Dolutegravir (DTG), a new anti-retroviral first line drug, has generated a lot of debate leaving policy-makers in low to middle-income countries divided.
DTG is a preferred drug for inclusion in anti-retroviral therapy regimens given its tolerability, efficacy and high resistance barrier.
DTG has been found to improve and prolong lives of millions of people living with HIV who suffer side-effects and resistance to treatment.
However, a recent safety concern of excess neural tube defects in infants born to mothers who conceived while on DTG has been reported.
Data from the Tsepamo study in Botswana indicates that 0,9 percent of babies (four of 426) who were exposed to DTG had neural tube defects compared with 0,1 percent (14 of 11 173) who were exposed to other HIV medicines during pregnancy.
WHO co-ordinator of treatment and care in the department of HIV/Aids, Dr Meg Doherty, said the warning has caused controversy over the balance between the risks and benefits of DTG-based treatment for women living with HIV and stalled plans to introduce DTG-based treatment in some countries in sub-Saharan Africa.
“The news of potential safety problem and the subsequent guidance from regulatory agencies and WHO has caused some ministries of health in lower and middle-income countries to pause in their plans to implement DTG-based treatment as the preferred first line treatment.
Seven countries have already decided not to offer DTG to women of child-bearing age and six countries have decided to allow women to take DTG only if they are using contraception.
Dr Rebecca Zash of Beth Israel Deaconess Medical Centre, Boston, speaking at the recent 22nd International Aids Conference held in The Netherlands, stressed that the results are a preliminary safety signal and require further follow-up.
“The findings from the Botswana surveillance study, led to safety warnings. Many health agencies warned that women living with HIV who can become pregnant shouldn’t use integrase inhibitor DTG without effective contraception,” said Dr Zash.
“Subsequent WHO treatment guidelines stress the importance of consistent and reliable contraception if women of child-bearing potential opt to take the drug.”
Updated WHO guidelines advise DTG as a preferred drug in first line and an option in second line and third line ART.
“It is advised that women of child-bearing potential who do not currently want to become pregnant can receive DTG together with consistent and reliable contraception,” reads part of the guidelines. A neural tube defect occurs when the spinal cord, brain and related structures do not form properly and it develops between two and eight weeks of gestation.
The most common cause of neural tube defects is lack of folic acid during pregnancy but defects can also be caused by some medications. Health and Child Care Ministry director of Aids and TB, Dr Owen Mugurungi, said numerous clinical trials showed DTG to be superior to all other first-line treatments.
“New regimens including DTG offer great potential for better and less costly HIV treatment,” he explained.
“DTG has been the drug of choice for the last two years for people living with HIV in high-income countries as it has very few side effects, is easier to take than currently used formulations (one small tablet taken daily) and patients are less likely to develop resistance. These are important developments as we move towards HIV treatment for all in need.”
More than 18 million people are on life-long HIV treatment worldwide, and an almost equal number do not have access to treatment yet.
In Zimbabwe, approximately 1,4 million people are living with HIV, of which 86 percent are on ARVs. In Africa, Kenya was the first country to introduce the generic version of DTG for routine use.
Health experts, however, emphasise that until further data is available, caution should be exercised to avoid conception occurring in women taking DTG.
They also posit that women should be engaged in decision-making regarding ART choices while being provided with information of the risks and benefits of DTG, and ready access to reliable and effective contraception.
“DTG as a product compared to others is cheaper to manufacture and when this product is taken to scale, there will be incredible savings to health programmes,” added Dr Mugurungi.
Approximately, 1,5 million women living with HIV become pregnant each year, 90 percent of whom live in resource-poor settings and continue to present late in their pregnancy with untreated HIV.
Ms Martha Akello, communications officer at International Community of Women Living with HIV Eastern Africa, told the Amsterdam conference that: “With regards to DTG-based treatment, we want to exercise choice. This isn’t a one dress fits all situation.”
Starting ART in the third trimester is associated with failure to achieve viral suppression by delivery, which is critical for prevention of mother-to-child transmission. DTG treatment at the time of conception is associated with a higher risk of neural tube defects in infants exposed to the drug when compared to Efavirenz.
“The risk of neural tube defects is highest at the time of conception and in the first trimester of pregnancy, so it’s important to rule out any harmful effects of drugs taken at this time,” Dr Mugurungi explained.
A modelling study presented by Dr Caitlin Dugdale of Massachusetts General Hospital showed that avoiding use of DTG in women of child-bearing age carried more risks than neural tube defects.
“. . . assuming DTG is more effective than Efavirenz in suppressing viral load and assuming that neural tube defects occur at a similar prevalence to that reported in the Tsepamo study and other studies of Efavirenz, DTG would save 24 400 more adult lives than Efavirenz, prevent 52 800 more cases of sexual transmission and prevent 5 000 more infant infections than Efavirenz.
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