Abstract and Introduction
Abstract
Objective: Nelfinavir exhibits potent anticancer properties against a range of tumours. However, in 2006/2007, nelfinavir supplies were accidently contaminated with a carcinogen. This analysis investigated the association between nelfinavir use and cancer risk in HIV-positive persons.
Design: Observational cohort study.
Methods: D:A:D study data was analysed using Poisson regression models to examine associations between cancer incidence and cumulative nelfinavir exposure, current nelfinavir exposure, and exposure to nelfinavir between 1 July 2006–30 June 2007.
Results: A total of 42 006 individuals (50% white, 73% male) contributed 303 005 person-years of follow-up between 1 January 2004 and 1 February 2014. At study enrolment, median age was 40 [interquartile range (IQR) 33–46] years and 8305 individuals had a history of nelfinavir use [median duration 1.7 (IQR 0.7–3.4) years]. During follow-up, nelfinavir was used by 2476 individuals for a median of 1.7 (IQR 0.7–3.8) years; 1063 were exposed to nelfinavir between 1 July 2006 and 30 June 2007. Overall, 2279 cancers were diagnosed at a rate of 0.75 [95% confidence interval (95% CI) 0.72–0.78] per 100 person-years. Neither greater cumulative exposure to nelfinavir [adjusted risk ratio (aRR) 0.93 for every additional 5 years, 95% CI 0.82–1.06, P = 0.26] nor current use of nelfinavir (aRR 0.98 vs other protease inhibitor use, 95% CI 0.68–1.41, P = 0.92) were associated with cancer risk. The adjusted risk of cancer for participants exposed to nelfinavir between 1 July 2006 and 30 June 2007 compared to those receiving other treatment over this period was 1.07 (95% CI 0.78–1.46, P = 0.68).
Conclusion: Nelfinavir use was not associated with a lower cancer incidence than other protease inhibitor regimens. As of February 2014, exposure to the 2006/2007 contamination of nelfinavir does not appear to be associated with increased cancer incidence.
Introduction
Protease inhibitors were designed specifically to inhibit HIV protease, yet serendipitously have been found to have broad antineoplastic and antiviral activity.[1,2] In particular, nelfinavir exhibits anticancer properties (e.g. inhibition of Akt signalling, induction of cancer cell autophagy and apoptosis, proteasome inhibition) against a range of cancers including myeloma, breast cancer, ovarian cancer, liposarcoma, melanoma, nonsmall cell lung cancer, diffuse large B-cell lymphoma, glioma, hepatocellular carcinoma, and prostate cancer.[3–15] It has also been shown to suppress Kaposi's sarcoma-associated herpesvirus replication in vitro.[16] Since the approval of nelfinavir as an antiretroviral in 1997, more efficacious alternatives with fewer adverse effects have taken over the role of protease inhibitors in antiretroviral therapy (ART). However, clinical trials are currently being undertaken to investigate whether nelfinavir could be repositioned as an anticancer agent.[17–26]
All ART, by increasing CD4 cell count, substantially reduces the risk of AIDS and non-AIDS-defining cancer in HIV-positive individuals.[27–29] Portsmouth et al. reported that the incidence of Kaposi's sarcoma in the HIV-positive population decreased from 30/1000 person-years before 1995 (the pre-ART era) to 0.03/1000 person-years in 2001 and that nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART had a similar protective effect to protease inhibitor-based ART.[29] However, the relative efficacy of nelfinavir-based ART compared with other ART in preventing cancer has only been clinically evaluated in one small study of HIV-positive individuals which found no difference between regimens.[30] The potentially protective effect of nelfinavir against Kaposi's sarcoma and other specific cancers has not been assessed in any HIV cohort.
In June 2007, Viracept (nelfinavir mesylate) was subject to an international recall because of a manufacturing fault that led to the product containing high levels of ethyl mesylate, a genotoxic substance that has been associated with increased rates of lung, kidney, brain, liver, breast, and uterine cancer in animal models.[31] The contamination arose from Roche's manufacturing plant in Switzerland. All nelfinavir users living outside of the USA, Canada, and Japan (where nelfinavir supplies were not manufactured by Roche) at the time were considered to be at risk of exposure. In the worst case scenario, up to 25 000 people may have consumed contaminated nelfinavir between late 2006 and early 2007. The most severely contaminated batches were distributed between March 2007 and June 2007 and individuals may have taken highly contaminated nelfinavir for up to 3 months.[32–34] Following a review of toxicology studies,[31,35–45] the European Medicines Agency concluded that the contamination did not increase the risk of developing cancer and that further follow-up of affected individuals was not required.[33] Nevertheless, long-term clinical data supporting this decision have not been reported.
The objective of this analysis was to evaluate the potential of nelfinavir as a cancer preventive in HIV-positive persons enrolled in a very large cohort study, and to assess the rates of cancer in individuals exposed to nelfinavir between late 2006 and early 2007.
AIDS. 2016;30(10):1629-1637. © 2016 Lippincott Williams & Wilkins
Lippincott Williams & Wilkins
