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PrEP Truvada/2nd Generation; FDA Advisors Endorse Truvada PrEP--But Big Questions Remain       Mark Mascolini An FDA advisory panel left little doubt that Truvada, the once-daily pill combining tenofovir and emtricitabine, will get its license extended to cover pre-exposure prophylaxis (PrEP) of HIV infection in adults with a high risk of picking up HIV sexually. But the thorny deliberations leading to that endorsement in a marathon 12.5-hour session posed several tough questions about how Truvada PrEP will work in practice: -- Will people take Truvada consistently enough to protect themselves from HIV? -- If they take Truvada haphazardly and get infected, will resistance mutations evolve quickly? -- Will providers religiously test people for HIV before prescribing PrEP, and how often should they retest? -- Will Truvada PrEP work in women as well as men? -- Will taking PrEP make people abandon condoms and other HIV-evading tactics? -- How often must PrEP takers be monitored for kidney and bone problems? -- Will the side effects seen with Truvada prove too high a price for healthy HIV-negative people? The FDA's Antiviral Drugs Advisory Committee wagered that the answer to the last question will be no, at least not for sexually active people with risky liaisons. Panelists voted 19 to 3 to recommend Truvada PrEP for HIV-negative men who have sex with men (MSM) and 19 to 2 (with 1 abstention) for HIV-negative people with a positive partner (HIV-discordant couples). The vote favoring PrEP for "other individuals at risk for acquiring HIV through sexual activity" was 12 to 8 with 2 abstentions. The tepid endorsement of PrEP for "other individuals" reflected committee discomfort with a relative lack of evidence that daily Truvada wards off HIV in people not studied in the two big placebo-controlled trials Gilead Sciences relied on to buttress its PrEP application: iPrEx enrolled 2499 MSM in South and North America, South Africa, and Thailand [1], and Partners PrEP signed up 4747 HIV-discordant couples in Kenya and Uganda [2]. A smaller trial, TDF2, assessed daily Truvada PrEP in heterosexual Batswana women and men not necessarily in partnerships [3]. HIV risk reduction with Truvada in primary analyses of those three placebo-controlled trials stood at 44% in iPrEx, 75% in Partners PrEP, and 62% in TDF2. In Partners PrEP tenofovir alone cut HIV acquisition risk 67%. But Truvada did not protect high-risk African women from HIV in the FEM-PrEP trial, largely because of poor adherence to the daily regimen in these 2120 women [4]. The VOICE trial in 5029 African women closed its tenofovir-only arm when early results showed this strategy wasn't working [5]. VOICE also shut down its 1% tenofovir vaginal gel arm, but a blinded comparison of Truvada and placebo continues. PrEP has not been tested in US women or heterosexual men, so no one can say certainly how well Truvada PrEP will work for them or whether they will even consider taking a sometimes-toxic pill every day to shield themselves from HIV. But there seems little doubt that we'll find out. Although an advisory committee recommendation does not oblige the FDA to follow suit, the FDA probably will: Scrutinizing PrEP trial data, FDA analysts determined that those findings support the "safety and efficacy of [Truvada] for the prevention of HIV-1 infection in high-risk individuals." The FDA presentation leading to that conclusion did dwell deliberately on toxicity data, and the agency underlined the risk of kidney trouble in its premeeting briefing conclusion: "The decision to prescribe [Truvada] for the prevention of sexual acquisition of HIV infection should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity" [6]. Can PrEPers withstand the side effects? Not hurting people more than you help them is a hallowed tenet of medical practice, cited more than once at the FDA PrEP hearing. Clinicians rarely prescribe medicines for otherwise healthy people. Probably the most notable exception relevant to HIV care is prescription of hormonal contraceptives to women living in areas with high HIV prevalence because the family-planning benefit seems to outweigh a possibly heightened risk of HIV infection, the World Health Organization says [7]. Emtricitabine is among the least toxic drugs on pharmacy shelves, but tenofovir carries two much-studied risks--kidney trouble and bone density loss. Partly because of these threats, Gilead scientists are racing to develop a potentially gentler tenofovir prodrug, labeled GS-7340, to replace tenofovir in QUAD, the 4-in-1 tablet also containing emtricitabine, elvitegravir, and cobicistat [8-10], and possible in a 2-in-1 tablet with emtricitabine. But tenofovir-containing Truvada is the PrEP pill people will have to take for now. In the successful PrEP trials completed so far--iPrEx [1], Partners PrEP [2], and TDF2 [3]--people took Truvada for an average of about 2 years, so you can't judge the long-term side effect