FDA regulators recognized the kidney threat posed by long-term TDF when they stipulated that TDF/FTC PrEP should not be used by "HIV-uninfected individuals if creatinine clearance is below 60 mL/min."7 In iPrEx,4 Partners PrEP,5 and TDF2,6 PrEP users took TDF -- often inconsistently -- for medians of 1.2, 1.9, and 1.1 years in the primary published reports, and TDF did provoke some renal wrinkles in these HIV-negative study participants (Table 2). In the iPrEx trial of MSM and transgender women, investigators recorded 41 creatinine elevations during follow-up, 26 (2%) in people randomized to TDF/FTC and 15 (1%) in those randomized to placebo, a difference approaching statistical significance (P = 0.08).4 Eighteen creatinine elevations (44%) remained in the normal range, and 36 elevations (88%) disappeared on the next test. Five people randomized to TDF/FTC (5%) and none randomized to placebo had creatinine jumps on more than 1 consecutive test. Ten creatinine gains led iPrEx participants to stop study drug, 7 in the TDF/FTC group and 3 in the placebo group. Nine people resumed their assigned regimen.
|Table 2. Key Findings on Kidney Health in HIV-Negative at-Risk People Taking or Not Taking TDF|
HERS, HIV Epidemiology Research Study; MACS, Multicenter AIDS Cohort Study.
In the Partners PrEP trial of HIV-discordant African couples, frequency of creatinine or phosphorus abnormalities did not differ between the TDF arms and the placebo arm.5 Three people taking TDF alone and 2 taking TDF/FTC had grade 2 or 3 creatinine elevations, with both frequencies below 1%. Four Partners PrEP participants stopped TDF or TDF/FTC because creatinine clearance dropped below 50 mL/min, while 1 stopped placebo because of declining clearance. Seven Partners PrEP participants permanently stopped their assigned regimen, 6 of them because of grade 2 renal toxicity (3 taking TDF alone, 2 taking TDF/FTC, and 1 taking placebo). Grade 2 and 3 drops in phosphorus affected 8% and 1% taking TDF alone and 8% and 1% taking TDF/FTC.
In the TDF2 study of high-risk heterosexual African women and men, 1 person (0.2%) randomized to TDF/FTC and none randomized to placebo had a creatinine elevation, while 23.2% randomized to TDF/FTC and 26.2% randomized to placebo had low phosphorus.6
A phase 2 trial of TDF alone versus placebo to prevent HIV infection in high-risk women of Cameroon, Ghana, and Nigeria collected primary safety data from two sites.11 Comparing 363 women randomized to TDF and 368 randomized to placebo for 210.2 and 217.6 person-years of follow-up, researchers recorded no grade 2, 3, or 4 creatinine elevations in either study arm. There were 13 grade 1 elevations in the TDF group (6.5 per 100 person-years) and 15 in the placebo group (7.1 per 100 person-years). Phosphorus drops also proved uncommon and did not differ between groups.
Together these findings suggest that TDF taken as PrEP for 1 to 2 years poses only a small risk of negative kidney marker changes, and by some (but hardly all) measures that risk was greater with TDF or TDF/FTC than with placebo.
What about kidney health in people not taking TDF but with more than a passing risk of HIV infection, in other words, PrEP candidates? Multiple PubMed searching strategies turned up two reports of kidney function in such people, one in men and one in women (Table 3).
|Table 3. Kidney Risk Factors in HIV-Negative but at-Risk Men and Women|
|Men in MACS12 (n = 150)||Women in HERS15 (n = 425)|
|One third black||Half black|
|Hypertension in 37%||Antihypertensive therapy in 24.2%|
|Diabetes in 13%||HCV in 47.5%|
Renal lab abnormalities in 6.6%
|HERS, HIV Epidemiology Research Study; MACS, Multicenter AIDS Cohort Study.|
The study in men involved 738 HIV-positive and 150 HIV-negative gay and bisexual men in MACS.12 MACS is an ongoing prospective study of gay and bisexual men with and without HIV infection recruited in Baltimore, Chicago, Pittsburgh, and Los Angeles.
