Antiretroviral therapy in pregnant women living with HIV: a clinical practice guidelineBMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3961 (Published 11 September 2017) Cite this as: BMJ 2017;358:j3961
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All rapid responses
Authors respond Re: Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline
As authors of the two BMJ Open systematic reviews and the BMJ guideline based on those results, we thank Dr Cohn and colleagues and Dr Gilleece for their separate comments. We refer them to our earlier responses, which answer many of the issues they raise (1,2). In the following, we reiterate key prior points, and address new substantive issues.
We agree that some observational studies did not find a significant association between tenofovir use and stillbirths or neonatal mortality. However, we caution against concluding that tenofovir or emtricitabine (FTC) is safe from these unsystematically selected observational studies. Confounders – both known and unknown – invariably influence observational evidence (3). Both respondents seem to argue that more trust should be placed in the conclusions of three other earlier systematic reviews that did not identify harms while only ours did. The scientific standards of evidence summarization have made enormous advances in the last 30 years; counting up studies while ignoring study design was long ago rejected as a legitimate approach. Our work adheres to these methodologic standards, as noted by the BMJ peer reviewer from the World Health Organisation who stated “I really like their analysis and approach - its beautifully done” and “cannot find flaw with the methodology”.
Two of the reviews to which the authors refer were written by the same investigators who, inappropriately, pooled observational and randomised evidence; the other is outdated. By contrast, the systematic review meta-analysis that informed our recommendation considered the entirety of the observational literature and came to a different conclusion:
“Observational studies reported conflicting results…No study controlled for most of the critical confounders such as socioeconomic status, immune/disease status and cointerventions…the evidence from observational studies is of very low certainty due to the observational design, imprecision, inconsistency and risk of bias.”(4)
Dr. Cohn and colleagues’ points regarding prioritising a reduction in vertical transmission over patient-centred concerns and the impact of market forces do not relate to our patient-centred question about the choice of combination antiretroviral (cART). We are not the only ones who have highlighted the importance of considering women's voices, and human rights, when making public health decisions (5). We do however question their apparent suggestion that it is acceptable for cART options for women and their children to be driven by funding rationales rather than good science and the preferences of the women affected. Moreover, we were surprised to see that they did not disclose any conflicts of interest in their letter: The Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) proudly highlights their “robust partnership” with Gilead Sciences:
“Gilead’s support has been instrumental in helping EGPAF reach more mothers” (6).
Dr. Gilleece suggests that we should have considered evidence from the full recruitment period of the PROMISE trial for the comparison tenofovir/FTC vs. zidovudine (AZT)/lamivudine, despite the fact that tenofovir/FTC was not introduced until the second phase. This approach breaches randomisation and effectively turns a randomised trial into an observational study. We therefore focused on the phase where women could have been randomised to either tenofovir/FTC or AZT/lamivudine. Preserving the benefits of randomisation is critical for balancing all known and unknown confounders – an approach that cannot be replicated with any observational research design (3). Nevertheless, we also performed sensitivity analyses including data from the full trial period; the signal for harm with tenofovir/FTC was robust to these sensitivity analyses (4).
Dr. Gilleece also argues that the number of stillbirths and early neonatal deaths were unexpectedly low in the AZT/lamivudine arm in the PROMISE trial during phase 2 when tenofovir/FTC was an option but not during phase 1. The differences in key outcomes in the AZT/lamivudine group could have easily been explained by chance: very preterm delivery, 3.4% in phase 1 vs. 2.6% in phase 2 (P=0.60); infant deaths, 1.4% in phase 1 vs. 0.6% in phase 2 (p=0.39). The results did not substantively change when results of the AZT/lamivudine arm from both phase 1 and 2 were included in sensitivity analyses (4).
We disagree that perinatal mortality, a worldwide standard reproductive measure, was the wrong outcome. We prespecified the composite outcome stillbirth and early neonatal mortality because death is the adverse outcome that matters, not its suspected aetiology. Most early neonatal deaths and stillbirths are caused by in utero factors and most women are likely to place a similar value on preventing both stillbirths and neonatal deaths. In the PROMISE trial and two smaller trials, stillbirths and early infant deaths occurred more frequently in the tenofovir/FTC arms compared to the AZT/lamivudine arms: pooled RR 4.40, CI 1.75 to 11.01; I2=0%; low-to-moderate certainty.
