Long-Acting Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency Virus

  title={Long-Acting Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency Virus},
  author={Chasity D. Andrews and William R. Spreen and Hiroshi Mohri and Lee Moss and Susan L. Ford and Agegnehu Gettie and Kasi E. Russell-Lodrigue and Rudolf P Bohm and Cecilia Cheng‐Mayer and Zhi Hong and Martin Markowitz and David D. Ho},
  pages={1151 - 1154}
Keeping HIV at Bay? Preexposure prophylaxis involving daily doses of drugs can, with variable success rates, interrupt HIV transmission for individuals at high risk of acquiring HIV infection. However, one reason for the variability seen in the response to such drugs is a lack of adherence to the prescribed regimen. Andrews et al. (p. 1151) formulated a potent integrase inhibitor as a long-acting agent that protected macaques from repeated intrarectal challenges of simian HIV. Decay of plasma… 

A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge

The long-acting integrase inhibitor GSK744 protects macaques from three high-dose SHIV challenges at plasma drug concentrations that could be achieved with quarterly injections in humans and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV rhesus macaque challenge model.

The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge

It is shown in macaques that the long-acting integrase inhibitor GSK744, at concentrations achievable in humans by quarterly injections, afforded protection against repeated vaginal simian HIV challenges, and this findings support the clinical development of G SK744 LA as a PrEP agent for HIV prevention in women.

Long-Acting Cabotegravir for HIV/AIDS Prophylaxis.

Cabotegravir (CAB)-LA, which inhibits integrase strand transfer activity, has in recent clinical trials been shown to prevent HIV-1 acquisition more effectively than once-daily oral dosed reverse transcriptase inhibitors.

A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges.

The efficacy of long-acting raltegravir in preventing vaginal HIV transmission was demonstrated and two high-dose HIV vaginal challenges were evaluated in BLT mice.

Cabotegravir in the treatment and prevention of Human Immunodeficiency Virus-1

CAB is efficacious when used in combination therapy orally or given intramuscularly every 4 to 8 weeks and its availability in a long-acting injectable formulation makes it a valuable, novel drug to treat HIV-1 infection when combined with long- acting injectable rilpivirine (RPV-LA).

Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251

These results support the clinical investigation of CAB long acting as PrEP in people who inject drugs and appear to be more important for protection than sustaining therapeutic plasma concentrations with the second CABLong acting injection.

Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection

The authors show emergence of integrase mutations associated to CAB LA PrEP that confer pan-integrase inhibitor resistance, and identify G118R and E92Q in viruses from vaginal and rectal fluids.

Cabotegravir long-acting for HIV-1 prevention

PrEP, after approval of Truvada, continues to evolve to address adherence limitations of daily dosing, and cabotegravir long-acting permits quarterly dosing and demonstrated high efficacy in macaque models supporting dose selection and clinical development.

Pharmacokinetics and Pharmacodynamics of Cabotegravir, a Long-Acting HIV Integrase Strand Transfer Inhibitor

Here, the existing literature on the preclinical and clinical pharmacokinetics and pharmacodynamics of LAI cabotegravir are reviewed, with emphasis on the actual pharmacokinetic challenges of this novel formulation, as well as its potential to act as a victim or perpetrator of drug–drug interactions.

GSK1265744 Demonstrates Robust In Vitro Activity Against Various Clades of HIV-1

The relative effective concentrations of GSK744 against a panel of recombinant viruses containing integrase coding regions derived from various clades of HIV-1 were determined to determine a next generation global PrEP agent.



Intermittent Prophylaxis with Oral Truvada Protects Macaques from Rectal SHIV Infection

It is shown that in monkeys a more realistic medication schedule may work just as well as daily doses of antiretroviral drugs, and it is important to evaluate treatments based solely on exposure, as these would not require ongoing prophylactic drug treatment and would minimize any drug toxicity.

Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir

This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection.

Long-acting injectable antiretrovirals for HIV treatment and prevention

Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates and offer the potential for combination use for HIV pre-exposure prophylaxis.

Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques

Investigation of whether plasma concentrations of antibody corresponding to relatively modest neutralization titers in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus–HIV chimera that uses the CC chemokine receptor 5 (CCR5) co-receptor suggests lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.

Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study

These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL, and dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen.

Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges.

It is demonstrated that treatment with oral TDF provided partial protection against SHIV infection but ultimately did not protect all TDF treated animals against multiple virus challenges.

Emtricitabine-Tenofovir Concentrations and Pre-Exposure Prophylaxis Efficacy in Men Who Have Sex with Men

PrEP using oral FTC-TDF tablets is a robust intervention for preventing HIV acquisition among men who have sex with men, and specific drug concentrations associated with protection from HIV-1 acquisition in the iPrEx trial are estimated.

Preexposure prophylaxis for HIV infection among African women.

Prophylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo, and drug adherence appeared to be low.

Mucosal Transmission and Induction of Simian AIDS by CCR5-Specific Simian/Human Immunodeficiency Virus SHIVSF162P3

The efficient mucosal transmission of a CCR5-specific chimeric simian/human immunodeficiency virus, SHIVSF162P3, is described and this controlled model provides the setting to investigate immunologic responses and putative host-specific susceptibility factors that alter viral transmission and subsequent disease progression.

Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.

Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine, thus meeting the criterion for superiority.