Trial of Vitamin D in HIV Progression (TOV4)

The purpose of this study is to determine the efficacy and safety of vitamin D3 (cholecalciferol) supplementation on HIV progression and incidence of pulmonary tuberculosis among HIV-positive Tanzanian adult men and women initiating highly active antiretroviral therapy (HAART).

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Dietary supplement: Vitamin D3 (cholecalciferol); Other: Placebo

Detailed Description

HIV-infected adults initiating antiretroviral therapy in resource-limited settings experience high mortality, pulmonary tuberculosis, and other comorbidity rates during the first year of HIV treatment. Observational studies have shown low vitamin D is a risk factor for HIV progression and incidence of pulmonary tuberculosis among adults initiating HAART; however, whether this relationship is causal and if vitamin D supplementation starting at HAART initiation can improve health outcomes has not been determined. This study is a randomized, double-blind, placebo-controlled trial conducted to examine the effect of vitamin D3 supplementation on morality and pulmonary tuberculosis for adults initiating HAART. Participants are HIV-positive Tanzanian men and women aged 18 years and older, who are initiating HAART at the time of randomization whose baseline 25-hydroxyvitamin D (25(OH)D) concentration is <30ng/mL. Eligible individuals are randomized to receive a) a vitamin D3 regimen consisting 50,000 IU of vitamin D3 taken orally once per week for 4 weeks (weeks 0, 1, 2, 3) followed by 2,000 IU of vitamin D3 supplements taken orally once per day starting at 4 weeks until study discharge at 12 months or b) placebo pills taken once weekly for 4 weeks (weeks 0, 1, 2, 3) followed by placebo pills taken daily starting at 4 weeks until study discharge. Participants will be followed for 12 months after ART initiation.

• Study Type: Interventional
• Enrollment (Actual): 4000
• Phase: Phase 3

Contacts and Locations

Study Locations

• Tanzania
  • Dar es Salaam, Tanzania
    • Management and Development for Health (MDH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-positive
• Men or Women
• 18 Years of Age or older
• Initiating HAART at time of randomization
• 25(OH)D concentration <30 ng/mL at HAART initiation

Exclusion Criteria:

• Pregnant Women
• Enrolled in another micronutrient trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo pills taken once weekly for 4 weeks (weeks 0, 1, 2, 3) followed by placebo pills taken orally once per day starting at 4 weeks until study discharge at 12 months
Experimental: Vitamin D3 (cholecalciferol)	Dietary supplement: Vitamin D3 (cholecalciferol); Supplements containing 50,000 IU of vitamin D3 (cholecalciferol) taken orally once per week for 4 weeks (weeks 0, 1, 2, 3) followed by 2,000 IU of vitamin D3 (cholecalciferol) supplements taken orally once per day starting at 4 weeks until study discharge at 12 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
All-cause death	within 12 months after randomization
Pulmonary tuberculosis	within 12 months after randomization

Secondary Outcome Measures

Outcome Measure	Time Frame
CD4+ T-cell count	6 and 12 months after randomization
Physician diagnosis of comorbidities	within 12 months after randomization
Parathyroid hormone (PTH)	1, 6, and 12 months after randomization
Alkaline phosphatase (ALP)	1, 6, and 12 months after randomization
>10% weight loss	monthly from month 1 to month 12
Wasting (BMI <18.5 kg/m2)	monthly from month 1 to month 12
Hypercalcemia	1, 6, and 12 months after randomization
Physical activity	6 and 12 months after randomization
Immunologic biomarker levels (IL-2, IL-12, IFN-γ, and cathelicidin)	1, 6, and 12 months after randomization
Depression and anxiety scores	6 and 12 months after randomization

Collaborators and Investigators

• Sponsor: Harvard School of Public Health (HSPH)
• Collaborators: Management and Development for Health (MDH)
• Investigators: Principal Investigator: Wafaie W Fawzi, MBBS, DrPH, Harvard School of Public Health (HSPH); Principal Investigator: Ferdinand M Mugusi, MD, Management and Development for Health (MDH)

Publications and helpful links

General Publications

• Sudfeld CR, Mugusi F, Aboud S, Nagu TJ, Wang M, Fawzi WW. Efficacy of vitamin D3 supplementation in reducing incidence of pulmonary tuberculosis and mortality among HIV-infected Tanzanian adults initiating antiretroviral therapy: study protocol for a randomized controlled trial. Trials. 2017 Feb 10;18(1):66. doi: 10.1186/s13063-017-1819-5.
• Muhihi A, Fawzi WW, Aboud S, Nagu TJ, Ulenga N, Wang M, Mugusi F, Sudfeld CR. Cholecalciferol Supplementation Does Not Affect the Risk of HIV Progression, Viral Suppression, Comorbidities, Weight Loss, and Depression among Tanzanian Adults Initiating Antiretroviral Therapy: Secondary Outcomes of a Randomized Trial. J Nutr. 2022 Aug 9;152(8):1983-1990. doi: 10.1093/jn/nxac096.
• Sudfeld CR, Mugusi F, Muhihi A, Aboud S, Nagu TJ, Ulenga N, Hong B, Wang M, Fawzi WW. Efficacy of vitamin D3 supplementation for the prevention of pulmonary tuberculosis and mortality in HIV: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2020 Jul;7(7):e463-e471. doi: 10.1016/S2352-3018(20)30108-9.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2014
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): March 31, 2019

Study Registration Dates

• First Submitted: February 21, 2013
• First Submitted That Met QC Criteria: February 22, 2013
• First Posted (Estimate): February 26, 2013

Study Record Updates

• Last Update Posted (Actual): August 9, 2019
• Last Update Submitted That Met QC Criteria: August 8, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• 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; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: R01DK098075 (U.S. NIH Grant/Contract)