Nelfinavir treatment has no effect on risk of cancers

Treatment with the protease inhibitor nelfinavir (Viracept) is not independently associated with a reduced risk of cancers, US investigators report in a study published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

Nelfinavir was a widely used drug in early antiretroviral regimes. It has since fallen out of favour after ritonavir-boosted protease inhibitors were shown to have a more potent and durable anti-HIV effect. Furthermore, it temporarily lost its licence in Europe in 2007 after batches of the drug became contaminated with excess levels of a potentially cancer-causing agent during manufacture. Subsequent analysis showed that this did not involve an increased risk of cancer for patients.

Recently nelfinavir has been examined as an anti-cancer drug. Preliminary studies have suggested that the drug has activity against the AIDS-defining cancer Kaposi’s sarcoma (KS), skin cancer, prostate cancer, multiple myeloma and a variety of other malignancies. Phase I clinical trials are currently underway to study the safety and efficacy of the drug as part of cancer therapy in HIV-negative patients.

No previous study, however, has evaluated the impact of nelfinavir as a component of antiretroviral therapy on rates of AIDS-defining and non-AIDS-defining cancers in HIV-positive patients. Therefore investigators from the US HIV Natural History Study performed a retrospective analysis of the impact of nelfinavir on the risk of cancer involving 2499 patients.

Median CD4 cell count at diagnosis was 500 cells/mm³, with median viral load being 25,000 copies/ml. Triple drug antiretroviral therapy was used by 75% of patients at some time during follow-up, and was initiated at a median CD4 cell count of 340 cells/mm³. During the study a total of 108 cancers were diagnosed including 39 AIDS-defining cancers and 69 non-AIDS-defining cancers.

A total of 839 patients (34%) were treated with nelfinavir. The median duration of therapy with this drug was 17 months. Triple drug HIV treatment was initiated by patients with experience of nelfinavir when their median CD4 cell count was 339 cells/mm³. After starting treatment with nelfinavir, 45 patients developed cancer. This included 16 cases of AIDS-defining cancers and 29 non-AIDS-defining malignancies. The duration of nelfinavir therapy did not differ between the patients who did and did not develop cancer (p = 0.06).

The risk of developing cancer was identical for patients who received a combination of three anti-HIV drugs including nelfinavir and for those who took triple HIV therapy without nelfinavir (HR = 1; 95% CI, 0.5-1.7). Rates of AIDS-defining and non-AIDS-defining cancers were also comparable in these two groups of patients.

These findings remained the same when the investigators included the CD4 cell count at the time antiretroviral therapy was initiated, and the calendar year HIV treatment was started.

Any protease inhibitor was used by 60% of the study population. The risk of developing any cancer was similar for patients who took protease inhibitor-based antiretroviral therapy and those who took triple drug treatment that did not include a protease inhibitor.

Unsurprisingly, the investigators found that overall cancer rates, as well as rates of AIDS-defining cancers and non-AIDS-defining cancers were significantly lower in patients who took nelfinavir, or any antiretroviral regimen than patients who did not take anti-HIV drugs.

“This study shows that despite reports that nelfinavir may reduce the risk of cancer, we found no specific relationship between nelfinavir use and cancer occurrences among HIV-infected persons who used nelfinavir as part of their antiretroviral regimen”, write the investigators.

Although the study found that treatment with nelfinavir did reduce the risk of AIDS-defining cancers, the investigators think that this “was likely due to immune reconstitution rather than nelfinavir or protease inhibitors themselves because the risk of cancer was not different based on type of antiretroviral regimen used.”

The investigators suggest a number of possible reasons why they failed to find that treatment with nelfinavir protects against cancer:

• Neither nelfinavir nor any other protease inhibitor independently protects against cancer.
• Higher doses of nelfinavir are needed to protect against cancer than are used in HIV treatment.
• A larger cohort of patients was needed to detect an effect.

However, the researchers believe their cohort was large enough that it could reasonably have been expected to show any protective effect.

“Additional studies using large registries and postmarketing surveillance are needed to provide further data on the possible relationship between nelfinavir and other protease inhibitors and cancer inhibition amongst HIV-infected persons”, conclude the investigators.