We found that tenofovir/FTC may increase stillbirth/early neonatal death and early premature delivery compared with AZT/lamivudine, but certainty is low when they are not co-prescribed with lopinavir/ritonavir (4). From the perspective of women who have both options available, we did not identify any compelling reasons to choose tenofovir or FTC over AZT and lamivudine (7). Dr. Gilleece appears to agree that the quality of evidence is not high, although she provides no evidence, nor a clear rationale, for her conclusion that tenofovir/FTC should be recommended rather than AZT/lamivudine and that fully informed women would choose tenofovir/FTC. We believe, consistent with the views of the women living with HIV on our panel, that they would not.
Dr. Gilleece ends by writing that women considering pre-exposure prophylaxis (PrEP) in pregnancy should not consider the evidence suggesting possible harm from tenofovir/FTC. We systematically searched for all randomised trials of tenofovir/FTC in pregnancy, including those used for PrEP, and although we did identify some randomised evidence of PrEP in pregnancy, there was not sufficient power to exclude harm (4). To accurately estimate harm, all available evidence for PrEP must be considered, including indirect evidence from pregnant women living with HIV. Thus we are surprised by Dr. Gilleece’s confident and definitive statement that HIV-negative women (who may become pregnant) should ignore the possibility that tenofovir/FTC could increase the risk of stillbirth/neonatal mortality as it is not supported by high-quality evidence.
Worryingly, BHIVA issued a very early anonymous statement (8) prior to its recent consultation on the BHIVA HIV in Pregnancy Guidelines, whose Writing Group Dr. Gilleece chaired (9). This consultation document did not make reference to the two BMJ Open systematic reviews although it dismisses the BMJ Rapid Recommendation guidance, which was informed by these reviews (4,7).
Our recommendations differ from the proposed BHIVA guidelines in several important ways. First, we do not include anyone with a financial or intellectual conflict of interest - the BHIVA draft guidelines are not transparent on this issue. Second, we reviewed empirical evidence on patient values and preferences (7) as well as including valuable input from three women living with HIV who are unconflicted advocates in this field. Lastly, our peer-reviewed BMJ Rapid Recommendations meet all of the Institute of Medicine criteria for developing trustworthy guidelines (10).
We respectfully suggest that BHIVA should re-examine its internal processes. We also hope that EGPAF will place due priority on the needs and preferences of the women that they serve, while balancing difficult funding considerations. HIV clinicians have a moral and legal duty to explicitly discuss the benefits, harms and uncertainties of each prescription with their patients, so that women who are, or may become, pregnant can decide what is best for themselves. In this case, failing to mention the possibility that TDF and/or FTC may lead to spontaneous abortion and neonatal death breaches these ethical responsibilities. Well before pregnancy or its adverse outcomes, from diagnosis or first prescription, the BHIVA’s members should offer all women living with HIV and/or considering combination ART the information contained in the BMJ Rapid Recommendation.
The BMJ Rapid Recommendation systematic review authors and guideline panel
Reed A. Siemieniuk
Gordon H. Guyatt
Per O. Vandvik
Henry Namme Luma
Jinell Mah Ming
Malgorzata M Bala
Olufunmilayo A Lesi
Patrick Mbah Okwen
Paul E Alexander
Rhonda Marama Mullen
1. Siemieniuk RAC, Taylor GP, Guyatt GH, Lytvyn L, Chang Y, Alexander PE, Lee Y, Agoritsas T, Merglen A, Kirpalani H, Bewley S. Authors respond to "Comment from PROMISE team" Re: Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline 10 October 2017 http://www.bmj.com/content/358/bmj.j3961/rr-0
2. Siemieniuk RAC, Guyatt GH, Lytvyn L, Bewley S on behalf of the Rapid Recommendation panel members The BHIVA and US DHHS wrongly dismiss new evidence 30 October 2017 http://www.bmj.com/content/358/bmj.j3961/rr-2
3. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401-406. doi:10.1016/j.jclinepi.2010.07.015.
4. 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 2017;7:e019022. doi:10.1136/bmjopen-2017-019022.
5. Welbourn A. WHO’s poor consultation with patients on HIV guidance has denied women choice in drug treatment. http://www.bmj.com/content/348/bmj.f7601
6. Donors and Collaborators - Elizabeth Glaser Pediatric AIDS Foundation. http://www.pedaids.org/about/donors-and-collaborators/ (Accessed March 8, 2018)
7. 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;7(9):e019023
8. British HIV Association (BHIVA) response to BMJ article "Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline" published 11 September 2017. 21 September 2017 http://www.bhiva.org/BHIVA-response-to-BMJ-article.aspx (Accessed 27 February 2018)
9. British HIV Association guidelines for the management of HIVinfection in pregnant women 2018. Consultation version. http://www.bhiva.org/guidelines.aspx (last accessed 27 February 2018)
10. Steinberg E, Greenfield S, Wolman DM, Mancher M, Graham R, editors. Clinical practice guidelines we can trust. National Academies Press 2011;Jul 16.