potential. But you can reckon the 2-year risk in PrEP takers, and you can gauge longer-term risks in HIV-positive people taking tenofovir alone, in Truvada, or in Atripla. (from Jules: see my report on 2nd generation PrEP where there are numerous additional PrEP therapies in research now, of course the efficacy & safety may or may not be better than Truvada or GS-7340. Although intermittent Truvada is an alternate being researched, discussed in my 2nd Generation PrEP Report, and may have less safety concerns regarding renal/bone side effects, but this remains to be seen & intermittent Truvada means timing it before & after sex so there are inherent risks of poor timing.) CROI: Next/2nd Generation PrEP for Men & Women: intravaginal rings, injectables, long-acting, rectal gel, intermittent PrEP - (04/14/12) in this report long-acting rilpivirine is discussed: 13th Intrntl Wrkshp Clinical Pharm HIV: Clinical Pharmacology at the 13th Workshop on Clinical Pharmacology of HIV Therapy - Courtney V. Fletcher, Pharm.D. - (05/14/12) Intermittent Prophylaxis with Oral (Gel) Truvada Protects Macaques from Rectal SHIV Infection - (05/15/12) CROI: Intermittent Oral PrEP with Truvada Prevents Vaginal SHIV Transmission in Macaques - (04/14/12) CROI: Safety, Acceptability and Pharmacokinetic Assessment (Adherence) of Monthly Dapivirine Vaginal Microbicide Rings (Ring-004) for HIV Prevention - (04/14/12) CROI: INTRAVAGINAL RING DELIVERY OF THE PYRIMIDINEDIONE IQP-0528 RESULTS IN PROTECTIVE CONCENTRATIONS IN VAGINAL BIOPSIES OF PIGTAILED MACAQUES - NOVEL MODELS TO ASSESS PK/PD - (04/14/12) Hardly any men in iPrEx had gastrointestinal trouble after starting Truvada, and rates of diarrhea, nausea, vomiting, and all GI disorders were similar in the Truvada and placebo groups. Men randomized to Truvada did endure abdominal pain more often than placebo takers (4% versus 2%, P = 0.01), and they lost weight slightly more often than the placebo group (3% versus 2%, P = 0.04). But all side effect rates in iPrEx must be judged in light of the poor overall adherence in that trial (see "Will people without HIV take Truvada regularly?" below). In the TDF2 study of heterosexual men and women in Botswana [3], nausea, vomiting, and dizziness affected significantly more people randomized to Truvada than placebo [6]. In its review at the PrEP hearing, the FDA noted that 7 iPrEx men interrupted Truvada because of climbing creatinine, compared with 3 men assigned to placebo. Six of these 7 Truvada takers restarted Truvada "without further incident." Four Partners PrEP participants stopped tenofovir or Truvada because creatinine clearance fell to or below 50 mL/min, while 1 stopped placebo for that reason. Creatinine clearance climbed back above 50 mL/min after tenofovir stopped. In both trials, the FDA said, creatinine changes were not linked to clinical problems or other lab abnormalities. Hypophosphatemia was the leading moderate to severe adverse event related to study drugs in Partners PrEP, affecting 11% assigned to tenofovir alone, 14% assigned to Truvada, and 13% assigned to placebo [6]. Only 6% in any study arm had serum phosphorus levels below 2 mg/dL at any point during follow-up. Neutropenia affected slightly more people taking Truvada (18%) than tenofovir alone (15%) or placebo (13%). Seven people permanently stopped their study drug in Partners PrEP, 6 because of grade 2 renal toxicity: 3 people taking tenofovir, 2 taking Truvada, and 1 taking placebo [6]. Five of these 6 toxicities occurred in women, and all 5 had normal estimated creatinine clearance. Treatment-emergent creatinine elevations were recorded in 5% randomized to tenofovir, 7% randomized to Truvada, and 5% randomized to placebo. Only 0.2% of Partners PrEP participants had creatinine elevations judged to be drug-related, 3 people taking tenofovir alone and 5 taking placebo. In an iPrEx bone mineral density (BMD) substudy, average BMD rose in the placebo group during the trial, while the Truvada group had small but significantly greater losses in hip and spine BMD compared with placebo takers [6]. DEXA scans done after Truvada stopped showed BMD values inching back toward baseline levels. In a DEXA-based BMD analysis of the CDC 4323 PrEP study in 210 MSM [11,12], 10% of study participants had low BMD (a Z score at or below -2.0) when they entered the trial [12]. Median age in these men was 41. About 70% were white and 5% black. Men who used amphetamines had almost a 6 times higher risk of low BMD, and men who used inhalants had more than a 4 times higher risk. Men taking multivitamins, calcium, or vitamin D had about a 75% lower risk of low BMD. Over time, men randomized to tenofovir had an average 1.1% drop in BMD at the femoral neck compared with the placebo group, an average 0.8% drop at the total hip, and an average 0.7% drop at the lumbar spine. After 24 months, 13% of men randomized to tenofovir and 6% randomized to placebo had more than 5% BMD loss at the femoral neck, but that difference stopped