Two longitudinal studies and three randomized trials implicate TDF in BMD loss in HIV-positive men and women (Table 6). A large Veterans Affairs (VA) analysis determined that every year of TDF use inflates the risk of osteoporotic fracture 12%.43 The longitudinal studies and trials did not tally fracture rates or found no higher rate with TDF than with other regimens.
|Table 6. Key Findings on Bone Health in HIV-Positive People on Long-Term TDF|
BMD, bone mineral density.
The VA study involved 56,660 US veterans seen from 1998 through 2009, 98% of them men.43 Two thirds took antiretrovirals for at least 1 month. During follow-up 951 vets had an osteoporotic fracture, ascertained by ICD-9 code and defined as the first new spine, hip, or wrist fracture "selected on the basis of their likelihood of being related to osteoporosis." Veterans who sustained fractures were generally middleaged and only moderately older than those who did not (46 versus 44 years). People with fractures were more likely to be white (57% versus 45%) and more likely to smoke (56% versus 32%), have diabetes (25% versus 15%), have a body mass index below 20 kg/m2 (49% versus 33%), and have HCV infection (51% versus 31%) (P < 0.0001 for all comparisons).
The VA investigators sized up fracture risk factors in two multivariate models; the first factored in race, age, tobacco use, diabetes, body mass index, chronic kidney disease, HCV status, and cumulative exposure to TDF, abacavir, zidovudine or stavudine, any boosted PI, and any nonnucleoside; the second model added concomitant exposure to other antiretrovirals. Neither model considered other possibly telling variables, such as exercise, vitamin D or calcium, or use of steroids, alcohol, or illicit drugs; and the researchers could not evaluate BMD. Because the cohort included few women, results may not apply to them.
Through an average follow-up of 5.4 years, both multivariate models figured that every year taking TDF hiked the osteoporotic fracture risk 6%, but in both analyses the 95% confidence interval just crossed 1.0 (0.99 to 1.12 in model 1 and 0.99 to 1.14 in model 2).43 When the researchers limited the analyses to 33,439 vets who entered the cohort in the combination antiretroviral era (starting January 1, 1996), every year taking TDF independently upped the fracture risk about 12% (model 1 hazard ratio [HR] 1.13, 95% CI 1.05 to 1.21, P = 0.001; model 2 HR 1.12, 95% CI 1.03 to 1.21, P = 0.011). Adding a boosted PI to a TDF regimen inflated the risk slightly more (HR 1.16, 95% CI 1.04 to 1.30). Cumulative antiretroviral use did not make fractures more likely, but several classic risk factors did: white race, older age, tobacco use, and body mass index below 20 kg/m2.
Longitudinal analysis of total body BMD in HIV-positive men and women in the Nutrition for Healthy Living Study linked greater bone loss to steroids and two antiretrovirals -- TDF and didanosine.44 The Nutrition for Healthy Living Study is a prospective cohort of HIV-positive adults living in Massachusetts and Rhode Island. This analysis included 283 men and 96 women seen between August 1996 and September 2003 who had at least two whole-body DEXA scans at least 1 year apart. Median age was 42.7 in men and 39.4 in women; 59.4% and 34.4% were white, 25.4% and 51.0% were black. Smoking rates were high in both men and women (43.3% and 66.7%), as was a history of injection drug use (32.2% and 44.8%). Among women, 17.7% were postmenopausal. While 30% of men reported strength training in the previous week, only 11.6% of women did.
Statistical analysis adjusted for age, race, sex, menopause, and smoking linked greater loss of total BMD to TDF use, longer didanosine use, prednisone or hydrocortisone use, lower body mass index, and lower albumin.44 TDF use conferred an average 2.04% drop in total BMD among men and an average 1.74% decline in premenopausal women. Strength training mitigated loss of total BMD.
A longitudinal study of 671 antiretroviral-treated people in Spain included 483 men (72%) and 188 women, only 18 of them (10%) postmenopausal.45 Median age for the whole group was 42.1 years, median time on antiretroviral therapy 7.4 years, and median time on tenofovir 2.2 years. Almost half of the study group (47.5%) had osteopenia, and almost one quarter (23%) had osteoporosis.
