We review key, recent clinical pharmacology studies to aid interpretation of completed pre-exposure prophylaxis (PrEP) randomized clinical trials (RCTs) using antiretroviral (ARV) drugs. The goal is to establish concentration–response between and within studies to identify effective target drug concentrations and other influential variables, like adherence, that affect PrEP efficacy. Target concentrations, once established, guide dose optimization and development of ARVs in the PrEP pipeline.
SELECTION OF ANTIRETROVIRALS FOR PRE-EXPOSURE PROPHYLAXIS
Since 2002, numerous vaginal microbicides for PrEP contained luminally active agents – detergent, polyanionic, or pH buffering mechanisms of action – which did not contain ARVs. These were selected for study, in part, to avoid resistance to treatment ARVs, limit systemic toxicity possible with oral drugs, and achieve high local concentrations at the putative mucosal site of action. As these non-ARV formulations failed to prevent HIV infection, treatment-proven tenofovir (TFV) was studied in a vaginal gel formulation and in its licensed oral formulations, tenofovir disoproxil fumarate (TDF) alone (Viread) and coformulated with emtricitabine (Truvada) [1–6]. Extensive pharmacokinetic, safety, and antiviral data established for treatment accelerated development of TFV-containing oral and topical formulations for PrEP. Applying these drugs to sexual HIV prevention, however, required additional data to guide rational dosing and formulation development, especially for topical application, to understand the complex interactions of many influential drug and HIV-related variables (Fig. 1), including vaginal and rectal tissue pharmacokinetics, mucosal tissue toxicity (which might reduce adherence if symptomatic or increase HIV susceptibility), and luminal distribution of HIV within the female genital tract and colon to assure adequate distribution of ARVs in development .
Tenofovir and emtricitabine (FTC) remain the only ARVs proven efficacious in clinical PrEP trials. TFV, an adenine nucleoside analog reverse transcriptase inhibitor, is a component of first-line highly active ARV therapy (HAART). TFV is a phosphonate, which requires only two phosphorylation steps by human nucleoside kinases to form the active moiety, tenofovir diphosphate (TFV-DP), which remains in the cell with an extended 150–180 h half-life in peripheral blood mononuclear cells (PBMCs) of HIV patients, far longer than the 17 h plasma half-life of the parent drug [8–11]. The oral formulation, TDF, is an esterified prodrug with increased bioavailability compared with TFV. FTC is a cytidine nucleoside analog reverse transcriptase inhibitor which, compared with TFV, has a shorter half-life of both parent drug in plasma and the active intracellular anabolite, emtricitabine triphosphate, 8–10 h and 39 (range 29–56) h, respectively [12,13].
Pharmacology of oral and topical pre-exposure prophylaxis
Pharmacokinetics-focused studies describe the concentration–time course of TFV and FTC in diverse anatomic sites relevant to HIV protection.
HIV distribution after intercourse
Identification of the viral target in space and time enables optimization of PrEP ARV formulation and dosing to assure that the ARV outdistances and outlasts the virus at the site of infection. Over a decade ago, murine and primate models of retrovirus infection indicated that virus passes from vaginal lumen to mucosal tissue rapidly within 1 h and infects T cells in genital mucosa and regional lymph nodes, both directly and indirectly via dendritic cells, within 24 h [14–16]. Recently, Louissaint et al.[17▪] described the distribution of cell-free and cell-associated HIV surrogates (virus-sized particles and autologous white blood cells) in the colon and vagina following simulated sex. Rectally dosed HIV surrogates distributed to the recto-sigmoid colon, were associated with rectal biopsies taken 5 h after simulated sex, and were usually cleared within 24 h [17▪]. Vaginally dosed HIV surrogates were concentrated in the peri-cervical area, with no evidence of uterine distribution, through 8 h, at which time surrogates were found in vaginal tissue biopsies, but little remained at 24 h [18▪]. In both colon and vagina, the cell-free and cell-associated surrogates shared a largely coincident luminal distribution. Taken together, these animal and human studies indicate that optimal PrEP drugs, whether oral or topical, deliver HIV-inhibiting ARV concentrations to the peri-cervical region or into the recto-sigmoid prior to and for at least 24 h following sex.
