The pharmacokinetics and prolonged half-life of maraviroc support once-daily dosing . Also, because of its mechanism of action, the serum half-life is less important than the length of time maraviroc remains bound to the CCR5 receptor, which appears to be on the order of days . In addition, clinical studies reveal that maraviroc is concentrated in vaginal secretions (three-fold to eight-fold higher)  and rectal tissue (eight-fold to 26-fold higher) [19▪] compared with blood levels. Maraviroc is metabolized by the cytochrome P450 enzyme system and drug–drug interactions may be expected . Viral drug resistance to maraviroc is uncommon ; virologic breakthrough on a maraviroc-containing regimen is most commonly accompanied by the emergence of dual-tropic virus, rather than drug-resistant viral strains .
In summary, maraviroc is generally safe and well tolerated, with favorable pharmacokinetic properties allowing once-daily dosing, concentration in target tissues, and uncommon development of drug resistance. In addition, maraviroc is used infrequently in HIV treatment regimens, with current guidelines listing it as ‘acceptable’ for initial treatment . Recognizing the limited safety data in HIV-uninfected individuals, an NIH-sponsored phase 2 study of maraviroc recently opened to accrual (HIV Prevention Trials Network Study 069/AIDS Clinical Trials Group study 5305 ).
Raltegravir requires twice-daily dosing for HIV treatment. Although early pharmacokinetic studies suggested once-daily dosing might be possible , a large randomized, phase 3 noninferiority trial showed that HIV-infected patients who were randomized to a standard regimen that included twice-daily RAL dosing had significantly better virologic suppression rates than the investigational regimen using once-daily RAL dosing . A pharmacokinetic study in seven HIV-negative female volunteers demonstrated that concentrations of raltegravir in cervicovaginal fluid (CVF) approximated those in blood, whereas the median half-life in CVF of 17 h was about twice as long that seen in blood . Another pharmacokinetic study of 15 HIV-negative men demonstrated raltegravir levels 1.5–7-fold higher in gut-associated lymphoid tissue (GALT) compared with blood levels . Raltegravir is metabolized primarily by glucuronidation, and thus has few drug-drug interactions .
Raltegravir has a low genetic barrier to resistance; single substitutions in the integrase gene have been associated with drug resistance to raltegravir and dual substitutions occur commonly following virologic failure on a raltegravir-containing regimen . In addition, cross-resistance to other integrase inhibitors such as elvitegravir has been shown in vitro and clinically [34,35]. However, as a newer HIV drug, resistance to raltegravir currently is thought to be uncommon in the community .
Raltegravir was assessed as PrEP in the same animal model that was used to assess maraviroc, as discussed above . In this study, six mice received daily dosing of raltegravir for a week and were compared with eight control mice after a vaginal challenge of HIV-1 on day 4. During the follow-up period, all of the control mice were HIV infected, whereas none of the raltegravir-treated mice had evidence of HIV infection.
In summary, raltegravir is generally safe and well tolerated, concentrates in vaginal secretions and GALT, and demonstrates efficacy as PrEP in an animal model, but may require twice-daily dosing, has a low genetic barrier to resistance, and is used commonly in HIV-treatment regimens. Due to these limitations, no current clinical studies of raltegravir PrEP are planned.
A parenteral, long-acting form of rilpivirine (RPV-LA) was developed with the goal of improving treatment adherence and testing as a potential agent for PrEP . Using nanotechnology to produce this parenteral form of rilpivirine, a proof-of-concept study was conducted in mice and dogs showing sustained concentrations of the drug for over 3 weeks and 3 months, respectively . These encouraging results led to a clinical pharmacokinetic study in which 27 female volunteers were given intramuscular injections of RPV-LA at three doses, 300, 600, or 1200 mg with six male volunteers given a single injection of 600 mg . In this study, RPV-LA was generally well tolerated and achieved concentrations in genital tract tissue, suggesting efficacy for its use in PrEP. Compared with plasma, RPV-LA concentrations were 1.2–1.95-fold higher in female genital tract fluid and 0.48–1.0-fold in vaginal tissue, and in men, similar (0.89–0.92-fold) in rectal tissue. Else et al.  updated these data in 10 women and six men who received a single 600 mg intramuscular injection of RPV-LA and found that cervicovaginal fluid and rectal tissue concentrations were equivalent to plasma, but vaginal tissue concentrations were lower and rectal fluid concentrations were much lower. Rilpivirine is metabolized by the hepatic CYP3A isoenzyme system, and drug–drug interactions may be expected .