Among people who took TDF for 1 year or less, 20% had osteoporosis, while in those who took TDF for more than 5 years, 37% had osteoporosis.45 Taking TDF at the time of the most recent DEXA scan upped the odds of declining BMD 44% (OR 1.44, 95% CI 1.03 to 2.20, P = 0.03). Among 105 people with at least 5 years of follow-up, DEXA scans confirmed progression to osteopenia in 18% and to osteoporosis in 29%. Odds of BMD loss or progression to osteopenia or osteoporosis rose with longer time taking TDF (OR 1.08, 95% CI 1.03 to 1.14, P < 0.0019), longer time taking a PI (OR 1.18, 95% CI 1.12 to 1.24, P < 0.0001), and current PI use (OR 1.64, 95% CI 1.35 to 2.04, P < 0.0001)
Through 144 weeks of follow-up in the 517-person international trial comparing TDF/FTC with ZDV/3TC (both with efavirenz) in antiretroviral-naive adults, 6 people in the TDF group and 8 in the ZDV/3TC group broke a bone.23 Trauma caused all fractures, and the investigators attributed none of the breaks to study drugs. The researchers did not report changes in BMD. This trial excluded people with a history of "clinically significant bone disease."
After 144 weeks in the trial comparing TDF/3TC with stavudine/3TC in 602 previously untreated adults, researchers charted a greater drop from baseline lumbar spine BMD in the TDF group (-2.2% TDF versus -1.0% stavudine, P = 0.001).24 BMD faded even more at the hip in both study groups, and the difference between groups approached statistical significance (-2.8% TDF and -2.4% stavudine, P = 0.06). The researchers noted, though, that BMD waning generally occurred through weeks 24 to 48 then stabilized. Five people randomized to TDF and 11 randomized to stavudine broke a bone during follow-up.
ACTG protocol A5224s was a substudy of a trial that randomized antiretroviral-naive adults to TDF/FTC or abacavir (ABC)/3TC with open-label efavirenz or atazanavir/ritonavir.46 Of the 269 study participants, 229 (85%) were men, and median age was similar across the four arms (38 years overall). Almost half of enrollees (47%) were white non-Hispanic, 33% were black non-Hispanic, and 16% were Hispanic. Almost one third (32%) broke a bone in the past.
After 96 weeks spine BMD decreased significantly more in the TDF/FTC arms than in the ABC/3TC arms (-3.3% versus -1.3%, P = 0.004), as did hip BMD (-4.0% versus -2.6%, P = 0.024).46 ABC/3TC plus efavirenz was the only combination not linked to a significant 96-week drop in spine BMD. From study entry to week 48, declines in BMD were greater with TDF/FTC than with ABC/3TC at the lumbar spine (-1.66%, P = 0.005) and hip (-1.43%, P = 0.007). But from weeks 48 through 192, mean percent change in BMD per year did not differ between the two groups. Regression analysis that factored in age, sex, race/ethnicity, and pretreatment viral load, CD4 count, and body mass index reckoned significant associations between ABC/3TC (versus TDF/FTC) and greater BMD at both the spine (parameter estimate 1.90, P = 0.003) and hip (parameter estimate 1.28, P = 0.033) at week 96. About 1 in 20 people had a trauma-related fracture during 96 weeks of followup, but neither fracture rate nor time to first fracture differed by treatment assignment.
What can one make of the bone data medley from studies of people who run some risk of HIV infection and may consider TDF/FTC PrEP? First, the PrEP trials themselves show that taking TDF to ward off infection depletes bone mineral density -- but only in small proportions of people during these trials' 1 to 2 years of follow-up.4,6,7,32 And taking TDF for PrEP had no impact on fracture risk during any of these placebo-controlled trials.4-7,9,32
How longer-term TDF PrEP will affect bone health depends on how consistently people take their PrEP pills and what other bone risk factors they have. Several studies of HIV-negative but at-risk men and women in the United States and the Netherlands leave no doubt that people likely to consider PrEP bear a hefty burden of low-BMD risk factors,32-36,38-40 including cigarette smoking, use of alcohol and injected or noninjected drugs, methadone maintenance, lack of exercise, previous fractures, diabetes, and HCV infection.
