Study of Effects of Tenofovir on Bone Health and Kidneys During Pregnancy and Breastfeeding

Maternal and Infant Monitoring for Evidence of Toxicity Related to Tenofovir Exposure: The Bone and Kidney Health Substudy of the IMPAACT 1077 PROMISE Protocol (Promoting Maternal and Infant Survival Everywhere)

The purpose of this study is to look at the effects of tenofovir disoproxil fumarate (an anti-HIV medication) on the bone health and kidneys of women with HIV during pregnancy and while breastfeeding. The study will also look at the changes in overall health, bone health and how the kidneys work in the infants of these women.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Tenofovir disoproxil fumarate (TDF)

Detailed Description

A small number of adults (who are not pregnant) and children who take anti-HIV medications develop problems with their kidneys and with the strength of their bones. These problems may be more common when tenofovir disoproxil fumarate (TDF) is used. Studies about these bone and kidney effects have not been done in pregnant and breastfeeding women and their infants.

This is a substudy of a larger study (IMPAACT 1077 PROMISE [Promoting Maternal and Infant Survival Everywhere]) to evaluate the safety of anti-HIV medications used in pregnancy and during breastfeeding. Only participants in the larger study randomly assigned to receive maternal tenofovir disoproxil fumarate (TDF) or no maternal TDF during pregnancy or during breastfeeding will be enrolled in this substudy.

This substudy will look at two groups of participants:

• An antepartum exposure group to look at the effects of TDF during pregnancy
• A postpartum exposure group to look at the effects of TDF during breastfeeding

All mother-infant pairs in the substudy will be followed for 74 weeks after delivery. During this time, the women and their infants will have medical checkups and tests. The tests will include tests of blood, urine, cord blood, and breast milk. Some of the women and infants will have a special x-ray called a dual energy e-ray absorptiometry (DXA) scan to measure bone strength. The timing of the tests-at enrollment, at delivery, at 6, 10, 26, or 74 weeks-will vary dependent on which part of this substudy women and infants are enrolled in. Those in charge of the substudy will try to schedule medical visits and tests at the same time as tests scheduled for the larger IMPAACT 1077 study.

• Study Type: Observational
• Enrollment (Actual): 1765

Contacts and Locations

Study Locations

• Malawi
  • Blantyre, Malawi
    • Blantyre CRS
  • Lilongwe, Malawi
    • Malawi CRS
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 1862
      • Soweto IMPAACT CRS
    • Johannesburg, Gauteng, South Africa, 2001
      • Shandukani Research CRS
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4001
      • Umlazi CRS
    • Durban, KwaZulu-Natal, South Africa, 4001
      • Durban Paediatric HIV CRS
  • Western Cape Province
    • Tygerberg, Western Cape Province, South Africa, 7505
      • Family Clinical Research Unit (FAM-CRU) CRS
• Uganda
  • Mpigi
    • Kampala, Mpigi, Uganda
      • MU-JHU Research Collaboration (MUJHU CARE LTD) CRS
• Zimbabwe
  • Chitungwiza, Zimbabwe
    • St Mary's CRS
  • Chitungwiza, Zimbabwe
    • Seke North CRS
  • Harare, Zimbabwe
    • Harare Family Care CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

For antepartum (AP) exposure part of P1084s: Mother/infant pairs enrolled in the antepartum components of 1077BF or 1077FF (1077BA and 1077FA respectively) at African clinical sites approved as P1084s DXA sites.

For postpartum (PP) exposure part of P1084s: Mothers and their infants enrolled in the postpartum component of 1077BF (107BP) at African clinical sites approved as P1084s DXA sites.

Description

Antepartum (AP) Part of Study (TDF Exposure During Pregnancy)

Inclusion Criteria:

• Mother-infant pair enrolled in 1077BA or 1077FA
• At a clinical site that has been approved as a P1084s DXA site
• Enrolled in the substudy up to the Week 2 visit of 1077BA/1077FA (within 21 days after 1077BA/1077FA study entry) and prior to the start of labor
• Willing and able to provide written informed consent to participate in this substudy

Exclusion Criteria:

• None

Postpartum (PP) Part of Substudy (TDF Exposure During Breastfeeding) (Note: this applies only to the new enrollment to P1084s, i.e., those who were not enrolled to P1084s while on the AP component)

Inclusion Criteria:

• Mother and their infant enrolled in 1077BP
• At a clinical site that has been approved as a P1084s DXA site
• Enrolled in the substudy within 6 to 14 days of delivery, on the same day as enrollment in 1077BP
• Willing and able to provide written informed consent to participate in this substudy

Exclusion Criteria:

• TDF exposure during pregnancy [NOTE: TDF use for up to 12 days beginning at labor allowed]
• Enrolled in the AP part of P1084s

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Maternal/infant antepartum exposure; HIV-infected women exposed to TDF during pregnancy; Infants of HIV-infected women exposed to TDF during pregnancy	Drug: Tenofovir disoproxil fumarate (TDF); Some participants will receive varying doses of TDF during pregnancy or breastfeeding as part of the larger study (IMPAACT 1077 PROMISE).
Maternal/infant postpartum exposure; HIV-infected women exposed to TDF while breastfeeding; Infants of HIV-infected women exposed to TDF while breastfeeding	Drug: Tenofovir disoproxil fumarate (TDF); Some participants will receive varying doses of TDF during pregnancy or breastfeeding as part of the larger study (IMPAACT 1077 PROMISE).
Maternal/infant antepartum no exposure; HIV-infected women not exposed to TDF during pregnancy; Infants of HIV-infected women not exposed to TDF during pregnancy
Maternal/infant postpartum no exposure; HIV-infected women not exposed to TDF during breastfeeding; Infants of HIV-infected women not exposed to TDF during breastfeeding

