A review of cases of antiretroviral drug exposure reported
to the Antiretroviral Pregnancy Registry found no cases of neural tube defects
associated with integrase inhibitor exposure at conception or in the first
trimester up to 31 July 2018 in pregnant women followed prospectively. The
Registry held details of 1301 exposures (688 periconception, 150 in the first
trimester and 461 in the second or third trimester), of which 401 were to
dolutegravir, 294 to elvitegravir and 656 to raltegravir. Seven neural tube
defects have been reported to the registry retrospectively (i.e. after birth),
of which five are known to be associated with periconception exposure to
raltegravir or dolutegravir. The study authors say that the number of
pregnancies with periconception exposure reported to date is insufficient to
rule out an increased risk and appealed to healthcare providers to report
details of patients. (Albano)
Another research group attempted to untangle duplicate reports
to various pharmacovigilance databases established by regulatory agencies. They
found 165 cases across four databases containing reports on neural tube defects
in women exposed to antiretrovirals during pregnancy, but eventually
established that only 44 separate neural tube defects had been reported, with
no information on the total number of exposures of pregnant women (the
denominator). Andrew Hill and colleagues warned that current pharmacovigilance
databases are not a reliable mechanism for monitoring the risk of neural tube
defects and that prospective studies like the Tsepamo study of dolutegravir
introduction in Botswana are needed for a wide range of antiretrovirals. Pregnant
women should also be recruited into phase 3 licensing studies wherever possible, they say.
(Hill)
Lynn Mofenson warned that surveillance data on birth defects
must be treated carefully. Studies come from many different sources including
randomised trials, case reports, observational studies and registries. Each of
these sources has its own recruitment and treatment assignment biases,
which may exaggerate or underestimate the risk. Registries of birth defects
lack information on the total number of women exposed to the drug, and across
the board, there is difficulty in distinguishing between cases that occur associated
with exposure at conception or in the first trimester. In the case of neural
tube defects, it is important to know whether the case occurred in a country where
food is fortified with folate or where supplementation takes place, and to know
the background rate in the population. Lynn Mofenson pointed out that of the
174 cases of dolutegravir exposure reported to the Antiretroviral Pregnancy
Registry, most are from countries where food is fortified with folate, which reduces
the prevalence of neural tube defects.
She noted that the median prevalence of neural tube defects
in the general population in eight African countries was 0.12%, which is
similar to the level seen in the Ugandan study presented at CROI (see above).
In that study, the prevalence in infants born to mothers with HIV was 0.07%, in
line with the prevalence reported in Botswana in infants exposed to antiretrovirals
other than dolutegravir.
Further data from the Tsepamo study will be available later
in 2019 when data on at least 1400 pregnancy outcomes should be available. If
no new defects are reported in that study, the statistical likelihood is that
dolutegravir is not associated with an increased risk of neural tube defects.
But if additional cases are reported it will become necessary to accumulate
data on the outcomes of many more pregnancies – up to 2500 according to modelling
published last year – before researchers can advise that dolutegravir does not
increase the risk of neural tube defects.