short of statistical significance (P = 0.13). In the TDF2 PrEP trial of men and women in Botswana, people randomized to Truvada had small but significantly greater BMD declines in the forearm, hip, and lumbar spine than did with people assigned to placebo [6]. DEXA scanning was not part of the Partners PrEP protocol. Long-time tenofovir toxicity findings in HIV-positive populations may not apply directly to HIV-negative PrEP users because the virus itself could affect kidney function and bone density, because HIV-positive people may have other conditions that affect kidneys and bones, and because people with HIV are taking other possibly toxic antiretrovirals. But results of several studies provide some perspective on what long-term tenofovir can do, and often statistical analyses in these studies considered the impact of other kidney and bone risk factors. One long-term tenofovir study involved 10,841 HIV-positive US veterans, 98% of them men [13]. While 4303 (40%) had taken tenofovir, 6538 had not. Median age in this national sample was 45 years (interquartile range [IQR] 39 to 52) in the tenofovir group and 47 (IQR 40 to 52) in the no-tenofovir group. About half in both groups (47% tenofovir, 51% no tenofovir) were black, while 46% and 39% were white. In the tenofovir group, 38% had hypertension, 7% diabetes, 15% abnormal lipids, and 14% hepatitis C virus infection. Only 18% smoked. Proportions were similar in the no-tenofovir group. The researchers evaluated potential associations between tenofovir use and time to first occurrence of three kidney-related endpoints: (1) proteinuria (two consecutive urine dipstick measurements ≥ 30 mg/dL), (2) rapid decline in kidney function (≥ 3 mL/min per 1.73 m annual decline), and (3) chronic kidney disease (CKD, estimated glomerular filtration rate < 60 mL/min per 1.73 m). Median follow-up ranged from 3.9 years for proteinuria to 5.5 years for CKD. Maximum follow-up reached 11 years. Multivariate analysis that factored in demographics, HIV-related factors, other morbidities, and other antiretrovirals determined that each year of tenofovir use independently raised the risk of all three endpoints: Increase in risk of new renal endpoint with each year of tenofovir therapy [13]: -- 34% for proteinuria (95% confidence interval [CI] 25 to 45, P < 0.0001) -- 11% for rapid decline in kidney function (95% CI 3 to 18, P = 0.0033) -- 33% for CKD (95% CI 18 to 51, P < 0.0001) Having kidney disease risk factors, CKD, diabetes, or hypertension before starting tenofovir did not seem to worsen tenofovir's impact on the kidney. Among people who stopped tenofovir, risk of these kidney changes did not appear to drop during follow-up (see note 14). These researchers believe their findings "provide strong evidence that tenofovir may cause clinically significant toxicity to the kidney that is not reversible." They note that "the balance between [tenofovir] efficacy and probable adverse effects requires further study." That is all the more true for people taking tenofovir to prevent HIV rather than to treat it. A systematic review of 17 prospective studies (including 9 randomized trials) comparing tenofovir-containing treatment regimens with nontenofovir regimens documented a significantly greater loss of kidney function in the tenofovir group (mean difference in calculated creatinine clearance 3.92 mL/min, 95% CI 2.13 to 5.70) and a greater risk of acute renal failure (risk difference 0.7%, 95% CI 0.2 to 1.2) [15]. This analysis yielded no evidence that tenofovir heightened risk of severe proteinuria or hypophosphatemia. "Although [tenofovir] use was associated with a statistically significant loss of renal function," these investigators concluded, "the clinical magnitude of this effect was modest" [15]. They do not believe these findings suggest a need to restrict tenofovir use in places "where regular monitoring of renal function and serum phosphate levels is impractical." Another Veterans Affairs study, this one involving 56,660 HIV-positive people seen from 1998 through 2009, found that every year of tenofovir therapy upped the risk of osteoporotic fracture about 12% in the combination antiretroviral era [16]. Of these 56,660 people (98% of them men), 39,277 (69%) took antiretrovirals for at least 1 month. The researchers defined osteoporotic fracture as fracture of the wrist, vertebrae, or hip. They weighed potential osteoporotic risk factors in two multivariate models, the first controlling for race, age, tobacco use, diabetes, body mass index, and hepatitis C status, the second controlling for all those factors plus concomitant antiretroviral exposure. Neither model factored in other possibly telling variables, such as glucocorticoid use or vitamin D deficiency. The study did not evaluate BMD and could not verify the fractures as osteoporotic. Multivariate analysis determined that each year of tenofovir therapy raised the risk of osteoporotic fracture 6% (hazard ratio [HR] 1.06), but the 95% confidence intervals