We thank Dr. Fowler and colleagues for taking the time to consider and comment on our BMJ Rapid Recommendation (1). They speculate on reasons why tenofovir and emtricitabine increased the risk of neonatal mortality and early preterm delivery in their trial (2) and then say that the current evidence does not support a recommendation for alternative NRTIs over a tenofovir-based antiretroviral therapy (ART) regimen. We do agree that most, but not all, of the evidence comes from a single study, which may have overestimated harm. Our systematic review attempted to generate the current best evidence, and is not definitive: it is moderate-to-low quality for key outcomes (3). However, we disagree with the implication that based on this evidence, most women would choose a tenofovir-based ART regimen.
The PROMISE authors suggest that results of the comparison between tenofovir-ART and AZT-ART are untrustworthy because the risk of neonatal death was lower in the AZT-ART arm in the earlier period 1 before the tenofovir-ART arm was introduced (2). However, the difference between the two time-periods in the AZT-ART arm could easily be explained by chance (neonatal mortality 1.4% in period 1 vs. 0.6% in period 2, p=0.39; very preterm delivery 3.4% in period 1 vs. 2.6% in period 2, p=0.60). Regardless, the only reliable comparison between tenofovir-ART and AZT-ART is during period 2 when randomisation to both AZT and tenofovir-based ART occurred. Despite these reservations, we performed sensitivity analyses that included data from the AZT-arm in period 1 before the tenofovir-ART arm was introduced (3). The increased risk of early preterm delivery and stillbirth with tenofovir/emtricitabine remained statistically significant and interpretation does not change when data from period 1 is included. Dr. Fowler and colleagues have also suggested that there may have been “some unknown confounder” wherein tenofovir-ART caused harm during period 2, but would not have been harmful to the participants in period 1 (2, 4). We consider this unlikely. Even if true, no such confounder has been identified and women faced with choosing an ART regimen will not know whether or not tenofovir-ART has the potential for harm in their case.
We agree that when tenofovir and emtricitabine are used in combination with lopinavir/ritonavir, it is possible that the risk is higher than with efavirenz; although it is unlikely that if tenofovir is indeed the ‘culprit’ medication, that there would be no risk at all when combined with efavirenz. Put another way, even if the risk of premature delivery and neonatal death is low with tenofovir/emtricitabine plus efavirenz, based on the available evidence, the risk with AZT/lamivudine plus efavirenz may be even lower.
We did not state that the pathophysiology of stillbirth and early neonatal death are the same. Perinatal mortality has long been a global standard outcome measure of maternal and perinatal healthcare (5) and is likely to be similarly important to women, thus our panel pre-specified that it was appropriate to combine them in our evidence summary.
We agree with their concern regarding the possibility that all combination ART regimens may increase the risk of prematurity (versus no ART or monotherapy), albeit this is uncertain and not the focus of this guidance. Given the unique physiology (and pathophysiologies) of pregnancy, the lack of an understood biological rationale at this stage should neither lead to a definitive conclusion nor reassurance. It remains possible that potential pharmacokinetic interactions, and failing or restoring immune systems are different in pregnancy. These are all good reasons to recognise that work from non-pregnant male and female adults cannot always be applied directly to pregnant women. Instead, these are strong justifications for further pregnancy-specific research. We believe that pregnant women (and their babies) should have an equitable standard of research evidence, and thus disagree that it is unlikely that there will be other randomised trials. It is imperative that further randomised trials are conducted. Regulatory authorities, and perhaps the WHO, have a responsibility to ensure that the appropriate studies are performed by the pharmaceutical industry to ensure that pregnant women are not disadvantaged.
Fowler et al. assert that the available observational evidence should provide reassurance to pregnant women. In this, we believe they are misguided. We reviewed the entirety of the observational evidence, including the single observational study that they cite (6); it cannot provide such assurance. First, even the highest quality observational studies are at high risk of residual confounding (7). Second, none of the studies controlled for all of the most important known confounders, including HIV disease status (CD4 count and viral load), socioeconomic status, and availability and quality of healthcare. Third, the studies were inconsistent with some showing harm with tenofovir and others benefit. Fourth, the results were imprecise with the confidence intervals including a magnitude of harm that almost all women would find important.
We strongly disagree with any implication that most women would be willing to risk the health of their child when other options exist. The decision about which vertical transmission strategy or combination ART regimen to use should rest squarely with each informed woman, based on her own values and preferences. This message was consistent from the linked systematic review on the values and preferences of women living with HIV (8), from the three women living with HIV on the guideline panel, as well as an associated opinion piece written by a woman living with HIV (9). Avoiding death in a newborn child is tremendously important to all or almost all women and even if the increased risk of stillbirth or neonatal mortality is extremely low with tenofovir/emtricitabine, almost all women would choose to use a different regimen. Unless future randomised trials show that tenofovir/emtricitabine is safe, we believe that most fully informed women would choose an alternative. Efforts should be made to share the best available evidence and empower women who are pregnant or might consider pregnancy to choose their medications for themselves rather than a ” one size fits all” approach to HIV treatment.
Reed A.C. Siemieniuk, Graham P. Taylor, Gordon H. Guyatt, Lyubov Lytvyn, Yaping Chang, Paul E. Alexander, Yung Lee, Thomas Agoritsas, Arnaud Merglen, Haresh Kirpalani, Susan Bewley
1. Siemieniuk RA, Lytuyn L, Ming JM et al. Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline. BMJ 2017;358:j3961.
2. Fowler MG, Qin M, Fiscus SA, et al. Benefits and risks of antiretroviral therapy for perinatal prevention. N Engl J Med 2016;375:1726-37.
3. Siemieniuk RA, Foroutan F, Mirza R et al. Antiretroviral therapy for pregnant women living with HIV or hepatitis B: a systematic review and meta-analysis. BMJ Open 207;7:e019022.
4. Peer review of Siemieniuk RA, Foroutan F, Mirza R et al. Antiretroviral therapy for pregnant women living with HIV or hepatitis B: a systematic review and meta-analysis. BMJ Open 207;7:e019022. Available at: http://bmjopen.bmj.com/content/bmjopen/7/9/e019022.reviewer-comments.pdf Accessed October 9, 2017.
5. World Health Organization. “Maternal and perinatal health.” http://www.who.int/maternal_child_adolescent/topics/maternal/maternal_pe... Accessed October 9, 2017.
6. Zash R, Jacobson DL, Diseko M, et al. Comparative Safety of Antiretroviral Treatment Regimens in Pregnancy. JAMA Pediatr. 2017 Oct 2;171(10):e172222.
7. Agoritsas T, Merglen A, Shah ND, O'Donnell M, Guyatt GH. Adjusted Analyses in Studies Addressing Therapy and Harm: Users' Guides to the Medical Literature. JAMA. 2017 Feb 21;317(7):748-759.
8. Lytvyn L, Siemieniuk RA, Dilmitis S, et al. Values and preferences of women living with HIV who are pregnant, postpartum or considering pregnancy on choice of antiretroviral therapy during pregnancy. BMJ Open. 2017 Sep 11;7(9):e019023.
9. Welbourn, A. WHO and the rights of women living with HIV. BMJ Opinion. Available at: http://blogs.bmj.com/bmj/2017/09/11/alice-welbourn-who-and-the-rights-of... Accessed October 9, 2017.
Competing interests: No competing interests