Competing interests: No competing interests
The Writing Group for the BHIVA HIV in Pregnancy Guidelines would like to comment on the BMJ article “Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline” .
This BMJ systematic review has “strongly recommended” that pregnant women living with HIV should not be treated with the combination tenofovir/emtricitabine/lopinavir/ritonavir due to higher rates of early neonatal death reported in the PROMISE, randomised clinical trial . We disagree with this recommendation. The PROMISE trial compared the efficacy of zidovudine/single-dose nevirapine with combination protease inhibitor-based (lopinavir-ritonavir) ART using zidovudine/lamivudine or tenofovir/emtricitabine backbone to prevent mother-to-child transmission in women with CD4 cell count >350 cells/mm3 . PROMISE enrolled during two study periods and the analysis used as the main evidence base for the BMJ clinical practice guidelines was performed on women recruited only in the second study period, which considered only one third of all women recruited to the PROMISE trial. The systematic review also made a “weak recommendation” that zidovudine/lamivudine should be used preferentially over tenofovir/emtricitabine as the nucleoside backbone in pregnant women because of the lower number of stillbirths and early neonatal deaths in this arm of the PROMISE study. The endpoints of stillbirth and neonatal death were considered as separate endpoints in the PROMISE trial due to differing etiologies associated with each outcome but were combined as a single outcome in the BMJ recommendation. Where the main difference between zidovudine/lamivudine and tenofovir/emtricitabine based ART emerged was in infants delivering <34 weeks, with more problems seen in the tenofovir/emtricitabine arm. Also, there were an unexpectedly low number of neonatal deaths in the second study period of the PROMISE trial (2 vs 15 in the first period) and this, as well as the lack of any biological explanation, reduces the ability to interpret with any certainty why these differences may have occurred.
As both arms received lopinavir/ritonavir, the BMJ panel postulates that tenofovir/emtricitabine is the cause of the difference. Despite the BMJ panel’s assertion that pharmacokinetic interactions between tenofovir and lopinavir/ritonavir are not relevant, no specific studies were done as part of the PROMISE study to support the BMJ panel’s assertion. Also, BHIVA does not recommend the use of lopinavir/ritonavir for the treatment of HIV in adults, including in pregnant women, and certainly not at the 50% higher dose used in the 3rd trimester in the PROMISE trial. In addition, PROMISE investigated outcomes in women initiating therapy. Most women in the UK will conceive on ART, most commonly with TDF/FTC backbone and this study does not address that cohort.
Three previous systematic reviews [3–5] reported no increase of birth adverse events or safety events (and no increased risk of congenital anomalies) in infants exposed to tenofovir compared to non-tenofovir-containing regimens in HIV-exposed infants, although data remain limited and studies evaluating neonatal mortality, infant anthropometry and bone growth are required. The WHO used these systematic reviews to inform their guidelines on HIV and pregnancy, which include the use of tenofovir-containing regimens.
In addition to these systematic reviews, there are numerous observational studies showing tenofovir/emtricitabine to be safe in pregnancy. For example, Zash et al  published a birth surveillance study of 47,027 pregnant women in Botswana, including 11,932 women with HIV, where preterm birth, very preterm birth, small and very small size for gestational age, stillbirth, and neonatal death were evaluated. In this very large cohort, the risk for any adverse or severe adverse birth outcome was lowest among infants exposed to a combined regimen of tenofovir, emtricitabine and efavirenz but all tenofovir/emtricitabine-based regimens were found to be safer than those with zidovudine/lamivudine as a backbone and the highest risk of adverse outcomes with observed in those women receiving lopinavir-based regimes.
The BHIVA Pregnancy Guidelines Writing Group agrees that any decision regarding ARVs should always be discussed in full with every woman. Currently, our recommendation remains to continue or to start tenofovir or abacavir with emtricitabine or lamivudine as the nucleoside backbone (Grading: 2C). The third agent should be one of the following: efavirenz, raltegravir, rilpivirine, ritonavir-boosted darunavir or ritonavir-boosted atazanavir, as per national BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy . In addition, the BHIVA Pregnancy Guidelines Writing Group does not think this data should influence decisions to use tenofovir/emtricitabine for pre-exposure prophylaxis in women of child-bearing potential.
