Gibb DM, Kizito H, Russell EC, Chidziva E, Zalwango E, et al. Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial. PLoS Med 9(5): e1001217. doi:10.1371/journal.pmed.1001217 (15 May 2012)
To compare the impact of tenofovir (TDF)-containing antiretroviral therapy (ART) regimens vs. non-TDF-containing regimens on pregnancy outcomes and long-term infant outcomes in HIV-infected African women taking ART for their own health, specifically potential long-term adverse effects associated with in utero tenofovir (TDF) exposure.
Entebbe and Kampala, Uganda; Harare, Zimbabwe.
Longitudinal observational study conducted within the Development of AntiRetroviral Therapy in Africa (DART) trial.(1)
HIV-infected women (n=302) who became pregnant during the DART trial; surviving infants (n=182) whose mothers had consented for them to participate.
Mothers: Miscarriage or induced termination (<22 weeks); early (22-28 weeks), late (>28 weeks), and intrapartum stillbirth; and live birth. Low birth weight (LBW) was defined as <2,500 grams in an infant ≥37 weeks. Prematurity was defined as <37 weeks gestation. Infants: Mortality; clinical status; adverse events; feeding; weight, head, and mid-upper-arm circumference (MUAC); and growth.
DART was an non-blinded randomized trial that ran from 2003-2009 and compared routine laboratory and clinical monitoring vs. clinical monitoring. 2,156 ART-naïve HIV-infected women with CD4 <200 cells/mm3 enrolled in DART. Women received TDF, nevirapine (NVP)- or abacavir (ABC)-containing first-line ART; in a substudy in Uganda 369 women were randomized to receive NVP or ABC.(2) All others (n=1,787) received TDF- or NVP-containing first-line ART. Data on infants born to DART mothers were collected in a separate longitudinal observational study.
Of 2,156 women enrolled in DART, 1,867 were <45 years of age. During a median follow-up of 5.1 years, there were 382 pregnancies in 302 (16%) women. There were 390 pregnancy outcomes, including 226 (58%) live births, 27 (7%) stillbirths, and 137 (35%) miscarriages or terminations. Four women died, two during pregnancy (one from severe malaria, one from septic abortion) and two at delivery (one from post-partum hemorrhage, one from an unknown cause). Seven (3%) of the 226 children born alive had congenital abnormalities; four (out of 141) with whose mothers took TDF for ≥90% of their pregnancies and three (out of 72) with no TDF exposure (exact p=0.69). Among women on TDF for ≥90% of their pregnancies vs. those not on TDF, there was no significant difference in the distribution of live births, stillbirths and miscarriages/terminations (exact p=0.19). Sixteen percent (34/209) of all live-born infants with recorded birth weights and 13% (25/189) of those with gestational ages ≥37 weeks had LBW. Of infants with no exposure to TDF in utero, 13/69 (19%) had LBW, compared to 19/130 (15%) in infants with ≥90% TDF exposure (Χ2p=0.44). Seven of the 226 infants died of perinatal causes in the first two weeks.
Of the 219 surviving infants, data from 182 (83%) from 152 mothers were included in follow-up analyses of infant outcomes. Sixty-two (34%) infants had no TDF exposure and 111 (61%) had ≥90% TDF exposure. Nine (5%) had 20%-89% TDF exposure and were excluded from TDF comparisons. Infants were followed-up at 6, 12, and 24 weeks, and then at 24-week intervals up to age 4 years.
Seventy-three (40%) infants were breastfed for a median of 94 (inter-quartile rating [IQR] 75-212) days. One hundred seventy-two (95%) of 182 infants were tested for HIV; none (0%) were infected. Ten infants were not tested; two were lost to follow-up and eight died before testing. The eight infants died of respiratory infection (n=3), sepsis (n=2), burns (n=1), measles (n=1), and an unknown cause (n=1). The 10 untested infants were last seen at median age 12 months (range 2-34 months). Last weight-for-age z-scores (available for 7/10) were all above -2 except for one infant with -3.5. Clinic notes and clinical case report forms describe 9/10 of the untested children as normal in neurodevelopment. Six additional HIV-uninfected children died during the follow-up period. A total of 14 infants died at median age 9 (IQR 3-23) months. Seven had ≥90% TDF exposure in utero, six had no exposure, and one had 20%-89% exposure. Four of the 14 were ever-breastfed. In surviving children, TDF exposure 3 in utero had no effect on growth after two years (p>0.38). There was no difference between children with ≥90% TDF exposure in utero and those with no exposure in regard to weight, MUAC or head circumference by age (p>0.1 at first measurement; p>0.8 at last measurement). Creatinine, phosphate and hemoglobin values were similar between infants with ≥90% TDF exposure and those with no exposure. In 109 measurements, four children with ≥90% TDF exposure and one child with no exposure experienced a single occurrence of 1+ proteinuria. No child had a bone fracture.