Luminal drug distribution
Methods developed by Cao et al.[19▪] and Goldsmith et al.[20▪] enable description of the luminal distribution and clearance of rectal microbicide formulations using noninvasive single photon emission computed tomography (SPECT). In feasibility studies, a rectal gel achieved the greatest accumulation in the recto-sigmoid colon, similar to the HIV surrogate studies above, with the maximal extent of distribution into the sigmoid and even the descending colon in a small subset of individuals. Gel migrated retrograde with time and was visible within the colon throughout 24 h. These methods are being used to optimize development of rectal microbicides.
Mucosal tissue distribution and clearance of antiretrovirals
Schwartz et al.[21▪▪] studied the 24-h blood and genital tract pharmacokinetics of single and multiple doses (14 days) of 1% TFV (40-mg) vaginal gel in 49 women. Multiple days of vaginal dosing with one or two doses daily resulted in little or no accumulation of TFV in plasma, compared with a single dose. The systemic multiple dose concentrations are 7.5 and 40 times lower than trough and peak TFV concentrations, respectively, after a daily oral 300 mg TDF dose in a comparable cohort of healthy women . In the multiple-dose group, TFV and TFV-DP were detected in 100 and 27% of vaginal biopsies, respectively. Tissue TFV peaked 4 h after dosing at 2.7 × 104 ng/ml; TFV-DP peaked at 8 h at 3.1 × 103 ng/ml (among the 27% of detectable samples). There was no difference in vaginal tissue TFV between the proximal and distal biopsy locations.
Microbicide Trials Network (MTN)-001 employed a cross-over design in which 144 African and US participants received daily doses of 300 mg oral TDF, 1% (40 mg) TFV vaginal gel, or both, each for 6 weeks in randomized sequence. Findings included 1-h peak TFV in both blood and tissue, 60-fold greater serum concentrations after oral dosing compared with vaginal, and more than 130-fold higher vaginal tissue TFV-DP concentrations with vaginal compared with oral dosing [23▪]. TFV-DP was detected in greater than 90% of women in the vaginal dose phase. Rectal fluid TFV concentrations were greater after vaginal dosing than after oral dosing, consistent with a previous study in macaques by Nuttall et al., suggesting vaginal dosing may provide some level of rectal protection.
MTN-001 also documented high 94% adherence using self-reported, but serum TFV concentrations indicated inconsistent TFV use in 64% of participants. Further, compared with African women, United States women showed a 2–5-fold greater predose serum TFV concentration (greatly influenced by timing of the prior unobserved dose), despite having a similar peak and half-life after an observed clinic dose [23▪]. This indicated similar pharmacokinetics, but large adherence differences.
In a study, Rectal Microbicide Program-02/MTN-006, Anton et al. compared a single 300 mg oral TDF dose to a rectal 1% (40 mg) TFV gel dose (single and seven daily doses). Similar to vaginal dosing, plasma TFV concentrations were 23-fold greater after oral compared with rectal dosing, tissue TFV-DP concentrations were 10-fold greater after rectal compared with oral dosing, and rectal dosing achieved measurable TFV concentrations in cervico-vaginal fluid. Unique among the small pharmacokinetic studies, Anton et al. challenged rectal biopsies with HIV ex vivo and saw an increasing TFV-DP concentration associated with decreasing HIV replication.
In a 12-patient, single-dose oral TDF/FTC (Truvada) study with 2 weeks of postdose sampling, Patterson et al.[26▪▪] identified a tri-phasic concentration–time course with a 49 h terminal (gamma) half-life. Twenty-four hours after dosing, rectal biopsy homogenates in six men demonstrated TFV-DP concentrations more than 100 times greater than TFV-DP in vaginal biopsy homogenates in six women. Whereas TFV-DP was still detectable 2 weeks later, the rectal–vaginal difference had disappeared. Cervical TFV-DP was erratically detected, though at similar concentrations to vaginal tissue. In contrast, FTC-TP was 10-fold greater in vaginal tissue compared with rectal tissue, but was not detectible in either beyond 2 days [26▪▪].
