Only the bold would try to wrest overarching conclusions from the data payload explored in the preceding two sections. But a few suggestions seem feasible.
First, the limited studies of kidney function in HIVnegative people with a possibly high risk of infection offer no evidence that PrEP candidates, as a group, have notably fragile kidneys just waiting for a nephrotoxic insult.12,15 But in the MACS study of HIVpositive and negative gay and bisexual men, the negative group had concerning rates of two kidney risk factors -- hypertension (37%) and diabetes (13%).12 And although HIV-positive women in the HERS analysis had a significantly higher rate of renal lab abnormalities than HIV-negative women, more than 1 in 20 women in the negative group did have such warning signals.15 Findings like these buttress FDA7 and CDC28,29 advice to screen PrEP candidates for creatinine clearance, to probe for other kidney risk factors (including smoking) before prescribing TDF/FTC, and to continue monitoring kidney function in PrEP takers.
PrEP trials showing low rates of creatinine elevations or phosphorus slumps in HIV-negative people randomized to TDF offer some reassurance.4-6,11 Remember, though, that these trial participants got monitored more than PrEP takers would in clinical practice, and that follow-up in these trials ranged from 1 to 2 years.
Clinical trials and cohort studies of HIV-positive people taking TDF found low to modest rates of elevated creatinine, slowed creatinine clearance, or chronic kidney disease.23,27 But three large cohort studies in the United States and Europe linked TDF therapy to possibly ominous changes in kidney markers,17,20,25 though one of the US studies discerned a higher risk of chronic kidney disease with TDF only in people also taking a ritonavir-boosted PI.20
The study tying longer TDF use to three unpropitious kidney outcomes in US veterans raised the additional concern that these ill-trending renal markers did not improve readily when TDF stops.17,17A These investigators cite two other studies confirming incomplete reversibility of TDF-linked kidney changes, though one of these studies involved only 24 men30 and the other was cross-sectional.31 And two singlecenter studies documented improving kidney markers in most people with compromised kidney function who stopped TDF.18,19 Still, prudent prescribers will keep the veterans findings in mind when evaluating people for PrEP and charting their progress.
FDA regulators7 and CDC experts28,29 do not suggest screening all PrEP candidates for bone mineral density (BMD) before starting TDF/FTC PrEP. But, without differentiating between TDF/FTC for PrEP or HIV therapy, the FDA counsels prescribers to check BMD in people with "a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss."7 Prescribing information suggests "supplementation with calcium and vitamin D ... may be beneficial" for people with a high risk of bone loss but notes that this strategy remains unstudied.
PrEP trials offer a look at BMD changes and fracture risk in HIV-negative people randomized to daily TDF, and the literature features several analyses of bone changes in HIV-negative people at risk of HIV infection or people with newly diagnosed HIV (Table 5). PrEP trial data on TDF-related bone toxicity must be interpreted cautiously because of the poor TDF/FTC adherence reported among many trial participants.
|Table 5. Key Findings on Bone Health in HIV-Negative at-Risk People Taking or Not Taking TDF|
BMD, bone mineral density.
The iPrEx PrEP trial of HIV-negative men and transgender women who have sex with men4 included a bone substudy of 503 participants, summarized in the Truvada license.7 People randomized to TDF/FTC had greater declines in BMD than those randomized to placebo; these drops ranged from -0.4% to -1.0% across total hip, spine, femoral neck, and trochanter. Bone mineral changes migrated back toward baseline values after TDF/FTC stopped. While 6% of iPrEx participants randomized to placebo lost at least 5% of spine BMD during follow-up, 13% randomized to TDF/FTC lost that much. But fracture rates did not differ between the TDF/FTC group and the placebo group (1.7% and 1.4%), and BMD changes did not correlate with fractures.
