Dolutegravir: need to consider all pros and cons before switching in pregnancy
Polly Clayden, HIV i-Base
A young pregnant woman who switched from dolutegravir (DTG)-based ART, in response to the neural tube defect safety signal, experienced viral rebound on her new regimen. She needed to be switched back to DTG to achieve re-suppression and prevent vertical transmission.
This case study reported in a letter to the Journal of Virus Eradication by doctors from the Imperial College NHS Trust illustrates the complexity of managing women in early stages of pregnancy presenting on a DTG-based regimen, and the need for careful consideration when responding to new data.
A young woman taking a fixed dose combination (FDC) of DTG, lamivudine (3TC) and abacavir (ABC) visited the HIV clinic with an unplanned five-week pregnancy – according to her dates.
At the visit her results were good: CD4 count was 848 cells/mm3, CD4:CD8 ratio 0.5 and viral load <20 copies/mL.
She had been diagnosed at six years of age. She had a long history of poor adherence and in 2016 presented with disseminated mycobacterium avium intracellulare and a nadir CD4 count of 5 cells/mm3.
Despite antimicrobial therapy and excellent immune reconstitution on DTG-based ART, her recovery was complicated by bilateral hearing loss that needed augmentation.
A few days before, the increased rate of neural tube defects in infants conceived on DTG in the Botswana cohort was reported. Four out of 426 infants with these defects gave a rate 0.9% compared to an expected rate of 0.1%.
The statement from the European Medicines Agency (EMA) that followed the Botswana data recommended: “If pregnancy is confirmed in the first trimester while a woman is taking dolutegravir, switch to an alternative treatment unless there is no suitable alternative”.
After discussions with the young woman and her supporter, she switched to darunavir/ritonavir (DRV/r) + ABC/3TC and received additional folic acid. The authors noted that concerns with adherence and previous resistance mutations, favoured a boosted protease inhibitor regimen over raltegravir (RAL) or efavirenz (EFV)-based ART.
At follow up, she reported difficulties with adherence, nausea and tiredness. Despite 16 months with undetectable viral load on DTG-based ART, only 21 days following the switch her viral load was 1,505,162 copies/mL and her CD4 count had dropped to 242 cells/mm3 and CD4:CD8 ratio was 0.2.
A week later she switched back to the DTG-based FDC at 10 weeks’ gestation. Her CD4 count was now 161 cells/mm3 and she needed to restart Pneumocystis jirovecii pneumonia prophlaxis.
At the time the letter was published, she continued to be followed up fortnightly until she regained viral suppression.
The authors note that this case highlights the current complexities of managing women in the early stages of pregnancy presenting on DTG-based regimens. Particularly among those with a history of poor adherence and outcomes of treatment switches, that increase both pill burden and potential toxicity.
By five weeks’ gestation, the foetal neural tube is already closed raising the question of benefit of switching after this time.
“When responding to new data, there is an important decision to be made, between the potential, uncertain risk of teratogenicity against the potential increased risk of in uterovertical transmission of HIV”, the authors wrote.
The challenge she has now is to achieve undetectable viral load before delivery to prevent vertical transmission. This is complex for a young woman who has struggled with adherence and now has the added anxiety that ART might harm her unborn child. ‘In retrospect perhaps there was no ‘suitable alternative’ the authors conclude.
The recommendation by EMA, as well as BHIVA, that women who conceive on DTG should switch in the in the first trimester seems over cautious beyond the very early window of risk of 0–28 days, when few pregnancies are confirmed.
Foster C et al. Careful consideration when responding to new data: dolutegravir and pregnancy. J Virus Erad. Published online July 2018.