In another single-dose oral TDF study, collecting paired rectal and vaginal biopsies in six women, Louissaint et al.[27▪] confirmed several of the key Patterson et al. findings: 49 h terminal TFV plasma half-life and greater than 100-fold rectal-to-vaginal concentration ratio at 24 h that did not persist at 2 weeks. Because these were paired biopsies in the same women, the colon-to-vaginal ratio cannot be attributed to sex differences. However, when the investigators looked at TFV-DP concentrations in the highly relevant CD4+ T cells extracted from tissue, the rectal-to-vaginal TFV-DP ratio was only 20-fold. In addition, they demonstrated a complex biphasic PBMC TFV-DP peak – first peak at 8–16 h, second peak at 96 h – before beginning terminal elimination with a 48 h PBMC half-life, similar to the plasma TFV gamma decay estimate, and a longer 112 h half-life in CD4+ T cells. This complex early biphasic peak and delayed time to terminal decay may partly explain the shorter PBMC TFV-DP half-life estimates compared with the 150–180-h estimates in studies of HIV patients [9–11]. The half-lives in homogenates and unselected cells extracted from vaginal and rectal tissue were similar to PBMCs with CD4+ cell half-lives typically longer. A second six-woman, single oral TDF dose study by Chen et al.[28▪] replicated this complex biphasic TFV-DP pattern between days 1 and 3 before a terminal elimination half-life of 64 and 100 h in PBMC and CD4+ cells, respectively.
Other ARVs with potential benefits over TDF/FTC are in earlier phases of PrEP development. CCR5 inhibitor, maraviroc, does not have other in-class drugs to raise resistance concerns, demonstrates greater vaginal (2-fold) and rectal (26-fold) tissue homogenate concentrations when compared with blood plasma after oral dosing, and cervico-vaginal fluid concentrations exceeded plasma concentrations 3 days after dosing [29,30]. However, given poor adherence in some PrEP RCTs, a 16-h plasma maraviroc half-life, far shorter than TFV-DP, may be a liability if similarly brief in tissue. The 50-h plasma half-life of rilpivirine, a licensed oral non-nucleoside reverse transcriptase inhibitor, is far longer than maraviroc and lacks the initial phosphorylation delay seen with TFV-DP and FTC-TP – characteristics which may have advantages if its tissue distribution and clearance are favorable . Directly attacking the adherence issue, an injectable rilpivirine formulation sustains blood, vaginal tissue, and rectal tissue concentrations in men and women for 28 days . Also addressing adherence, a monthly vaginal ring containing dapivirine, an experimental non-nucleoside reverse transcriptase inhibitor, is being studied in two RCTs scheduled for completion in 2015. Importantly, rilpivirine and dapivirine have potential for within-class cross-resistance.
Pharmacokinetic data inform randomized clinical trials
Sparse pharmacokinetic data embedded in PrEP RCTs, especially when linked to smaller bridging pharmacokinetic studies, enhance understanding of concentration–response and modifying factors essential for dose selection and future trial design.
Several PrEP RCTs included pharmacokinetic data which provide evidence of concentration–response (Table 1). Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 showed a decrease in HIV incidence with cervico-vaginal fluid TFV concentrations higher than 1000 ng/ml . In the iativa Profilaxis PreExposicion (iPrEx) study, presence of TFV and FTC moieties in blood plasma and in PBMCs was associated with 92% relative risk reduction compared with only 42% in all participants randomized to drug . Partners PrEP reported a smaller bump in relative risk reduction in both TDF and TDF/FTC arms rising to 86 and 90%, respectively, when TFV was detected [using a more sensitive assay than in the iPrEx study] [35▪▪]. In the Centers for Disease Control and Prevention (CDC) TDF2 study, TFV and FTC were more commonly detected in nonseroconverters (80 and 81%, respectively), compared with seroconverters (50%) for both drugs [36▪▪]. In FEM-PrEP, concentrations at the beginning and end of the seroconversion window appeared to be less frequently detectible in seroconverters (15%) compared with nonseroconverting participants at similar time intervals (26%), but these were not statistically significant [37▪▪].
