October 15, 2007 EU RO PE AN JOUR NAL OF MED I CAL RE SEARCH 427 Eur J Med Res (2007) 12: 427-434 © I. Holzapfel Publishers 2007 CCR5 ANTAGONISTS IN THE TREATMENT OF TREATMENT-NAÏVE PATIENTS INFECTED WITH CCR5 TROPIC HIV-1 U. Fritz Bredeek1 and Michael J. Harbour2 1University of California, Los Angeles, Division of Infectious Disease; Sylmar, California, USA, 2Stanford University School of Medicine, Palo Alto, California, USA Abstract What are the mechanisms and risks of tropism A new class of antiretroviral drugs is now available to change? What is the role and needed frequency of tro- the HIV provider: The CCR5 Antagonists belong to a pism testing, and what efficacy is seen in patients with group of entry inhibitors with a novel mechanism of dual-tropic/mixed infection in the long term? Clearly action. While these antagonists do not directly inter- until we have answers to these questions CCR5 antag- fere with any of the steps of HIV replication, they onists should be reserved for the treatment-experi- block the CCR5 receptor, one of the co-receptors enced patient population with limited treatment op- HIV uses to enter its target cell. Thus CCR5 antago- tions. nists are able to prevent infection of the cell and rep- resent a new and unique mechanism for the treatment INTRODUCTION of HIV. There is great interest in utilizing this new drug class in early treatment of HIV to prevent infec- Maraviroc is now approved in both the European tion of large cell pools; CCR5 antagonists even may Union and the United States for the treatment of HIV be useful tools in the various settings of exposure pro- infection. This is the first medication belonging to the phylaxis. Maraviroc is now approved in both the Euro- new class of CCR5 antagonists, and the first approval pean Union and the United States for the treatment of of an oraly available drug in a new class since 1996. HIV infection. This is the first medication belonging Yet another new class, the integrase inhibitors, are to the new class of CCR5 antagonists, and the first ap- available in expanded access programs and are likely to proval of an orally available drug in a new class since become approved in 2007. The opportunity of provid- 1996. ing two new drug classes revolutionizes the care of the Aplaviroc, maraviroc, and vicriviroc are small mole- treatment experienced patient in a manner not seen cule inhibitors of CCR5 that block HIV-1 infection in since the mid-1990’s. With other drugs available in the vitro and reduce plasma HIV-1 RNA in HIV infected salvage setting, like the third generation protease in- subjects by approximately 1.5 log10 copies/mL over hibitors darunavir or tipranavir, it is now possible for 10-14 days when given as single agents. Very limited many patients to receive a fully suppressive antiretrovi- data is available on the use of CCR5 antagonists in ral regimen. treatment naïve patients due to early termination of Past experience in the HIV field has taught us that many trials because of inferior performance or toxici- drugs initially approved for the treatment-experienced ty and at the time of this writing in August 2007 there often become treatment options for naïve patients is only one ongoing non-inferiority trial in the naïve over time. This is true for commonly used drugs like patient population. The 48 week interim results of this Lopinavir/ritonavir, Fosamprenavir, Atazanavir and trial using twice daily maraviroc were reported at the Tenofovir; it follows to ask what is the efficacy of International AIDS Society meeting in July 2007. Mar- CCR5 antagonists in the treatment-naïve population. aviroc compared to efavirenz was non-inferior in re- Most of the clinical trials involving CCR5 antagonists gards to percentage of subjects reaching viral loads were conducted in groups of highly treatment experi- below 400 copies/mL, but not so for the analysis of enced patients, for whom there is the greatest need for subjects reaching viral loads below 50 copies/mL. On new medications. Designs of these trials often use the the other hand maraviroc had a superior side-effect CCR5 antagonist as an add-on drug to an optimized profile, fewer adverse events and a greater increase of background regimen (OBR) based on individual resis- CD4 cell count than efavirenz. These data will revital- tance test results compared to OBR. Data from these ize the interest in CCR5 antagonists as a treatment op- trials have very little value for the evaluation of CCR5 tion for the treatment-naïve patients. antagonist use in treatment-naïve patients. Since the In order to be used as first line drugs, CCR5 antag- early proof-of-concept studies demonstrated prompt onists face a number of challenges: They will have to reductions in plasma HIV-1 RNA, averaging approxi- be proven to be as potent, durable, safe, and