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News Analysis

Dolutegravir Preconception Signal: Time Is Up for Shoddy Surveillance

July 12, 2018

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The news in May 2018 of a potential risk of neural tube defects in infants born to women taking dolutegravir (DTG) at the time of conception sent shockwaves through the HIV community.

But, despite massive global investment, aggressive transition plans -- as well as calls for years for more systematic recording of outcomes when women receive ART in pregnancy -- few prospective birth registrieshave been established in other settings that can refute or confirm this finding.

Meanwhile, women of child-bearing age, whether they intend to become pregnant or not, are being told that they must stick with (or go back to) efavirenz (EFV) -- a drug that, before this news, was in the process of being replaced with DTG.


The Botswana Data

On 18 May 2018, the World Health Organisation (WHO) issued a statement after a potential safety signal with DTG was identified relating to neural tube defects in infants who had been exposed to this antiretroviral at the time of conception.1

The safety signal was found at a preliminary, unscheduled analysis of an ongoing observational study in Botswana. The Tsepamo study is a birth surveillance programme, started after the introduction Option B+ (lifelong ART for all pregnant women) in Botswana. When it was designed, there was still some uncertainty about EFV and birth defects.

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Tsepamo compares birth outcomes with exposure from conception and/or during pregnancy to the most common ART regimens used in the country since 2014. Surveillance is conducted at eight maternity wards in government hospitals, representing about 45% of all births. Data are extracted from all consecutive births at 24 weeks or more gestational age, using obstetric records. Livebirth and stillbirth outcomes in HIV positive are also compared to those in HIV negative women.

Botswana is an ideal setting to do this analysis. There is high HIV prevalence (about 22%), high uptake of ART in pregnancy (about 90%) and the majority of women (over 95%) deliver in a healthcare facility. Due to changes in national guidelines there has been a variety of regimens to compare since the study began. Botswana began using DTG as preferred first-line in May 2016.

The study had previously reported reassuring data (similar to that with EFV) with DTG started during pregnancy.2,3 The most recent figures, published in Lancet Global Health online 4 June 2018, includes 1729 pregnant women who started DTG-based ART and 4593 EFV-based ART in pregnancy.4 The risk for any adverse birth outcome among women on DTG versus EFV was similar: 33-2% vs 35-0%; aRR 0-95 (95% CI 0-88 to 1-03). As was the risk of any severe birth outcome: 10-7% vs 11-3% (95% CI 0-94 0-81 to 1-11).

But adverse pregnancy outcomes among HIV positive women continue to be elevated compared with HIV negative women, despite ART. When these data were released the Tsepamo investigators emphasised that the findings were reassuring but not the whole story. And that birth outcomes with DTG exposure from conception still needed to be evaluated.

The preconception analysis revealed four cases of neural tube defects (spina bifida, anencephaly, encephalocele/iniencephaly) out of 426 births to women who became pregnant while taking DTG.

This rate of approximately 0.9% compares with a 0.1% risk of neural tube defects in infants born to women taking other ARVs at the time of conception.


Confusing Communications

WHO's May statement was followed by several others, including from US President's Emergency Plan for AIDS Relief (PEPFAR), US Food and Drug Administration (FDA), European Medicines Agency (EMA), US Department of Health and Human Services (DHHS), as well as a Dear doctor letter from ViiV Healthcare.5-9 The recommendations suggest varying degrees of caution.

The WHO statement advises that pregnant women who are already taking DTG should not stop ART and should speak with their health provider for additional guidance. For women of childbearing age starting ART, including pregnant women, it says, treatment should be based on drugs for which adequate efficacy and safety data are available; an EFV-based regimen is a safe and effective first-line regimen. DTG might be considered in cases where consistent contraception can be assured (if other first-line ART cannot be used in women of childbearing age).

PEPFAR encourages countries to continue with their transition to tenofovir disoproxil fumarate, lamivudine, and DTG (TLD), but states that transition times might be altered to allow for the use of EFV-based regimens for certain women. Until further data are available, it recommends that women with HIV who wish to become pregnant should take EFV-based regimens. Any mention of contraception for women who do not wish to become pregnant is notable by its absence.

