One study evaluated bone health by tibial quantitative ultrasound, finding no significant difference between infants at 23 months (median age) born to mothers receiving TDF-based ART compared with non–TDF-based ART (mean difference in tibial speed of sound −0.20, 95% CI: −2.28 to 1.88, 1study).20 In one study, tenofovir-unexposed and -exposed children had similar mean levels of bone markers (C-terminal telopeptide of type I collagen, CTX; and bone-specific alkaline phosphatase, BAP) at 6 months (CTX: 0.62 versus 0.55 ng/mL, P = 0.122; BAP: 384 versus 362 U/L, P = 0.631).18
However, more recently, neonatal BMC measured by DXA scan at 0–21 days of age was evaluated in HIV-exposed infants in a substudy of a randomized clinical trial comparing different approaches to prevention of in utero perinatal HIV transmission in HIV-infected African women with CD4+ T-cell counts >350 cells/mm3 (the PROMISE trial, described earlier).37 Whole-body BMC was significantly lower in infants whose mothers received either TDF-based ART compared with zidovudine/single-dose nevirapine (estimated mean difference 9.73 grams, 95% CI: 5.49 to 13.96, P < 0.001) or non–TDF-based ART compared with zidovudine/single-dose nevirapine (estimated mean difference 7.97 g, 95% CI: 3.97 to 11.96, P < 0.001). However, there was no significant difference between infants exposed to TDF-based ART vs. those on non–TDF-based ART (estimated mean difference 1.76 g, 95% CI: −2.43 to 5.95, P = 0.41).37 No significant difference was seen between any of the study arms when lumbar spine BMC measurements were compared.
Our data on congenital anomalies are consistent with data from the Antiretroviral Pregnancy Registry. The registry has recorded sufficient numbers of first-trimester TDF exposures to confidently rule out 1.5-fold increased risk of overall birth defects, with a prevalence of birth defects with first-trimester TDF exposure of 2.3% as compared to 2.7% total prevalence in the US population.9 To date, available human data suggest that the use of TDF-based ART during pregnancy does not increase the risk of major congenital anomalies.
One study, the PROMISE trial, reported elevated rates of neonatal (age <14 days) mortality in infants born to mothers receiving TDF-based ART compared with those born to mothers receiving non–TDF-based ART.34 This study enrolled HIV-infected pregnant women with CD4+ counts >350 cells/mm3 and randomized them to receive zidovudine alone plus intrapartum single-dose nevirapine, TDF-based ART (TDF/emtricitabine/lopinavir–ritonavir), or non–TDF-based ART (zidovudine/lamivudine/lopinavir–ritonavir). In the initial 1½ years of enrollment (during which 65% of participants enrolled), only women with hepatitis B virus coinfection were allowed to be randomized to the TDF ART arm, but after a protocol modification, in the second 1½ years of enrollment (accounting for 35% of enrollment), all HIV-infected women regardless of hepatitis B status were randomized among all 3 arms. TDF ART comparisons were limited to the second part of the study with concomitant randomization to all arms. There were no significant differences between the TDF ART and non–TDF ART arms in maternal grade ≥2 AEs, spontaneous abortion, stillbirth, preterm delivery <37 weeks, low birth weight <2500 grams, very low birth weight <1500 grams, or grade ≥3 infant AEs between infants born to mothers in the TDF ART and non–TDF ART arms. However, there was a lower rate of very preterm delivery (<34 weeks) in the non–TDF ART compared with TDF ART arm (2.6% vs. 6.0%, respectively, P = 0.04), which led to a difference in neonatal mortality (age <14 days) (0.6% with non–TDF ART vs. 4.4% with TDF ART, P = 0.001), as most deaths were among very preterm infants. It is important to note, however, that there was not a significant difference between the TDF ART arm and zidovudine/single-dose nevirapine arm in very preterm delivery (6.0% vs. 3.2%, respectively, P = 0.10) or neonatal mortality (4.4% vs. 3.2%, P = 0.43). In addition, of the 17 neonatal deaths in the non–TDF ART arm, 88% (N = 15) occurred during the initial period of the trial and only 12% (N = 2) during the period of comparison with TDF ART. This suggests that the non–TDF ART arm may have had artificially low rates of very preterm delivery and infant mortality during the 3-arm comparative period of the study, and not that the TDF-ART arm had elevated risk of these events.