The 6972 cohort members, including 3501 men with HIV, make study visits twice a year. This cross-sectional analysis involved men with serum creatinine and urine protein excretion measured between September 2006 and April 2007. One third in each group was black, and 2% or fewer injected drugs. The HIVpositive and negative men had similar chronic kidney disease risk factors, except that a higher proportion of HIV-positive men had HCV infection (10% versus 4%) and high liver enzymes. Proportions with diabetes were similar in the HIV-positive and negative groups (10% and 13%), while more than one third in each group (38% and 37%) had hypertension, another kidney disease risk factor.
A significantly higher proportion of men with than without HIV had proteinuria (17% versus 2%, P < 0.01). Median creatinine was similar in the two groups (1.0 mg/dL without HIV and 0.9 mg/dL with HIV, P = 0.41), while median cystatin C, an alternative kidney function marker, was significantly higher in the HIV group (0.76 versus 0.85 mg/dL, P < 0.01). Median estimated glomerular filtration rate (eGFR) using serum creatinine was similar in the two groups (103.1 mL/min without HIV versus 105.2 mL/min with HIV, P = 0.78), while eGFR using cystatin C was significantly greater in men without HIV (108.0 versus 94.6 mL/min/173m2, P < 0.01).
The National Kidney Foundation lists normal eGFR as above 60 mL/min,13 while labtestsonline.org gives 90 to 120 mL/min as normal.14 Either way, both HIVpositive and HIV-negative men in this MACS analysis fell within the normal range as a group. Interquartile ranges also fell entirely within the 90-to-120 normal range for both groups of men with both eGFR estimating formulas.
The HIV Epidemiology Research Study (HERS) prospectively monitored HIV-positive women and HIVnegative women with a high HIV risk recruited in Baltimore, the Bronx, Detroit, and Providence.15 An analysis involving 885 HIV-positive women and 425 without HIV who made twice-yearly visits from 1993 through 2000 tracked overall and condition-specific hospital admissions, including admissions for diabetes mellitus and nonacute renal conditions. About two thirds of women in the positive and negative groups were between 31 and 44 years old; 61% of positive women and 53% of negative women were black, and 17% and 15% were Hispanic.
While 21.7% of HERS women with HIV had renal lab abnormalities, 6.6% of HIV-negative women did, a highly significant difference (P < 0.0001).15 The hospital admission rate for nonacute renal causes was more than 14 times higher in women with than without HIV (rate ratio 14.4, P = 0.0033). Diabetes admissions were 3.6 times more likely in women with than without HIV (P = 0.04). Overall admission rates were 54.9 per 100 person-years in the HIV group and 15.1 per 100 person-years in the HIV-negative group. In 2009 the hospital discharge rate for all US women was 13.8 per 100 person-years, according to the CDC.16 So the overall admission rate for HIVnegative women in HERS is largely in line with the general-population rate.
Although these HERS findings indicate that US women at risk of HIV infection have lower rates of kidney problems and kidney-related and overall hospital admissions than women with HIV, other findings show that both groups had high rates of two renal risk factors. About one quarter of women with and without HIV (27.0% and 24.2%) were taking antihypertensives, a nonsignificant difference. Hypertension quintupled the risk of nonacute renal hospital admissions in women with HIV (rate ratio 5.1, 95% CI 2.1 to 12.4); the researchers did not perform a similar analysis for HIV-negative women. While 61.4% of HIV-positive women tested positive for HCV antibody, 47.5% without HIV had a positive HCV antibody result (P < 0.0001). Drug injection probably accounted for the high HCV prevalence, as 60.7% of HIV-positive women and 54.1% of HIV-negative women had an injection history.
Together these two studies suggest that US men and women at risk of HIV infection do not have more compromised kidney function than the general population. However, the high hypertension prevalence in MACS men and HERS women without HIV offers a vivid example of kidney threats faced by prime PrEP candidates. The same can be said for the high HCV-antibody positivity rate in HIV-negative HERS women.