with model 1 and model 2 both just crossed 1.00 (0.99 to 1.12 and 0.99 to 1.14). Among 33,439 people who entered the cohort in the combination antiretroviral era, each year of tenofovir therapy independently inflated fracture risk 12% to 13% (model 1 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). Taking tenofovir with a protease inhibitor made osteoporotic fracture even more likely (HR 1.16, 95% CI 1.04 to 1.30). White race, older age, tobacco use, body mass index below 20 kg/m2, and HCV coinfection also heightened fracture risk; but cumulative antiretroviral use, chronic kidney disease, and diabetes did not. AIDS Clinical Trials Group (ACTG) study A5224s sized up DEXA-measured changes in spine and hip BMD in 269 antiretroviral-naive people randomized to tenofovir/emtricitabine versus abacavir/lamivudine plus efavirenz or atazanavir/ritonavir through 96 weeks of treatment [17]. Most participants (85%) were men, and median age was 38 years; 47% were white, 33% black, and 16% Hispanic. One third (32%) had broken a bone before signing up for the study. At week 96 mean percent decline in spine BMD was greater with tenofovir/emtricitabine than with abacavir lamivudine (-3.3% versus -1.3%, P = 0.004), as was hip BMD decline (-4.0% versus -2.6%, P = 0.024). A 96-week regression analysis that accounted for gender, age, race/ethnicity, and pretreatment viral load, CD4 count, and body mass index found significant associations between abacavir/lamivudine versus tenofovir/emtricitabine and greater BMD at the spine and hip. Abacavir/lamivudine plus efavirenz was the only combination not associated with a significant 96-week drop in spine bone density. One in 20 people (5.6%) had trauma-related fracture during the study, but the fracture rate and time to first fracture did not differ by treatment assignment during these 96 weeks of observation. A Spanish longitudinal study of 671 antiretroviral-treated people found higher odds of BMD loss or progression to osteopenia/osteoporosis with longer time taking tenofovir (odds ratio [OR] 1.08, 95% CI 1.03 to 1.14, P < 0.0019), longer time taking a protease inhibitor (OR 1.18, 95% CI 1.12 to 1.24, P < 0.0001)), and current protease inhibitor use (OR 1.64, 95% CI 1.35 to 2.04, P < 0.0001) [18]. Most cohort members (72%) were men, median age was 42.1, median time on antiretroviral therapy was 7.4 years, median time on tenofovir was 2.2 years, and 52.5% were taking tenofovir at the time of evaluation. Through 2.5 years of follow-up, 12.5% of study participants had a new diagnosis of osteopenia and 15.6% a new diagnosis of osteoporosis. Together these PrEP trials and antiretroviral therapy studies confirm that taking tenofovir for even a few years poses threats to kidneys and bones. In licensing tenofovir and Truvada for antiretroviral therapy, the FDA judged that the benefits of tenofovir-containing regimens outweigh these risks at the population level. In voting to recommend Truvada as PrEP for HIV-negative people, the Antiviral Drugs Advisory Committee figured that the preventive benefit of this 2-in-1 pill outweighs these risks on the population level. But the individual risk/benefit equation clearly varies from person to person. For example, black men in the United States run a higher risk of chronic kidney disease than white men. At the same time, black MSM account for a disproportionate fraction of new HIV infections in the United States [19]. As a result, they are prime candidates for Truvada PrEP. How aggressively clinicians evaluate kidney function in HIV-negative men before prescribing Truvada--and how closely they follow kidney function after PrEP begins--remain pressing questions, especially in blacks. (Notably, fewer than 10% of iPrEx MSM were black and only 10% lived in the United States.) On the other hand, white men in the United States run a higher risk of BMD loss than black men. So clinicians will have to ask the same questions about evaluating and monitoring bone loss in white MSM eager to try Truvada PrEP. Will people without HIV take Truvada regularly? Whether people will take Truvada PrEP consistently enough to ward off HIV is anyone's guess. Some undoubtedly will take the pill daily or almost daily--as long as it causes no side effects that they feel or that monitoring detects. But others may ignore instructions and decide to take the pill only when they expect to have sex, or they may remember to take it only after sex, turning the strategy into postexposure prophylaxis. Irregular Truvada taking may yield blood and cell drug levels too low to shut out HIV. Truvada PrEP trials and other findings offer some insight into possible Truvada adherence outside the clinical trial arena. In iPrEx pill-dispensation rates indicated that Truvada use dropped from 99% to 91% during the first year of the study [1]. But adherence looked much worse when the investigators measured levels of tenofovir diphosphate--the drug's active form--in blood cells. This analysis showed better adherence in men