May 1, 2007
Treatment Action Group (TAG) supports the approval of maraviroc for treatment of HIV infection in patients with prior antiretroviral experience.
Maraviroc is an orally-available small molecule that binds to and alters the shape of CCR5, a cell surface protein found on certain immune cells. HIV infects target cells through a process that involves binding to CCR5. In the presence of maraviroc the efficiency of HIV binding to CCR5 is inhibited and treated cells are resistant to infection. Maraviroc has been demonstrated to effectively block HIV infection in vitro and reduce HIV RNA levels in infected patients in clinical trials.
However some varieties of HIV are able to infect target cells using alternate cellular receptors (primarily CXCR4) and HIV may develop mutations that allow entry via CCR5 even in the presence of maraviroc; therefore it is recommended that an individual’s HIV be tested-using a so-called tropism assay-to determine susceptibility to inhibition by maraviroc before therapy with the drug is begun.
Maraviroc has demonstrated a short-term safety profile similar to placebo in randomized clinical trials in both treatment-naïve and highly treatment-experienced patients. Despite toxicities observed with other CCR5 antagonists (liver failure with aplaviroc; cardiac rhythm [QTc] abnormalities with SCH C), these so far appear to have been drug specific and not characteristics of the class. A cluster of cancers in clinical trial participants receiving Schering’s vicriviroc was determined not to be statistically significant. The incidence of cancers in maraviroc studies has to date been no different from background rates.
The long term safety of CCR5 antagonism is not known. Due to concerns about potentially increased susceptibility to certain infections or cancers, comprehensive surveillance and follow up of clinical trial participants for up to five years has been recommended. The basis for these concerns is that blocking CCR5 function may disable certain normal immune functions that are CCR5 dependent, such as those involving trafficking of CCR5-expressing effector T cells to sites where they are needed.
CCR5 inhibition was selected as a viable therapeutic approach partly due to observations that a small proportion of the human population is born without functioning CCR5 receptors and develop normal immune responses. This provided reassurance that blocking CCR5 was likely to be safe. However concerns have been raised that these rare individuals may have developed compensatory immune mechanisms that will not be present in individuals taking a CCR5 antagonist. Although data from mouse studies have been cited to support these concerns, murine immunity seems to depend on CCR5 in a way that human immunity does not. Nevertheless, a mouse study that found increased susceptibility to West Nile Virus in animals treated with a CCR5 antagonist is reinforced by a human epidemiological survey that observed a disproportionate number of West Nile Virus infections among individuals born lacking CCR5. Although no unusual cases of the mosquito borne virus have been detected in clinical trial participants who received maraviroc or similar drugs, long term surveillance for this and other unusual infections will require developing follow-up mechanisms to be put in place after the approval of maraviroc.
The HIV variant that uses CCR5 binding to enter target cells is almost universally dominant in recently infected individuals. However, over time, and on a population basis, the proportion of people with a dominant CCR5 strain declines until, in a group of people with CD4 counts below 50, less than half will carry the CCR5 strain exclusively. The most common secondary receptor used for viral entry is CXCR4. There have been concerns that because CXCR4 HIV is more often found in individuals with advanced HIV disease, it was responsible for causing the catastrophic immunodeficiency of late stage AIDS. In particular there was fear that by keeping HIV from using CCR5, the virus would be forced to mutate to use CXCR4 and immune collapse would follow. Fortunately this has not been observed in clinical trials, including in people who had emergent CXCR4 HIV after exposure to maraviroc.
Again, the short term safety of maraviroc should be confirmed with careful long-term follow-up in structured programs designed to detect the impact of the drug on immune function. One preliminary but provocative observation is that some individuals in ongoing clinical trials who remained on maraviroc despite emergent CXCR4 virus and detectible viral load, experienced increases in CD4 cell counts. Although this must be confirmed with larger studies, one speculative explanation might be that suppression of CCR5 HIV has benefits that are independent of the suppression of total viral load. Alternatively, CD4 increases in the blood could be a consequence of disrupted T cell trafficking to tissues. Careful long term follow-up designed to monitor the safety of maraviroc may also provide insights into immune effects that are difficult to determine in smaller and shorter term studies.
The use of a phenotypic CCR5 tropism assay (Trofile, from Monogram Biosciences) to determine susceptibility of an individual’s HIV to maraviroc will likely be recommended before prescribing the drug. However use of the assay presents a significant barrier to initiating maraviroc therapy. Currently the time to receive a tropism report can take from three to seven weeks. The cost of the assay is also likely to be significant.
The current assay is unable to detect minor populations (under 5-10%) of non-susceptible HIV, and emergent CXCR4 populations can be expected in a small percentage of people receiving maraviroc. Although next generation assays are being developed, none may be expected for several years. Research should be conducted to find alternative methods of determining susceptibility to maraviroc, including studies of the safety, efficacy, and cost effectiveness of treating without first determining HIV tropism. Because of the higher prevalence of CCR5 HIV among more recently infected individuals, evaluating the indication of maraviroc for treating HIV infection in treatment naïve individuals should continue. In addition, studies of maraviroc in people with higher CD4 cell counts should be undertaken to establish the long-term safety and effectiveness in this population. Sub-studies in all patient groups should incorporate extensive evaluation of advanced immune parameters to explore the impact of selective inhibition of CCR5 HIV. Finally Pfizer should support investigations of maraviroc as an active agent in topical microbicides for prevention of HIV transmission.
Treatment Action Group commends Pfizer for developing the first new drug in a new class of antiretroviral agents. Throughout the development process Pfizer engaged with and solicited the opinion of a group of HIV treatment advocates, although full openness with the community was impeded by Pfizer’s insistence on confidentiality under consulting agreements.
Treatment Action Group urges Pfizer to continue its program of responsible HIV drug development by pricing maraviroc competitively with first-line HIV agents in the United States, and to take all necessary steps to assure that maraviroc will be available on a worldwide basis wherever it is likely to be a useful and lifesaving option.