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antepartum Component: Creatinine clearance (CrCl)	Antepartum Component: Creatinine clearance (CrCl)	For women and infants: at delivery/birth, up to Week 1
Antepartum Component: Bone resorption (Dpyr)	Antepartum Component: Bone resorption (Dpyr)	For women and infants: at delivery/birth, up to Week 1
Antepartum Component: Lumbar spine bone mineral density (BMD) via dual energy e-ray absorptiometry (DXA)	Antepartum Component: Lumbar spine bone mineral density (BMD) via dual energy e-ray absorptiometry (DXA)	For women: at delivery/birth, up to Week 1
Antepartum Component: Lumbar spine bone mineral content (BMC) and whole body BMC via DXA	Antepartum Component: Lumbar spine bone mineral content (BMC) and whole body BMC via DXA	For infants: at delivery/birth, up to Week 1
Antepartum Component: Length-for-age Z-score	Antepartum Component: Length-for-age Z-score	For infants: at delivery/birth, up to Week 1 and Week 26
Postpartum Component: CrCl	Postpartum Component: CrCl	For women: at postpartum entry (delivery/birth, up to Week 1) and Week 74; for infants: at Week 26
Postpartum Component: Dpyr	Postpartum Component: Dpyr	For women: at Week 74; for infants: at Week 26
Postpartum Component: Lumbar spine BMD via DXA	Postpartum Component: Lumbar spine BMD via DXA	For women: at postpartum entry (delivery/birth, up to Week 1) and Week 74
Postpartum Component: Lumbar spine BMC via DXA	Postpartum Component: Lumbar spine BMC via DXA	For infants: at Week 26
Postpartum Component: Length-for-age Z-score	Postpartum Component: Length-for-age Z-score	For infants: at postpartum entry (delivery/birth, up to Week 1) and Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CrCl	CrCl	For women: Weeks 6, 26, and 74; for infants: at Weeks 10, 26, and 74
BMD	BMD	For women: at delivery and change in hip BMD from delivery to Week 74
Dpyr	Dpyr	For women: at Weeks 6, 26, and 74; for infants: at Weeks 10, 26, and 74
Mineral composition of breast milk	Mineral composition of breast milk	For women: at Weeks 1, 6, 26, and 74
Lumbar spine BMC	Lumbar spine BMC	For infants: Week 26
Infant growth	Infant growth	For infants: at Weeks 10 and 74
Concentration of hormonal growth factors (for infants)	Concentration of hormonal growth factors (for infants)	For infants: at birth and Weeks 10, 26, and 74

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Gilead Sciences
• Investigators: Study Chair: George K. Siberry, MD, MPH, NICHD/NIH; Study Chair: Lynda Stranix-Chibanda, MBChB, MMED, University of Zimbabwe

Publications and helpful links

General Publications

• Nurutdinova D, Onen NF, Hayes E, Mondy K, Overton ET. Adverse effects of tenofovir use in HIV-infected pregnant women and their infants. Ann Pharmacother. 2008 Nov;42(11):1581-5. doi: 10.1345/aph.1L083. Epub 2008 Oct 28.
• Baltrusaitis K, Makanani B, Tierney C, Fowler MG, Moodley D, Theron G, Nyakudya LH, Tomu M, Fairlie L, George K, Heckman B, Knowles K, Browning R, Siberry GK, Taha TE, Stranix-Chibanda L; PROMISE P1084s Study Team. Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial. BMC Infect Dis. 2022 Jul 20;22(1):634. doi: 10.1186/s12879-022-07608-8.
• Foster C, Lyall H, Olmscheid B, Pearce G, Zhang S, Gibb DM. Tenofovir disoproxil fumarate in pregnancy and prevention of mother-to-child transmission of HIV-1: is it time to move on from zidovudine? HIV Med. 2009 Aug;10(7):397-406. doi: 10.1111/j.1468-1293.2009.00709.x. Epub 2009 May 12.
• Stranix-Chibanda L, Tierney C, Sebikari D, Aizire J, Dadabhai S, Zanga A, Mukwasi-Kahari C, Vhembo T, Violari A, Theron G, Moodley D, George K, Fan B, Sommer MJ, Browning R, Mofenson LM, Shepherd J, Nelson B, Fowler MG, Siberry GK; PROMISE P1084s study team. Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial. PLoS One. 2021 Feb 5;16(2):e0246272. doi: 10.1371/journal.pone.0246272. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2011
• Primary Completion (Actual): November 30, 2015
• Study Completion (Actual): November 30, 2015

Study Registration Dates

• First Submitted: February 9, 2010
• First Submitted That Met QC Criteria: February 9, 2010
• First Posted (Estimate): February 10, 2010

Study Record Updates

• Last Update Posted (Actual): September 23, 2022
• Last Update Submitted That Met QC Criteria: September 22, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: tenofovir; pregnancy; breastfeeding; mother to child transmission; renal and bone toxicity
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir
• Other Study ID Numbers: P1084s (PROMISE); 10790 (Registry Identifier: DAIDS ES); IMPAACT P1084s