VOICE B: Bone Mineral Density Sub-study of VOICE -- Vaginal and Oral Interventions to Control the Epidemic
1. What is the aim of VOICE B, or the Bone Mineral Density Sub-study?
VOICE B, also known as the Bone Mineral Density Sub-study, is an observational study within a larger trial called VOICE -- Vaginal and Oral Interventions to Control the Epidemic, which is looking at whether some of the same antiretroviral (ARV) medicines used successfully for treatment of HIV are safe and effective for HIV prevention, as either a vaginal microbicide or an oral tablet. The ARV tablets being tested in VOICE are called tenofovir (also known as Viread®) and Truvada®. Although they are considered safe and effective for treating people with HIV as part of combination drug therapy, researchers have observed modest decreases in bone mineral density (thinning of bone) in HIV-infected people during treatment with tenofovir. As such, researchers are conducting VOICE B to determine the potential effects, if any, these oral drugs may have on bone health in HIV-negative women, and in particular, pre-menopausal women in Africa. African women generally have higher bone mass density than women elsewhere in the world, yet other factors may put them at risk for bone loss. VOICE B will provide valuable data that will help inform a field looking at the promise of ARV-based approaches for prevention of HIV, especially among women in Africa.
2. Who is conducting and funding the study?
As a sub-study of VOICE, VOICE B is funded by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID). Both studies are being conducted by a team of researchers working in the Microbicide Trials Network (MTN). The MTN is an HIV/AIDS clinical trials network established and funded in 2006 by DAIDS/NIAID with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all components of the U.S. National Institutes of Health (NIH). As a co-sponsor of VOICE, Gilead Sciences Inc., of Foster City, California, USA, is providing the oral study products free of charge. Sharon Riddler, M.D., M.P.H., of the University of Pittsburgh School of Medicine, is the protocol chair leading VOICE B.
3. Where is VOICE B being conducted?
VOICE B is being conducted at two VOICE Study sites: the Makerere University-Johns Hopkins University Research HIV Clinical Trial Unit in Kampala, Uganda; and the University of Zimbabwe-University of California-San Francisco HIV Prevention Trials Unit in Harare, Zimbabwe.
4. When did the VOICE B sub-study begin and how long will it last?
The Bone Mineral Density Sub-study is taking place concurrently with VOICE, which began September 2009. Women in both studies will be followed for up to three years.
5. How is the VOICE B sub-study designed?
VOICE B will involve about 300 sexually active, HIV-negative women who are participating in the VOICE Study and who have been randomly assigned to one of the trial’s three groups testing the oral tablet regimen. Each study participant who is randomized to the tablet regimen takes two tablets once a day, one that looks like tenofovir and one that looks like Truvada, although one contains the oral dose of the drug to which the participant was assigned (tenofovir, Truvada or placebo) and the second is an inactive placebo tablet. Neither the participants nor the researchers know who is in which tablet group because the study is “blinded.” Two other groups in VOICE apply a vaginal gel daily – either tenofovir gel or a placebo gel. Women in the gel groups will not be enrolled in VOICE B.
In order to determine if there are changes in bone health associated with use of the study tablets, participants in VOICE B undergo a specialized test called a DXA scan (short for dual energy x-ray absorptiometry) every six months. The DXA test assesses bone strength in the spine and hips and helps predict risk of bone fracture due to progressive bone loss, a condition called osteoporosis. In addition to the DXA scans, women in VOICE B have tests of their blood and urine to look for changes of bone-related minerals, such as calcium and phosphate; measurements of height and weight; and assessments of diet and nutrition. Women also are asked about their use of contraception, history breast feeding and physical activity, all of which can influence overall bone health.
6. What does the DXA scan involve?
The DXA scan is a safe and painless diagnostic procedure considered the most reliable way to assess bone strength and predict fracture risk. As the individual being tested lies on a cushioned table, a scanner passes over the body, capturing specialized images of bone. The DXA scan uses low-level x-rays, so the risk of radiation exposure is minimal The test takes about 10 minutes. DXA scanners have been installed at both VOICE B study sites and staff have been trained in its operation and how to read results. As part of routine quality control, sites will send scans electronically to the University of Pittsburgh Osteoporosis Center, where they will be reviewed a second time by a team of specialists in the field.
