Spine and hip bone mineral density (BMD) fell slightly but significantly in the first 24 weeks of pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (Truvada) taken by HIV-negative men who have sex with men (MSM) and transgender women in the iPrEx trial. These declines were much smaller than those seen in HIV-positive people starting TDF as part of an antiretroviral regimen.
Daily and as-needed PrEP prevented HIV infection in trials of MSM, heterosexual women and men, and injection drug users. In the United States, the Centers for Disease Control and Prevention (CDC) recommend daily PrEP "as one prevention option" for sexually active MSM and heterosexuals "at substantial risk of HIV acquisition," and for at-risk injection drug users. PrEP should be discussed with HIV-negative partners of HIV-positive people, the guidelines add.
Because BMD falls when HIV-positive people start tenofovir as part of their antiretroviral therapy, investigators in the iPrEx trial -- the first to demonstrate the protective effect of PrEP against HIV infection -- conducted a substudy. The substudy involved 247 participants randomized to TDF/FTC and 251 randomized to placebo. All participants had DXA scans to measure BMD before starting PrEP and then at 24-week intervals. iPrEx recruited the participants from North and South America, South Africa and Thailand. Age averaged 28 years in the bone substudy.
After the first 24 weeks of PrEP, spine BMD fell 0.91% and hip BMD fell 0.61% in people randomized to tenofovir/emtricitabine -- small but significant declines. BMD dropped an average of 0.12% in subsequent 24-week intervals, and these declines were not statistically significant. BMD did not change through 96 weeks in the placebo group. In study participants with intracellular tenofovir-diphosphate levels indicating consistent daily dosing, spine and hip BMD loss at week 24 averaged 1.42% and 0.85%. BMD changes at 24 weeks correlated inversely with intracellular tenofovir-diphosphate.
Among participants who stopped PrEP, spine BMD tended to rebound. Hip BMD also trended upward after PrEP stopped. Fracture incidence did not differ between participants taking tenofovir/emtricitabine and those taking placebo in this young population. Participants with fractures during the trial did not have BMD levels that met standard criteria for osteoporosis before or during the trial.
BMD falls an average of 4% to 6% in the first 6 to 12 months of antiretroviral therapy including tenofovir, and then typically stabilizes or rises. The researchers note that "bone loss among highly adherent PrEP users" in this substudy "was still less than that observed after starting combination antiretroviral therapy for HIV infection." The clinical significance of small BMD declines in healthy young and middle-age HIV-negative people, the authors observe, is unknown.
The iPrEx researchers believe their findings suggest no reason to modify the CDC's advice that routine DXA is not warranted for people taking PrEP unless they have additional fracture risk factors. But because MSM and transgender women in this and other studies tend to have low BMD, the authors suggest that those starting PrEP should be counseled about limiting alcohol and tobacco, increasing weight-bearing exercise, and getting enough calcium and vitamin D.
The French Ipergay trial found that two doses of tenofovir/emtricitabine before sex and two after sex -- rather than daily tenofovir/emtricitabine -- protects MSM from HIV acquisition. As-needed tenofovir/emtricitabine dosing may have a smaller impact on BMD.
Mark Mascolini is a freelance writer focused on HIV infection.