A study of HIV-negative gay and bisexual men recruited for a TDF PrEP trial in San Francisco found that 10% had low BMD of the spine, total hip, or femoral neck before they started PrEP, and that taking amphetamines or inhalants boosted the risk of low BMD.32 This finding resonated in a Dutch study of men (91% gay or bisexual) with primary HIV infection, 45% of whom had osteopenia and 6% of whom had osteoporosis.35 The researchers found mixed evidence on whether the spiking viremia of acute infection caused or contributed to this high rate of depleted BMD or whether that rate could be more firmly tied to pre-HIV risk factors. Rates of osteopenia or osteoporosis were high and similar in 49-year-old and older HIV-positive and negative but at-risk men in a New York City study (55% and 51%).34 A large majority of men in this study, 89%, used illicit drugs, and 47% were on methadone maintenance.
Together these findings indicate that middle-aged male PrEP candidates in the United States and perhaps Western Europe -- including gay men and drug injectors -- may have compromised bone health before starting TDF/FTC PrEP. Clinicians considering PrEP for men like these would do well to heed FDA advice to check them for "a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss."7 A pre-PrEP bone scan may be in order for some men. Notably, the early San Francisco PrEP trial found that men taking multivitamins, calcium, or vitamin D trimmed their risk of low BMD.32 And the FDA suggests calcium or vitamin D supplements may have a role in slowing BMD decline.7
Unlike these studies of men at risk of HIV infection or with acute HIV infection,32-35 studies of at-risk mostly premenopausal US women in two cohorts did not find an undue burden of osteopenia or osteoporosis.36,38-40 Two studies saw links between methadone maintenance and low BMD in women36,38 (as did one in HIV-positive and at-risk men34). All these studies recorded lofty rates of classic bone risk factors in women with and without HIV, and these risk factors inflated the odds of low BMD in statistical analyses. Providers discussing PrEP with women should review the list of bone risk variables in Table 1 and might consider DEXA scanning, vitamin D, and calcium for women with an apparently high risk.
Three longitudinal studies of HIV-positive people were unanimous in linking TDF use to either a higher osteoporotic fracture rate43 or to dwindling BMD.44,45 The large Veterans Affairs study that established a magnified fracture risk with TDF is limited in that it could not determine changes in BMD; it could not clinically confirm fractures, which were ascertained by ICD-9 codes; and almost all study participants were men.43 The two much smaller longitudinal studies that confirmed declining BMD in people taking TDF did not report fracture rates.44,45 A Spanish study tied TDF use to progression from normal BMD to osteopenia or osteoporosis through 5 years of follow-up.45 Three randomized trials found equivalent or lower fracture rates with TDF regimens than with comparison regimens.23,24,46 But two of these studies confirmed greater declines in BMD with TDF combinations than with non-TDF combinations.24,46 In the two trials that tracked BMD, the dips occurred mostly in the first year of therapy and then stabilized.
Anyone who prescribes antiretrovirals or scans FDA prescribing information for TDF7 knows that this reverse transcriptase inhibitor can muddle kidney function or deplete bone mineral. Gilead Sciences, TDF's maker, plainly acknowledges the drug's toxic potential in its full-tilt development of GS-7340, a defanged TDF facsimile the company hopes will stymie HIV better than TDF but with less toxic sting.47-50
Although two large randomized trials left no doubt that TDF has a cleaner safety record than the nucleosides it displaced, zidovudine and stavudine,23,24,27 long-term TDF therapy clearly poses some kidney and bone risk. Some research indicates that TDFlinked kidney toxicity dissipates when TDF stops,18,19 but a 10,000-person Veterans Affairs study found that it may not.17 Another prospective veterans study figured that every year of TDF use boosts the risk of osteoporotic fracture 12%,43 while other cohort studies and trials confirmed dwindling bone mineral density with TDF but found no greater fracture risk.23,24,44,46 TDF PrEP trials showed that the drug leaves a thin toxic trail in kidney and bone of HIV-negative people, though toxicity rates were low during the 1 to 2 years of follow-up in these studies.4-6,9,32
Cohort studies leave no doubt that men and women at risk of HIV infection have histories full of kidney and bone risk factors, summarized in Table 1. And some -- but hardly all -- studies of HIV-negative people disclosed an above-average rate of kidney and bone disease in these people.
PrEP prescribers should keep all this in mind when pondering risks and benefits of TDF/FTC with PrEP candidates. And they should follow FDA and CDC advice to avoid PrEP in people with creatinine clearance below 60 mL/min and to consider DEXA scans for candidates with a past fracture or other bone loss risk factors.7