Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline

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” [1].

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 [2]. 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 [2]. 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 [6] 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 [7]. 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.

References
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.
7. http://www.bhiva.org/HIV-1-treatment-guidelines.aspx

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.

References
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

Dear Editor:

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.

Sincerely,
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

References
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.