In the TDF2 PrEP trial of high-risk Botswana men and women, people in the TDF/FTC group had significantly greater BMD drops in the forearm, hip, and lumbar spine than did people randomized to placebo.6 But fracture rates did not differ between the two groups (1.1% with TDF, 1% with placebo) through a median 1.1 years of follow-up. The Partners PrEP trial of TDF and TDF/FTC PrEP in HIVdiscordant African couples did not measure BMD. But again fracture rates during a median 1.9 years of follow-up were similar in people randomized to a TDF regimen and those randomized to placebo (0.8% and 0.6%).5,7 Fractures were even less frequent in the FEM-PrEP trial of African women, 0.1% in the TDF/FTC group and 0.2% in the placebo group.9
These placebo-controlled trials of TDF/FTC PrEP are unanimous in finding no excess fracture incidence with TDF/FTC PrEP versus placebo during 1 to 2 years of follow-up. But BMD did decline significantly more with TDF than with placebo in iPrEx4 and TDF2.6
A pre-iPrEx placebo-controlled trial of TDF PrEP in gay and bisexual men in San Francisco offers admonitory data on bone risk in US men who may take PrEP.32 Before anyone swallowed a single pill, DEXA scanning determined that 20 of 210 men (10%) had a BMD z score at or below -2.0 at the L2-L4 spine, total hip, or femoral neck. These men had a median age of about 40. Taking amphetamines inflated the odds of low BMD almost 6 times (OR 5.86, 95% CI 1.70 to 2.20), and using inhalants (poppers, amyl nitrate, nitrous oxide, glue) more than quadrupled the odds (OR 4.57, 95% CI 1.32 to 15.81). Men who took multivitamins, calcium, or vitamin D had lower chances of deficient BMD than did men not taking these supplements.
These researchers tracked BMD changes in 184 men, half of whom began TDF or placebo after a 9-month hiatus to appraise changes in pill-associated risk behavior.32 Compared with men who started placebo or no study drug, those starting TDF had a 1.1% net drop in BMD at the femoral neck (P = 0.004), a 0.8% decline at the total hip (P = 0.003), and a 0.7% dwindling at the L2-L4 spine (P = 0.11). After 24 months, 13% of men randomized to TDF versus 6% randomized to placebo or taking no study drugs had more than a 5% fall in BMD at the femoral neck, a nonsignificant difference (P = 0.13).
The investigators believe their findings "suggest that low BMD may pre-date HIV infection among men at risk for acquisition of HIV, and use of tenofovir in these individuals leads to a small but statistically significant decline in BMD."32
A MACS cohort analysis of HIV-positive and at-risk gay or bisexual US men at least 30 years old found a similar osteoporosis-related fracture incidence in the HIV-positive and negative groups.33 But after statistical adjustment for body mass index and race, men with HIV had a higher fracture incidence starting at age 50. This analysis involved 5106 men who made study visits every 6 months at some point between 1996 and 2011. Age averaged 45.2 in men with HIV and 47.5 in men without HIV, and respective proportions of whites were 70% and 82%. In the HIV and no-HIV groups, 31% and 24% smoked and 42% and 45% smoked at the past.
During follow-up the MACS team counted 53 FRAXdefined fractures in the HIV group and 50 in the HIV-negative groups for crude incidence rates of 0.15 per 100 person-years with HIV and 0.13 per 100 person-years without HIV. But after statistical adjustment for body mass index and race, incidence was higher in HIV-positive men than negative men 50 to 64 years old (1.78 versus 0.74 compared with 30- to 39-year-olds) and higher in HIV-positive men than negative men 65 or older (3.50 versus 2.44 compared with 30- to 39-year-olds) (Figure 3).
|Figure 3. New Fracture Rate by Age in US Gay Men With Versus Without HIV|
Compared with US gay and bisexual men from 30 to 49 years old in the Multicenter AIDS Cohort Study, risk of new osteoporosisrelated fractures was higher in HIV-positive men than in HIV-negative men from 50 to 64 years old or 65 and older.33
A New York City study compared BMD in men with HIV and at risk of HIV, all of them at least 49 years old (median 55).34 This study involved 328 HIV-positive men in the Cohort of HIV at-risk Men's Prospective Study (CHAMPS) and 231 HIV-negative cohort members. HIV-negative men had a high risk of HIV infection because they injected drugs or had high-risk sex. Most men (89%) used illicit drugs, and 56% were black. High proportions of HIV-positive and negative men had classic risk factors for low BMD, including 90% who smoked or once smoked, 47% in a methadone maintenance program, 30% who used heroin in the past 5 years, 52% who exercised less than once a week, and 54% with serum testosterone below 300 ng/dL.
Of the 559 men studied, 299 (54%) had osteopenia or osteoporosis, and that rate did not differ significantly between men with and without HIV (55% versus 51%, P = 0.4).34 The osteopenia rates in these men were similar to national estimates among white men 50 and older. But the proportion of men with osteoporosis in this study, 14%, was higher than in the general population.
Statistical analysis adjusted for age, weight, race, testosterone level, and prednisone and illicit drug use found lower BMD at the femoral neck and lumbar spine in men with than without HIV. HIV infection, older age, nonblack race, lower weight, low testosterone, prednisone use, heroin use, and current methadone maintenance were independently associated with low BMD at the femoral neck, lumbar spine, or both sites. Osteopenia or osteoporosis independently raised the fracture risk, but HIV infection did not.