7. What do we know about tenofovir and Truvada?
The full name for tenofovir is tenofovir disoproxil fumarate (TDF). It is also known by the brand name Viread. Truvada is the brand name for a combination drug that contains tenofovir and another active ingredient called emtricitabine. Both drugs are manufactured by Gilead Sciences, Inc., of Foster City, California. Participants in VOICE are given the same daily doses of tenofovir and Truvada used for treating HIV as part of a regimen called antiretroviral therapy (ART). Both drugs have extensive safety profiles and are well tolerated by most HIV-infected people. In some, occasional minor side effects may be upset stomach, dizziness, headache, joint pain or fever. Serious side effects are rare, but can include liver function problems and kidney damage or failure.
HIV-positive women who are treated with an ART regimen that includes either tenofovir or Truvada can sometimes experience moderate bone loss. According to an ongoing Gilead-sponsored study following both men and women receiving tenofovir as part of ART, changes in bone mineral density have not been associated with increased risk of bone fracture. The effects of tenofovir and Truvada on bone health in HIV-negative individuals has not been studied.
8. Why is the Bone Mineral Density Sub-study important?
If a trial such as VOICE finds daily use of either tenofovir or Truvada effective for preventing HIV, and the approach becomes more widely available, it will be important to understand the potential effects, if any, on bone in women who are otherwise in good health. It is especially important to gain understanding of the effects on women in sub-Saharan Africa who are among those at highest risk for acquiring HIV. Although data are limited, African women seem to have comparatively higher bone mass density than women elsewhere in the world. Other factors, however, could contribute to changes in bone health if coupled with a daily regimen of tenofovir or Truvada. For instance, Depo-Provera, a contraceptive popular in many African countries, can result in gradual loss of bone-mineral density that usually returns to baseline once Depo-Provera is discontinued. VOICE researchers anticipate about half of its participants will be using Depo-Provera based on experience from the recently completed HPTN 035 study of PRO 2000 gel. Breastfeeding is another potential risk factor for bone loss, although any effects on bone are usually reversed when breastfeeding is stopped. Women who are pregnant or are breast feeding are not eligible to participate in VOICE, but it will still be important to fully evaluate the impact of prior breastfeeding on bone density changes during the course of the study. VOICE B will track bone density as a means of evaluating product safety and improving understanding of the effects of such drugs in healthy pre-menopausal, HIV-negative women.
9. Is bone health monitored in all VOICE participants?
All participants in the VOICE Study will undergo regular monitoring to assess how product use (gel or tablet) may be affecting bone, although more extensive monitoring is done in women who are also participating in VOICE B.
10. How is safety being monitored in VOICE B?
As part of the VOICE Study, VOICE B is being conducted according to rigorous standards to protect the safety and well-being of its participants. VOICE incorporates a multi-tiered safety review process, which begins at the site level, and includes strict national and international procedures for monitoring and reporting. Safety data collected in the Bone Mineral Density Sub-study will be reviewed by the VOICE Protocol Safety Review Team and the NIAID Vaccine and Prevention Data Safety Monitoring Board (DSMB), together with all other VOICE Study safety data.
11. Were special approvals required to conduct VOICE B?
VOICE B and VOICE were reviewed as separate studies by NIAID, the U.S. Food and Drug Administration, government and regulatory authorities in trial-site countries and by each trial site’s Institutional Review Board (IRB) or Ethics Committee (EC). IRBs and ECs ensure that studies are scientifically valid and ethically sound and provide oversight throughout the duration of the trial.
12. Will women participating in VOICE B provide informed consent?
This Bone Mineral Density Sub-study is for women who have already agreed to be in the VOICE Study, and who have been assigned to the oral tablets regimen. Participation is voluntary. Women who decide not to join VOICE B can still be in the VOICE Study. A separate written consent is obtained prior to screening and enrollment using forms translated into local languages. An extensive education process is employed to ensure that women understand the procedures, as well as possible risks and benefits of the study, a process that continues throughout the study.
13. What are the medical benefits for women participating in the study?
Study participants in VOICE receive free laboratory tests and physical exams, counseling on preventing HIV infection and free condoms. STI risk-reduction counseling, testing and treatment is provided at no charge to both women and their partners. Both VOICE and VOICE B provide pregnancy testing at every clinic visit and link participants with services related to contraception. Participants who acquire HIV during the trial will be counseled appropriately and receive referrals to community-based programs for care and support. Women in VOICE have the opportunity to undergo sophisticated medial assessments, including with technology that is not readily available in their countries. Results of the DXA scan, for instance, may indicate that a participant would benefit from calcium supplements, which study staff will provide at no cost during the course of the study.
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The VOICE Study is being conducted by a team of researchers working in the Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network established and funded in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all components of the U.S. National Institutes of Health (NIH). Additional information about the VOICE Study can be found at http://www.mtnstopshiv.org/news/studies/mtn003
27-April-2010
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