A crucial step in the propagation of the HIV is the integration of viral nucleic acids into the host genome. This process occurs with the help of the HIV-1 integrase enzyme. Raltegravir is the first approved antiretroviral (ART) drug that works by inhibiting the HIV-1 integrase enzyme, thereby preventing strand transfer. Although raltegravir exhibited satisfactory safety profiles and was approved for use in 2010, increased incidence of cancers was observed in patients who were given a raltegravir-based drug regimen. Recent in vitro data demonstrated that small doses of raltegravir could lead to large rearrangements in the host genome, including insertions and deletions, which would be conducive to developing malignancies.
However, these observations and the in vitro data have yet to be substantiated. A recent study published in HIV Medicine sought to address this question, to determine if raltegravir indeed increases the risk of developing cancer. Co-investigators, Amanda Mocroft, PhD, and Ole Kirk, PhD, led the study.
The authors utilized the EuroSIDA cohort, an on-going prospective study that consists of 18,931 individuals from 111 hospitals in 34 countries currently living with HIV. The cohort was divided into 3 groups: those that started raltegravir-based therapy on or after December 2007, those that added a new antiretroviral drug (not raltegravir) to their regimen between January 2005 and December 2007 (termed HIST), and those that added a new antiretroviral drug (not raltegravir) to their regimen after December 2007 (termed CONC). The raltegravir cohort consisted of 1470 patients, with 4058 person-years of follow-up (PYFU). The other 2 cohorts, HIST and CONC, consisted of 3787 (4472 PYFU) and 4467 (10,691 PYFU) respectively. The authors assessed 4 outcomes: newly diagnosed cancers, both AIDS and non-AIDS related, liver-related events, lipodystrophy, and mortality.
The majority of the patients, across the 3 cohorts, were white males. In addition, the mode of HIV transmission was similar in the 3 cohorts, with 40% of patients being men who have sex with men (MSM). A total of 20% acquired HIV through heterosexual contact, and the remaining patients were persons who inject drugs (PWID).
In the raltegravir cohort, 24% of patients discontinued the drug, with 11% discontinuing the drug within 3 months. These early discontinuations were generally due to raltegravir-related gastrointestinal toxicity or patient choice. The later discontinuations seemed to be mostly due to decisions made by the monitoring physician, with 71 out of the 312 longer-term discontinuations due to this reason.
Overall, the authors found that there was no evidence that the patients in the raltegravir cohort were at increased risk of cancer or death in comparison to those given alternative ART regimens. The study confirms that raltegravir is a safe as a therapeutic option for HIV, particularly for patients who have a history of failed therapy or in patients intolerant towards other ART drugs. However, the authors caution the reader against drawing firm conclusions from the study as it was an observational cohort study and not a randomized clinical trial. In other words, this study is unable to exclude confounding variables, such as lifestyle choices like smoking.
By Samar Mahmoud