Both HIV and Tenofovir Tied to Skeletal Deficits in Young People

By Marilynn Larkin

July 07, 2021

NEW YORK (Reuters Health) - HIV is associated with "substantial" skeletal deficits toward the end of puberty, especially among girls, as is the antiretroviral tenovir disoproxil fumarate (TDF), a cross-sectional study shows.

"Currently TDF is in use, and quite literally saving many millions of lives around the world," Dr. Celia Gregson of the University of Bristol, UK, told Reuters Health by email. "We are not suggesting that TDF should be suddenly stopped, because alternative drugs are often not as readily available as we would wish."

That said, she added, "Children (with) HIV who are not treated with TDF have better bone density than children who receive TDF for four or more years, and this degree of difference in bone density usually equates to a 50% difference in risk of fracture."

"The weight of evidence is building against use of TDF as a first-line anti-retroviral treatment," she noted. "It is already known that TDF negatively affects the skeleton in adults; hence, TDF is no longer used as a first-line treatment in high-income countries where there are other, more expensive, alternative drugs available."

"But thought now does need to be given, for example by the World Health Organization, as to whether international guidelines for HIV management in children and adolescents in LMICs should be reviewed," she said.

As reported in The Lancet Child and Adolescent Health, Dr. Gregson and colleagues analyzed data from 303 children with HIV (mean age 12.4; 50% girls) and 306 children without HIV with similar demographics. For those with HIV, the median age of diagnosis was three years and the median ART duration was 8.1 years. TDF was included in ART for 34% of children.

Dual-energy X-ray absorptiometry was used to measure the bone outcomes of total-body less-head bone mineral content for lean mass adjusted for height (TBLH-BMCLBM) and lumbar spine bone mineral apparent density (LS-BMAD), with low scores defined as Z-scores of less than -2.0.

Children with HIV had a higher prevalence of low TBLH-BMCLBM Z-score (10% vs. 6%) and of low LS-BMAD Z-score (14% vs. 6%) compared to those without HIV.

Further, HIV and male sex were associated with earlier pubertal (Tanner) stage.

The negative associations between HIV and Z-scores for TBLH-BMCLBM and LS-BMAD were more pronounced with pubertal maturation, particularly in girls.

In adjusted analyses, TDF exposure and orphanhood were associated with lower TBLH-BMCLBM Z-scores among children with HIV.

Current TDF use (vs. non-TDF-based ART) was associated with a 0.41 reduction in the TBLH-BMCLBM Z-score, and a 0.31 reduction in the LS-BMAD Z-score.

Dr. Gregson's team is recruiting youngsters with HIV in Zimbabwe and Zambia into a trial of high-dose vitamin D and low-dose calcium to see whether bone density improves with a year of treatment. (

Dr. Ellen Cooper, Medical Director of the Pediatric and Adolescent HIV Program at Boston Medical Center, commented on the study in an email to Reuters Health. She noted that the authors emphasize the importance of nutritional vitamin D and calcium. "This is an important tool in reducing whatever negative effect that TDF has on bone development," she said. "It will not negate this effect, but could definitely reduce the total negative effect."

As the authors note, she said, "There is a newer formulation of a prodrug tenofovir (TAF), which is used in the U.S. and Europe and has less effect on the bone and kidney. Until there is TAF availability in resource-limited areas (or other antivirals altogether), it is most important to remind readers of steps that can be used to optimize bone health."

Dr. Joseph Alvarnas, a clinical professor in City of Hope's Department of Hematology and Hematopoietic Cell Transplantation in Duarte, California, also commented by email "This article provides a stark reminder that even effectively treated HIV infection continues to have a significant impact upon infected patients."

"While the study subjects were recruited from Zimbabwe, the analysis is far more broadly applicable," he said. "These data have relevance for clinicians who care for young and adolescent patients with HIV infections. Monitoring growth and bone development in HIV-infected children and adolescents needs be included as part of the care management of this vulnerable patient population."

SOURCE: Lancet Child and Adolescent Health, online June 14, 2021.