In contrast to the PROMISE trial results, rates of very preterm delivery were similar to TDF ART (combined with efavirenz) compared with non–TDF ART exposure in a Botswana study by Zash et al,38 and no differences in neonatal mortality were observed with TDF ART exposure (primarily combined with nevirapine) compared with non–TDF ART exposure in a study in Uganda/Zimbabwe.17 It is important to note that the PROMISE trial used lopinavir, a protease inhibitor (PI) that is coformulated with ritonavir (LPV/r)-based ART regimens, whereas the Botswana and Uganda/Zimbabwe studies use non–PI-based ART regimens. In addition, in the PROMISE trial, the LPV/r dose was increased during the third trimester, based on studies showing decreased lopinavir–ritonavir levels with standard doses in pregnancy.40 A pharmacokinetic interaction has been reported with concurrent administration of tenofovir and lopinavir–ritonavir, which could result in increased plasma and intracellular tenofovir levels.41,42 Of note, the WHO-recommended first-line ART regimen for HIV-infected pregnant women [TDF + FTC (or 3 TC) + EFV] is distinct from the LPV/r-based ART regimen used in the PROMISE study. The results from other studies have not suggested that TDF is associated with excess adverse outcomes. By contrast, PIs, including LPV/r, have been reported to be associated with prematurity and low birth weight.43–45 As LPV/r-based regimen is recommended for second-line ART regimen,1 toxicity associated with such ART regimens needs further research. The PROMISE team is evaluating this further.
Available data do not indicate any difference in anthropometric measurements at birth with in utero tenofovir exposure, but there are conflicting data on whether there might be some delayed effects at age 6 months–1 year.17,31 The biologic plausibility of later emergence of growth effects due to in utero tenofovir exposure, especially when they are not observed at birth and there is not continued exposure (studies analyzed were in formula-fed populations), is unclear. Again, there are limited longitudinal data to determine whether such findings persist or have clinical relevance; 2 studies with longer follow-up (to age 2–5 years) did not find any differences in growth with TDF exposure. More data in larger cohorts are needed to be able to determine whether there are any adverse effects of in utero tenofovir exposure on bone or long-term growth.
Strengths of our meta-analysis include use of a standard protocol, a comprehensive and updated literature search strategy, and involvement of 2 independent reviewers in all stages of the review process. There are also limitations of the study that should be considered. First, some of the studies had small sample sizes. Second, the review was limited by the small number of studies reporting most of the outcomes of interest. Most of the pooled estimates should be interpreted with caution, and more research with larger sample sizes is needed to confirm these findings. We applied the I2 value to assess heterogeneity. It is worth considering that I2 values are typically high, and potentially exaggerated, when combining observational studies; therefore, interpreting the I2 values should be performed with caution.47 Finally, inclusion of observational studies may lead to bias because unknown confounding that were not adjusted for, other than ART, might be responsible for maternal or infant AEs.
In summary, although the available data suggest that use of a TDF-containing ART regimen seems to be safe for HIV-infected pregnant women and their infants, the data remain limited and few studies addressed maternal toxicity or infant growth and bone effects. In consideration of these data, the good safety and efficacy data of TDF-containing first-line therapy overall, and the programmatic advantages of harmonizing ART across populations, the latest WHO guidelines continue to recommend TDF + FTC (or 3 TC) + EFV as first-line ART for adults, including pregnant women. Nevertheless, given the expected global increase in TDF use with implementation of WHO guidelines for universal treatment for all HIV-infected individuals, including pregnant and nonpregnant women, additional research on the safety of TDF in pregnancy is needed, particularly prospective longitudinal data on growth and maternal/infant bone density measurements.
We thank Ms. Caroline Connor, PhD, for reviewing and providing editing services for this manuscript.
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