The hunt for a cure

January 6, 2020 0 By S Harachand

The buzz around finding a cure for HIV/AIDS is growing stronger. Researchers working in this area appear increasingly sanguine about ending this scourge in the near future. 

Today, they say, we have all the tools to halt the epidemic through treatment, prevention and education. It is possible for people with HIV today to live long and healthy lives, thanks to the advances in treatment. 

But don’t expect a panacea, they hasten to add. 

A cure for this global pandemic has proven to be elusive even four decades after the virus was first reported. 

This is partly because a ‘cure’ for this virus, which can lie dormant in the body for years, involves not just a treatment-free remission of the disease, but also the complete eradication of the virus from the system.

Going by the most promising treatments for the virus, any eventual cure is unlikely to be simple and would probably involve a combination of approaches.

Sustained remission & future of ART

It is now certain that adherence to antiretroviral therapy (ART) can maintain the virus at undetectable levels in the blood. Individuals undergoing such courses pose no risk of sexually transmitting HIV. They also experience little or no symptoms or complications associated with the infection. 

The latent virus, however, continues to remain in the body, and pathogen from the so-called ‘reservoir’ cells rebounds to high levels as soon as these people stop taking medication.

Sustained ART-free remission or a so-called functional cure, would allow a person living with HIV to keep the latent virus suppressed without daily medication. 

But daily dosing is still a challenge. To overcome this, researchers are now developing drugs that could be taken only once a week, once a month, or less often. 

The optimisation of therapy through long-acting medications may eventually be able to suppress HIV for extended periods, apart from offering greater convenience, cost savings and ease of use.

The Long-Acting/Extended Release Antiretroviral Resource Program (LEAP), initiated by National Institute of Allergy and Infectious Diseases under NIH, seeks to foster research in this direction. 

An investigational, once-monthly injectable regimen of long-acting HIV drugs cabotegravir + rilpivirine has been granted a Priority Review Designation by the USFDA with an expected action date of December 29, 2019. 

Data from ATLAS-2M study, showing similar efficacy for cabotegravir and rilpivirine administered every eight weeks compared to their four-week administration, has recently been reported by ViiV Healthcare, a global specialist HIV company.

Investigators are now toying with the idea of whether the combination of monthly injections of cabotegravir LA and monthly infusions of an NIAID-discovered, broadly neutralizing antibody called VRC01LS can keep HIV suppressed in people whose infections were previously controlled by antiretroviral therapy. 

Such long-acting antiretroviral medication is also being tested for preventive use.

Defeating resistance

Medications that use different approaches to incapacitate the virus are also underway. 

GS-6207, a first-in-class capsid inhibitor developed by Gilead Sciences, is one such experimental drug.

The capsid, a cone-shaped structure that encloses the viral genome, is critical for HIV-1 to replicate. 

GS-6207 is designed to act at multiple stages of the HIV replication cycle. First, it interferes with the disassembly of the capsid and the transport of the viral genetic material into a host cell’s nucleus, and later with the assembly of capsids for the newly produced virus, resulting in immature viral particles that cannot infect other cells. 

Phase 1 data show that a single injection of GS-6207 resulted in sustained concentrations for at least 24 weeks. Using 300mg and 450mg doses, estimated plasma levels at week 12 remained well above the 95% effective concentration.

Based on these findings, a phase Ib, proof-of-concept study is now going on to determine the optimal dose and frequency of administration in people living with HIV.

New drugs with unique mechanisms of action have the advantage of being effective against HIV strains with resistance – a big threat facing current ART drugs.

The most recent report from the WHO showed that resistance to efavirenz and nevirapine — the two widely used NNRTIs (non-nucleoside reverse transcriptase inhibitors) — exceeded 10% in two-thirds of the countries.

“An area of high unmet medical need in HIV is among heavily treatment-experienced (HTE) people living with HIV (PLHIV), a small subset of whom are running out of treatment options due to multi-drug resistance and the exhaustion of most or all antiretroviral (ARV) classes,” says
Dr Harmony P Garges, Chief Medical Officer, ViiV Healthcare. 

Investigating compounds with a novel mechanism of action with no cross-resistance to other ARV classes is therefore extremely important for this population due to their complex resistant profiles, she adds. 

Fostemsavir, a drug that blocks HIV from infecting immune cells by attaching to the gp120 protein on the virus’ surface, has been specifically studied in the HTE patient population.

ViiV presented the week 96 data from the BRIGHTE study at the 10th International AIDS Society Conference of HIV Science (IAS 2019) in Mexico City. 

The two-cohort (randomised and non-randomised), phase III clinical trial demonstrated continued improvement in virologic suppression and clinically significant CD4 T cell recovery in HTE PLHIV through 96 weeks of therapy in combination with optimised background treatment. 

Islatravir (EFdA or MK-8591Al), an experimental drug belonging to a class of drugs known as nucleoside reverse transcriptase translocation inhibitors, and maturation inhibitors — investigational drugs that target the same stage of the HIV lifecycle as protease inhibitors but act by a different mechanism — are also in development, supported by NIAID.