The BHIVA guidelines on the management of HIV in pregnancy will be published for consultation early in 2018.
1. Siemieniuk RAC, Lytvyn L, Mah Ming J 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; IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med 2016; 375: 1726–1737.
3. Nachega JB, Uthman OA, Mofenson LM et al. Safety of tenofovir disoproxil fumarate–based antiretroviral therapy regimens in pregnancy for HIV-infected women and their infants: a systematic review and meta-analysis. J AIDS: 2017; 76: 1–12.
4. Wang L, Kourtis AP, Ellington S et al. Safety of tenofovir during pregnancy for the mother and fetus: a systematic review. Clin Infect Dis 2013; 57: 1773–1781.
5. Mofenson LM, Baggaley RC, Mameletzis I. Tenofovir disoproxil fumarate safety for women and their infants during pregnancy and breastfeeding. AIDS 2017; 31: 213–232.
6. Zash R, Jacobson DL, Diseko M et al. Comparative safety of antiretroviral treatment regimens in pregnancy. JAMA Pediatr 2017; Epub ahead of print.
Competing interests: No competing interests
To the BMJ Editor,
The rapid recommendation and accompanying review and meta-analysis recently published in BMJ Open by Siemieniuk and co-authors provide a strong recommendation that HIV-infected pregnant women should be treated with a combination of zidovudine and lamivudine (AZT-3TC) over tenofovir and lamivudine (TDF-3TC) or emtricitabine (TDF-FTC) combination antiretroviral therapy. EGPAF, an organization that has provided evidence-based, WHO-recommended ART to over 1.8 million HIV-infected pregnant women in sub-Saharan Africa does not agree with these recommendations and continues to support the WHO recommendations on treatment of HIV-infected pregnant women.
The BMJ recommendation is primarily based on findings from a single randomized-controlled trial, the PROMISE trial,1 despite multiple other observational studies demonstrating the safety of TDF-based ART in pregnant women. 2,3,4 Due to important limitations of the PROMISE trial findings, the PROMISE study investigators and others, such as the British HIV Association and the US Department of Health and Human Services do not support the conclusions of Siemieniuk et al regarding the use of TDF-based ART in pregnant women. 5,6 While supporting the need for additional safety data on ART regimens in pregnant women and infants, these experts have outlined the limitations of the PROMISE study findings that preclude the ability to draw firm conclusions on the safety of TDF-FTC versus AZT-3TC (see responses to Siemieniuk et al, 2017). Other recently-published systematic reviews that included the PROMISE trial as well as evidence from other studies have concluded that TDF-based ART is safe to use to treat HIV in pregnancy. 7,8
Further, Siemieniuk et al. suggest that preferred regimens for HIV-infected pregnant women may include AZT-3TC plus abacavir or rilpivirine. In non-pregnant women, studies have suggested that these regimens may lead to inferior virologic control and higher side effects as compared to other regimens that include 2NRTIs and efavirenz, including TDF-containing regimens. 9,10,11 While some alternative options recommended by SIemieniuk et al, such as AZT-3TC + darunavir-ritonavir, appear to have good efficacy in non-pregnant populations, evidence supporting their use in pregnant women, particularly those living in low- and middle-income contexts, is lacking and the regimens are also not widely available in these countries.
When making recommendations that have broad implications for HIV-infected women and their children living in low- and middle-income countries, a public health approach that carefully considers the available evidence is of utmost importance but must also consider important implementation and logistical issues. Based on high-quality systematic reviews, the WHO continues to recommend TDF-FTC or 3TC-efavirenz as first-line treatment, including for pregnant women. Other major expert organizations, such as the US Department of Health and Human Services and the British HIV Association support this recommendation. Not only is there significant evidence supporting the safety of TDF-based ART in pregnant women, there is also extensive experience using the combination of TDF-FTC + efavirenz in adults in low- and middle-income countries, with over 11 million people living with HIV on TDF-containing regimens in 2016. 12
The ultimate impact of ART on reducing mother-to-child transmission and improving infant outcomes is determined not only by randomized, controlled clinical trials of ART regimens but also by the practical realities in real-world settings that influence ART access, utilization, and adherence. Drug availability, dosing frequency, and pill burden, as well as regimen complexity tolerability, and cost, are additional important factors in selecting optimal ART regimens for different settings. The TDF-FTC or 3TC + efavirenz combination is a single tablet, once-daily, widely available and affordable regimen, leading to low pill burden and simple regimens for patients and health systems. AZT-3TC is dosed twice daily and is not available for the recommended triple drug regimens as a single tablet formulation in low- and middle-income countries. Twice daily regimens and those with higher pill burdens may lead to decreases in adherence. 13
Ensuring optimal drug availability and lower costs facilitates harmonization of regimens across countries and populations. The recommendation by Siemieniuk et al would fragment the ART market across populations in low and middle income countries, thereby likely increasing risk of stock outs, raising prices and complicating supply chains. These operational realities are critical to consider when making ART recommendations that affect low- and middle-income countries, but, unfortunately, appear to not be adequately considered by the authors. Given the current clinical evidence from completed studies, experience treating pregnant HIV-infected women with TDF-based ART, and operational realities in low and middle income countries, EGPAF supports the continued use of TDF-based ART as part of safe and effective HIV-treatment for pregnant women and prevention of HIV transmission for their infants, but also encourages the collection of additional data on drug regimen safety and effectiveness among these populations.
