratogens. So while HIV medicines could protect developing babies, we needed to know which ones are teratogens and not use them in pregnant women.
When Efavirenz was released, we had good reason to believe that it was a teratogen, increasing risk for a birth defect that disrupted normal development of the spinal cord . Efavirenz or Atripla would not be given to pregnant women. But since HIV treatment is chronic and life long, there was a concern of women taking the drug and later becoming pregnant while on it. A woman could be switched to a different treatment after becoming pregnant, but they don’t even become aware they are pregnant for several weeks. It is these early weeks of pregnancy when teratogenic drugs are most dangerous to a fetus. Nevertheless, women wanted to have access to this treatment.
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In an effort to protect mothers from harming their developing fetus through the use of Efavirenz or Atripla, we required women of childbearing age to sign a consent committing to using barrier contraception (e.g. condoms, diaphragm). The goal was to not become pregnant while taking it.
But in 2012, a report by the World Health Organization conducted an intensive evaluation of over a decade of birth data and found very little harm with the use of Efavirenz in pregnancy. Wow! It took almost 14 years to show safety. The drug was now recommended for pregnancy and expanded treatment options in developing countries.
So now, the drug Dolutegravir is becoming increasingly available in developing countries. Dolutegravir combined with FTC and tenofovir started being used in the African country of Botswana. HIV+ women giving birth in Botswana were being carefully monitored for birth outcomes. In 2018, there were reports of babies being born to women taking Dolutegravir who developed the same birth defect we thought to be caused by Efavirenz. Initially, there were four babies born with defects out of 426 births.
The rate was low (0.9%) but still about 9 times higher than the normal rate, which is very low (about 0.1% in Botswana). For many clinicians and scientists, this seemed like Deju Vu. We revisited the history with Efavirenz. Was this effect real? What would this mean for HIV treatment in Africa where we desperately needed new, effective treatment options? And why didn’t we see this birth defect in other groups of pregnant women who had received dolutegravir?
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In considering this last question, we must be mindful that supplementation with folic acid during pregnancy is one of the best ways to protect against this type of birth defect, but this is not routinely done in Botswana. Also, as mentioned, this birth defect had not been seen in pregnant women taking dolutegravir in other parts of the world. Alerts were issued to restrict its use, but we really had to wait for more deliveries.
The good news is that more and more babies were being born without the defect. At the International AIDS Society (IAS) conference held July 2019 in Mexico City, it was reported that the rates of this defect had fallen to 5 cases out of 1683 births, or 0.3%, as of spring 2019. This is the rate of defect when dolutegravir was taken during conception and appears more acceptable. If dolutegravir is started later in pregnancy, the rate is even lower.
This reduction in rate, in addition to the fact that this defect has not been seen in other populations make us think that the risk of harm to the fetus from the mother taking Dolutegravir is low. Women who want Dolutegravir during pregnancy now have the green light! This time, we didn’t have to wait over ten years.
Medical professionals and public health officials should always take precautions when we detect a potential problem related to medication safety. Sometimes, it’s a false alarm but we do the best with the information we have. First and foremost, “Do no harm”.
Dr. Crawford has over 25 years of experience in the treatment of HIV. While at Howard University School of Medicine, he worked in two HIV-specialty clinics at Howard University Hospital. He then did clinical research as a visiting scientist with the AIDS Clinical Trials Group (ACTG) at Johns Hopkins University School of Medicine. He served as the Assistant Chief of Public Health Research with the Military HIV Research Program where he managed research studies under the President’s Emergency Plan for AID Relief (PEPFAR) in four African countries.
He is currently working in the Division of AIDS in the National Institutes of Health. He has published research in the leading infectious diseases journals and serves on the Editorial Board of the journal AIDS. Any views and perspectives in his articles on blackdoctor.org are not representative of any agency or organization but a reflection of his personal views.