Annihilation through antibodies

HIV scientists are now betting big on broadly neutralizing antibodies (bNAbs), which they believe can annihilate the cells that have already been infected. 

bNAbs can stand up to the extreme genetic diversity of HIV and block many different viral variants from establishing infection. 

Considering this unique ability of bNAbs, researchers seem to have developed a consensus that an ideal HIV vaccine will need to induce these highly specialised proteins.

bNAbs are Y-shaped proteins made by B cells. They can attach themselves to a certain part of HIV’s surface and stop it from infecting healthy cells. 

bNAbs do develop naturally in some people with HIV. But they usually do so either in amounts too small to provide a significant benefit or too late after infection to control the rapidly replicating and mutating virus.

These proteins are also being harnessed for antibody-mediated prevention (AMP) using a method called passive immunization. 

Unlike vaccine studies, participants in AMP trials receive an anti-HIV bNAb through intravenous infusions.

“In an HIV vaccine study, participants get a vaccine that is intended to “teach” their bodies to make anti-HIV antibodies (or other immune responses) to fight HIV. In an HIV bNAb study like AMP, participants get anti-HIV antibodies directly, through the infusion. The participants’ bodies do not make the antibodies,” explains Larry Corey MD, Principal Investigator for HVTN & Protocol Chair for the Antibody Mediated Prevention (AMP) studies, HIV Vaccine Trials Network. 

HVTN is the world’s largest publicly funded international collaboration focused on the development of vaccines to prevent HIV/AIDS, headquartered at the Fred Hutchinson Cancer Research Center in Seattle.

The AMP studies were designed to determine whether an antibody can prevent HIV infection in people and, if so, how much of it is needed to prevent transmission. 

In contrast, in HIV vaccine efficacy trials, study participants get an HIV vaccine regimen and investigators evaluate if the elicited vaccine-induced antibody and cellular immune responses are elicited that may prevent HIV infection. 

By determining if and at what titers bNAbs can prevent HIV infection in humans, the AMP studies may help inform the HIV vaccine field. 

Thus far, HIV vaccines have not induced broadly neutralizing antibodies in most people, while efforts are increasing now to design vaccines that do so, reveals Dr Corey.

A key challenge with bNAbs is that their efficacy is not durable. The levels of infused bNAbs — and any protection they might provide against HIV — would diminish over time. 

Two large clinical trials testing a bNAb candidate, VRC01, are now fully enrolled and ongoing in the Americas, Europe and across sub-Saharan Africa. 

Several bNAbs are going through animal testing and smaller, early-phase clinical trials. Researchers are looking at testing long-lasting bNAbs, as well as combinations of antibodies and new ways of introducing bNAbs to the body, including via an injection.

In October last year, the International AIDS Vaccine Initiative announced a collaboration with Serum Institute of India, the world’s largest vaccine maker by volumes, to develop and manufacture affordable monoclonal products for HIV.

Studies are also evaluating approaches with existing antibody drugs. An early-phase clinical trial in which people living with HIV that was well controlled with ART received infusions of vedolizumab, an anti-alpha-4-beta-7 antibody that is FDA-approved for ulcerative colitis and Crohn’s disease. These volunteers received both ART and vedolizumab at the beginning of the study, paused ART while continuing to receive the antibody, and finally stopped all treatment. The regimen was safe and well-tolerated, but did not generate lasting control of the virus.

Kicking the ‘reservoirs’

An HIV cure requires the elimination of the reservoir of all virus-carrying cells. At the end of this process, HIV would be completely absent from an individual’s body. 

Researchers find this to be the most formidable challenge, because the HIV DNA can remain invisible to the immune system and antiretroviral drugs and survive in this resting state for years, even for life.

Two experimental strategies are, currently, being tried to be used in tandem. The first step would prompt latent HIV to replicate so that the cells in the HIV reservoir express HIV proteins. This would be followed by the enhancement of the immune system of the person living with HIV or the use of other agents to recognise and kill the cells expressing HIV proteins.

Several latency-reversing agents are under investigation in the laboratory and in human clinical trials for this “kick and kill” strategy.

Once the latent HIV begins to replicate after the “kick” stage, components of the immune system or therapeutic agents kill the HIV-infected cells to ensure complete eradication of the latent HIV reservoir. 

VRC07-αCD3, a double-headed protein which is a kind of bispecific T-cell engager, or BITE, was developed by a team of researchers at NIAID. One arm of this protein binds to a receptor on HIV-infected CD4 T-cells, prompting that cell to display HIV proteins on its outer membrane. In a separate step, the other arm of VRC07-αCD3 then binds to these HIV membrane proteins while the original arm attaches to a killer T-cell in order to activate it and bring it in proximity to the infected cell. The activated killer T cell then kills the infected cell. 

To eliminate HIV viral reservoir, the main obstacle in achieving a cure, drug makers are also considering the potential of certain therapeutic molecules as well. 