RPV-LA appears to be a promising drug for PrEP on the basis of its infrequent dosing that results in prolonged plasma and tissue levels. However, the parenteral formulation is investigational and early in clinical development. Further studies are necessary to assess its safety and tolerability and efficacy as PrEP. Additional areas of concern are the lower genetic barrier to resistance with resultant cross-resistance in the NNRTI class, and the fact that rilpivirine (and the other NNRTIs) are used commonly for HIV treatment.
S/GSK1265744 is an investigational HIV integrase inhibitor in early clinical development. A complex phase I/IIa study assessed oral S/GSK1265744 (vs. placebo) in 18 HIV-negative individuals with single escalating doses (5, 10, 25, and 50 mg), in 30 HIV-negative individuals at daily doses (5, 10, or 25 mg) for 14 days, and in 11 HIV-infected men not on other antiretrovirals who received 30 mg once daily for 10 days, 3 days of no treatment, and then 14 days of combination antiretroviral therapy . Overall, S/GSK1265744 was generally well tolerated with similar rates of adverse events compared with the placebo arms. In the 11 HIV-infected participants, S/GSK1265744 was associated with a median HIV RNA decrease of 2.6 log copies per ml, suppression of HIV RNA less than 50 copies/ml in all but one participant by day 14, and no emergence of drug resistance mutations.
Pharmacokinetic assessment of S/GSK1265744 demonstrated a long half-life of 30 h, suggesting the need for infrequent dosing . S/GSK1265744 also is available in a long-acting parenteral form . S/GSK1265744 has a similar drug resistance profile to dolutegravir, an investigational integrase inhibitor in phase 3 development . Further studies are ongoing to assess safety and efficacy in HIV-negative volunteers , including in a pilot study in combination with RPV-LA . Despite current limited safety and tissue penetration data, the long-acting parenteral formulation of S/GSK1265744 appears to be a promising agent for PrEP, although integrase inhibitors are used commonly in HIV treatment.
Ibalizumab (previously known as TNX-355 and Hu5A8) is an investigational monoclonal antibody that binds to an area of the CD4 receptor that results in a distortion of the CD4–gp120 complex that prevents binding to the chemokine receptor, thereby inhibiting viral entry [48,49] (Fig. 1). Notably, although related monoclonal antibodies also exert an immunosuppressive effect, no effect has been reported with ibalizumab due to its indirect actions on the CD4 receptor that do not interfere with normal major histocompatibility complex class II binding .
Ibalizumab is a parenteral drug that has been given via weekly or biweekly injections in phase I and II clinical trials of HIV-infected individuals [51–53]. These studies showed ibalizumab was generally well tolerated with minimal adverse events. In a single-dose study, ibalizumab was associated with reductions in HIV RNA levels of 0.5–1.7 log copies per ml . However, in one study, viral load levels returned to baseline by the end of the study period, suggesting that ibalizumab monotherapy resulted in the development of resistance . As a monoclonal antibody, ibalizumab is not expected to have drug–drug interactions.
A randomized, double-blinded, placebo-controlled, phase I pilot study is ongoing to assess the safety, tolerability, and pharmacokinetics of ibalizumab with three dosing schedules among at-risk, HIV-negative volunteers .
Favoring ibalizumab for PrEP is its novel mechanism of action, initial favorable safety/tolerability profile, and pharmacokinetics supporting infrequent dosing of as few as every 4 weeks. Issues with its role for PrEP are the limited safety/tolerability data, theoretical safety risks as a CD4 attachment antagonist, the lack of data on tissue distribution including the genital tract and rectum, the observation of drug resistance when used as monotherapy in HIV-infected individuals, and the possible need for weekly or biweekly parenteral dosing.
The next generation of candidate oral PrEP agents appears promising and several alternatives to TDF/FTC are on the horizon. Although immediate consideration is being given to oral agents that already are FDA approved for HIV treatment (MVC, RAL), there are also investigational long-acting parenteral drugs that are being further explored for PrEP (RLV-LA, S/GSK1265744, ibalizumab). The future of PrEP will likely entail a patient-centered approach in which one regimen does not fit all and selection of the best agent(s) will depend on consideration of a number of characteristics related to the patient, the PrEP regimen, and their community.
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 612).
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.
2▪▪. Baeten JM, Donnell D, Ndase P, et al.
Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367:399–410.
This is the largest PrEP study reported to date; in a heterosexual African population, HIV incidence was reduced 67% among those that received tenofovir alone and 75% among those that received tenofovir in combination with emtricitabine.
