Adverse Events of Raltegravir and Dolutegravir

Luigia Elzi; Stefan Erb; Hansjakob Furrer; Matthias Cavassini; Alexandra Calmy; Pietro Vernazza; Huldrych Günthard; Enos Bernasconi; Manuel Battegay

Disclosures

AIDS. 2017;31(13):1853-1858. 

In This Article

Discussion

The large study, involving 4041 HIV-individuals who have started a raltegravir or dolutegravir-containing ART within the SHCS, illustrates in a real-life setting an overall low rate of ART modification because of adverse events or intolerance for both INSTIs (<5%). The rate of neuropsychiatric adverse events was very low (<2%). There were higher discontinuation rates of dolutegravir (1.7%) compared with raltegravir (0.6%) because of neuropsychiatric adverse events. The only independent risk factor of discontinuing a raltegravir or dolutegravir containing ART within the first year of treatment because of adverse events was female sex. Importantly, we found an outstanding drug potency with an extremely low rate of treatment failures for both drugs (<0.5% of the patients).

Our results are somewhat in contrast with those recently reported in the literature,[7–9] assigning clearly higher rates of treatment discontinuation because of any adverse events (7.6–13.7%) and neuropsychiatric adverse events (5.6–9.9%) for dolutegravir. One explanation might be the smaller number of patients included in those studies which may contribute to an overestimation of the neuropsychiatric adverse events of dolutegravir. In the study by Hoffmann et al.,[9] the rates of neuropsychiatric adverse events leading to discontinuation within 12 months was estimated to be 5.6% for dolutegravir, affecting mainly women and older patients, but only 0.7% for elvitegravir and 1.9% for raltegravir. Results from a Spanish cohort of 2021 HIV-infected individuals treated with INSTIs showed a relatively low discontinuation rate of dolutegravir because of neuropsychiatric complaints (2.7 per 100 patient-years) as well, however, only in patients with an abacavir–lamivudine backbone, but not with tenofovir–emtricitabine.[11] In our study neither sex, age, nor the backbone, was associated with discontinuation of dolutegravir compared with raltegravir because of toxicity of the central nervous system.

Very recent data from a North American cohort including 2180 patients receiving dolutegravir and 917 raltegravir did not show an increased risk of psychiatric disorders or ART discontinuations because of psychiatric adverse events related to the use of dolutegravir, although more patients treated with dolutegravir had a psychiatric disease at baseline.[12] This might be explained by the favorable profile of dolutegravir concerning the risk of drug–drug interactions in patients treated with psychiatric medications as well as the convenience of a one-pill regimen in this particular patient population.

Interestingly, female patients in our study showed a higher risk of INSTI discontinuation because of any toxicity adverse event compared with male patients. If different pharmacokinetics or lower body weight may have contributed to higher rate of INSTI-related adverse events in female patients remains hypothetical. Of note, recently, a correlation between plasma concentration of dolutegravir and neuropsychiatric side-effects was shown in a small set of HIV-infected individuals.[13]

The sequential introduction of raltegravir and dolutegravir could have impacted on the probability to discontinue raltegravir when dolutegravir was available as alternative ART compound since 2013. After 2013, most patients started ART-containing dolutegravir (n = 1944, 79%) compared with raltegravir (n = 516, 21%). However, we did not find any difference among multivariate models of the probability to discontinue the integrase inhibitor regardless of the main reason and because of neuropsychiatric side-effects when analyses were restricted to the time period before and after 2013.

Our study has some important limitations: information bias might have occurred, as imprecise coding of the reasons for discontinuation of the ART regime cannot be excluded. However, in case of specific symptoms/adverse effects, the proper reason is relatively easy to capture. The reasons for discontinuation are collected by predefined codes in the SHCS database; thus, more detailed information are lacking. Precise descriptions of the particular symptoms and data of minor side-effects not leading to discontinuation of the ART are not available. Therefore, the real burden of all neuropsychiatric events (including minor events) might be underestimated. Only toxicity data leading to the discontinuation of the ART regime are collected in the SHCS database, which, however, represents a highly valuable and representative endpoint. The raltegravir and dolutegravir group differed in some of the baseline characteristics. In addition, other characteristics than those available in the SHCS could have been associated with adverse events. We did not consider data on adherence to treatment for our analysis, and, finally, no data on plasma concentration of INSTI were available for this study.

The main strengths are the large sample size of our study population, the real-life setting, and the prospective collection of patient data including reasons for ART discontinuation.

In conclusion, our study confirms the excellent tolerability of the INSTIs raltegravir and dolutegravir in the treatment of HIV-infected individuals. Raltegravir or dolutegravir drug toxicity is an infrequent reason for treatment modification. Although neuropsychiatric complaints are indeed observed more frequently in patients on dolutegravir compared with raltegravir, in overall these adverse events remain relatively rare. Patient information and monitoring of adverse events are important for early detection of neurotoxicity. In case neuropsychiatric side-effects occur with dolutegravir, a switch to an alternative INSTI remains a valuable option.

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