Among-study concentration–response in oral studies
The TFV plasma concentrations reported in completed oral PrEP RCTs indicates a concentration–response among these studies (Fig. 2), with the exception of iPrEx, which has a unique risk population [34,35▪▪–37▪▪,38]. TFV concentration data contain substantial heterogeneity due, most likely, to variability between individuals and in time of unobserved prior doses. Similarly, confidence intervals of relative risk reduction are also large in some studies due to few seroconversions or small sample size.
iPrEx is the outlier among oral studies with median detectible ARV concentrations around 10 ng/ml, not much different from FEM-PrEP; yet, iPrEx had a 42% relative risk reduction compared with none [34,37▪▪]. As receptive anal intercourse is the primary HIV risk for the men who have sex with men (MSM) in iPrEx, two adjustments are warranted. First, several oral dose pharmacokinetic studies indicate active drug TFV-DP concentrations are 20 to more than 100 times greater in rectal tissue, most relevant in iPrEx, when compared with vaginal tissue [26▪▪,27▪]. As plasma TFV, not rectal tissue, is measured in RCTs, this colon-to-vaginal ratio effectively shifts the ‘effective’ iPrEx plasma concentration rightward along the concentration axis. There is a second countering leftward shift in ‘effective’ TFV concentration due to increased risk of HIV infection via receptive anal intercourse in iPrEx compared with vaginal or penile exposures, which are the dominant risks in the other oral studies. The magnitude of site of infection and anatomic variation in active drug tissue concentration effects are too imprecise to make specific adjustments, but these factors may combine to bring iPrEx more closely in line with the concentration–response seen among the other studies.
Adherence influential in oral studies
The variation in concentration among RCTs far exceeds variability attributable to either inter-individual variability in prior pharmacokinetic studies or prescribed daily dosing time in the day prior to clinic blood sampling. Comparison of geographic sub-populations in MTN-001 found five-fold differences in predose serum TFV concentration. As predose concentration is influenced by timing of the prior unobserved dose and individual pharmacokinetic variation, which was not seen following observed doses, we attribute most of these concentration differences to adherence.
Factors mitigating beneficial antiretroviral effect in topical studies
As tissue concentrations with topical dosing exceed those after oral dosing by more than 100-fold, one would anticipate topical dose studies to have the best HIV protection. Even assuming the low level of adherence seen in FEM-PrEP, expected tissue concentrations in CAPRISA 004, and MTN-003 [Vaginal and Oral Interventions to Control the Epidemic (VOICE)] gel arm would exceed Partner's PrEP vaginal tissue concentrations by 10-fold. Results to the contrary – only 39% relative risk reduction in CAPRISA 004 and none in VOICE TFV gel arm – we postulate an unexplained dose-related variable at work that reduces the efficacy of topical dose regimens. Excessively high local concentrations of drug or the gel delivery vehicle are potential candidates worthy of additional exploration. If these are at fault, a simple formulation change (dose reduction and/or gel modification) could transform topical TFV dosing into a highly effective PrEP method.
Small clinical pharmacology studies richly inform our interpretations of concentration–response in oral PrEP RCTs and indicate that differences in adherence and anatomic site of HIV risk are both powerful explanatory variables which can guide selection of alternative regimens to achieve target concentrations. The underperformance of topical PrEP studies cannot be explained by low adherence and may be due, in part, to some product-related factor mitigating the high level of protection expected based on the concentration–response seen in oral studies. Beyond simply informing interpretation of their trial outcomes, earlier completion of these clinical pharmacology studies should improve the drug development process for the next generation of PrEP agents.
Conflicts of interest
Disclosures for this work: None.
Dr Hendrix has received research funding from Gilead Sciences, managed by Johns Hopkins University.
The authors also wish to thank the organizations who provided support for most of the research cited herein: NIH/Division of AIDS through the Microbicide Trial Network, HIV Prevention Trials Network, and the Integrated Pre-Clinical/Clinical Program for Topical Microbicides; the Centers for Disease Control and Prevention; CONRAD; Bill and Melinda Gates Foundation; Gilead Sciences.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 607–608).
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This is the first study to simulate and quantitatively assess the distribution of HIV surrogates in semen, both cell-free and cell-associated, in the distal colon, and found that HIV surrogates migrate relatively little after simulated sex, only to the recto-sigmoid colon. These findings are useful in guiding formulation development of gels or enemas for use to prevent HIV from receptive anal intercourse.