1. Fowler MG, Fiscus SA, Currier JS, et al. Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention. N Engl J Med 2016;375:1726-37.
2. Zash R, Souda S, Chen JY, et al. Reassuring birth outcomes with tenofovir/emtricitabine/efavirenz used for prevention of mother-to-child transmission of HIV in Botswana. J Acquir Immune Defic Syndr. 2016; 71:428–436.
3. Gibb DM, Kizito H, Russell EC, et al. Pregnancy and infant outcomes among HIV-infected women taking long-term art with and without tenofovir in the DART trial. PLoS Med. 2012;9:e1001217.
4. Ransom CE, Huo Y, Patel K, et al. Infant growth outcomes after maternal tenofovir disoproxil fumarate use during pregnancy. J Acquir Immune Defic Syndr. 2013;64:374–381.
5. British HIV Association: http://www.bhiva.org/BHIVA-response-to-BMJ-article.aspx
6. US Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0
7. Nachega JB, Uthman OA, Mofenson LM, et al. Safety of Tenofovir Disoproxil Fumarate-Based Antiretroviral Therapy Regimens in Pregnancy for HIV-Infected Women and Their Infants: A Systematic Review and Meta-Analysis. J Acquir Immune Defic Syndr. 2017 Sep 1;76(1):1-12.
8. Mofenson L, Baggaley R and Mameletzis I. Tenofovir disoproxil fumarate safety for women and their infants during pregnancy and breastfeeding. AIDS. 2017; 31(2):213-232.
9. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA 3rd, et al.; AIDS Clinical Trials Group Study A5095 Team. Triple‐nucleoside regimens versus efavirenz‐ containing regimens for the initial treatment of HIV‐1 infection. N Engl J Med 2004; 350 (18):1850‐1861.
10. Cruciani et al. Virological efficacy of abacavir: systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy, Volume 69, Issue 12, 1 December 2014, Pages 3169–3180,
11. Stephan C et al. Impact of baseline HIV-1 RNA levels on initial highly active antiretroviral therapy outcome: a meta-analysis of 12,370 patients in 21 clinical trials. HIV Medicine. 2013; 14(5): 284–292.
12. CHAI. ARV Market Report. September 2017. Available at https://clintonhealthaccess.org/content/uploads/2017/09/2017-ARV-Market-.... Accessed on 24 October, 2017.
13. Buscher A, Hartman C, Kallen M et al. Impact of Antiretroviral Dosing Frequency and Pill Burden on Adherence among Newly Diagnosed, HAART Naïve, HIV Patients. Int J STD AIDS. 2012 May; 23(5): 351–355.
Competing interests: No competing interests
As Dr. Ciaranello notes, two groups who develop national guidelines (the British HIV Association [BHIVA] and the U.S. Department of Health and Human Services [DHHS]), have placed comments about our BMJ Rapid Recommendations into the public domain. Their hasty dismissals have been further circulated via pharma-funded patient information websites (e.g. http://i-base.info/htb/32680).
In contrast to prior recommendations, ours meet all of the Institute of Medicine criteria for a trustworthy clinical practice guideline (1). We included women living with HIV at every step of the guideline development process. The panel did not include anyone with financial conflicts of interest. We considered the entire body of relevant evidence, including performing two new rigorous systematic reviews to inform the recommendations: we did not restrict ourselves to randomised controlled trials (RCTs) comparing tenofovir/emtricitabine with alternatives in pregnant women but also examined all of the observational data in pregnant women living with HIV or hepatitis B, all RCTs in non-pregnant adults (2), as well as published evidence of women's values and preferences (3).