The EMA advises avoiding DTG for women who are trying to become pregnant and contraceptive use for those who are not. But they add that if pregnancy is confirmed in the first trimester while a woman is taking DTG, switch to an alternative treatment unless there is no suitable alternative. This last recommendation seems a little overcautious, unless the pregnancy is recognised extremely early, given that the risk window for neural tube defects is 0-28 days. Both the Southern African Clinicians Society and the British HIV Association (BHIVA) have also taken this approach.10,11

Many low- and middle-income countries have already begun to transition (or are in the process of transitioning) to DTG-based regimens and are reviewing their policies based on this new information. It appears that several countries are taking a conservative approach and giving all women of reproductive age EFV-based first-line irrespective of their circumstances. The Kenyan Ministry of Health has pretty much banned DTG for women aged 15-49.12

WHO is working with many stakeholders worldwide to follow pregnant women with preconception DTG exposure to ensure more information is available to inform countries' recommendations.13


Data From Clinical Trials

New antiretrovirals are usually introduced with major gaps in information on their safety in pregnancy.14,15 In low- and middle-income countries women of child-bearing age make up nearly half (44%) of the population who are on ART, or need to be so, and might become pregnant.16

Typically, pregnant women are excluded from registration and strategic trials of new drugs and even data from non-pregnant women are scant when approval is sought or a drug is recently approved. See Table 1 for numbers of women in DTG registrational and post marketing studies.


Table 1: Number of Women in ViiV Dolutegravir Studies
StudyDesignResultsWomen DTG arm (n)
SINGLE

Phase 3

DTG + ABC/3TC vs

EFV/TDF/FTC

833 ART naive participants

144 weeks

DTG arm superior (driven by lower rate of discontinuation) 67
SPRING-2 Phase 3

2NRTI + DTG vs

2NRTI + RAL

822 ART naive participants

96 weeks

DTG non-inferior 63
FLAMINGO Phase 3b

2NRTI + DTG vs

2NRTI + DRV/r

484 ART naive participants

96 weeks

DTG superior 31
SAILING Phase 3

OB + DTG vs OB + RAL

719 treatment experienced participants

48 weeks

DTG superior 107
STRIIVING Phase 3b

2NRTI/DTG vs current ART

551 suppressed participants, switch

24 weeks

DTG non-inferior 77
SWORD 1+2 Phase 3

RPV + DTG vs current ART

1024 suppressed participants, switch

48 weeks

DTG + RPV non-inferior 120
ARIA Phase 3b

DTG/ABC/3TC vs

ATV/r + TDF/FTC

495 treatment naive women

48 weeks

DTG non-inferior 250
DAWNING Phase 3b

2NRTI + DTG vs2NRTI + LPV/r

627 experienced participants

48 weeks

DTG superior

Week 24 data and large subsets from weeks 36 and 48

116
INSPIRING Phase 3b

2NRTI + DTG twice daily vs2NRTI + EFV with RIF-based co-treatment

113 participants

48 weeks

DTG 50 mg twice daily with RIF safe + effective at 24 weeks 36
TOTAL 867

Key: ABC, abacavir; ART, antiretroviral treatment; ARV, antiretroviral; ATV/r, atazanavir/ritonavir; DTG, dolutegravir; DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; NRTI, nucleos/tide reverse transcriptase inhibitor; OB, optimised background; RAL, raltegravir; RIF, rifampicin; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; VL, viral load; 3TC, lamivudine


There are data from a few women who became pregnant in DTG phase 3 trials and post marketing but these are not in sufficient numbers to pick up a rare adverse event such as a neural tube defect, nor have a comparator.17-19

Preclinical safety data did not show developmental toxic effects or teratogenicity -- although these categories are no longer used, DTG is FDA category B.20,21

In their excellent soon-to-be-published tour de force, HIV treatment in pregnancy, Bailey et al raise the important question of whether more regulatory push is needed to make sure that pharmaceutical companies expedite appropriate studies to generate pregnancy data (similar to that for paediatrics).16

Beyond regulatory trials, strategy trials of new drugs should also follow up women who become pregnant within the study remaining on the study drug unless there is a good reason not to.22

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Dolutegravir: Need to Consider All Pros and Cons Before Switching in Pregnancy
Why the Dolutegravir Pregnancy Warning Is Important -- and What We Should Do Now



This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
 

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