CANCER RISK IN HIV-INFECTED PATIENTS
Persons with HIV/AIDS have a much higher rate of various malignancies than the general population. One retrospective analysis of 375,933 persons with HIV infection over 22 years showed that in HIV-infected persons, the incidence of a variety of malignancies was significantly higher (Table 2). In this study, standardized incidence ratios were used to compare the incidences of malignancies in HIV-infected persons with the expected incidences of malignancies in the general population. The study included all malignancies, not just the CDC AIDS-defining malignancies, ie, Kaposi sarcoma, NHL, and cervical cancer.
While these data provide compelling evidence that HIV-infected persons are at increased risk for malignancies, they do not estimate the expected incidence of malignancy over a defined period. Other studies explore the incidence rates of various malignancies in HIV-infected patients. One study shows that the incidence of NHL in HIV-positive patients ranged from 42.9 per 10,000 patient-years to 86.0 per 10,000 patient-years.17 The higher incidence was observed for years 1993 and 1994 and the lower incidence for years 1997 and 1998. Because highly active antiretroviral therapy was not available until the later period, the reduction between the two periods is likely explained by the use of highly active antiretroviral therapy and subsequent lower viral loads and higher CD4 counts. Furthermore, the publication of the results from the Strategies for Management of Antiretroviral Therapy (SMART) study reinforces the idea that HIV-infected patients are at increased risk for malignancies not typically associated with HIV infection, especially those patients who are not receiving therapy, suggesting that a lower CD4 count and higher viral load may be causative factors for cancer development in persons infected with HIV.18
CANCER RISK IN CLINICAL TRIALS OF CCR5 ANTAGONISTS
In 2006 when 5 malignancies were observed in the treatment group in an interim analysis of the AIDS Clinical Trials Group (ACTG) 5211 study, which was a phase 2 trial of vicriviroc in treatment-experienced patients, concerns that vicriviroc had a causative role in these cases were raised.19
Three CCR5 coreceptor antagonists have reached phase 2 or 3 testing, one of which is now approved. GlaxoSmithKline decided not to move forward with their compound aplaviroc because of elevated transaminase levels seen in an interim analysis in a phase 2 trial. Pfizer and Schering-Plough have moved forward with their compounds, maraviroc and vicriviroc, respectively, and maraviroc is now approved. There are currently data from two phase 2 trials of vicriviroc in treatment-experienced patients. At 48 weeks in the ACTG 5211 trial, 6 malignancies in the vicriviroc treatment arms and 2 in the control group were ultimately observed (Table 3). Malignancies observed in the second vicriviroc trial, the Vicriviroc (SCH 417690) in Combination Treatment With Optimized ART Regimen in Experienced Subjects (VICTOR-E1) study, were not delineated in the primary study presentation.20 However, in a pooled analysis of adverse events in patients randomized to receive vicriviroc in the ACTG 5211 and VICTOR-E1 studies and of adverse events in patients rolled over (from the placebo and vicriviroc arms) to receive open-label vicriviroc at the end of the 48-week study periods, 13 malignancies among 205 patients who received vicriviroc were recorded (Table 4).21 The mean duration of vicriviroc therapy in these 205 patients was 96 weeks (range, 1 to 216 weeks), and 196 received vicriviroc for more than 12 weeks. While there was no placebo group comparison, the incidence rate of malignancies remained nearly constant over time rather than increasing as the cumulative exposure to vicriviroc increased, suggesting that vicriviroc exposure likely does not increase the already elevated risk of malignancy in this study population.
The Epstein-Barr virus (EBV) has been implicated in the pathogenesis of Hodgkin lymphoma and Burkitt lymphoma in HIV-infected persons.22 A recent study sought to discover whether vicriviroc may have a role in increasing EBV replication in these persons,23 thereby giving a mechanistic explanation for the potential role that vicriviroc may have played in the lymphoma occurrences in patients in ACTG 5211 trial. The study showed that there was no increased replication of EBV in the 116 subjects for whom samples existed after vicriviroc administration. There is no statistical evidence suggesting an association between vicriviroc administration and development of lymphoma, and this study also disproves a potential mechanism.