conve- mately 1.5-1.7 log10 copies/mL over 10-14 days when nient as current available options. Important questions CCR5 antagonists were administered as single agents unique to this new class will have to be answered: (Schurmann D et al. 2007, Fatkenheuer G et al. 2005) 428 EUROPEAN JOURNAL OF MEDICAL RESEARCH October 15, 2007 it is clear that these potent agents have a larger role in combination with COM twice daily. Plasma from beyond just as add-on drugs. Three CCR5 inhibitors, baseline and virologic failures were assessed for co-re- aplaviroc, vicriviroc and maraviroc entered into Phase ceptor tropism and APL susceptibility. Efficacy data 2b and Phase 3 clinical development studies. All of were presented in the Intent-to-Treat (ITT) format them have also been studied for the treatment of which included all subjects who received at least one naïve patients. Unfortunately a number of challenges dose of randomized treatment. The primary efficacy have hindered the development in regards to the treat- analysis was based on the ITT population, which was ment naïve population: Vicriviroc’s treatment-naive the proportion of responders at week 12 as defined by study was terminated due to non-inferior performance the “time-to-loss-of-virologic-response” (TLOVR) al- of vicriviroc compared to efavirenz. Similarly, once gorithm. The study population included 147 subjects daily maraviroc performed not non-inferior compared with R5-tropic virus who were enrolled from sites in to efavirenz. Safety of the drug class has been a major Europe, the United States and Canada, of which 145 concern; aplaviroc’s development was halted due to subjects received study medication (“ITT popula- hepatotoxicity seen in trials. Several subjects receiving tion”). The demographics were similar across the vicriviroc developed malignancies. It remains unclear treatment groups, including a mean age of 39 years, whether these cases are drug associated adverse events 75% Caucasian and 83% male. Baseline characteristics or unfortunate coincidences. were similar across treatment groups with regards to HIV viral load, CDC classification, HIV risk factor APLAVIROC and co-infection status with Hepatitis B or C Virus. The majority of patients had stable tropism readouts Aplaviroc in a 10-day monotherapy trial showed im- with 140 of 145 subjects testing R5-tropic at screening pressive results with a mean change in HIV RNA be- and remaining R5-tropic at baseline tween 1.03 and 1.66 log10 for the 400mg and 600mg twice daily dosing arm (Lalezari J et al. 2005). In the Results: subsequent development steps two trials using aplavi- Because of early termination of the study, data were roc in treatment-naïve patients were initiated. Both presented on only 142/145 (98%) of the subjects ran- trials were planned as 96-week studies but were pre- domized at least 12 weeks prior to study termination. maturely terminated due to idiosyncratic hepatotoxici- Similar CD4+ cell increases were seen across treat- ty on September 15th, 2005 (Nichols WG et al. 2005; ment groups. The proportion of subjects with Ryan CT, 2005). vRNA<400copies/mL at week 12 (ITT) was 53% In the ASCENT trial, fixed-dose combination zi- (95%CI: 40%, 67%) for the group taking APL 600mg dovudine/lamivudine (COM) was used as backbone twice daily, 50% (37%, 63%) for the group taking APL (Currier J. et al. 2006), and in the EPIC trial fixed-dose 800mg twice daily and 66% (46%, 82%) for those on lopinavir/ritonavir (LPV/r) was used as backbone COM+EFV. Plasma HIV-1 RNA change from base- (Yeni P et al. 2006). Both of these trials were dose- line was seen with a mean of 3 log10 copies/mL de- finding trials using different doses of aplaviroc and cline across all treatment groups at the 12 week time were sponsored by the manufacturer of aplaviroc, point. However, there was a greater variability in re- GlaxoSmithKline. Both trials had similar designs as sponse seen in the two APL treatment arms compared randomized, partially double-blinded, multicenter, par- to the control. Eight subjects met the criteria for viro- allel-group studies with primary endpoints defined as logic failure, in 6/8 subjects the mutation M184V was the proportion of responders with vRNA <400 detected confirming resistance to lamivudine. Grade copies/mL at week 12, as well as the short-term safety 2-4 increases of ALT, AST and bilirubin were seen in and tolerability of different oral doses of aplaviroc more than 10% of patients on aplaviroc. One subject (APL). The secondary endpoints were to determine withdrew due to hepatic cytolysis. This case led subse- HIV-1 RNA decay rate over the initial weeks of treat- quently to the premature termination of the study and ment and long-term safety and antiviral activity of to the termination of the APL program by GSK.