Raltegravir has demonstrated a favorable safety profile in addition to its potent efficacy based on data from comparative phase III trials against efavirenz (with background of tenofovir and emtricitabine) in treatment-naïve patients [2
] and against placebo (with OBT) in treatment-experienced patients [4
]. Long-term data from the phase II studies in treatment-naïve and treatment-experienced populations, which include data to week 144, show a similar safety profile [9
Rash is frequently observed with several antiretroviral and other agents commonly used in the treatment of HIV infection [11
]. In clinical trials, rash was observed in raltegravir-treated patients at a higher frequency than placebo but at a lower frequency than efavirenz. The incidence of rash was also higher among patients taking raltegravir and darunavir than in patients taking raltegravir without darunavir or darunavir without raltegravir. In general, rash was reported as mild to moderate and did not lead to discontinuation of raltegravir. It is important to note that raltegravir is only administered in combination with other antiretroviral agents, thus the reports of rash are confounded by concomitant antiretroviral and often other therapies, many known to be associated with rash. A number of antiretroviral agents have been associated with SJS [15
]. This event was added to the raltegravir labeling after several post-marketing reports of SJS were received, even though the reports were confounded by the use of concomitant medications. There were no cases of SJS in the raltegravir phase III studies.
Depressive disorders appear to be more common in persons with HIV infection than in the general population [16
]. Neuropsychiatric symptoms have been associated with efavirenz, particularly in the short term after initiation of therapy [17
]. Depression, including suicidal thoughts and behaviors, was added to the raltegravir product labeling after identification of several post-marketing cases, including those reported in the literature [23
]. In the phase III studies of raltegravir, depression occurred at generally similar rates between raltegravir and comparator, and one suicide attempt was reported.
IRIS has been reported with multiple HAART regimens [24
] and is often associated with a specific diagnosis of an opportunistic infection or malignancy. Reports of IRIS in patients receiving raltegravir are consistent with what has been reported with other classes of antiretroviral agents.
Lipodystrophy is a common metabolic complication of antiretroviral therapy [31
]. The incidence of lipodystrophy in the raltegravir phase III trials was low in treatment-naïve patients overall. Analysis of body fat content by dual energy x-ray absorptiometry (DEXA) scanning in a subset of patients showed similar degrees of fat gain through 96 weeks for each treatment group, with a greater increase in trunk than limb adiposity [3
]. Also, raltegravir had minimal effect on serum lipid levels in treatment-naïve patients [2
]. In treatment-experienced patients, lipodystrophy occurred at generally similar rates in the raltegravir and placebo groups, but these rates are confounded by the background prevalence of lipodystrophy (approximately 44-45% in both groups) and frequent concomitant use of other classes of antiretroviral therapies for which lipodystrophy/fat maldistribution have been reported.
Elevations of CK have been seen in clinical trials at a higher incidence for raltegravir than placebo; however, these were generally isolated laboratory findings, without clinical manifestations and did not lead to discontinuation. Although not seen in the comparative phase III studies, there have been several reports of rhabdomyolysis in expanded access programs for raltegravir, as well as in the post-marketing environment, including some reports in patients with confounding factors, such as concomitant use of medications known to be associated with this condition, including HMG-CoA reductase inhibitors and fibric acid derivatives. Rhabdomyolysis is included in product labeling for raltegravir.
Increased liver enzymes and, to a lesser degree, related clinical hepatic events, are common complications of antiretroviral and other therapies in HIV infected individuals; furthermore, interpretation may be confounded by the common occurrence of dual infection with HIV and hepatitis B or C virus. In clinical trials, aminotransferase elevations occurred at modest and similar rates in raltegravir and comparator groups. While these abnormalities were more frequent in patients with (than without) viral hepatitis co-infection, they occurred similarly in the raltegravir and comparator groups. Aminotransferase abnormalities were not associated with unexplained hyperbilirubinemia or clinical hepatic toxicity, and rarely limited therapy. Thus, raltegravir does not appear to be associated with important hepatotoxic effects, including in patients with hepatitis B or C co-infection.
Malignancies have been closely monitored since early in the development program after a possible signal was identified with slight excess in cancers observed in the BENCHMRK studies at the first interim analysis of partial data. With additional follow-up in subsequent analyses, the data demonstrate a RR (95% CI) of 0.75 (0.30, 1.91) indicating no difference in cancer risk between raltegravir and comparator. Possible explanations for the early, transient signal include a premature assessment of limited data, and the occurrence of IRIS acting to bring subclinical malignancies to early clinical detection in the setting of prompt virologic suppression and CD4 cell recovery. Two observational cohort studies have begun which will further assess this issue in the post-licensure environment.
This paper has presented all available comparative phase III data for raltegravir. The data have some limitations: in the BENCHMRK studies in highly treatment-experienced patients, the patient year exposure was 2-3 fold higher for raltegravir than comparator due to frequent virologic failure in the placebo group, resulting in retention of patients with the most advanced disease in the raltegravir group. Provision of both unadjusted frequencies and exposure adjusted rates for BENCHMRK data were an effort to offer an unbiased perspective on the occurrence of early versus late adverse experiences. Women represented <20% of patients enrolled in these phase III studies. Other limitations include the defined inclusion/exclusion criteria used in the context of clinical trials. However, these studies allowed enrollment of patients with advanced HIV disease, substantial laboratory abnormalities, active hepatitis B or C co-infection, and stable prior cancer at study entry, in order to include a reasonably representative study population. In addition, the BENCHMRK studies allowed patients to use investigational agents in their OBT.
A cumulative meta-analysis of safety was conducted including all available data from adult patients in the raltegravir clinical development program who received the 400 mg bid dose, thus including substantial additional raltegravir exposure beyond the phase III studies included in this report. This meta-analysis demonstrated a safety profile generally consistent with the STARTMRK and BENCHMRK studies, acknowledging the diversity of a population including both treatment-naïve and highly treatment-experienced patients.
In aggregate, data from the raltegravir clinical development program have demonstrated potent and durable efficacy in a broad patient population with HIV infection [2
]. This manuscript provides an overview of the favorable safety profile established for raltegravir to date, and supports the use of this agent in combination regimens for the treatment of HIV infection. The safety of raltegravir will continue to be monitored in ongoing clinical trials, including studies in other patient populations such as pediatric patients, and by pharmacovigilance activities in the marketed environment, which include the continuous review of spontaneous reports of adverse experiences, and the conduct of prospective observational cohort studies.