Two phase 3 trials of maraviroc in treatment-experienced patients have been conducted. Both trials had identical designs but were conducted in different geographical locations. The data from both trials were combined, analyzed, and published in 2008.24 This publication did not report the rates of non–AIDS-defining malignancies observed in the study groups.
These incidence data are somewhat difficult to interpret. None of these trials were sufficiently powered to ascribe causality given the low incidence of malignancies observed. Another difficulty in interpreting differences in cancer incidence between the treatment arms of CCR5 antagonist trials and the placebo groups is that all of the studies had many more patients in the treatment arms than in the control arms, and patients in the placebo arms were more likely to discontinue treatment early for virological failure. As a result, instead of absolute numbers, the percentage of patients in whom a malignancy develops while they are receiving therapy might correct for the smaller size of the placebo groups, and exposure-adjusted analysis might correct for the shorter duration of follow-up in the patients who received a placebo.
Adverse event data from the maraviroc phase 2 trial in treatment-experienced patients were recently reanalyzed and exposure-adjusted. Both unadjusted and exposure-adjusted rates of malignancies were higher in the placebo group than in either dose group of maraviroc at 48 weeks (Table 5). The 96-week data from this trial were recently presented and showed similar results. The unadjusted rates of malignancies were 5.3%, 4.3%, and 4.5% in the placebo, maraviroc once-daily, and maraviroc twice-daily arms, respectively.25
While there were 3 times as many malignancies in the vicriviroc arms of the ACTG 5211 study than in the placebo group, there were also more than 3 times as many patients in the vicriviroc arms. The maraviroc phase 3 data show that cancer incidence rates were actually higher in the placebo group, which may have to do with the fact that lower rates of virological suppression and lower CD4 counts were observed in the placebo group and more advanced disease is associated with higher cancer risk in HIV-infected persons.
Finally, there are 2 studies of CCR5 antagonists in treatment-naive patients. The 48-week data from a study of maraviroc in treatment-naive patients showed that there was both a higher absolute number and percentage of malignancies observed in the comparator group: 16 (4.4%) versus 10 (2.8%) in the efavirenz(Drug information on efavirenz) and maraviroc arms, respectively.26 The published report of the 48-week data from another study of vicriviroc in treatment-naive patients states that one case of exacerbation of preexisting Kaposi sarcoma was seen in the placebo group, but the report does not mention any other malignancies.27
This article examines 3 sources of data regarding the cancer risk with the use of CCR5 antagonists in HIV-infected patients: basic science research concerning the role of CCR5 in cancer pathogenesis, epidemiological studies of cancer rates in patients with congenital lack of functional CCR5, and clinical data of cancer rates in CCR5 antagonist studies. Available preclinical evidence suggests that CCR5 is critical to the development and progression of certain tumors and that, at least theoretically, blocking CCR5 seems unlikely to increase cancer risk. Epidemiological data in non–HIV-infected persons do not show a significantly different rate of the delta-32 mutation in persons with several different malignancies compared with matched controls without malignancies. In fact, persons with HIV infection and the delta-32 mutation appear to have a decreased risk of NHL.
Finally, while the available clinical data from trials of CCR5 antagonists show that malignancies have developed in patients in the treatment arms, they do not demonstrate a cancer risk that is significantly different from that in patients in the control groups. Given that development of malignancies is typically a long-term process, and only 2 of the studies of CCR5 antagonists have published data extending beyond 48 weeks, long-term studies are needed to more definitively establish whether CCR5 antagonism reduces, increases, or has no effect on cancer risk.
Dr McNiff is an employee of Pfizer, the manufacturer of the CCR5 antagonist maraviroc (Selzentry). No potential conflict of interest relevant to this article was reported by Dr Dezube.