3▪▪. Thigpen MC, Kebaabetswe PM, Paxton LA, et al.
Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367:423–434.
A PrEP study that also evaluated the safety and efficacy of tenfovir and emtricitabine combination therapy; HIV incidence was reduced by 62%.
4. Viread [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2012.
8. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 359:1429–1441.
9. Fatkenheuer G, Nelson M, Lazzarin A, et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008; 359:1442–1455.
10. Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis 2010; 201:803–813.
11. Walmsley S, Campo R, Goodrich J, editors. Low risk of malignancy with maraviroc in treatment-experienced and treatment-naive patients across the maraviroc clinical development program [abstract TUPE0157]. In: Abstracts of the XVIII International AIDS Conference; 18–23 July 2010; Vienna, Austria.
12. Ayoub A, Alston S, Goodrich J, et al. Hepatic safety and tolerability in the maraviroc clinical development program. AIDS 2010; 24:2743–2750.
13. Gulick R, Fatkenheuer G, Burnside R, et al.
, editors. 5-year safety evaluation of maraviroc in HIV-1-infected, treatment-experienced patients [abstract TUPE029]. In: Abstracts of the XIX International AIDS Conference; 22–27 July 2012; Washington, DC.
14. Fleishaker DL, Garcia Meijide JA, Petrov A, et al. Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. Arthritis Res Ther 2012; 14:R11.
15. Telenti A. Safety concerns about CCR5 as an antiviral target. Curr Opin HIV AIDS 2009; 4:131–135.
16. Rosario MC, Jacqmin P, Dorr P, et al. Population pharmacokinetic/pharmacodynamic analysis of CCR5 receptor occupancy by maraviroc in healthy subjects and HIV-positive patients. Br J Clin Pharmacol 2008; 65 (Suppl 1):86–94.
17. Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005; 11:1170–1172.
18. Dumond JB, Patterson KB, Pecha AL, et al. Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women. J Acquir Immune Defic Syndr 2009; 51:546–553.
19▪. Brown KC, Patterson KB, Malone SA, et al. Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men. J Infect Dis 2011; 203:1484–1490.
A study that evaluated tissue concentrations of maraviroc and found that concentrations in rectal tissue were eight-fold to 26-fold higher compared with blood levels.
20. Selzentry [package insert]. Freiburg, Germany: ViiV Healthcare; 2010.
21. Soulie C, Malet I, Lambert-Niclot S, et al. Primary genotypic resistance of HIV-1 to CCR5 antagonists in CCR5 antagonist treatment-naive patients. AIDS 2008; 22:2212–2214.
22. Neff CP, Ndolo T, Tandon A, et al. Oral preexposure prophylaxis by antiretrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model. PLoS One 2010; 5:e15257.
23. National Institutes of Health. Evaluating the safety and tolerability of antiretroviral drug regimens used as pre-exposure prophylaxis to prevent HIV infection in men who have sex with men. http://www.clinicaltrials.gov/ct2/show/NCT01505114
. [Accessed 19 July 2012].
24. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374:796–806.
25. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359:339–354.
26. DeJesus E, Rockstroh J, Lennox J, et al.
, editors. Raltegravir-based therapy demonstrates superior virologic suppression and immunologic response compared with efavirenz-based therapy, with a favorable metabolic profile through 4 years in treatment-naïve patients: 192 week results from STARTMRK [abstract 405]. In: Abstracts of The Infectious Diseases Society of America Annual Meeting; 20–23 October 2011; Boston.
27▪. Mayer KH, Mimiaga MJ, Gelman M, Grasso C. Raltegravir, tenofovir DF, and emtricitabine for postexposure prophylaxis to prevent the sexual transmission of HIV: safety, tolerability, and adherence. J Acquir Immune Defic Syndr 2012; 59:354–359.
A study in which raltegravir was used as a part of a postexposure prophylaxis regimen and showed safety and tolerability in 100 HIV-uninfected individuals.
28. Molto J, Valle M, Back D, et al. Plasma and intracellular (peripheral blood mononuclear cells) pharmacokinetics of once-daily raltegravir (800 milligrams) in HIV-infected patients. Antimicrob Agents Chemother 2011; 55:72–75.
29. Eron JJ Jr, Rockstroh JK, Reynes J, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 noninferiority trial. Lancet Infect Dis 2011; 11:907–915.
30. Jones A, Talameh J, Patterson K, et al.
First-dose and steady-state pharmacokinetics (PK) of raltegravir (RAL) in the genital tract (GT) of HIV uninfected women [abstract O_06]. In: Abstracts of the 10th International Workshop on Clinical Pharmacology of HIV Therapy; 15–17 April 2009; Amsterdam, The Netherlands.
