There are fears that dolutegravir, which is prescribed as a first line core-agent to treat newly diagnosed HIV patients in Botswana may be causing birth defects involving the brain, spine and spinal cord.
Preliminary data from a study in Botswana found four cases of neural tube defects (NTDs), such as spina bifida, in babies born to mothers who became pregnant while taking the drug. Spina bifida is a congenital defect of the spine in which part of the spinal cord and its meninges are exposed through a gap in the backbone. It often causes paralysis of the lower limbs, and sometimes learning difficulties. The FDA issued an alert on Friday about serious cases of neural tube birth defects involving the brain, spine and spinal cord that have been reported in babies born to women treated with dolutegravir used to treat HIV. Europe’s medicines regulator has also issued a statement that it was assessing evidence that GlaxoSmithKline’s successful HIV drug might be linked to birth defects, adding it should not be prescribed to women seeking to become pregnant. GSK said on Friday that it was notifying doctors of the issue and working with healthcare authorities to better understand the potential risk. Approved by the FDA in 2013, dolutegravir has been on the market for five years, and is available as a single-ingredient product under the brand name Tivicay (ViiV Healthcare) and as a fixed-dose combination tablet with other HIV medicines under the brand names Juluca and Triumeq.
Botswana two years ago became the first country in Africa to introduce dolutegravir which was hailed as the magic pill. There were however concerns over the secrecy surrounding the deal between suppliers of the wonder drug ViiV Healthcare and the Ministry of Health. The Botswana government’s agreement with ViiV Healthcare is classified. ViiV which is a global specialist HIV company is a subsidiary of GlaxoSmithKline (GSK), one of the world’s leading research-based pharmaceutical and healthcare companies. Since its launch in 2016, the drug has been used in Botswana’s HIV/AIDS ‘treat all’ campaign. The target was 100 thousand people. This is everybody who is infected with HIV but yet not on any treatment.
Dolutegravir is an FDA-approved antiretroviral therapy used with other antiretrovirals to treat HIV. Dolutegravir works by blocking integrase, an HIV enzyme, to prevent the virus from multiplying, and can reduce the viral load.
The FDA however issued a statement this week that, “health care professionals should inform women of childbearing age about the potential risk for neural tube defects when a dolutegravir-containing regimen is used at the time of conception and early in pregnancy. In addition: Health care professionals should weigh the benefits and the risks of dolutegravir when prescribing antiretroviral medicines to women of childbearing age; Alternative antiretroviral medicines should be considered. Discuss the relative risks and benefits of appropriate alternative antiretroviral therapies; If the decision is made to use dolutegravir in women of childbearing age, health care professionals should reinforce the consistent use of effective birth control; .Perform pregnancy testing before initiating a dolutegravir-containing regimen in women of childbearing age to exclude pregnancy.”
FDA further stated that “ongoing monitoring will continue as part of the observational study in Botswana. Additional birth outcomes are projected from pregnant women who were exposed to dolutegravir at the time of becoming pregnant. The FDA will conduct a comprehensive review of the results and any other data that become available.”
Dolutegravir (Tivicay) is an integrase strand transfer inhibitor (INSTI) for use in combination with other antiretroviral agents for the treatment of HIV. Integrase inhibitors block HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. The agreement is considered the largest tender ever secured by ViiV Healthcare in sub- Saharan Africa, a region particularly impacted by the HIV epidemic. As part of the agreement, ViiV Healthcare committed to providing dolutegravir 50mg. The medicine would be used as a first line core-agent to treat newly diagnosed patients tested under the programme in Botswana.
The high costs of the drug has been subsidised by the President’s Emergency Plan for AIDS Relief (PEPFAR) which is a US government initiative to address the global HIV/AIDS epidemic.
GSK said it was notifying doctors of the issue and working with healthcare authorities to better understand the potential risk.
“There is no known mechanism linking dolutegravir with these types of birth defects and there are no relevant findings in pre-clinical studies,” GSK said in a statement.
“Animal models are generally predictive of drug-induced birth defects and it is very unusual to see an effect in humans if no evidence is observed in animal models.”
The World Health Organisation already advises against using the drug during pregnancy or breast-feeding due to insufficient safety and efficacy data in this population, and this guidance remains unchanged.
The role of dolutegravir in the four birth defects in Botswana has yet to be established, since NTDs are also associated with risk factors like folic acid deficiency and obesity.