The authors did not find any evidence that TDF-containing ART had any adverse effects on pregnancy outcomes or on congenital, renal, bone, or growth abnormalities up to age 4 years among children born to women with severe HIV immunodeficiency at ART initiation and exposed throughout the intrauterine period.
The overall risk of bias in this study is low. The DART trial used a computer-generated sequentially numbered randomization list (with variable block sizes), and stratified randomization by study center. Allocation concealment was unclear, and blinding would not have been appropriate. Loss to follow-up analyses are appropriate. Outcome reporting(1) compares favorably to the trial's protocol.(3) Using a nine-point scale to assess the study rigor, the follow-up observational study of infant outcomes received seven points. The study design included pre/post intervention data; it included a comparison group; it included a cohort; the comparison groups were equivalent socio-demographically and at baseline on outcome measures. The authors conducted statistical tests to control for potential confounders in the analysis. The study's follow-up rate was well over the rigor scale's specification of 75%. Outcome reporting compares favorably to the study protocol.(4)
Recently, long-term TDF therapy has been associated with declines in renal function in adults,(5, 6) especially those with low body mass indices,(7) and in decreased bone mineral density.(8) The United States Pediatric HIV/AIDS Cohort recently reported a small but statistically significant association between intrauterine TDF exposure and lower head circumference-for-age and length-for-age z-scores in uninfected infants at age 1 year.(9) The 2010 World Health Organization (WHO) guidelines on ART for treating pregnant women and preventing HIV in infants(10) recommend TDF-based regimens as a first-line alternative for women taking ART for their own health. Complete results of the DART trial had not been published at the time these guidelines were in preparation, and one of the Cochrane reviews(11) underpinning these guidelines was only able to consider a conference abstract, which did not include data from the infant follow-up study.(12) New WHO guidelines on preventing mother-to-child HIV transmission will be released in 2013.
In keeping with current WHO guidelines, TDF-containing ART regimens should be a first-line alternative recommendation for women taking ART for their own health.
- Mugyenyi P, Walker AS, Hakim J, Munderi P, Gibb DM, DART Trial Team. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. Lancet. 2010 Jan 9;375(9709):123-31. Epub 2009 Dec 8. PubMed PMID: 20004464; PubMed Central PMCID: PMC2805723.
- Dart Trial Team. Twenty-four-week safety and tolerability of nevirapine vs. abacavir in combination with zidovudine/lamivudine as first-line antiretroviral therapy: a randomized double-blind trial (NORA). Trop Med Int Health. 2008 Jan;13(1):6-16. PubMed PMID: 18290996; PubMed Central PMCID: PMC2635484.
- ISRCTN13968779. Development of AntiRetroviral Therapy in Africa - A randomised trial of monitoring practice and structured treatment interruptions in the management of antiretroviral therapy in adults with HIV infection in Africa. [Accessed 23 May 2012]
- Follow-up of infants born to HIV-infected women in the DART study (study protocol). [accessed 23 May 2012]
- Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of renal disease among people living with HIV: a systematic review and meta-analysis. BMC Public Health. 2012 Mar 23;12(1):234.
- Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010 Sep 1;51(5):496-505. Review.
- Nishijima T, Gatanaga H, Komatsu, H, et al. Renal function declines more in tenofovir- than in abacavir-based antiretroviral therapy in low-body weight treatment-naïve patients with HIV infection. PLoS One 2012; 7(1):e29977.
- Rasmussen TA, Jensen D, Tolstrup M, et al. Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial. PLoSOne 1012; 7(3):e32445.
- Siberry GK, Williams PL, Mendez H, Seage GR 3rd, Jacobson DL, Hazra R, Rich KC, Griner R, Tassiopoulos K, Kacanek D, Mofenson LM, Miller T, Dimeglio LA, Watts DH; for the Pediatric HIVAIDS Cohort Study (PHACS). Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS.2012 Jun 1;26(9):1151-1159.
- World Health Organization (WHO). Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: Recommendations for a public health approach. [accessed 23 May 2012].
- Chang LW, Harris J, Humphreys E. Optimal monitoring strategies for guiding when to switch first-line antiretroviral therapy regimens for treatment failure in adults and adolescents living with HIV in low-resource settings. Cochrane Database Syst Rev. 2010 Apr 14;(4):CD008494. Review. PubMed PMID: 20393969.
- Mugyenyi P, Walker S, Hakim J, Munderi P, Gibb D, Kityo C, Reid A ,Grosskurth H, Darbyshire J, Ssali F, Bray D, Katabira E, Babiker A, Gilks C. Impact of routine laboratory monitoring over 5 years after antiretroviral therapy (ART) initiation on clinical disease progression of HIV-infected African adults: the DART trial final results. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa 2009.