The medical literature is loaded with studies of how TDF does -- or does not -- affect kidney function when taken for several years by people with HIV (Table 4). Because of differences in study populations, design, and follow-up time, these analyses yield varying, and sometimes seemingly contradictory, results.
|Table 4. Key Findings on Kidney Health in HIV-Positive People on Long-Term TDF|
The biggest TDF-kidney study involved 10,841 HIVpositive US veterans, almost all of them (98%) men.17 While 40% of this nationally representative sample had taken TDF, 60% had not. Median age in this prospective study was similar in TDF takers and TDF naives (45 and 47), and similar proportions were black (47% and 51%). Among kidney risk factors, baseline hypertension prevalence was 39% without TDF experience and 38% with TDF experience, diabetes prevalence 7.9% and 6.8%, abnormal lipids 15% in each group, HCV positivity 17% and 14%, proteinuria 21% and 19%, and smoking prevalence 19% and 18%.
The VA team examined associations between TDF use and time to three kidney endpoints: (1) proteinuria (two consecutive urine dipstick measurements at or above 30 mg/dL), (2) rapid decline in kidney function (at least 3 mL/min annual decline), and (3) chronic kidney disease (eGFR below 60 mL/min). Median follow-up before an endpoint was reached stretched from 3.9 years for the proteinuria endpoint to 5.5 years for chronic kidney disease. TDF-treated veterans took the drug for an average 1.3 years.
Multivariate analysis that considered demographics, HIV-related factors, other illnesses, and other antiretrovirals figured that each year of TDF therapy independently raised the risk of all three endpoints (Figure 2). The risk of chronic kidney disease jumped by one third for each year of TDF therapy.
|Figure 2. Increased Risk of Kidney Toxicity With Each Year of TDF|
Each year of TDF therapy independently raised the risk of three kidney dysfunction endpoints in a study of 10,841 HIV-positive US veterans, 98% of them men and half black.17 Endpoints are defined in the text, and risks are calculated as hazard ratios (proteinuria 1.34, 95% CI 1.25 to 1.45, P < 0.0001; rapid decline in kidney function 1.11, 95% CI 1.03 to 1.18, P = 0.0033; chronic kidney disease 1.33, 95% CI 1.18 to 1.51, P < 0.0001).
Having chronic kidney disease, diabetes, or hypertension before starting TDF had little further impact on these kidney endpoints in people taking TDF. And stopping TDF during follow-up did not reverse these three signals of kidney toxicity (see note 17A).
The VA investigators suggested their findings "provide strong evidence that tenofovir may cause clinically significant toxicity to the kidney that is not reversible,"17 adding that "the balance between [TDF] efficacy and probable adverse effects requires further study." Further study is certainly in order for people taking TDF to prevent HIV rather than treat it. The researchers noted that their analysis is limited by their inability to measure eGFR directly, and no one can say whether the findings apply to women as well as men.
Two small single-center studies found, however, that impaired kidney function usually does improve when people stop TDF.18,19 The larger of these two studies, from Barcelona, found that TDF-associated kidney deficits reversed course in well over half of those who stop the drug.18 The study involved 183 people, 85% of them men, with a median age of 44 (interquartile range [IQR] 40 to 50). This group took TDF for a median of 39 months (IQR 22 to 63) and endured baleful changes in kidney markers during that time. The researchers used logistic regression to evaluate factors associated with a return to normal kidney markers, which they defined as eGFR at or above 60 mL/min, creatinine at or below 1.20 mg/dL, phosphate at or above 2.69 mg/dL, proteinuria below 30 mg/dL, and glycosuria below 20 mg/dL in people without diabetes.
A median of 22 months (IQR 13 to 49.5) after people stopped TDF, renal values returned to normal in 59% of this group, improved without reaching normal benchmarks in 10%, and did not improve in 31%. Median time to reaching normal values measured 4 months (IQR 2 to 15.75). Follow-up time stood below 12 months in 30% of people with no improvement in kidney values. Higher nadir CD4 count predicted higher odds of returning to normal kidney function (odds ratio [OR] 1.002 per 1-cell increase, P = 0.034), as did higher CD4 count when TDF stopped (OR 1.033 per 1-cell increase, P = 0.030). These associations, the researchers proposed, suggest "a role of preserved cellular immunity in renal recovery" after stopping TDF.