who reported unprotected receptive anal intercourse, men over 25 years old, and men with at least a secondary education. But in all these analyses, fewer than half of the men tested had detectable tenofovir diphosphate in blood cells [6]: Proportions of iPrEx men with tenofovir diphosphate detectable in blood cells: -- Reported unprotected receptive anal intercourse: 44 of 103 (43%) -- Reported no unprotected receptive anal intercourse: 7 of 30 (23%) -- 25 or older: 31 of 68 (46%) -- Younger than 25: 20 of 65 (31%) -- At least secondary education: 43 of 103 (42%) -- Less than secondary education: 8 of 30 (27%) -- Remained HIV-negative: 51 of 133 (38%) -- Became infected with HIV: 4 of 48 (8%) It's important to remember, though, that only 10% of iPrEx enrollees lived in the United States, in San Francisco or Boston. When iPrEx investigators measured tenofovir diphosphate levels in blood cells, they detected tenofovir in 94% of US men versus 43% of non-US men, a highly significant difference (P < 0.001). An FDA analysis presented at the PrEP hearing indicated that iPrEx men with measurable intracellular drug concentrations had an 87.5% lower risk of HIV infection (95% confidence interval 66% to 95%) than men taking placebo. African women with a high HIV risk had poor adherence in FEM-PrEP [4]. Fewer than 26% had consistently detectable tenofovir levels in plasma, and the trial stopped because researchers determined adherence was too low to assess efficacy. In contrast, pill counts indicated that 97% of Partners PrEP women and men (HIV-negative people with positive partners) adhered to daily Truvada [2]. Analysis of tenofovir plasma levels in a subset of Partners PrEP participants determined that tenofovir was always measurable in 63% of people who remained HIV-negative and sometimes measurable in 28% who remained negative. But tenofovir could always be measured in plasma among only 15% who became infected during the trial and could sometimes be measured in 46%. Taken together, these findings suggest that HIV-negative people who know their partner has HIV (like Partners PrEP participants) will adhere to Truvada PrEP better than HIV-negative people who don't know their partners' HIV status (like iPrEx and FEM-PrEP participants). And adherence rates may well be lower in clinical practice, because follow-up will be less stringent than in trials and because clinicians will have less time to preach adherence than trial staffers do. Researchers in these PrEP trials instructed participants to take Truvada daily, but modeling work by iPrEx investigators suggests less frequent dosing may yield drug concentrations high enough to block HIV [20]. This analysis figured that taking 7 Truvada doses weekly pumped intracellular concentrations high enough to lower HIV risk 99% compared with placebo (95% CI 96% to >99%), while taking only 4 doses per week cut the risk by 96% (95% CI 90% to >99%). But intracellular concentrations attained with twice-weekly dosing trimmed the HIV risk by only 76% (95% CI 56% to 96%). Reviewing these findings at the FDA hearing, iPrEx principal investigator Robert Grant (University of California, San Francisco) stressed that daily dosing should still be recommended with Truvada PrEP because that's the only dose schedule tested in trials and because it's easier to follow than 4-times-weekly dosing. But he suggested that once-daily dosing does provide some forgiveness if adherence falls short of 100%: "If they miss a few [doses per week], there will be some protection," he proposed. At the hearing the FDA stressed that regular adherence counseling will be essential with PrEP. Does PrEP work in women as well as men? Truvada's failure to protect high-risk African women from HIV in FEM-PrEP [4], its success among MSM in iPrEx [1], and the higher infection rate in women than men in Partners PrEP [2] left some with the impression that the strategy works better in men than women. But gender-based analyses of Partners PrEP [2] and TDF2 [3] disclose no significant difference in Truvada PrEP efficacy between women and men. TDF2, the smaller of those two studies, randomized 1219 heterosexual adults in Botswana, 557 of them (46%) women, and the trial was not powered to support conclusions based on gender [3]. But comparisons of HIV seroconverters in the Truvada arm versus the placebo arm suggest that Truvada protected both women and men from HIV. In the primary analysis involving 33 seroconverters, Truvada lowered HIV risk 80.1% among men (95% CI 24.6% to 96.9%, P = 0.026) and 49.4% in women (95% CI -21.7% to 80.8%, P = 0.107). Limiting the analysis to 23 people who seroconverted during the trial, the investigators calculated 75.5% protective efficacy in women (95% CI 23.8% to 94.4%, P = 0.021) and 82.4% efficacy in men (95% CI -2.8% to 99.1%, P = 0.065). Results are more clearcut in the larger Partners PrEP trial, which randomized 4747 HIV-discordant couples to tenofovir alone, Truvada, or placebo; approximately one third of HIV-negative