A Netherlands study of 33 young men just infected with HIV found that more than half had osteopenia or osteoporosis.35 Some evidence from this study hinted HIV itself accounted for low BMD in at least some of these men, but other evidence suggested low BMD preceded HIV infection in these men.
Of the 33 men assessed, 30 were gay or bisexual, none were injection drug users, and none had HCV or HBV infection.35 Their age averaged 38 years, and their body mass index averaged 22.7 kg/m2 (within the normal range of 18.5 to 24.9). Only 1 man had taken antiretrovirals -- for 9 days -- when DEXA scans measured BMD of the lumbar spine, femoral neck, and total hip. Low BMD risk factors abounded in these men: Twenty-six men (79%) were white, 22 (67%) currently used drugs, 18 (55%) smoked, and 7 (21%) downed more than 3 alcoholic drinks a day. Ten men (30%) had low osteocalcin levels, which may betoken flagging bone formation. Twelve men (36%) had broken a bone before getting infected with HIV. About half of these men also had some bone-boosting habits -- multivitamin use by 17 men (52%) and strenuous exercise for at least 20 minutes at least 3 times a week by 19 men (58%).
Average lumbar spine t score (-0.8) and z score (-0.7) and average femoral neck t score (-0.5) were significantly lower than in a reference population. Fifteen of 33 men (45%) met World Health Organization criteria for osteopenia, and 2 of 33 (6%) met osteoporosis criteria. "These numbers," the authors observed, "are much higher than would be expected in a relatively young male population like ours."35
Can recent HIV infection -- and the resulting lofty viral load -- explain low bone density in these men? Or did their multiple bone risk factors, maybe coupled with genetics, account for these formidable rates of osteopenia and osteoporosis? Perhaps both. But it's hard to dismiss the big list of risk factors -- including an impressive fracture history -- these men brought into the study. One statistical analysis these researchers ran suggested spiking viremia during primary HIV infection did contribute to low BMD in these men: Linear regression analysis adjusted for age and body mass index saw a link between higher viral load and lower total hip t score (β -0.2, P = 0.02). But reduced BMD in these men could not be tied to biochemical evidence of brisk bone turnover or systemic inflammation, which the researchers noted might be expected during primary HIV infection. Citing the San Francisco study of HIV-negative gay and bisexual men,32 the Dutch team proposed their findings also raise the question "whether it is actually the recent HIV-1 infection causing rapid bone loss shortly after transmission, or whether these bone disorders predate HIV infection and are caused by other risk factors."35
Several studies scrutinized bone variables in HIVnegative women with some risk of HIV infection. A 2001-2003 study of HIV-positive women and negative women at risk of infection found that HIV independently raised the risk of low BMD, but only in nonblack women.36 Overall prevalence of low BMD in these middle-aged women (27% in the HIV group and 19% in the negative group) lagged national estimates of osteopenia and osteoporosis, perhaps because of the high proportions of black and overweight women in this cohort.
The study involved 263 women with HIV and 232 without HIV in the New York City-based Menopause Study, a longitudinal analysis of menopause and its impact on women with and at risk of HIV infection.36 The women averaged 44.5 years in age; racial/ethnic proportions were 59% and 44% black in the HIV and no-HIV groups, 34% and 42% Hispanic, and 6% and 12% white. Only 8% of women were postmenopausal, though about 74% were rated perimenopausal (older than 40 and not amenorrheic). Proportions of overweight women (25 to 29.9 kg/m2) were 36% with HIV and 22% without HIV, and respective proportions of obese women were 32% and 62%.
Moderately high proportions of these women -- 61% with HIV and 54% without HIV -- reported regular exercise, though a similar proportion -- 53% in both groups -- reported watching more than 4 hours of TV daily. High proportions (63% with HIV and 72% without HIV) smoked, while 27% and 19% had smoked in the past. About 8% of women had used prednisone, and about 15% had used estrogen. About 20% had an earlier fracture. Drug use was not rare in women with or without HIV: heroin in past 5 years (22% and 33%), cocaine in past 5 years (44% and 45%), and current methadone maintenance (23% and 44%).
Compared with HIV-negative women, those with HIV had significantly lower BMD at the femoral neck and lumbar spine, significantly lower t scores at both sites, and significantly lower z scores at the femoral neck. But low BMD affected these women less often than women in the general population. While 51% to 70% of white women in the US at least 50 years old have reduced BMD (up to 50% with osteopenia and 20% with osteoporosis),37 nonblack women in this study group had a 25% prevalence of osteopenia and a 5% rate of osteoporosis. The researchers suggested the low overall rates of reduced BMD in their cohort (27% of women with HIV and 19% without HIV) reflect the high proportion of black women (who have a diminished risk of low BMD compared with whites) and the "extremely high prevalence" of overweight and obesity.
