A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection

Abstract

Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.

Keywords: Bictegravir; Cabotegravir; Dolutegravir; Elvitegravir; HIV; Integrase strand transfer inhibitor (INSTI); Pre-exposure prophylaxis; Raltegravir; Treatment naïve.

Fig. 1

FDA approval timeline of INSTI single and fixed dose combination products used for HIV-1 treatment and prevention *discontinued, 3TC lamivudine, ABC abacavir, COBI cobicistat, FTC emtricitabine, HD high dose, RPV rilpivirine, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate

Fig. 2

Clinical considerations for choosing between INSTIs. ^aCabotegravir has a higher genetic barrier to resistance than first generation INSTIs (RAL and EVG) with limited cross-resistance to these latter INSTIs; however, CAB may have a lower genetic barrier to resistance than other second generation INSTIs (DTG and BIC). BIC bictegravir, CAB cabotegravir, DTG dolutegravir, EVG elvitegravir, HBV hepatitis B virus, RAL raltegravir, STR single tablet regimen, TB tuberculosis