partners in these couples were women [2]. During the trial, 45 women became infected, 8 in the tenofovir-only arm, 9 in the Truvada arm, and 28 in the placebo arm. Among the 37 men who became infected during the study, 9 were taking tenofovir alone, 4 were taking Truvada, and 24 were taking placebo. The higher infection incidence in women, who made up a lower proportion of HIV-negative partners, probably reflects the higher susceptibility of women than men to HIV during vaginal sex. Among people randomized to tenofovir alone, protective efficacy was 71% in women (95% CI 37% to 87%, P = 0.002) and 63% in men (95% CI 20% to 83%, P = 0.01), and the difference between genders was not significant (P = 0.65). Among people assigned to Truvada, protective efficacy was 66% among women (95% CI 28% to 84%, P = 0.005) and 84% among men (95% CI 54% to 94%, P < 0.001). And again the between-gender difference was not significant (P = 0.24). Chances of resistance and risk compensation seem low Two other concerns about Truvada PrEP in practice are resistance and so-called risk compensation--the possibility that people taking Truvada PrEP will feel invulnerable to HIV and stop using condoms or taking other measures to avert infection. Neither threat became reality in the main trials dissected at the FDA hearing, iPrEx [1], Partners PrEP [2], TDF2 [3], and FEM-PrEP [4]. Resistance mutations could be detected in trial participants assigned to Truvada, but in every case analyzed, those people appeared to have undetected HIV infection when the trial began or to become infected with resistant virus. Of course the same thing could happen when PrEP is deployed in the community if providers do not rigorously test people for HIV right before prescribing Truvada PrEP, if people have early infection that does not register on standard antibody testing when they start PrEP, or if people get infected after their last negative HIV test and then start PrEP. Once an HIV-negative person starts Truvada PrEP, though, emergence of resistant virus seems unlikely. Based on resistance data gathered so far, Robert Grant proposed that tenofovir and emtricitabine concentrations high enough to select resistant virus should also be high enough to prevent infection. And Grant is no novitiate when it comes to HIV resistance: much of his pre-iPrEx research focused on HIV resistance. Another resistance expert who spoke at the FDA hearing, John Mellors (University of Pittsburgh), put it this way: no or low drug exposure with PrEP will allow infection but will not select resistant virus, while good drug exposure will block infection and so obviate any risk of resistance. But Mellors did leave the resistance-risk window open a crack, saying "resistance is still possible at drug exposures that permit infection but also provide selection of resistant virus," though he added that this possibility "appears to be uncommon." iPrEx and Partners PrEP produced no evidence of risk compensation when people started taking pills. In fact, results indicate that people practiced safer sex once the trials began--perhaps because of regular on-study counseling and because taking antiretrovirals every day reminded them of HIV risk. In iPrEx 60% of MSM reported unprotected receptive anal intercourse when the trial began, Grant reported at the hearing. That rate fell to about 30% at study week 12 and stayed there through 144 weeks of follow-up. Baseline prevalence of any sexually transmitted infection (STI) stood at 16% in both the Truvada arm and the placebo arm. During iPrEx, STI incidence was 12.6 per 100 person-years among those assigned to Truvada and 12.2 per 100 person-years in the placebo group. Partners PrEP investigator Jared Beaten (University of Washington, Seattle) reported that 27% of couples in that trial said they had unprotected sex in the past month when they enrolled. That proportion fell steadily throughout the trial to about 10% at month 30. At the hearing the FDA concluded that "risk compensation was not observed" in iPrEx or Partners PrEP and that "resistance was identified only in individuals who took tenofovir or tenofovir/emtricitabine during early infection, prior to diagnosis." The drug-level/resistance dynamics observed in these trials will probably apply to routine Truvada PrEP use. But it's easy to imagine that risk compensation will differ with sexually active adults who make clinic visits and get reinforcement less often than trial participants, as discussed in the next section. "Risk mitigation," HIV testing, and safety monitoring To help PrEP users hew to safer sex practices, Gilead devised a risk evaluation and mitigation strategy (REMS) that provides "comprehensive education and information materials emphasizing the importance of (1) a comprehensive HIV prevention strategy, (2) regular HIV testing (before initiation and regularly while on PrEP), and (3) provider assessment for acute HIV infection prior to starting and continuing PrEP." The REMS package Gilead promised will include: -- A notification letter to healthcare providers on details of PrEP -- Full prescribing information -- Medication guide with every bottle of Truvada -- Training guide for healthcare professionals -- Prescriber safety brochure -- Individual safety brochure -- Truvada wallet card Advisory Committee chair Judith Feinberg (University of Cincinnati) argued that Gilead's REMS is "utterly passive" and does not jibe with a point the FDA underlined in defining the elements of REMS: "Drug will be dispensed to patients with evidence of safe-use conditions." Feinberg and other committee members urged Gilead and the FDA to hammer out a tougher plan that encourages prescribers to test PrEP users regularly for HIV--and possibly HBV--and to watch for side effects, while coaxing PrEP users to keep wearing condoms. In response the FDA affirmed that the agency and Gilead must agree on REMS before the agency takes regulatory action. At the same time Advisory Committee members and FDA officials agreed that requirements for HIV testing and safety monitoring cannot be so burdensome that they discourage high-risk people from trying PrEP or sticking with it. Finding a balance between a REMS that is not too wimpy yet not too wearisome will require Solomonic sagacity. The CDC has already taken a stab at striking that balance in its interim guidance for PrEP in MSM, outlined at the end of this article [21]. Besides REMS and heightened pharmacovigilance for Truvada PrEP, Gilead promised an array of benefits for providers and PrEPers: -- Free HIV and HBV testing -- Free condoms -- Subsidized HIV-1 resistance testing for people who get infected -- An opt-in reminder service for HIV and STI testing -- Voluntary participation in a PrEP registry for prescribers and users -- Support for community education activities -- Truvada PrEP assistance program for people without prescription coverage The last item may assume greater or lesser importance depending on whether insurers cover Truvada PrEP. The annual tab for daily Truvada as treatment exceeds $10,000. And some panelists wondered whether the PrEP registry should be voluntary or mandatory. One member observed that rates of miscarriage and birth defects with isotretinoin (Accutane) remained unacceptably high until creation of the mandatory iPLEDGE registry for women, men, prescribers, and pharmacies [22]. In its briefing document for the PrEP hearing [6], the FDA set out some guidelines for Truvada PrEP prescribing, HIV testing, and follow-up: -- "The decision to prescribe [Truvada] for the prevention of sexual acquisition of HIV infection should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity. -- "Education about PrEP and behavioral counseling are critically important. -- "Baseline evaluation of individuals should include HIV testing, assessment of renal function, serum phosphorous, and assessment for the presence of risk factors for development of renal or bone toxicities. -- "Consideration should also be given to providing the individual with vitamin D and calcium supplementation. -- "Periodic evaluation of the individual during PrEP administration should include regular HIV testing and monitoring for the development of renal dysfunction. -- "DEXA scans prior to and periodically during treatment may be considered for some individuals." When iPrEx investigators first detailed their findings in 2010 [1], the CDC promptly issued "interim guidance" for Truvada PrEP in MSM [22]. Fundamentals of that advice will probably carry over to provider and user guidelines formulated by the FDA. The CDC calls for HIV and HBV testing before starting PrEP, daily Truvada dosing, prescriptions with no more than a 90-day supply, repeat HIV testing every 2 to 3 months, and regular adherence counseling and STI testing. But those guidelines, which follow here, say nothing about side-effect monitoring: CDC interim guidance for health-care providers electing to provide preexposure prophylaxis (PrEP) for the prevention of HIV infection in adult men who have sex with men and who are at high risk for sexual acquisition of HIV [1] Before initiating PrEP Determine eligibility -- Document negative HIV antibody test(s) immediately before starting PrEP medication. -- Test for acute HIV infection if patient has symptoms consistent with acute HIV infection. -- Confirm that patient is at substantial, ongoing, high risk for acquiring HIV infection. -- Confirm that calculated creatinine clearance is ≥60 mL per minute (via Cockcroft-Gault formula). Other recommended actions -- Screen for hepatitis B infection; vaccinate against hepatitis B if susceptible, or treat if active infection exists, regardless of decision about prescribing PrEP. -- Screen and treat as needed for STIs. Beginning PrEP medication regimen -- Prescribe 1 tablet of Truvada (TDF [300 mg] plus FTC [200 mg]) daily. -- In general, prescribe no more than a 90-day supply, renewable only after HIV testing confirms that patient remains HIV-uninfected. -- If active hepatitis B infection is diagnosed, consider using TDF/FTC for both treatment of active hepatitis B infection and HIV prevention. -- Provide risk-reduction and PrEP medication adherence counseling and condoms. Follow-up while PrEP medication is being taken -- Every 2-3 months, perform an HIV antibody test; document negative result. -- Evaluate and support PrEP medication adherence at each follow-up visit, more often if inconsistent adherence is identified. -- Every 2-3 months, assess risk behaviors and provide risk-reduction counseling and condoms. Assess STI symptoms and, if present, test and treat for STI as needed. -- Every 6 months, test for STI even if patient is asymptomatic, and treat as needed. -- 3 months after initiation, then yearly while on PrEP medication, check blood urea nitrogen and serum creatinine. On discontinuing PrEP (at patient request, for safety concerns, or if HIV infection is acquired) -- Perform HIV test(s) to confirm whether HIV infection has occurred. -- If HIV positive, order and document results of resistance testing and establish linkage to HIV care. -- If HIV negative, establish linkage to risk-reduction support services as indicated. -- If active hepatitis B is diagnosed at initiation of PrEP, consider appropriate medication for continued treatment of hepatitis B. References 1. 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. http://www.nejm.org/doi/full/10.1056/NEJMoa1011205. 2. Baeten J, Donnell D, Ndase P, et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 29. http://www.natap.org/2012/CROI/croi_57.htm. 3. Thigpen MC, Kebaabetswe PM, Smith DK, et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011 Rome. Abstract WELBC01. 4. Van Damme L, Corneli A, Ahmed K, et al. The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 32LB. http://www.natap.org/2012/CROI/croi_19.htm. 5. National Institute of Allergy and Infectious Diseases. NIH modifies ÔVOICEÕ HIV prevention study in women: oral tenofovir discontinued in clinical trial. September 29, 2011. http://www.niaid.nih.gov/news/newsreleases/2011/Pages/VOICEmodified.aspx. 6. FDA Review Team for NDA 21-752/S-30. Background Package for NDA 21-752/Supplement 30. April 16, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM303213.pdf. 7. World Health Organization. Hormonal contraception and HIV: technical statement. February 16, 2012. http://whqlibdoc.who.int/hq/2012/WHO_RHR_12.08_eng.pdf. 8. Ruane P, DeJesus E, D Berger D, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir disoproxil fumarate 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 103. http://www.natap.org/2012/CROI/croi_29.htm. 9. Markowitz M, Zolopa A, Ruane P, et al. GS-7340 demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects. 18th Conference on Retroviruses and Opportunistic Infections. February 27 to March 2, 2011. Boston. Abstract 152LB. 10. Ramanathan S, Wei X, Custodio J, et al. Pharmacokinetics of a novel EVG/COBI/FTC/GS-7340 single tablet regimen. 13th International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18, 2012. Barcelona. Abstract O_13. http://www.natap.org/2012/pharm/Pharm_13.htm. 11. Grohskopf L, Gvetadze R, Pathak S, et al. Preliminary analysis of biomedical data from the phase II clinical safety trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-exposure prophylaxis (PrEP) among U.S. men who have sex with men (MSM). 18th International AIDS Conference. July 18-23, 2010. Vienna. Abstract FRLBC102. http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200741348. 12. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One. 2011;6(8):e23688. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0023688. 13. Scherzer R, Estrella M, Li Y, Choi AI, Deeks SG, Grunfeld C, Shlipak MG. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26:867-875. http://www.natap.org/2012/HIV/Associatiotenofovirexposurekidney98985.pdf. 14. "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 CKD (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" [13]. 15. 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. 16. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS. 2012;26:825-831. http://www.natap.org/2012/HIV/Osteoporoticfractureriskassociatedwith989961.pdf. 17. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203:1791-1801. http://jid.oxfordjournals.org/content/203/12/1791.long. 18. Bonjoch A, Figueras M, Estany C, et al. High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study. AIDS. 2010;24:2827-2833. 19. Prejean J, Song R, Hernandez A, et al. Estimated HIV incidence in the United States, 2006-2009. PLoS One. 2011;6(8):e17502. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017502. 20. Anderson P, Liu A, Buchbinder S, et al. Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 31LB. 21. 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(03);65-68. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6003a1.htm?s_cid=mm6003a1_w. 22. PubMed Health. Isotretinoin. Last revision February 1, 2011. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000532/.