The human immunodeficiency virus continues to evade a cure even after several decades of its discovery. Around 36.9 million people worldwide were living with HIV/AIDS at the end of the year 2017, according to UNAIDS figures.
Global efforts have helped to bring down the mortality rates of the HIV-infected significantly. Cocktails of highly active antiretrovirals help manage the HIV infection — whose diagnosis was once considered a death sentence — like any other chronic ailment today.
Nevertheless, there has been no marked abating of the rate of new infections for over a decade now. An estimated 1.8 million individuals worldwide became newly infected with HIV in 2017, nearly 5,000 new infections per day.
Efforts to develop an effective vaccine against HIV are getting longer than expected as the tricky virus hoodwink every attempt by researchers to pin it down. Meanwhile, the emergence of drug-resistant strains of HIV appears to be casting a shadow over the UNAID’s stated goals of getting rid of the virus in the next 10-12 years.
Innovators in the field are now looking at alternate therapeutic strategies to tame the virus as a definitive solution that can totally eliminate the microbe is nowhere in sight.
Priming the immune system to combat the virus using broadly neutralizing antibodies (bNAbs) is one such an approach.
Rockefeller University researchers have come out with data from Phase 1b clinical trials showing that a combination of two bNAbs is capable of suppressing HIV for months at a time. Experimental antibodies 3BNC117 and 10-1074 fight HIV from two different pathways, significantly reducing chances of resistance if both drugs are administered together.
The researchers report that a six-week course of three injections of the two bNABs suppressed HIV for an average of 21 weeks, and for over 30 weeks in some patients. In a second study in viremic patients, published in Nature Medicine, the bNAb combo therapy reduced virus levels for up to three months.
Like immunotherapy which uses anti-cancer antibodies, bNAbs interact with the host immune system thereby prompting the body to produce HIV-fighting antibodies on its own by boosting natural immunity.
This way, bNAbs can probably address one of the major setbacks with the current antiretroviral therapy (ART). Even though ART can bring down the viral load to undetectable levels, these drugs cannot eliminate the latent virus. The lingering virus poses the threat of rising again in the form of more dangerous, resistant strains as soon as the patient discontinues the strict antiretroviral regimen.
bNAbs are currently being evaluated as an alternative to ART. Since bNAbs are long acting, they can obviate daily dosing. In terms of efficacy, bNAbs are also safe and better than any previously tested antibody therapy, indicate the results published in Nature.
“Due to their ability to suppress and prevent viral rebound, studies are also ongoing to evaluate their use as a passive immunotherapeutic agent. They are also being evaluated for treatment when administered alone or concomitantly with ART,” says Adar Poonawalla, CEO, Serum Institute of India (SII), Pune, India.
bNAbs have demonstrated their ability to neutralise several strains of HIV. In recent years, researchers have identified hundreds of bNAbs that are both potent and broadly cross-reactive against the majority of HIV variants circulating globally. Some of these bNAbs are now being explored for their potential ability to prevent, treat and cure HIV infection. The results of the first study of the efficacy of a bNAb for prevention of HIV infection are expected within the next two years, and additional bNAb combinations are advancing toward efficacy testing.
If turns out to be successful, bNAbs could change the way HIV infection is treated.
Antibody prophylaxis, however, can be costly, unlike conventional small molecule antiretrovirals that come for less than a dollar for a day’s pills pack. Significantly, the majority of people suffering from the HIV disease are located in the regions of the world where affordability and accessibility are abysmally low. Hence, the success of the therapy hinges on how promptly it can be made available across the globe, particularly in places where HIV infection rates remain unacceptably high.
In October, International AIDS Vaccine Initiative (IAVI) announced collaboration with SII to develop large-scale, low-cost manufacturing of antibody-based HIV products. Currently, the world’s largest vaccine producer, SII supplies vaccines to over 160 countries in the world.
The goal is to enable the most promising antibodies to be developed in the most promising combinations to maximize chances of success, according to IAVI. The collaboration between IAVI and SII brings together partners with complementary expertise to expedite the introduction of the drugs to regions with the highest disease burden.
The efficacy of antibody prophylaxis in blocking HIV infection, however, is yet to be ascertained. The bNAb researchers believe that these antibodies have the potential to not only treat HIV but also prevent the infection. Presently, pre-emptive antiretroviral medication is available for high-risk groups. Compliance is a big issue with this kind of prophylaxis, which requires daily dosing. Long-acting HIV bNAbs could probably allow people to achieve the desired outcome while obviating the need for daily pills.
Injectable ARVs as PrEP
Another promising approach which is being investigated as a possible alternative to the current daily-dosing ART regimen is long-acting injectable antiretrovirals.
In October, ViiV Healthcare, a global specialist HIV company established by GlaxoSmithKline and Pfizer, announced results from a 3-year study from LATTE-2, a phase IIb study investigating a long-acting, two-drug, injectable regimen of cabotegravir and rilpivirine.
Cabotegravir is an investigational integrase inhibitor (INI), whereas rilpivirine is a once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI). The NNRTI is currently used for the treatment of HIV-1 infection in combination with other antiretroviral agents in ART-naïve adult patients with a viral load = 100,000 HIV RNA copies/mL.
At 160 weeks, the data showed, 90% and 83% of the patients receiving the long-acting injectable regimen of cabotegravir and rilpivirine every eight and four weeks, respectively, remained virally suppressed. Some of the patients on the oral comparator arm elected to switch to the injectable regimen at week 96. Among them, 97% of those on the eight-week dosing schedule and 100% of those on the four-week remained virally suppressed at week 160.
