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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 r...
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.
To the BMJ Editor:
A recent analysis in BMJ Open accompanied by a clinical practice guideline on antiretroviral therapy (ART) in pregnant women living with HIV by Siemieniuk et al has concluded that “tenofovir/emtricitabine is likely to increase stillbirth/early neonatal death and early premature delivery compared with zidovudine/lamivudine” (1,2). While the clinical practice guideline was based on a systematic review, in reality, the conclusion was based solely on results of the PROMISE study (3). Evidence from large observational studies did not support this recommendation, but was viewed as too low quality to consider in making recommendations. As coauthors of the PROMISE study, we would like to comment on the authors’ conclusion.
The objective of the PROMISE trial was to compare the efficacy of zidovudine/single-dose nevirapine (AZT-alone) with protease inhibitor-based (lopinavir-ritonavir) combination ART (AZT-based ART [AZT-ART] or tenofovir-based ART [TDF-ART]) to prevent mother-to-child transmission in women with CD4 cell count >350 cells/mm3 (3).The study enrolled during two periods, and the comparisons of the TDF-ART arm to the other arms are restricted to the women who were concomitantly randomized among the three study arms, which occurred only in the second period of the study. In Period 1 – accounting for about two-thirds of enrollment - only hepatitis B virus (HBV)-coinfected women (~1% of overall enrollment) were randomized to TDF-ART vs...
The objective of the PROMISE trial was to compare the efficacy of zidovudine/single-dose nevirapine (AZT-alone) with protease inhibitor-based (lopinavir-ritonavir) combination ART (AZT-based ART [AZT-ART] or tenofovir-based ART [TDF-ART]) to prevent mother-to-child transmission in women with CD4 cell count >350 cells/mm3 (3).The study enrolled during two periods, and the comparisons of the TDF-ART arm to the other arms are restricted to the women who were concomitantly randomized among the three study arms, which occurred only in the second period of the study. In Period 1 – accounting for about two-thirds of enrollment - only hepatitis B virus (HBV)-coinfected women (~1% of overall enrollment) were randomized to TDF-ART vs AZT-ART vs AZT-alone. It was only in Period 2, enrolling 35% of the overall population, that all women, regardless of HBV status, were randomized to one of the three arms. Comparisons of TDF-ART with AZT-ART or AZT-alone were therefore restricted to this second period of time.
PROMISE did not analyze stillbirth in combination with early neonatal death. Contrary to the authors’ statement, the pathophysiology of stillbirth and early neonatal death are not necessarily the same and hence the PROMISE team did not feel it was appropriate to combine these endpoints. It is important to note that the rates of spontaneous abortion and stillbirth were not significantly different between AZT alone, AZT-ART and TDF-ART arms (Table 1). In their meta-analysis, the authors combined data on stillbirth/early infant death from two hepatitis B mono-infection studies (Pan and Wang) which had very few events and did not include HIV-infected pregnant women. The only two events in the HBV studies were from the Pan study: 1 stillbirth in the TDF-alone group in a woman who had a prior stillbirth, and one full-term newborn delivered with the use of forceps from a mother in the TDF-alone group who had declined a cesarean section and died on day 2 from intracerebral hemorrhage and aspiration pneumonia.
The PROMISE team noted that both the AZT-ART and TDF-ART regimens were associated with increased preterm delivery <37 weeks compared to the AZT-alone arm (Table 1); the rate of preterm delivery <37 weeks during Period 2 was not significantly different between AZT-ART and TDF-ART arms (p=0.77). It was only in the evaluation of very preterm delivery (<34 weeks) that a difference in ART arms was observed, with a higher rate of very preterm delivery observed in the TDF-ART compared to AZT-ART arm (p=0.04), although the TDF-ART very preterm delivery rate was not significantly different than AZT-alone arm (p=0.10) (Table 1). This would suggest that both ART regimens may be associated with prematurity, with AZT-ART increasing preterm delivery between 34-36 weeks and TDF-ART possibly increasing very preterm delivery <34 weeks. Given the lack of a biologic rationale for this difference and the small number of very preterm delivery events, the PROMISE team was not willing to draw a definitive conclusion from these data.