The second single-center study involved 80 people with TDF-associated kidney toxicity at an inner-city clinic in Chicago, including 86.5% with increasing serum creatinine and/or declining eGFR, 11% with proteinuria, and 2.5% with Fanconi syndrome.19 The investigators defined improved renal function as (1) eGFR rising to or above the baseline value, (2) qualitative or quantitative improvement in proteinuria, or (3) improvement or normalization of parameters defining Fanconi syndrome. Most study participants (84%) were men, and 74% were black. Median age stood at 53 years, and TDF duration averaged 27.4 months. Two thirds of the TDF regimens included a protease inhibitor (PI). Forty-nine people (61%) stopped TDF and 31 (39%) continued.
Kidney function values improved in 37 of 49 people (76%) who stopped TDF versus 17 of 31 (55%) who did not. Kidney disease progressed to end-stage renal disease in 2 of 49 people (4%) who stopped TDF. Multivariate analysis determined that stopping TDF nearly quadrupled odds of renal recovery (OR 3.76, 95% CI 1.26 to 11.27, P = 0.02). Factors that did not affect chances of recovery in this analysis were diabetes, hypertension, and use of other nephrotoxic drugs.
The VA investigators suggested that different mechanisms of TDF-induced kidney damage may explain why impairment improves in some people but not in others who stop TDF.17 TDF accumulation in the proximal renal tubule may be reversible, they proposed, whereas active tubular necrosis and tubulointerstitial scarring may not.
A large and long US multicenter study found a link between chronic kidney disease and regimens containing TDF plus a ritonavir-boosted PI, but TDF/nonnucleoside combos or a boosted PI without TDF did not send kidneys out of kilter.20 The study involved 3329 adults in HIV care who had at least one creatinine reading before and after starting antiretroviral therapy. One quarter (24.9%) took TDF with a ritonavir-boosted PI, 35.1% took TDF with a nonnucleoside, 11.9% took a PI without TDF, and 28.1% took a nonnucleoside without TDF. Median age stood at 40 years, 38.5% of study participants were black, and 18.7% were women. Rates of kidney disease risk factors were moderate to low -- 16.1% had hypertension, 14.9% had HCV infection, and 3.2% had diabetes. Median follow-up spanned 4.8 years, including a median of 23 weeks before antiretroviral therapy and 143 weeks on treatment.
Analyses adjusted for kidney risk factors determined that black race, HCV infection, and lower CD4 count and higher viral load during antiretroviral therapy swelled the risk of chronic kidney disease.20 Overall, antiretroviral therapy was associated with a slower eGFR decline. But taking a TDF/PI regimen (compared with a nonnucleoside without TDF) more than tripled the odds that eGFR would fall below 60 mL/min (OR 3.35, 95% CI 1.40 to 8.02, P = 0.006). Still, after 4 years taking a TDF/PI regimen, eGFR fell that low in only 5.7% of patients. Severe chronic kidney disease (eGFR below 30 mL/min) developed in only 16 people through more than 10,000 person-years of follow-up. Taking TDF without a boosted PI or taking a boosted PI without TDF did not independently hike the odds of an eGFR below 60 mL/min or 45 mL/min.
What about renal safety of TDF when combined with the integrase inhibitor raltegravir in previously untreated people? The STARTMRK trial randomized antiretroviral-naive people to raltegravir or efavirenz, both with TDF/FTC.21 After 3 years of followup, none of 281 people randomized to raltegravir and 1 of 279 randomized to efavirenz had creatinine levels at or above 1.9 times the upper limit of normal.