Linear regression analysis determined that HIV independently raised the risk of low BMD (defined as a t score at least 1 standard deviation below the average peak bone mass in young adult women) at the femoral neck and lumbar spine (β -0.026, P = 0.02; β -0.041, P < 0.01). Classic independent risk factors were older age, nonblack race, low weight, prednisone use, cocaine use, prior fracture, and methadone maintenance. In race-stratified analyses, HIV was independently associated with low femoral neck BMD (β -0.04, P < 0.01) in nonblack women, but the HIV association did not hold in black women. In women with HIV, neither nucleosides nor PIs were associated with low BMD.
This New York Menopause Study in women36 and the New York CHAMPS study in HIV-positive and at-risk men34 both linked methadone maintenance to low BMD. A recent comparison of BMD in HIVnegative women on methadone and healthy controls confirmed a lower total hip BMD in the methadone group, but not lower lumbar spine or femoral neck BMD.38 The study involved 11 young women taking methadone after heroin addiction and 30 healthy women without a heroin problem and not taking methadone. Ages ranged from 20 to 29 in the two groups, and the methadone group had taken this agent for 1.5 to 9 years (median 3). No women in either group had former or current low weight, though average body mass indices leaned toward the lower end of normal (21.9 kg/m2 with methadone and 20.5 kg/m2 without). Women taking methadone had other bone risk factors, including smoking, alcohol use, and cocaine use. DEXA scans found equivalent BMD in the spine and femoral neck in the methadone group and the comparison group, and marginally lower total hip BMD in women on methadone maintenance (P = 0.054 for BMD, P = 0.049 for t score). The researchers proposed that "long-term methadone substitution in HIV-negative women seems to slightly affect bone mass density."38
Two analyses of BMD and fractures in premenopausal women with HIV and at risk of HIV infection found lower BMD in the HIV group but no difference in fracture rates.39,40 Both studies come from the Women's Interagency HIV Study (WIHS), which recruits HIV-positive and at-risk women in the Bronx, Brooklyn, Washington, DC, Los Angeles, San Francisco, and Chicago.
The first study involved 100 women with HIV and 68 uninfected women who had DEXA scans of the femoral neck and lumbar spine at visits separated by a median of 2.5 years.39 At the first visit women with HIV had 5% lower BMD at both sites, but the annual drop in BMD through follow-up did not differ between groups. Statistical analysis adjusted for age, weight, and BMD at the initial visit confirmed similar BMD declines in women with and without HIV. Self-reported fracture incidence was nonsignificantly higher in the HIV-negative group (1.03 versus 0.74 per 100 person-years without and with HIV, P = 1.0).
As in other studies of US women at risk of HIV infection, this WIHS contingent carried more than a few bone risk factors: 65% smoked at the first visit and 78% ever smoked, 56% drank alcohol, 46% ever used cocaine, 23% injected drugs, 31% tested positive for HCV, and 5% had diabetes.39 On the plus side -- as far as BMD is concerned -- body mass index averaged 30.2 kg/m2, in the obese range. And 26% of women took vitamin D. Low weight and alcohol use were associated with low BMD in the whole study group. In HIV-positive women, CD4 count and antiretroviral class did not predict declining BMD.
A larger and longer comparison of mostly premenopausal HIV-positive and negative WIHS women found a fracture incidence of 1.8 per 100 person-years in women with HIV and 1.4 in women without HIV, a nonsignificant difference (P = 0.18).40 Median followup measured 5.4 years. Multivariate analysis did not tease out an association between HIV infection and fracture in this study. And HIV-positive women had a bone-risk disadvantage compared with HIV-negative women because they were older (average 40 versus 36 years, P < 0.0001), weighed less (74.5 versus 79.7 kg, P < 0.001), and were more likely to be postmenopausal and to have HCV coinfection. Hip and wrist fracture incidence rates in the HIV-positive women (0.2 and 0.3 per 100 person-years) were similar to hip and wrist fracture rates in the general population of premenopausal women in the United Kingdom.41,42
As in the smaller WIHS study,39 HIV-negative women in the larger analysis40 had their share of low-BMD risk factors: 51% smoked, 21% rated themselves moderate or heavy drinkers, 19% had a prior fracture, 14.5% had HCV infection. In the plus column, 28% took vitamin D. Bivariate analysis of the entire study group linked an array of classic risk factors to incident fracture: older age, white race, self-reported menopause, prior fracture, HCV infection, higher diastolic blood pressure, cigarette smoking, and injection drug or opiate use.