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.
Bone Changes With Long-Term TDF Therapy
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|
- A prospective study of 33,439 US veterans determined that every year of TDF use boosts the risk of osteoporotic fracture 12%.43
- Longitudinal analysis in a US Nutrition for Healthy Living Study involving 283 men and 96 women linked TDF use to an average 2.04% drop in total BMD among men and an average 1.74% drop in premenopausal women.44
- Longitudinal analysis of 483 men and 188 women in Spain determined that taking TDF at the time of the most recent DEXA scan raised odds of declining BMD more than 40%.45
- After 3 years of follow-up in a 517-person trial comparing TDF/FTC with ZDV/3TC in previously untreated adults, fracture rates were low and similar in the two treatment arms.23
- After 3 years of follow-up in a 602-person trial comparing TDF/3TC with stavudine/3TC in previously untreated adults, BMD waned more at the lumbar spine and hip with TDF/3TC, but fewer people in the TDF group broke a bone.24
- After 96 weeks of follow-up in a trial that randomized antiretroviral-naive adults to TDF/FTC or ABC/3TC, BMD declined more at the spine and hip in the TDF group.46 Fracture rates did not differ between the two arms.
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.
Implications of Studies of BMD and Fractures in PrEP Candidates and TDF Takers
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.
Bottom Line: Low TDF Toxicity Risk, but Caution Advised
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
- Brooks RA, Landovitz RJ, Kaplan RL, Lieber E, Lee SJ, Barkley TW. Sexual risk behaviors and acceptability of HIV pre-exposure prophylaxis among HIV-negative gay and bisexual men in serodiscordant relationships: a mixed methods study. AIDS Patient Care STDS. 2012;26:87-94.
- Heffron R, Donnell D, Rees H, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12:19-26.
- World Health Organization. Hormonal contraception and HIV: technical statement. February 16, 2012.
- Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599.
- Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399-410.
- Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423-434.
- US Food and Drug Administration. Truvada prescribing information. 2012.
- Cohen MS, Baden LR. Preexposure prophylaxis for HIV -- where do we go from here? N Engl J Med. 2012;367:459-461.
- Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411-422.
- Prejean J, Song R, Hernandez A, et al. Estimated HIV incidence in the United States, 2006-2009. PLoS One. 2011;6:e17502.
- Peterson L, Taylor D, Roddy R, et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials. 2007;2:e27.
- Estrella MM, Parekh RS, Astor BC, et al. Chronic kidney disease and estimates of kidney function in HIV infection: a cross-sectional study in the Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 2011;57:380-386.
- National Kidney Foundation. Three simple tests to check for kidney disease.
- labtestsonline.org. eGFR.
- Gardner LI, Klein RS, Szczech LA, et al. Rates and risk factors for condition-specific hospitalizations in HIV-infected and uninfected women. J Acquir Immune Defic Syndr. 2003;34:320-330.
- CDC. National Hospital Discharge Survey: 2009 table, Number and rate of hospital discharges.
- Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26:867-875.
17A. "Among those who discontinued tenofovir use, the time period following cessation was not significantly associated with either higher or lower risks of proteinuria (HR=1.05 per year, 95% CI: 0.93-1.18, p = 0.41) or rapid decline (HR=1.05 per year, 95% CI: 0.94-1.16, p=0.42), although there was a marginal association of time off tenofovir with [chronic kidney disease] (HR=1.22 per year, 95% CI: 0.99-1.50, p=0.055). All hazard ratios remained greater than unity, which suggests that the effects of tenofovir on kidney disease risk were not reversible following discontinuation."
- Bonjoch A, Echeverría P, Perez-Alvarez N, et al. High rate of reversibility of renal damage in a cohort of HIV-infected patients receiving tenofovir-containing antiretroviral therapy. Antiviral Res. 2012;96:65-69.
- Touzard Romo F, Livak B, Aziz M, et al. Recovery of renal function and virologic suppression following tenofovir discontinuation. Infectious Disease Society Association. San Diego. October 17-21, 2012.
- Kalayjian RC, Lau B, Mechekano RN, et al. Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care. AIDS. 2012;26:1907-1915.
- Rockstroh JK, Lennox JL, DeJesus E, et al. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis. 2011;53:807-816.
- Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51:496-505.
- Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr. 2008;47:74-78.
- Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191-201.
- Mocroft A, Kirk O, Reiss P, et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS. 2010;24:1667-1678.
- Campbell LJ, Ibrahim F, Fisher M, Holt SG, Hendry BM, Post FA. Spectrum of chronic kidney disease in HIV-infected patients. HIV Med. 2009;10:329-336.
- Gallant JE, Winston JA, DeJesus E, et al. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS. 2008;22:2155-2163.
- Centers for Disease Control and Prevention. Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR. 2011;60:65-68.
- Centers for Disease Control and Prevention. Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR. 2012;61:586-589.
- Wever K, van Agtmael MA, Carr A. Incomplete reversibility of tenofovir-related renal toxicity in HIV-infected men. J Acquir Immune Defic Syndr. 2010;55:78-81.
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