A meta-analysis of 17 studies comparing TDF regimens with non-TDF therapies found an average 3.92 mL/min lower creatinine clearance in TDF takers (95% CI 2.13 to 5.70) in 11 studies reporting that outcome.22 In 8 studies risk of acute renal failure was 0.7% higher in the TDF group (95% CI 0.2 to 1.2), but TDF takers did not have a higher rate of chronic kidney failure or end-stage kidney failure requiring long-term dialysis. Three of these studies had 86 to 96 weeks of followup, and 4 had 104 to 520 weeks. Renal function declined less in randomized trials than in observational studies, and less in people starting first-line TDF than in treatment-experienced people. This meta-analysis yielded no evidence that TDF heightened the risk of severe proteinuria or hypophosphatemia.
Among the longest individual studies of TDF in people with HIV are an international randomized trial comparing TDF/FTC with zidovudine/lamivudine (ZDV/3TC), each with efavirenz,23 an international randomized trial comparing TDF with stavudine in previously untreated adults,24 a EuroSIDA analysis of chronic kidney disease,25 and a study of HIV-positive people at two UK centers.26 (The meta-analysis22 included three of these studies.23,24,26) Side effect findings in the TDF trials must be interpreted with the understanding they excluded people with creatine clearance below 5023 or 6024 mL/min, people taking other kidney-toxic drugs,23 and people with a history of "clinically significant bone disease."23 As noted in the meta-analysis of 17 studies discussed above, renal function appears to drop less in randomized trials than in observational studies.22
The first trial involved 517 antiretroviral-naive adults, 14% of them women, with a median age of 37 years. Everyone had an eGFR above 50 mL/min when the trial began and creatinine below 1.5 mg/dL.23 After 144 weeks, more people stopped ZDV/3TC than TDF/FTC because of adverse events (11% versus 5%, P = 0.01), and no one dropped out because of kidney trouble. One person in the TDF group had a confirmed grade 1 creatinine elevation through 144 weeks, while 2 in the ZDV arm had a confirmed grade 2 elevation. Median eGFR dropped 12 mL/min (from 110 to 98 mL/min) in the TDF group while rising 1 mL/min (from 105 to 106 mL/min) in the ZDV group, a significant difference (P < 0.001).
The trial that established TDF efficacy in antiretroviral-naive people randomized 299 to TDF and 303 to stavudine, each with lamivudine and efavirenz.24 About 20% of participants were black. After 144 weeks of follow-up creatinine rose above 2 mg/dL in 2 of 296 randomized to TDF and 2 of 296 randomized to stavudine. Similar proportions in both arms had proteinuria (above 30 mg/dL) by week 144: 18% in the TDF arm and 23% in the stavudine arm. Creatinine clearance rose by an average 2 mL/min in the TDF group and 7 mL/min in the stavudine group through 144 weeks. No one dropped out of the study because of TDF-related kidney toxicity. A 1111-person 3-year analysis combining results of these two TDF trials23,24 determined that fewer than 1% in the TDF arms and the comparison arms had confirmed creatinine elevations above 1.5 mg/dL or serum phosphorus below 2 mg/dL.27
A EUROSIDA analysis of 6843 adults with at least three creatinine measures and a median follow-up of 3.7 years (IQR 2.8 to 5.7) found that TDF and three PIs -- atazanavir, indinavir, and lopinavir -- independently raised the risk of chronic kidney disease, defined as a confirmed eGFR falling below 60 mL/min or a 25% drop in eGFR for people starting below 60 mL/min.25 After adjustment for traditional risk factors, each year of TDF use raised the risk of chronic kidney disease about 15% (incidence rate ratio 1.16, 95% CI 1.06 to 1.25, P < 0.0001).
The UK cohort study involved 3439 HIV patients seen at two centers between January 1998 and December 2005.26 Follow-up ranged from 104 to 520 weeks. Among 843 people who took TDF during the study period, chronic kidney disease (eGFR below 60 mL/min for at least 3 months) developed in 26 people (3.1%), compared with an overall incidence of 2.4% in this study group. Of the 22 people who stopped TDF during follow-up, 21 did so because of kidney concerns. In people with chronic kidney disease, taking TDF was tied to a 3.7-fold faster decline in kidney function. And among people who started TDF during the study period, being 50 or older boosted the odds of chronic kidney disease 5.4 times, while an eGFR of 60 to 74 (versus 90 or higher) raised the odds 17.2 times.