Dolutegravir: A New HIV Integrase Inhibitor
Dolutegravir: A New HIV Integrase Inhibitor
Dolutegravir has been shown to have a favorable safety profile and overall is well tolerated with minimal adverse effects. Data from a safety study evaluating single and repeat doses of dolutegravir in small cohorts of healthy volunteers found dolutegravir to be well tolerated with no serious adverse events. The most common adverse effect after single and repeat doses was headache. This led to further evaluation of dolutegravir for 10-day monotherapy in HIV-1 infected patients. Of the 35 patients randomized to receive various doses of dolutegravir (2, 10, 50 mg) or placebo, dolutegravir demonstrated excellent tolerability with no serious adverse events. The most common drug-related adverse event reported in this small group of patients was diarrhea, which was mild-to-moderate and did not lead to any treatment discontinuations. In the SPRING-1 trial, three different doses of dolutegravir were compared with efavirenz in 205 patients. No dose-related trend in adverse effects was observed; however, more nausea and headache occurred in the dolutegravir arms, but did not lead to drug discontinuations. Overall, there were fewer discontinuations in the dolutegravir arm (3%) compared with the efavirenz arm (10%). In the SINGLE study, the most frequent treatment-related adverse effects reported at 48 weeks were insomnia (3%) and headache (2%). Both insomnia and headache were reported at lower rates (<1%) in the SPRING-2 study and in both studies the rates of treatment discontinuation were low (2%). Although the SINGLE study reported a higher overall rate of insomnia compared with previous studies, this was the only study that gave subjects a targeted questionnaire on insomnia.
Table 1 summarizes the most common adverse effects reported in the treatment-naive trials. Adverse effects to dolutegravir appear to be higher in some studies, which included all grades and all causes of adverse effects. Most adverse effects were grade 1–2 (mild-to-moderate in severity); however, dolutegravir treatment-related adverse effects as determined by the investigator were much lower (1–3%) overall. Dolutegravir can increase serum creatinine by inhibition of the organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1, which are responsible for the tubular secretion of creatinine. This increase is not associated with any change to the actual glomerular filtration rate. In the SPRING-1 study, the mean increase in serum creatinine observed at week 1 remained stable through week 24 and declined at week 48. The increase at week 96 was similar to what was observed at week 24 and this change was not driven by the backbone. The mean increase in serum creatinine from the SINGLE study was 0.12–0.15 mg/dl, was evident by week 2, and then stabilized through week 48. The increase in serum creatinine occurs early in treatment, typically within the first 2 weeks after initiation, and then plateaus.
Safety
Dolutegravir has been shown to have a favorable safety profile and overall is well tolerated with minimal adverse effects. Data from a safety study evaluating single and repeat doses of dolutegravir in small cohorts of healthy volunteers found dolutegravir to be well tolerated with no serious adverse events. The most common adverse effect after single and repeat doses was headache. This led to further evaluation of dolutegravir for 10-day monotherapy in HIV-1 infected patients. Of the 35 patients randomized to receive various doses of dolutegravir (2, 10, 50 mg) or placebo, dolutegravir demonstrated excellent tolerability with no serious adverse events. The most common drug-related adverse event reported in this small group of patients was diarrhea, which was mild-to-moderate and did not lead to any treatment discontinuations. In the SPRING-1 trial, three different doses of dolutegravir were compared with efavirenz in 205 patients. No dose-related trend in adverse effects was observed; however, more nausea and headache occurred in the dolutegravir arms, but did not lead to drug discontinuations. Overall, there were fewer discontinuations in the dolutegravir arm (3%) compared with the efavirenz arm (10%). In the SINGLE study, the most frequent treatment-related adverse effects reported at 48 weeks were insomnia (3%) and headache (2%). Both insomnia and headache were reported at lower rates (<1%) in the SPRING-2 study and in both studies the rates of treatment discontinuation were low (2%). Although the SINGLE study reported a higher overall rate of insomnia compared with previous studies, this was the only study that gave subjects a targeted questionnaire on insomnia.
Table 1 summarizes the most common adverse effects reported in the treatment-naive trials. Adverse effects to dolutegravir appear to be higher in some studies, which included all grades and all causes of adverse effects. Most adverse effects were grade 1–2 (mild-to-moderate in severity); however, dolutegravir treatment-related adverse effects as determined by the investigator were much lower (1–3%) overall. Dolutegravir can increase serum creatinine by inhibition of the organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1, which are responsible for the tubular secretion of creatinine. This increase is not associated with any change to the actual glomerular filtration rate. In the SPRING-1 study, the mean increase in serum creatinine observed at week 1 remained stable through week 24 and declined at week 48. The increase at week 96 was similar to what was observed at week 24 and this change was not driven by the backbone. The mean increase in serum creatinine from the SINGLE study was 0.12–0.15 mg/dl, was evident by week 2, and then stabilized through week 48. The increase in serum creatinine occurs early in treatment, typically within the first 2 weeks after initiation, and then plateaus.
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