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This is the first study to simulate and quantitatively assess the distribution of HIV surrogates, cell-free and cell-associated, in the femal genital tract indicating pooling of HIV surrogates around the exocervix without any uterine distribution. These findings are useful in guiding formulation development of gels or enemas for use to prevent HIV from receptive anal intercourse.
19▪. Cao YJ, Caffo BS, Fuchs EJ, et al.
Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging. Br J Clin Pharmacol 2012 [Epub 2012/03/13].
This study applies a novel three-dimensional tube-fitting algorithm (described in Goldsmith et al.) to describe the concentration–distance–time course of a rectally applied product. New pharmacokinetic parameters that quantify concentration over distance are introduced.
20▪. Goldsmith J, Caffo B, Crainiceanu C, et al. Nonlinear tube-fitting for the analysis of anatomical and functional structures. Ann Appl Stat 2011; 5:337–363.Epub 2011/06/29.
This is the newest version of several generations of three-dimensional fitting algorithms from this group and is applied to mapping rectal microbicide gel distribution in Cao et al. (above).
21▪▪. Schwartz JL, Rountree W, Kashuba AD, et al. A multicompartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel. PLoS One 2011; 6:e25974Epub 2011/11/01.
This is the first pharmacokinetic evaluation of vaginally applied tenofovir gel that included intensive sampling of blood, vaginal tissue, and cervico-vaginal fluid at multiple time points after single and multiple does. This is an excellent example of intensive pharmacokinetic study designs to gather maximal information to build multicompartment pharmacokinetic models.
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This study extends the methods in the study by Schwartz et al. by using a cross-over design in which women receive an oral dose and a vaginal dose, alone and together, enabling measurement of concentration differences due to route of dosing without comparison with an external study.
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This study makes essential comparisons between tenofovir and emtricitabine concentration in rectal tissue in men and compares with vaginal tissue drug concentrations, essential for understanding potential differences in drug coverage for anal and vaginal intercourse.
27▪. Louissaint N, Cao Y, Tannenbaum S, et al.
Single dose 14C-tenofovir distribution into blood, colon, and vagina in healthy volunteers. Keystone Symposium: protection from HIV: targeted intervention strategies; March 20–25, 2011; Whistler, British Columbia, Canada; 2011.
This is the first study reporting CD4 cell subsets extracted from vaginal and colon tissue which provides pharmacokinetic data of the cell type and location of greatest interest for pre-exposure prophylaxis which showed a much lower colon-to-vaginal concentration gradient than studies of tissue homogenate.
28▪. Chen J, Flexner C, Liberman RG, et al.
Phase 0 study of intracellular drug concentrations: accelerator mass spectrometry measurement of phosphorylated tenofovir and zidovudine. 12th International Workshop of Clinical Pharmacology of HIV Therapy 13–15 April; Miami; 2011.
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35▪▪. Baeten JM, Donnell D, Ndase P, et al.
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This is a critical randomized clinical trial which demonstrated preventive efficacy of tenofovir alone and tenofovir/emtricitabine when used by the susceptible partner in an HIV-discordant couple. Relatively sparse pharmacokinetic sampling allowed clear demonstration of concentration–response in this large study.
36▪▪. Thigpen MC, Kebaabetswe PM, Paxton LA, et al.
Safety and efficacy of daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: the TDF2 study. N Engl J Med 2012 [Epub ahead of print].
Similar in importance to Partners PrEP, this study demonstrated PrEP efficacy of tenofovir/emtricitabine in heterosexual men and women. This study also included pharmacokinetic sampling and demonstrated higher concentrations in nonseroconverters compared with seroconverters.
37▪▪. Van Damme L, Corneli A, Ahmed K, et al.
The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. N Engl J Med 2012 [Epub ahead of print].
This randomized clinical trial is one of the two ARV PrEP studies in women (along with VOICE) that were not successful in preventing HIV infection. Drug concentration data indicated numeric differences in drug concentration between seroconverter and nonseroconverter, but they were not statistically significant.
38. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329:1168–1174.Epub 2010/07/21.