The PROMISE team noted in the manuscript discussion that there was an imbalance in the neonatal deaths occurring during Period 1 and 2 in the AZT-ART group: 15 of 17 deaths, 88%, occurred during Period 1, and only 2 (12%) during Period 2, the time of comparison with TDF-ART (Table 1). This resulted in a very low rate of neonatal mortality in AZT-ART group during period 2. In contrast, in the AZT-alone comparison group, 39% of neonatal deaths (11/28) occurred during Period 1 and 61% during Period 2. Consequently, the AZT-ART group appears to have a very low rate of infant mortality during Period 2 (0.6%), the time it was compared to TDF-ART; this is supported by the fact that neonatal mortality was not significantly different between AZT-alone and TDF-ART arms (3.2% vs 4.4%, respectively).
The PROMISE team noted concerns about potential pharmacokinetic interactions between lopinavir and TDF; the BMJ authors dismiss the potential pharmacokinetic interaction as “unlikely”. The concern was about potential increase in tenofovir, not lopinavir levels, even though an increased dose of lopinavir was given in the third trimester in the PROMISE study. The use of the higher lopinavir dose was based on potentially lower levels in late pregnancy with standard dosing in studies in US women (4,5). However, some other studies have not noted a decrease in levels with standard dosing, particularly in Thai women with low body weight (6,7); pharmacokinetic studies have not been done in African women, the group enrolled into PROMISE. In studies of concomitant administration of tenofovir with standard lopinavir dosing (in non-pregnant adults), decreased renal clearance of tenofovir and increased plasma and intracellular levels, particularly in women, have been reported with concomitant administration (8-10). There have not been pharmacokinetic studies of tenofovir given with increased lopinavir dosing. Studies of stored specimens will need to be done to address this issue.
The PROMISE team did not feel it was appropriate to draw definitive conclusions from the study regarding the use of TDF-ART in pregnancy. The team specifically noted that because the study only included protease-inhibitor based ART, one cannot extrapolate data on TDF-ART based on other classes of drugs such as the efavirenz (EFV)-based ART regimen currently recommended in pregnancy by the World Health Organization (11).
While observational data are viewed as lower quality compared to data from randomized trials, the PROMISE team notes that it is unlikely that there will be other randomized trials and that there have been numerous observational studies suggesting the safety of TDF-ART in combination with non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. The BMJ authors state that observational data comparing ART are problematic because AZT-ART regimens are older and clinical practices might have been different than in TDF-ART era. However, a recent study from Botswana compared birth outcomes, including preterm delivery and neonatal death, among HIV-infected women starting 3-drug ART regimens and who delivered between August 2014 and August 2016; hence clinical practice would be the same for all women. Compared with a regimen of TDF-emtricitabine (FTC)-EFV, all other regimens, including AZT-based ART, were associated with higher risk of adverse outcome; increased risk of preterm birth, very preterm birth and neonatal death were observed for infants exposed to AZT-lamivudine (3TC)-lopinavir-ritonavir.
Thus, while the PROMISE team strongly supports further evaluation of the safety of ART regimens in pregnancy for the woman and her infant in order to find the optimal ART regimen, the PROMISE team does not agree that the PROMISE trial results support a recommendation against using a TDF-based ART regimen in pregnancy.
Mary Glenn Fowler MD, MPH, Johns Hopkins University School of Medicine, Baltimore, MD
Lynne Mofenson MD, Elizabeth Glaser Pediatric AIDS Foundation, Washington DC
Pat Flynn MD, St. Jude Children’s Research Hospital, Memphis, TN
Taha Taha MD, Johns Hopkins University School of Public Health, Baltimore, MD
1. 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.
2. Siemieniuk RA, Lytuyn L, Ming JM et al. Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline. BMJ 2017;358:j3961.
3. 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.
4. Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS 2006; 20: 1931-9. 17.
5. Mirochnick M, Best BM, Stek AM, et al. Lopinavir exposure with an increased dose during pregnancy. J Acquir Immune Defic Syndr 2008; 49: 485-91.
6. Calza L, Manfredi R, Trapani F, et al. Lopinavir/ritonavir trough concentrations with the tablet formulation in HIV-1-infected women during the third trimester of pregnancy. Scand J Infect Dis 2012;44:381-7.
7. Cressey TR, Jourdain G, Rawangban B, et al. Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy. AIDS 2010;24:2193-200.
8. Kiser JJ, Carten ML, Aquilante CL, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 2008; 83: 265-72.
9. Kearney BP, Mathias A, Mittan A, Sayre J, Ebrahimi R, Cheng AK. Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir. J Acquir Immune Defic Syndr 2006; 43: 278-83.
10. Pruvost A, Negredo E, Théodoro F, et al. Pilot pharmacokinetic study of human immunodeficiency virus-infected patients receiving tenofovir disoproxil fumarate (TDF): investigation of systemic and intracellular interactions between TDF and abacavir, lamivudine, or lopinavir-ritonavir. Antimicrob Agents Chemother 2009; 53: 1937-43.
11. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection – recommendations for a public health approach, second edition. June 2016; Geneva, Switzerland.
Table 1 Adverse Outcomes in PROMISE by Study Arm
Spontaneous abortion (<20 wks) or stillbirth (>20 wks)
Total, N=3239 in analysis
Total spontaneous abortion/stillbirth, N=95 (2.9%)
Period 1+2, AZT vs AZT-ART comparisons (total events, N=89)
AZT alone: 41/1451 (2.8%)
AZT-ART: 48/1447 (3.3%), AZT alone vs AZT-ART, p=0.45
Period 1, N=2201 (total events, N=78)
AZT alone: 3/1102 (3.0%)
AZT-ART: 45/1099 (4.1%)
Period 2, N=1038, 3 arm comparisons (total events, N=15):
AZT-alone: 8/349 (2.3%)
AZT-ART: 3/348 (0.9%)
TDF-ART: 6/341 (1.6%), AZT alone vs TDF ART, p=0.79; AZT-ART vs TDF-ART, p=034
Total events, N=5
Period 1 (total events 5)
AZT alone: 3 (<0.5%)
AZT-ART: 2 (<0.5%)
Period 2 (total events 0)
AZT alone: 0%
Total events, N=90
AZT alone: 38 (37 singleton, 1 multiple gestation)
AZT-ART: 46 (39 singleton, 7 multiple gestation)
TDF-ART: 6 (6 singleton)
AZT alone: 2.8%
AZT alone: 2.3%
Preterm birth (<37 weeks)
Total with data, N=3152
Total preterm <37 weeks, N=535 (17.0%)
Period 1+2 AZT vs AZT-ART comparisons (total events, N=473)
AZT alone: 185/1411 (13.1%)
AZT-ART: 288/1406 (20.5%), AZT alone vs AZT-ART, p<0.001
Period 1 (total events, N=359)
AZT alone: 139/1070 (13.0%)
AZT-ART: 220/1060 (20.8%)
Period 2, 3 arm comparisons (total events, N=176):
AZT-alone: 46/341 (13.5%)
AZT-ART: 68/346 (19.7%)
TDF-ART: 62/335 (18.5%), AZT alone vs TDF ART, p=0.09; AZT-ART vs TDF-ART, p=0.77
Very Preterm birth (<34 weeks)
Total with data, N=3152
Total very preterm <34 weeks, N=101 (3.2%)
Period 1+2 AZT vs AZT-ART comparisons (total events, N=81)
AZT alone: 37/1411 (2.6%)
AZT-ART: 44/1406 (3.1%), AZT alone vs AZT-ART, p=0.43
Period 1 (total events, N=61)
AZT alone: 26/1070 (2.4%)
AZT-ART: 35/1060 (3.3%)
Period 2, 3 arm comparisons (total events, N=20):
AZT-alone: 11/341 (3.2%)
AZT-ART: 9/346 (2.6%)
TDF-ART: 20/335 (6.0%), AZT alone vs TDF ART, p=0.10; AZT-ART vs TDF-ART, p=0.04
Infant mortality at <14 days1
Overall live births, N=3202
Total infant mortality, N=60 (1.9%)
Period 1+2 AZT vs AZT-ART comparisons (total events, N=45)
AZT alone: 28/1432 (2.0%)
AZT-ART: 17/1419 (1.2%), AZT alone vs AZT-ART, p=0.132
Period 1 (total events, N=32)
AZT alone: 17/1083 (1.6%); 17/28 deaths, 60.7% of deaths occurred in period 1
AZT-ART: 15/1073 (1.4%); 15/17 deaths, 88.2% of deaths occurred in period 1
Period 2, 3 arm comparisons (total events, N=28):
AZT-alone: 11/341 (3.2%); 11/28, 39.3% of deaths occurred in period 2
AZT-ART: 2/346 (0.6%); 2/17 deaths, only 11.8% of deaths occurred in period 2
TDF-ART: 15/341 (4.4%), AZT alone vs TDF ART, p=0.429; AZT-ART vs TDF-ART, p=0.001
1 Reported causes of neonatal mortality were prematurity (n=23), lower respiratory conditions (n=22), unknown causes (n=7), congenital malformations (n=5), sepsis (n=1), vitamin K deficiency (n=1), and persistent pulmonary hypertension of the newborn (n=1).