DAWN OF HOPE IN THE FIGHT AGAINST HIV/AIDS

The story of long acting Anti-retrovirals

By Dr Solomon A Feyissa

Very promising sign for future of pre exposure prophylaxis(PrEP) and potentially revolutionary step for antiretroviral therapy.

Advances in medical science have made HIV/AIDS a less lethal and chronically manageable medical problem. However we are still very far away from a cure or a vaccine. Antiretroviral medications have to be taken on a daily basis for life to manage the disease. Antiretroviral treatment requires adherence and compliance to be effective. It also causes significant side effects. In some parts of the world patients who are taking medications still face significant discrimination and stigma. Recent advances in long acting antiretroviral medications would address some of the current challenges of pre exposure prophylaxis and antiretroviral therapy including decreasing pill burden, side effects, stigma and discrimination and open the door for new opportunities and strategies of treatment and prophylaxis.

Recent studies shed light on the potentials of long acting antiretroviral:

Preexposure prophylaxis (PrEP) with oral tenofovir/emtricitabine, oral tenofovir, or tenofovir gel has protected some women and men from HIV in placebo-controlled trials. But all three strategies failed in two other trials involving African women, mainly because of poor adherence. A long-acting injected PrEP (post exposure prophylaxis) agent would obviate the need for daily adherence and could be a useful prophylactic for women and men who could get such a shot without fear of stigma.

Some antiretroviral have demonstrated that they have surprisingly very long half life after a single dose paving the way for possible monthly or quarterly administered therapy for pre exposure prophylaxis or chronic HIV/AIDS therapy. In one study,GSK1265744 (long acting Integrase Inhibitor) half-life ranged from 21 to 50 days after a single injection of various test doses in 56 HIV-negative volunteers .
Long-acting antiretrovirals could become preferred agents for HIV preexposure prophylaxis (PrEP) as well as for treatment of chronic HIV infection. GlaxoSmithKline and Janssen investigators conducted a trial (clinicaltrials.gov NCT01593046) to assess the safety, tolerability, and pharmacokinetics of GSK744 ( long-acting parenteral integrase inhibitor) with repeated intramuscular or subcutaneous doses in healthy adults, administered with TMC278 LA (long acting NNRTI) injected intramuscularly.There were no drug-related serious adverse events or significant laboratory abnormalities in this first repeat-dose 16-week study of these long-acting injected agents. Ongoing studies include evaluation of these two agents administered orally as a maintenance regimen for HIV-positive people. Pending results of this trial, injection of long-acting of these antiretrovirals may be tested in people with HIV.

In another study presented at the 20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta, researchers were able to demonstrate the following results; the study was conducted on macaque monkeys. Two doses of GSK1265744-LAP (long acting integrase inhibitor) protected eight macaque monkeys from a challenge with simian HIV (SHIV), a simian immunodeficiency virus with an HIV coat. The investigational integrase inhibitor is already being studied in humans. GSK1265744 half-life ranged from 21 to 50 days after a single injection of various test doses in 56 HIV-negative volunteers.
In this study US researchers collaborating with GlaxoSmithKline, developer of GSK1265744, tested the protective potential of GSK744LAP in 16 macaque monkeys, 8 of them given an intramuscular injection of GSK744LAP at a dose of 50 mg/kg at two points 4 weeks apart and 1 week before SHIV exposure. Eight control macaques received no GSK744LAP. All macaques were exposed once a week for up to 8 weeks with SHIV. The researchers monitored macaque monkeys for SHIV infection with real-time polymerase chain reaction amplification of viral gag sequences in plasma samples collected weekly. All animals tolerated GSK744LAP. The macaque monkeys not injected with the integrase inhibitor all became infected after a median of two SHIV exposures (range 1 to 7 weeks). None of the 8 macaques treated with GSK744LAP a week before SHIV challenge became infected during the 8 SHIV challenges or 3 weeks after the last challenge (P < 0.0001 versus control). No proviral DNA could be detected in peripheral blood mononuclear cells and no anti-SHIV antibodies could be detected in plasma of treated macaque monkeys. Both signals of infection could be detected in untreated animals. Plasma concentrations of GSK1265744 throughout the study period remained comparable to exposures achieved in humans with an 800-mg loading dose and another 400 mg 4 weeks later. GSK1265744 trough concentrations were also similar in macaque monkeys and humans.The researchers plan to monitor all macaque monkeys for at least 10 weeks after the last SHIV challenge. The animals will then be sacrificed to permit extensive tissue analysis for SHIV. The investigators also plan to study GSK744LAP in female macaque monkeys.They conclude that "GSK744LAP appears to be a promising next-generation PrEP agent suitable for monthly to quarterly injections."

On going extraordinary achievements and discoveries in the field of HIV is making more likely than ever that the day when pre exposure prophylaxis and potentially HIV therapy could be accomplished with long acting injectables with a monthly or quarterly administration of medications is finally within our reach. We will stay tuned for more exciting news in the fight against one of the deadliest disease of our generation.

References:

1. Andrews C, Gettie A, Russell–Lodrigue K, et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 24LB.

2. Spreen W, Ford SL, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. XIX International AIDS Conference. July 22-27, 2012. Washington, DC.

3. Spreen W, Williams P, Margolis D, et al. First study of repeat dose co-administration of GSK1265744 and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics, safety and tolerability in healthy adults. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract WEAB0103

About Tenayistilign

I am a physician trained at Jimma Institute of Health Sciences ( now Jimma University, in Jimma, Ethiopia) and Wayne State University ( Detroit, MI, USA). I teach and practice General Nephrology/Hypertension and Kidney Transplantation in the USA.
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3 Responses to DAWN OF HOPE IN THE FIGHT AGAINST HIV/AIDS

  1. solomon says:

    IW thanks for the comments. What you said is probably accurate however given the reckless nature of human behavior long acting injectable antiretroviral pre exposure prophylaxis would make sense for those who are at risk of contracting HIV including commercial sex workers and intravenous drug abusers. I also would like to point out these drugs would be more appealing for those who have difficulty of taking pills on a daily basis due to non compliance, non adherence, stigma or discrimination. This possibility also gives the effort of combating HIV/AIDS a very promising future in envisioning a chronic HIV therapy with monthly or quarterly injectables.

  2. IW says:

    That is a great discovery. I just want to emphasize that there is already an effective way of preventing HIV infection (avoid risky/unhealthy/unprotected sexual intercourse) at least for the most common way of transmission. Granted behavior is difficult to change as seen by the continued epidemic of HIV and that sexual practices are difficult to consistently controll but the same is true for compliance with the injections/pills and there is even risk people may engage into risky practices assuming they are protected. In any case i think it is a very helpful discovery but won’t solve the whole problem. An effective vaccine is much more attractive as it can give a longer protection with out the need for multiple treatment (which can be affected by compliance). This discovery could be very helpful in reducing transmission to new born babies from mother to child though breastmilk….,

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