31. Patterson K, Stevens T, Prince H, et al.
Antiretrovirals for prevention: pharmacokinetics of raltegravir in gut-associated lymphoid tissue (GALT) of healthy male volunteers [abstract O_11]. In: Abstracts of the 13th International Workshop on Clinical Pharmacology of HIV Therapy; 16–18 April 2012; Barcelona, Spain.
32. Isentress [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2011.
33. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008; 359:355–365.
34. Goethals O, Vos A, Van Ginderen M, et al. Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles. Virology 2010; 402:338–346.
35. Garrido C, Villacian J, Zahonero N, et al. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother 2012; 56:2873–2878.
36. Boyd SD, Maldarelli F, Sereti I, et al. Transmitted raltegravir resistance in an HIV-1 CRF_AG-infected patient. Antivir Ther 2011; 16:257–261.
37. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr 2012; 60:33–42.
38. Wilkin A, Pozniak AL, Morales-Ramirez J, et al. Long-term efficacy, safety, and tolerability of rilpivirine (RPV, TMC278) in HIV type 1-infected antiretroviral-naive patients: week 192 results from a phase IIb randomized trial. AIDS Res Hum Retroviruses 2012; 28:437–446.
39. Baert L, van ’t Klooster G, Dries W, et al. Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm 2009; 72:502–508.
40. Jackson A, Else L, Tija J, et al.
, editors. Rilpivirine-LA Formulation: Pharmacokinetics in Plasma, Genital Tract in HIV– Females and Rectum in Males [abstract 35]. In: Abstracts of the 19th Conference on Retroviruses and Opportunistic Infections; 5–8 March 2012; Seattle, Washington, USA.
41. Else L, Jackson A, Tjia J, editors. Pharmacokinetics of long-acting rilpivirine in plasma, genital tract and rectum of HIV-negative females and males administered a single 600 mg dose [abstract O_12]. In: Abstracts of the 13th International Workshop on Clinical Pharmacology of HIV Therapy; 16–18 April 2012; Barcelona, Spain.
42. Edurant [package insert]. Raritan, NJ: Tibotec Therapuetics; 2011.
43. Azijn H, Tirry I, Vingerhoets J, et al. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother 2010; 54:718–727.
44. Min S, DeJesus E, McCurdy L, et al.
, editors. Pharmacokinetics (PK) and safety in healthy and hiv-infected subjects and short-term antiviral efficacy of S/GSK1265744, a next generation once daily HIV integrase inhibitor [abstract H-1228]. In: Abstracts of the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; 12–15 September 2009; San Francisco, California, USA.
45. Spreen E, Ford SL, Chen S, et al.
, editors. Pharmacokinetics, safety, tolerability of the HIV intergrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults [abstract TUPE040]. In: Abstracts of the XIX International AIDS Conference; 22–27 July 2012; Washington, DC, USA.
46. National Institutes of Health. A Single Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Intramuscular and Subcutaneous Long Acting GSK1265744 in Healthy Subjects. http://clinicaltrials.gov/ct2/show/NCT01215006
. [Accessed 19 July 2012].
47. National Institutes of Health. Study to Investigate the safety, tolerability and pharmacokinetics of repeat dose administration of long-acting GSK1265744 and long-acting TMC278 Intramuscular and subcutaneous injections in healthy adult subjects. http://clinicaltrials.gov/ct2/show/NCT01593046
. [Accessed 19 July 2012].
48. Burkly LC, Olson D, Shapiro R, et al. Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody. Dissecting the basis for its inhibitory effect on HIV-induced cell fusion. J Immunol 1992; 149:1779–1787.
49. Moore JP, Sattentau QJ, Klasse PJ, Burkly LC. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changes in the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+ cells. J Virol 1992; 66:4784–4793.
50. Song R, Franco D, Kao CY, et al. Epitope mapping of ibalizumab, a humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients. J Virol 2010; 84:6935–6942.
51. Kuritzkes DR, Jacobson J, Powderly WG, et al. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 2004; 189:286–291.
52. Jacobson JM, Kuritzkes DR, Godofsky E, et al. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 2009; 53:450–457.
53. Khanlou H, Gathe J, Schrader S, et al.
, editors. Safety, efficacy and pharmacokinetics of ibalizumab in treatment-experienced HIV-1 infected patients: a Phase 2b study [abstract H2-794b]. In: Abstracts of the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 17–20 September 2011; Chicago, Illinois, USA.