Major findings

This study examined the effects of temsavir, the active moiety of the antiretroviral agent fostemsavir, on the QT interval in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. 1 . Fostemsavir is a prodrug of the human immunodeficiency virus attachment inhibitor temsavir (TMR) and is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV-1) infection.

Fostemsavir 1,200 mg twice daily did not result in a clinically meaningful change from placebo in baseline-adjusted Fridericia-corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg twice daily, the upper bound of the two-sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. 1 .

A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2-fold higher than the geometric mean TMR peak plasma concentration (C_max) of 1,770 ng/mL in heavily treatment-experienced HIV-1 infected patients administered fostemsavir 600 mg twice daily in the phase III BRIGHTE study (NCT02362503). 1 .

Benefits and risks

Benefits summary

Fostemsavir is a potential treatment option for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. 1 .

Risks summary

Supratherapeutic doses of fostemsavir were associated with QT interval prolongation. 1 . QT interval prolongation is associated with an increased risk of cardiac arrhythmias, so caution is warranted. 1 .

Study comparison

Study similarities

This study examined the effects of fostemsavir on the QT interval in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. 1 . Similar to other studies, this study indicated that fostemsavir is a potential treatment option for HIV-1 infection. 1 .

Study differences

This study evaluated the effects of fostemsavir on the QT interval at supratherapeutic doses. 1 . Unlike other studies, this study found that fostemsavir can prolong the QT interval. 1 .

Consistency and contradictions of the results

The results of this study suggest that fostemsavir does not prolong the QT interval at therapeutic doses, but it does at supratherapeutic doses. 1 . This study is the first to show that QT interval prolongation can occur with supratherapeutic doses of fostemsavir. 1 . Other studies have not investigated the effects of fostemsavir on the QT interval.

Points to note for real-life applications

The results of this study suggest that the risk of QT interval prolongation is low when fostemsavir is administered at therapeutic doses. 1 . However, this study found that fostemsavir can prolong the QT interval at supratherapeutic doses, which is associated with an increased risk of cardiac arrhythmias. 1 . Therefore, careful monitoring of the patient's QT interval is necessary when administering fostemsavir.

Limitations of the current research

This study was a small, phase I trial, and larger, longer-term studies are needed to further investigate the effects of fostemsavir on the QT interval. 1 .

Future research directions

Larger, longer-term studies are needed to investigate the effects of fostemsavir on the QT interval in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. 1 . These studies should involve larger numbers of patients to evaluate the safety of fostemsavir and identify potential risks. 1 .

Conclusion

Fostemsavir is a potential treatment option for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. 1 . However, fostemsavir has been shown to prolong the QT interval at supratherapeutic doses, which is associated with an increased risk of cardiac arrhythmias. 1 . Therefore, careful monitoring of the patient's QT interval is necessary when administering fostemsavir. 1 .

This study suggests that larger, longer-term studies are needed to further investigate the effects of fostemsavir on the QT interval. 1 . These studies should involve larger numbers of patients to evaluate the safety of fostemsavir and identify potential risks. 1 .