Gilead Sciences presented data from two studies of investigational toll-like receptor 7 (TLR7) agonists, recently. Phase 1 and
preclinical study results showed that vesatolimod and GS-986 can induce immune activation and potentially lead to viral remission, as part of combination regimens.

36 participants received escalating doses of vesatolimod (1-12 mg) in this double-blind, placebo-controlled phase 1 clinical study every other week. Vesatolimod at higher doses stimulated a range of immune responses. The results support studies into the potential role of vesatolimod as part of combination regimens aimed at achieving ART-free control of HIV, Gilead said.

London patient and gene editing

Strangely enough, some people living with HIV maintain low viral load even without therapy, indicating that their immune cells are protected from HIV. Other individuals claim to have had significant exposure to HIV but did not acquire the virus.

Studies revealed that people with stronger natural protection from HIV tended to have mutations in the gene that codes for a protein called CCR5. CCR5 exists on the surface of human immune cells, and it is one of the proteins that HIV uses to enter and infect cells. When CCR5 is dysfunctional or absent, HIV can no longer infect immune cells. 

If CCR5 dysfunction can be induced by mutating the CCR5 gene in the cells of adults who do not naturally have this rare mutation, people can better control or eliminate HIV infection. 

Clinicians have attempted to cure HIV in people who needed a bone marrow transplant by selecting a donor whose stem cells had the CCR5 mutation. The procedure can lead to a reconstitution of the immune system with cells that are impervious to HIV. This approach has succeeded only a couple of times in curing people of HIV. 

The extraordinary cases of “the Berlin patient” (2007) and “London patient” (2019), serve as “proofs of concept” that HIV can be cured. 

There was a lot of excitement in the HIV field following the second case. Of late, a third one in Dusseldorf, Germany has also reportedly been safely taken off antiviral drugs.

In spite of this, bone marrow transplant is not a realistic way to cure HIV in the millions of people around the world who are living with the virus as this highly risky, intensive and expensive procedure is performed only to treat life-threatening conditions in the absence of other options. Further, this HIV-resistant mutation is found in only 1% of Caucasian people of northern European origin. Over and above, the procedure has only been performed in patients with both HIV and blood cancers.

Altering the CCR5 gene through gene editing technologies to bolster the immune system’s ability to fight HIV is another possibility. This technique involves removing immune cells from an HIV-positive patient, editing the gene and then transfusing the cells back into the individual. In this case, a donor with an advantageous CCR5 mutation is not required, and the patient does not risk life-threatening rejection of donor tissue. Some preliminary research has been done to assess gene-editing as a strategy for both HIV treatment and cure. 

This emerging technology is also exploited to directly cut viral genes out of the DNA of latently infected cells or the HIV provirus. The virus inserts its own genome into the DNA of the cell it infects. Pre-clinical studies have shown that such proviral DNAs can be potentially located and excised using programmed DNA-slicing enzymes. Researchers are now working to find ways to efficiently deliver these gene-editing enzymes to all cells that make up the latent HIV reservoir without harming the patient. 

No longer a pandemic?

Between 2000 and 2018, new HIV infections fell by 37% and HIV-related deaths came down by 45%, according to WHO estimates. New infections appear to be levelling off, if not declining, in many regions, except in Africa, home to over two-thirds of the world’s 37.9 million people with HIV. 

The Center for Disease Control reports that the number of new HIV infections in the US was declining until 2013, when that number began to plateau at around 39,000 new infections per year. 

The lack of continued decline is attributed to inadequate access to HIV prevention and treatment, or people who still are not aware of their HIV status. Of the people living with HIV, only 59% are undergoing antiretroviral therapy, leaving more than an estimated 16 million people without the drugs they need to maintain their own health as well as reduce the risk of transmission.

Even when antiretrovirals keep HIV under control, their side effects leave the patients at a higher risk for blood cancer, cardiovascular complications and other problems.

In the meantime, the evolving virus continues to cast a shadow over efforts to tame it. 

In November, researchers at Abbott reported that they discovered a new strain of HIV.

The discovery, published in the Journal of Acquired Immune Deficiency Syndromes (JAIDS), marks the first time a new subtype of HIV-1 has been identified in nearly two decades.

Called HIV-1 Group M, subtype L, this new HIV subtype is part of the same group of viruses responsible for the global HIV pandemic that has infected 75 million people and claimed an estimated 32 million lives.

The discovery, say experts, is a reminder of the dangerous diversity of the HIV virus. The danger from the virus persists. It tells us that the HIV epidemic is still ongoing and evolving. 

A radically new viral strain could evade detection in the blood supply, avoid being controlled by drugs and render future vaccines ineffective. So, we must continue to outthink this continuously changing virus to find a solution. 

Diversity is “the calling card” of HIV. It is nothing but the diversity of the virus that has been defeating all efforts to create a vaccine.

“People think it’s not a problem anymore, and we’ve got it under control,’’ comments Jonah Sacha, a professor at the Vaccine and Gene Therapy Institute at Oregon Health & Science University. “But, really, we don’t.”