Apart from improving individual outcomes, adherence to ARV-therapy among people living with HIV is essential to curb ongoing transmission. Making the high-risk population comply with the strict daily oral medication is one of the major challenges faced by caregivers. A long-acting prevention method may improve treatment compliance and effectiveness, helping individuals who have difficulty taking daily antiretroviral prevention medicine, or complying with other prevention measures.
”ViiV Healthcare believes cabotegravir long-acting injection, administered as a single agent, may become an effective option for HIV prevention (pre-exposure prophylaxis, PrEP),” says Dr John Pottage, Chief Medical Officer, ViiV Healthcare.
ViiV is currently conducting 2 multinational Phase 3 clinical trials for PrEP in collaboration with the HIV Prevention Trials Network (HPTN). The first, HPTN 083, is being conducted in men who have sex with men (MSM) and transgender women, while protocol HPTN 084 is being conducted among women in sub-Saharan Africa.
The WHO has recommended PrEP for all groups at risk of infection. A study conducted by Kirby Institute at the University of New South Wales, Sydney on 3,700 men with high levels of adherence found that the incidence of HIV infection was less than 1 in 2,000 per year, compared with an expected incidence of 2 per 100 per year or higher in the absence of PrEP.
Recently, ViiV has also reported positive data on fostemsavir for treatment-resistant HIV infection. Treatment failure and antiviral resistance remain a concern for heavily treatment-experienced patients. Fostemsavir, an investigational prodrug of temsavir, is an attachment inhibitor of HIV-1.
Results from the 48-week data showed that 54% of patients in the randomised cohort achieved virologic suppression on treatment with fostemsavir plus optimised background therapy. Additionally, patients in the randomised cohort showed immunologic improvement through week 48 as demonstrated by an increase in CD4+ T-cell counts.
“We are moving towards medicines with new mechanisms of action and long-acting formulations, as we think about more options for patients and making HIV a smaller part of their lives,” says Dr Pottage.
In addition to fostemsavir, ViiV is pursuing maturation inhibitors and biologics and is partnering with University of North Carolina HIV Cure Center.
Towards a functional cure?
Abivax, a clinical-stage company headquartered in Paris, is currently working on an approach that seeks to block the viral RNA’s ability to multiply.
Experimental drug candidate ABX464 is an oral small molecule that inhibits HIV replication through an entirely new mechanism of action. In two Phase 2a clinical trials, ABX464 demonstrated up to 50% reduction of HIV-DNA in peripheral blood mononuclear cells after 28 days of combination treatment with ART.
Pre-clinical data suggest that ABX464 has the potential to reduce or eliminate the viral reservoirs in patients with HIV, thus delivering long-term control of the viral load and preventing the emergence of HIV mutants that are resistant to treatment after six months of treatment in vitro. It also offers the advantages of less frequent dosing.
“The biggest problem with current therapies in HIV is that they are unable to reduce the viral reservoir of HIV that lies latent in human immune cells. The viral reservoir is the integrated viral DNA within infected cells that perpetuates the production of viruses,” says an Abivax spokesperson.
Though ART can keep active viruses out of the bloodstream, existing reservoirs, or HIV “factories”, cannot be affected by ART. Therefore, if ART is terminated even for a short time, a viral rebound can occur.
ABX464 has a particular mechanism of action in HIV that is two-fold. Viral DNA integrated into infected cells codes for viral proteins that the cell is “tricked” into producing during translation. ABX464 is believed to inhibit a protein that is necessary for the shuttling of certain viral proteins out of the nucleus, thus preventing viruses from being reproduced within infected cells. ABX464 also induces splicing of certain sequences of viral RNA, the molecular products of which signal the immune system to attack the cells which are infected, according to the spokesperson.
Abivax believes the drug can offer a functional cure for HIV by way of this mechanism. That means the virus can be controlled without the need for ART, and not a complete eradication. Abivax is now preparing for Phase 2b trials of ABX464 in HIV.
Latency reversal agents
Clearly, a cure for the infection can be possible only by fully eliminating the virus from its reservoirs. Latent proviruses, which are competent to replicate, continue to persist in virally suppressed individuals on ART. Researchers are working on strategies to target these latently infected cells and allow immune recognition and the clearance of this reservoir.
Vorinostat is one such pharmacologic agent being evaluated in different studies to reactivate the latent reservoir so that infected cells can be recognized and targeted. A histone deacetylase inhibitor, vorinostat is currently approved by USFDA for the treatment of cutaneous T cell lymphoma. The efficacy of vorinostat is being tested in various clinical settings, including in conjunction with ART agents as well as with immunotherapy.
The ongoing RIVER trial explores whether a combination of a four-drug ART regimen that includes raltegravir, two anti-HIV vaccines and ten doses of vorinostat can effectively reduce latent HIV in resting CD4 cells in participants with newly diagnosed HIV.
VORVAX, a Phase I/IIa study, is looking at the effect of a combination of vorinostat and AGS-004 on latent HIV. AGS-004 is an investigational HIV immunotherapy designed to boost the immune system’s response to reactivated latent HIV. \
Another Phase I study is evaluating vorinostat in combination with an HIV-1 antigen- expanded specific T-cell therapy on reactivated latent HIV in adults whose HIV is well controlled by ART.