Why is it so difficult to treat HIV?
Will there ever be a cure for HIV?
Hear from Cal Cohen.
The human immunodeficiency virus (HIV) infection has come a long way since the disease was first presented in the 1980s. From the first anti-retroviral medication that could treat HIV in 1987, zidovudine (AZT) was given intravenously, but at the initial doses used, the drug was toxic. Now, new anti-retroviral therapies (ARTs) are not only able to treat or “cure” the disease to a point where the virus is undetectable and untransmissible, but they are also able to support the long-term health of people living with HIV (PLHIV). Cal Cohen, the executive director of medical affairs at Gilead Sciences talks about the current landscape of HIV treatment, why HIV is so difficult to cure, and if there will ever be a cure for HIV.
Stages of HIV infection
The human immunodeficiency virus (HIV) infection can be summarised in three stages:
It first starts with exposure to the virus. Not every exposure will lead to an infection, however, if it does the patient will enter the acute infection phase. Acute infection is the earliest stage of HIV infection and usually develops within two to four weeks. The patient will experience common viral symptoms such as fever or body rash. During the acute phase, the amount of virus in the blood stream can be very high.
The body’s immune system then starts to produce an immune response, which lasts between three to six months, to try to stop the virus from growing. In rare cases, the immune system performs well and the levels of HIV in the blood will be suppressed to very low levels.
Chronic or silent phase
The second stage of HIV infection is chronic HIV infection. During this stage, HIV continues to multiply but at variable levels – sometimes very low levels, and sometimes very high, depending on the status of the patient’s immune system. While people with chronic HIV infection may not present any HIV-related symptoms, the virus can still be transmitted to an uninfected person. This silent phase of HIV infection may last for a few years or longer, even decades.
Acquired immune deficiency syndrome (AIDS) is the final and most severe stage of HIV infection. We also call this phase the “major symptoms of untreated HIV”. Because the immune system is severely damaged and compromised, the body is easily infected by other serious infections, or malignancies associated with inflammation. It is also unable to control existing infections in body. Without treatment, people with AIDS typically survive only about one to three years.
Antiretroviral therapies available
Since the initial development of antiretroviral therapy more than 30 years ago, HIV has become a manageable chronic disease. To date, there are several classes of drug therapies including:
- Nucleoside reverse transcriptase inhibitors (NRTIs)
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Protease inhibitors (PIs)
- Integrase inhibitors (INSTIs)
- Chemokine receptor antagonist (CCR5 antagonist)
- Fusion inhibitor
- Entry inhibitors (CD4-directed post-attachment inhibitors)
Each class of drugs targets a different stage of a virus’ life cycle. Therefore, to understand how we can intervene, we need to understand the life cycle of HIV.
When HIV first enters the host, it attaches itself to a particular cell of the immune system called a CD4 T-cell. The virus attaches itself to the CD4 receptor on the cell’s surface in order to replicate and multiply. The discovery of this mechanism correspondingly led to the development of a few early-generation drugs, known as entry inhibitors, that inhibit the binding of the virus to the CD4 receptor. There is also a class of drugs called CCR5 antagonists that blocks the virus’ attachment to a second receptor called CCR5.
If the virus attaches and enters the cell, the virus goes through a replication process, called reverse transcription, using the host cell’s building blocks – converting its RNA into DNA. This led to two common antiretroviral drugs: 1) reverse transcriptase inhibitors (NRTIs) which mimic the cellular native nucleosides but are altered to cease the virus from forming its own DNA strand; 2) non-nucleoside reverse transcriptase inhibitors (NNRTIs) which interfere with the function of reverse transcriptase enzyme that HIV uses to replicate.
However, if the virus RNA is not stopped from replicating into DNA, the HIV DNA will be integrated into its host DNA. Integrase inhibitors (INSTIs) are deployed to inhibit the insertion or integration of the virus DNA and its host cell.
Should integration occur, the virus will at some point start to multiply turning the infected cell into a “virus factory”. Viral proteins are produced by the HIV protease enzyme and will enable the virus to assemble a new virus particle which can then spread to other cells. Protease inhibitors were thus developed to interfere at this stage.
Gilead is currently developing a drug candidate that can potentially block some of the last steps of virus maturation. Known as a capsid inhibitor, the investigational compound is currently in phase 1 clinical study, and is being developed as a long-acting injectable. The capsid inhibitor is the first drug in this novel class and has the ability to inhibit the process of viral assembly and disassembly of the capsid core of HIV. This inhibitor blocks three essential steps of the virus life cycle.
How have antiretroviral therapies changed over the years?
The treatment of HIV has evolved significantly since the beginning of the HIV/AIDS epidemic, and Gilead has been at the center of the evolution of the HIV treatment landscape.
In the mid to late 1990s, a typical person living with HIV or AIDS took approximately 30 pills a day to suppress the virus and prevent the opportunistic infections, often producing severe side effects. Today patients only need to take a single pill, once a day.
It took us more than 30 years of persistent dedication to scientific innovation and development to be able to turn HIV into a manageable disease. The main obstacles were overcoming viral drug resistance and drug toxicity. Through the years of research and development, we found that the three-drug combinations were most effective at delivering favourable outcomes – meaning long-term viral control without severe adverse reactions. The single tablet, triple drug combination therapies are now standard of care and recommended by international treatment guidelines. They are safer and more effective, allowing people to lead a normal life span.
Gilead’s latest innovative drug (BIC/FTC/TAF) is an example of a three-drug combination therapy, comprised of an integrase inhibitor (bictegravir) and two nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) drugs (emtricitabine/tenofovir alafenamide). Overall, there have been few reports of adverse events, with about 1% rate of discontinuation. In two large phase three studies, there have been no discontinuations due to drug-related adverse events. To date, no emergent drug resistance has been observed. The drug has a convenient dosing schedule and does not require food intake or genetic testing for HLA-B 5701 (which is needed for another NRTI). At the same time, durable viral suppression over time on sustained therapy means that there is essentially no chance of viral transmission to another person.
While we have come a long way since the 1980s, we cannot stop now: we are determined to transform and simplify treatment for patients so that they can lead better lives. We are continuously working on the next breakthrough, one of which is long-acting injectables, which are potentially effective at suppressing the virus for two to four months per dose. