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New Long-Acting PrEP: MK-8591
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Download the PDF here
Download the PDF here
Just published:
Once weekly oral MK-8591 protects macaques
https://academic.oup.com/jid/article/221/9/1398/5513016
Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3
Martin Markowitz, Agegnehu Gettie, Leslie St. Bernard, Chasity D Andrews, Hiroshi Mohri, Amir Horowitz, Brooke F Grasperge, James L Blanchard, Tao Niu, Li Sun ... Show more
The Journal of Infectious Diseases, Volume 221, Issue 9, 1 May 2020, Pages 1398-1406,
https://doi.org/10.1093/infdis/jiz271
https://academic.oup.com/jid/article/221/9/1387/5513001
Next-Generation Preexposure Prophylaxis: Choices For Effective HIV Prevention
Kenneth K Mugwanya, Jared M Baeten
The Journal of Infectious Diseases, Volume 221, Issue 9, 1 May 2020, Pages 1387-1389,
https://doi.org/10.1093/infdis/jiz273
Published:
07 June 2019
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MK-8591 Concentrations at Sites of HIV Transmission and Replication - (02/23/17) Rectal & vaginal tissue
EFdA / MK-8591 - HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection - (08/05/16)
Conclusions Our data demonstrated that 4'-ethynyl-2-fluoro-2'-deoxyadenosine efficiently prevents both vaginal and oral HIV transmission. Together with 4'-ethynyl-2-fluoro-2'-deoxyadenosine's relatively low toxicity and high potency against drug-resistant HIV strains, these data support further clinical development of 4'-ethynyl-2-fluoro-2'-deoxyadenosine as a potential pre-exposure prophylaxis agent to prevent HIV transmission in women and their infants.
IAS: First-in-Human Trial of MK-8591-Eluting Implants Demonstrates Concentrations Suitable for HIV Prophylaxis for at Least One Year - (07/25/19)
Antiviral Activity of EFdA [MK-8591] Against NRTI-Sensitive and -Resistant Strains of HIV-2 - (02/24/17)
CROI: MK-8591/Islatravir vs ART Resistance / Metabolics (04/09/20)
Phase 3 Doravirine/Islatravir - (03/12/20)
Islatravir Metabolic Outcomes in a Phase 2b Trial of Treatment-Naïve Adults with HIV-1 - (03/09/20)
WEEKLY ORAL ISLATRAVIR PROVIDES EFFECTIVE PEP AGAINST IV CHALLENGE WITH SIVMAC251 - (03/11/20)
Modeling-Supported Islatravir Dose Selection for Phase 3 - (03/12/20)
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Editor's Choice
Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3
2 pdfs attached
Download the PDF here
Download the PDF here
Abstract
Background
MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is a novel reverse transcriptase-translocation inhibitor.
Methods
We assessed MK-8591 as preexposure prophylaxis in the rhesus macaque model of intrarectal challenge with simian/human immunodeficiency virus (SHIV). In study 1, 8 rhesus macaques received 3.9 mg/kg of MK-8591 orally on day 0 and once weekly for the next 14 weeks. Eight controls were treated with vehicle. All rhesus macaques were challenged with SHIV109CP3 on day 6 and weekly for up to 12 challenges or until infection was confirmed. The dose of MK-8591 was reduced to 1.3 and 0.43 mg/kg/week in study 2 and further to 0.1 and 0.025 mg/kg/week in study 3. In studies 2 and 3, each dose was given up to 6 times once weekly, and animals were challenged 4 times once weekly with SHIV109CP3.
Results
Control macaques were infected after a median of 1 challenge (range, 1-4 challenges). All treated animals in studies 1 and 2 were protected, consistent with a 41.5-fold lower risk of infection (P < .0001, by the log-rank test). In study 3, at a 0.1-mg/kg dose, 2 rhesus macaques became infected, consistent with a 7.2-fold lower risk of infection (P = .0003, by the log-rank test). The 0.025-mg/kg dose offered no protection.
Conclusions
These data support MK-8591's potential as a preexposure prophylaxis agent.
Extended release of MK-8591 from implants formulated using a drug-eluting polymeric matrix has been demonstrated in both rats and nonhuman primates [33] MK-8591 release from these formulations is driven by dissolution and diffusion out of the matrix.
Antiretroviral agents are efficacious when taken as prescribed for preexposure prophylaxis (PrEP) against human immunodeficiency virus type 1 (HIV-1) infection [1, 2]. Fixed-dose combination tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) prevents HIV-1 infection in high-risk individuals when administered daily [3]. Efficacy has also been demonstrated with "on-demand" dosing [4]. In clinical trials, outcomes have been closely linked to adherence [5-9]. In high-risk heterosexual women [10, 11], TDF/FTC was ineffective, and studies were halted owing to futility, likely because <30% of participants were adherent to the treatment regimen, based on plasma drug concentration determinations. In the initial studies of men who have sex with men, overall efficacy was 44%, with a clear gap between those who were adherent (for whom efficacy was 90%) and those who were not [2]. Regimens that improve adherence are likely to represent important advances in the field. Identifying alternatives to daily oral PrEP has become a research priority, and MK-8591 is one such compound [12].
MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is a novel nucleoside reverse transcriptase-translocation inhibitor. Its unique mechanisms of action and distinct pharmacologic characteristics distinguish MK-8591 from approved antiretroviral agents [13-16]. MK-8591 has structural features that contribute to its pharmacologic attributes: 4'-ethynyl, 3'-hydroxyl, and 2-fluoro groups. The 4'-ethynyl group binds tightly to a conserved hydrophobic pocket in HIV-1 reverse transcriptase and interferes with translocation of the extended primer resulting in immediate chain termination [17-19]. The 3'-hydroxyl group, found in naturally occurring nucleotides, contributes to very high binding affinity for reverse transcriptase. Finally, the 2-fluoro on the adenine base ring renders the drug less susceptible to deamination by adenosine deiminase, contributing to its long intracellular half-life (t1/2) [20]. These unique structural elements and mechanisms of action confer MK-8591 with high antiviral potency and unique pharmacologic characteristics, making low-dose, infrequent administration feasible.
The potential for extended-duration dosing with MK-8591 was first demonstrated in rhesus macaques (RMs). MK-8591 triphosphate (MK-8591-TP), the active metabolite of MK-8591 [21], exhibited a 50-hour intracellular t1/2 in peripheral blood mononuclear cells (PBMCs) [22]. When administered to SIVmac251-infected RMs, 2 once-weekly doses ranging from 3.9 to 18.2 mg/kg resulted in a 1.8-log10 reduction in the plasma SIV RNA load. The 3.9-mg/kg/week dose provided a mean MK-8591-TP trough level at 168 hours of 0.53 pmol/106 PBMCs and was on the plateau of treatment efficacy. This informed the initial proof-of-concept experiments of once-weekly PrEP doses of MK-8591 described here [22].
Efficacy with weekly MK-8591 dosing has also been demonstrated in the clinic. In humans, MK-8591-TP has a long intracellular t1/2 (range, 78.5-128 hours in PBMCs) [23]. Single oral doses of MK-8591 of 0.5-30 mg reduced plasma HIV-1 levels by 1.2 to 1.8 log10 copies/mL over 7-10 days in HIV-1 infected individuals [24]. The MK-8591-TP trough level required for virologic efficacy was consistent with that observed in simian immunodeficiency virus (SIV)-infected RMs. At the 10-mg dose, which was well on the plateau of virologic response, the MK-8591-TP trough level was approximately 1 pmol/106 PBMCs. At steady state, daily oral dosing of 0.25 mg MK-8591 provides approximately the same PBMC MK-8591-TP trough level as after a single 10-mg dose [24].
SHIV109CP3 [25], a pathogenic clade C simian/human immunodeficiency virus (SHIV) swarm raised from a SHIV clone, SHIVC109.PB4, that contains an HIV-1 envelope from a recently infected Zambian individual was used as the challenge stock for these studies. This SHIV is CCR5 tropic and readily transmissible by the mucosal route. SHIV109CP3 was recovered from the third passage in a RM with rapidly progressing infection. This virus replicates to high levels in vivo and, during acute infection, depletes CD4+ T cells in the peripheral blood and the gastrointestinal lymphoid tissue of infected macaques [25].
Here we present the first preclinical studies of MK-8591 as a potential PrEP agent in the RM model of intrarectal challenge with SHIV, using doses of MK-8591 administered weekly.
Discussion
The protection against SHIV109CP3 infection provided by low-dose, weekly administration of MK-8591 demonstrates its potential as a next-generation PrEP agent. Intracellular levels of MK-8591-TP of ≥102 fmol/106 PBMCs resulted in complete protection in this model. The EC90 is estimated to be 24 fmol/106 PBMCs, which was achieved with a 0.1-mg/kg oral weekly dose. For comparison, it has been estimated that the EC90 of TDF is 22.6 fmol/106 PBMCs in RMs treated with oral TDF/FTC and 16 fmol/106 PBMCs in men participating in the iPrEx study [28]. The dose of MK-8591 required to obtain a target concentration of 24 fmol/106 PBMCs in humans, assuming a dose proportionality of <0.5 mg (the lowest dose for which human pharmacokinetic data are available), is approximately 0.25 mg weekly and <0.01 mg daily. The projected dose required to achieve efficacious drug levels for prophylaxis against HIV infection are therefore approximately 30 000-fold lower than that demonstrated for TDF. The low daily dose requirement, coupled with the long t1/2 of MK-8591-TP in humans, provides the opportunity for flexibility with regard to both dosing frequency and, potentially, route of administration.
MK-8591 has been evaluated in clinical trials in HIV-1-infected and uninfected individuals. MK-8591-TP exhibited an intracellular half-life of approximately 100 hours [23, 24]. In these studies, MK-8591-TP levels were well above the predicted EC90 for prophylaxis in excess of a month and suggests the potential for use with oral dosing regimens that are less frequent than once weekly and perhaps may couple efficacy with forgiveness for late or missed dosing [30].
There is current enthusiasm for developing long-acting formulations as PrEP. Cabotegravir (CAB), a potent integrase strand-transfer inhibitor, has been formulated as an injectable nanosuspension and is in phase 3 efficacy testing in men who have sex with men and in high-risk women [31]. It is administered intramuscularly every 8 weeks after a loading dose of 2 injections given 4 weeks apart. Long-acting injectable formulations have complicated clinical development plans. Currently, oral dosing is required before the administration of the first injection, to rule out drug hypersensitivity, because once injected the drug cannot be easily removed. There are also concerns regarding the pharmacokinetic tail (ie, the period during which circulating levels of CAB persist below efficacious levels in individuals after they cease treatment), which may increase the risk of resistance should infection occur [32]. This risk has prompted current clinical trials to use daily oral TDF/FTC treatment for a year after the last CAB injection. If dosed orally, MK-8591 has a projected pharmacologic tail that is predictably shorter than that of intramuscularly administered CAB. However, this remains hypothetical because final decisions regarding dosing and the route of MK-8591 have yet to be made, as the drug is amenable to dosing in an extended-release formulation.
Extended release of MK-8591 from implants formulated using a drug-eluting polymeric matrix has been demonstrated in both rats and nonhuman primates [33] MK-8591 release from these formulations is driven by dissolution and diffusion out of the matrix. Implants have some advantages over oral therapies and injectable agents in that they are potentially much longer lasting, can be removed in the event of untoward adverse events, and, once removed, do not have the pharmacokinetic tail associated with injectable formulations. Because MK-8591 has a substantially lower dose requirement, it may have longer durations of release from implants and a lower frequency of dosing than other agents (eg, tenofovir alafenamide) for which these types of drug-delivery systems are being pursued [34].
In summary, MK-8591 demonstrates robust efficacy as prevention in the RM model of intrarectal challenge with SHIV. The RM model of low-dose, intrarectal SHIV challenge has successfully predicted the clinical activity of TDF/FTC as PrEP in high-risk men who have sex with men [35], and our findings are encouraging. MK-8591 combines antiviral potency and pharmacokinetics that translate to flexibility in dosing level, route, and frequency of administration. Given these favorable attributes, clinical development of MK-8591 is highly anticipated, and much will be learned in the near future regarding its efficacy and safety as a potential addition to the armamentarium in both HIV-1 therapy and prevention.
RESULTS
In the first experiment involving rectal challenge with low-dose SHIV, study 1 (Figure 1A), 6 of 8 control macaques became infected after 1 challenge, 1 became infected after 2 challenges, and the last became infected after 4 challenges (Figure 1B). One control animal was euthanized on day 63 (56 days after infection was confirmed), owing to weight loss, diarrhea, and gastrointestinal bleeding. Plasma SHIV levels and CD4+ T-cell counts were not consistent with simian AIDS-related mortality and postmortem gastrointestinal pathology findings suggested concomitant infection with another viral pathogen. At this dosing level, all MK-8591-treated animals remained uninfected after 12 challenges, based on the absence of plasma viremia, of detectable proviral DNA in circulating PBMCs, and of seroconversion out to week 24 of the study (Figure 1C). This corresponded to a 41.5-fold lower risk of infection (95% confidence interval [CI], 7.3-237.9; P < .0001, by the log-rank test), compared with control animals. Intracellular levels of MK-8591-TP at the time of challenge ranged from 0.45 to 1.04 pmol/106 PBMCs (mean, 0.81 pmol/106 PBMCs; Figure 1D). To facilitate comparison of MK-8591 plasma concentrations to MK-8591-TP levels in PBMCs, the amount of MK-8591-TP in PBMCs was converted to micromoles/liter, assuming a volume of 200 fL/PBMC. Mean MK-8591 plasma concentrations at the time of challenge (2.8 nM) were approximately 2000-fold lower on average than mean intracellular concentrations of the active triphosphate moiety at the time of challenge (4.1 μM), consistent with the pharmacologic characteristics and mechanisms of action of MK-8591.
In study 2, all animals were protected at doses of 1.3 and 0.43 mg/kg/week, translating into a 41.5-fold (95% CI, 7.3-237.9-fold) lower risk of infection (P < .0001, by the log-rank test) when compared to study 1 controls (Figure 2B and 2C). Mean levels of MK-8591-TP at the time of challenge at these dosing levels were 0.28 pmol/106 (range, 0.20-0.33 pmol/106) and 0.10 pmol/106 (range, 0.08-0.12 pmol/106), respectively (Figure 2D).
Six of 8 animals were protected at the 0.1-mg/kg dose (Figure 3B). Unlike findings in untreated control animals, in which there was a clear eclipse phase of 1 week between infection and the appearance of viremia, plasma viremia and proviral DNA results in animal JT33 supported an eclipse phase of 2 weeks between infection and the appearance of viremia (Supplementary Table 2). Assuming a 2-week eclipse phase in these treated animals, we conclude that animal KF34 was infected after 2 challenges and animal JT33 was infected after 4 challenges. This translates into a 7.2-fold (95% CI, 2.0-26.2-fold) lower risk of infection (P = .003, by the log-rank test). At the lowest dose, 4 of 6 remaining animals became infected after 1-3 challenges (Figure 3C). This was comparable to findings for controls and was not statistically consistent with any degree of protection (hazard ratio, 3.37; 95% CI, .8-13.7; P = .089). Study 3 was concluded 2 weeks before the end of the planned washout period, 14 weeks as opposed to 16 weeks, because the drug proved to be ineffective at the lowest dosing level tested (Figure 3A).
Intracellular Concentrations of MK-8591-TP at the Times of Challenge
Mean intracellular levels of MK-8591-TP at the times of challenge for the various doses are shown in Table 1 and Figures 1D and 2D. Mean levels of MK-8591-TP were approximately linear as the MK-8591 dose decreased from 3.9 to 1.3 to 0.43 mg/kg. At the 0.1-mg/kg dose, the intracellular level of MK-8591-TP could not be reliably quantified. Therefore, based on the observed dose proportionality of intracellular MK-8591-TP levels at the time of challenge for the higher doses, the intracellular levels at the time of challenge for the 0.1-mg/kg weekly dose was estimated to be 24 fmol/106 PBMCs (0.13 μM). Given that this estimated level of MK-8591-TP protected 8 animals against a 29 of 32 challenges and that controls were infected by 1 challenge on average, this would translate to a prophylactic 90% effective concentration (EC90) of approximately 24 fmol/106 PBMCs, comparable to that estimated for tenofovir diphosphate in RMs when dosed daily at 22 mg/kg [28].
Characterization of Breakthrough Viruses and Seroconversion
Mean peak plasma levels (±SD) of SHIV109CP3 in treated animals with breakthrough infections were lower than in untreated animals (log10 3.89 ± 4.22 vs log10 6.86 ± 7.00 copies/mL; P = .0007, by the Mann-Whitney test). We believe that the presence of active drug was responsible for this difference. The time to seroconversion between treated animals and controls was not statistically different (3.6 and 2.5 weeks, respectively; P = .26, by the Mann-Whitney test). The 2 animals that remained aviremic had negative results of qualitative proviral DNA analyses at all time points and did not seroconvert.
Hypothetically, when antiretroviral agents are used to prevent infection, it is possible for drug-resistant variants to emerge and establish infection if there are subinhibitory drug concentrations. In vitro-passage experiments demonstrated that the main resistance-conferring mutations that reduce susceptibility to MK-8591 are M184V and M184I [13, 29]. We performed consensus sequencing of the reverse transcriptase coding region in all 6 MK-8591-treated animals with evidence of viremia 2 weeks on average after the first quantifiable plasma viral load determination, when mean plasma SHIV-1 RNA levels were 3.1 log10 copies/mL plasma. Neither M184V nor M184I was detected.
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Next-Generation Preexposure Prophylaxis: Choices For Effective HIV Prevention
Evidence supporting the use of antiretroviral medications to prevent new human immunodeficiency virus (HIV) infections-as both treatment to eliminate infectiousness and prophylaxis to block acquisition-has revolutionized thinking about HIV prevention. Indeed, HIV treatment and preexposure prophylaxis (PrEP) are now core components of US and global efforts to end the HIV epidemic [1]. Oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) was the first PrEP agent [2, 3], and its key regulatory and normative agency milestones have included Food and Drug Administration approval in 2012, Centers for Disease Control and Prevention and World Health Organization guidelines in 2014 and 2015, and drug regulatory approval and national guidelines currently in >40 countries worldwide [4]. PrEP with TDF/FTC pills is now standard of care for HIV prevention, and wide-scale implementation is underway globally.
TDF/FTC clinical trials found that individuals who had high-level adherence, as measured by drug levels in blood samples, were protected from HIV [5, 6]. Unsurprisingly, those who did not adhere well to oral TDF/FTC treatment were not protected. Implementation studies have subsequently shown the same virtual elimination of HIV risk in the women and men who take TDF/FTC, but critical gaps at the population level, with lack of access, stigma, and inability to or lack of interest in taking a daily pill, mean that many persons who could benefit from PrEP are not. Thus, while substantial reductions in new HIV infections have been realized in settings where PrEP has been implemented with high coverage [7], there is still far to go to achieve PrEP's full prevention potential at scale.
One medication option for PrEP is not enough. Just like PrEP, HIV treatment's clinical and prevention benefits are directly tied to adherence. Antiretroviral treatment has evolved markedly in the 3 decades since zidovudine was first approved, toward regimens that are easier to take and fit better into people's lives: initial regimens comprised multiple pills taken multiple times daily, subsequent regimens involved multiple pills taken once daily followed by single-tablet regimens, and recent regimens include injectable therapy administered at multiple-week intervals [8]. For PrEP, alternative options to a daily oral pill are needed to provide options that fit into people's diverse life experiences and preferences. Such next-generation PrEP candidates would ideally improve on TDF/FTC, with characteristics like less frequent or nonoral dosing, a better ability to be taken privately, and even greater forgiveness to less-than-perfect adherence.
In this issue of The Journal of Infectious Diseases, Markowitz et al report data from a rhesus simian/human immunodeficiency virus (SHIV) intrarectal challenge model by which they assessed the potential PrEP efficacy of oral MK-8591, a long-acting nucleoside reverse transcriptase-translocation inhibitor. MK-8591 is highly potent against HIV replication; its potency is approximately 10-1000-fold greater than that of existing antiretrovirals [9]. The results presented by Markowitz et al showed robust efficacy for protection against SHIV infection at weekly dosing of 1.3 and 0.43 mg/kg, which would translate into doses of <250 μg in humans, providing important evidence to advance MK-8591 into further clinical investigation. Notably, pharmacokinetic work predicts that MK-8591 could be dosed not only weekly, as tested in the current study, but instead monthly, maintaining concentrations that are estimated to provide HIV protection. A once-monthly pill would, of course, be a substantially different product than daily TDF/FTC treatment; in addition, the high potency of MK-8591 could make it attractive to formulate into long-acting injections or implants. Thus, the work by Markowitz et al is an important step toward a possible new PrEP option. MK-8591 already has some early human data [10], the next step toward eventual evaluation for safety and efficacy as PrEP in large-scale trials.
For all prevention interventions, including PrEP, users regularly weigh side effects, efficacy, life burden, and other factors when making choices. For another preventive action, contraception, multiple options exist, in a variety of forms, including several types of pills, injectable and implantable systemic medications, intrauterine devices that delivery little or no drug systemically, and options that can be called on for use only at the time of sex or, like, emergency contraception, even after sex. In the contraceptive field, there is broad appreciation that expanding options results in more individuals achieving effective prevention of unintended pregnancy [11]. Thus, for PrEP, having more options on the table will not necessarily mean that treatment for oral TDF/FTC users will be shifted to the next available thing but that, instead, and better, more options will allow more people to use PrEP and be protected from HIV.
User preferences will vary, across individuals and populations, and if multiple PrEP options can be developed, the result will be increased reach, coverage, and impact. Since a highly effective and safe daily pill option exists for TDF/FTC therapy, there is particular enthusiasm for developing longer-acting delivery approaches for PrEP, such as pills of high potency and long half-life, depot injectables, and vaginal rings or subdermal implants that slowly release medication, as well as on-demand products that people can use when needed. Recent studies of hypothetical prevention choices among adolescent girls and young women in Africa found that each different PrEP option appealed as a first choice to an important fraction of individuals [12]; thus, work will need to be done to determine how to facilitate decision-making once multiple options are available.
Seven years have passed since the Food and Drug Administration approved oral TDF/FTC treatment for PrEP, and a handful of new PrEP products appear to be on the horizon. For women, a flexible silicone intravaginal ring that slowly releases the antiretroviral nonnucleoside reverse transcriptase inhibitor dapivirine was recently demonstrated to provide HIV protection on the order of approximately 30% [13, 14], with protection potentially ≥50% with better use.
Now undergoing regulatory review, the monthly dapivirine vaginal ring could provide women, particularly those in settings where the HIV burden is high, with a longer-acting prevention option that is safe, reversible, and discreet. An updated version of TDF/FTC-daily oral tenofovir alafenamide (TAF) plus FTC-recently demonstrated a level of HIV protection comparable to that of TDF/FTC therapy [15], with a smaller pill, biomarkers that might suggest even better long-term safety, and some pharmacologic properties that could be more forgiving to missed doses. Two clinical trials (HPTN 083 and 084) are currently underway to evaluate the safety and efficacy of cabotegravir, an HIV integrase inhibitor formulated as a long‐acting injectable (CAB-LA), with results eagerly expected in a few years [16]. If CAB-LA treatment is safe and comparably efficacious to TDF/FTC therapy, it will provide an exciting new prevention option, but some individuals may have challenges with an intramuscular injection, some may have personal preferences about systemic medications, some may desire for reversibility (ie, to start and stop PrEP, as seems to be modestly common in TDF/FTC users [17] and is often the case for contraceptive users), and some may not like whatever potential side effects CAB-LA may have. Thus, none of these alone will be the best PrEP option for all potential users. All PrEP medications have some amount of pharmacokinetic "tail"-a period when the drug is still present in the body but unlikely to still be highly effective for prevention (although still potentially able to drive HIV resistance); longer-acting formulations in general have longer tails, with clinical and virologic consequences still to be determined. Other novel PrEP approaches, including implants, microarray patches, rapidly-acting vaginal and rectal inserts, rectal enemas, and other topical options, are in early phase studies [18], suggesting that we have only seen the beginning PrEP options.
We all want options so we can make the choice that best fits us. That sentiment is true in many aspects of our lives-in the consumer products we purchase, the work we choose to do, the entertainment that rounds out our lives, and the healthcare decisions that we make. HIV prevention is no different. We are at an exciting time for HIV prevention-oral TDF/FTC proved to the world that highly effective and safe PrEP was possible. Next-generation products will expand options in the not-too-distant future so that people can make the choices that will increase PrEP's prevention impact.
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