Both the anonymous BHIVA statement and the DHHS authors cite the literature selectively (“cherry-picking”), a time-honoured but now discredited approach to justify one’s views that has been superseded by the sort of systematic reviews we undertook. The DHHS statement cites old guidelines in which a large proportion of panel members had serious financial conflicts of interest. The DHHS makes two points in providing a rationale for continuing to favour tenofovir and emtricitabine over AZT and lamivudine: first, that AZT/lamivudine is dosed twice rather than once daily, and second that AZT is associated with a higher risk of haematologic adverse effects, particularly anaemia, than tenofovir.
Our guideline systematically examined these considerations and placed them in the context of the values and preferences of pregnant women living with HIV. All or almost all women place an extremely high value on avoiding the outcome of stillbirth or neonatal mortality (3).
In contrast, how are woman likely to view the laboratory abnormalities the DHHS panel seems to believe are so important? Based on moderate quality evidence, we found that tenofovir probably does not have a lower risk of serious maternal laboratory adverse effects than AZT/lamivudine (19 fewer per 1000, 95% confidence interval [CI] 57 fewer to 36 more). When serious haematologic adverse effects in pregnancy are considered alone, there is probably no difference for the mother (8.3% with tenofovir/FTC vs. 8.2% with AZT/lamivudine; 4 more per 1000, CI 26 fewer to 33 more) or the child (5.9% with tenofovir/FTC vs. 5.9% with AZT/lamivudine; 2 fewer per 1000, CI 30 fewer to 27 more) (2,4). When considering indirect randomised evidence from non-pregnant adults, AZT/lamivudine may have a small increased risk of anaemia, but certainty is low (3 trials, 2218 participants; 1.3% with tenofovir vs. 3.9% with AZT; RD 27 fewer per 1000, CI 54 fewer to no difference). The best evidence suggests that there is probably no increased risk of serious haematologic adverse effects with AZT/lamivudine during pregnancy.
Most women are very likely to choose to avoid the possible increased risk of the death of their child, and accept a possible – but as our evidence review shows, uncertain – small risk of laboratory abnormalities of questionable significance. When placed against the risk of losing their baby, all or almost all will consider the need to take medications twice daily rather than once daily a trivial issue. We encourage local, national, and international organisations to put aside any attachment to a prior stance (5), to properly engage with the new data, and seriously consider the precautionary principle. Failing to do so represents a disregard of the evidence of potential harm from tenofovir and/or emtricitabine.
At the core of our recommendations is the belief that women living with HIV who are, or intend to become, pregnant have the right to be fully informed about the evidence, including the possibility of harm. At the very least, recommendations from all organizations should acknowledge the absolute necessity for the full disclosure that will empower women choosing between alternative medications.
1. Siemieniuk RA, Agoritsas T, Macdonald H, Guyatt GH, Brandt L, Vandvik PO. Introduction to BMJ Rapid Recommendations. BMJ 2016;354:i5191. doi:10.1136/bmj.i5191 pmid:27680768.
2. 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 2017;7:e019022. doi:10.1136/bmjopen-2017-019022.
3. 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;7(9):e019023
4. Fowler MG, Qin M, Fiscus SA, et al. IMPAACT 1077BF/1077FF PROMISE Study Team. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. N Engl J Med 2016;375:1726-37. doi:10.1056/NEJMoa1511691 pmid:27806243.
5. Mercier H, Sperber D. Why do humans reason? Arguments for an argumentative theory. Behav Brain Sci 2011;34:57-74. doi:10.1017/S0140525X10000968
Competing interests: No competing interests
Two national guidelines committees have released statements in response to these recommendations by Siemieniuk et al. Both committees continue to recommend the use of tenofovir disoproxil fumarate:
British HIV Association: http://www.bhiva.org/BHIVA-response-to-BMJ-article.aspx
US Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0
Competing interests: I serve on the US Department of Health and Human Services Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission.
Authors respond to "Comment from PROMISE team" Re: Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline
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
Comment from PROMISE Team Re: Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline
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 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
Competing interest comment: We are the primary authors of the PROMISE study cited as the evidence for the recommendation in this paper ; we disagree with the final conclusion based on our data.
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).
Competing interests: We are the primary authors of the PROMISE study cited as the evidence for the recommendation in this paper ; we disagree with the final conclusion based on our data.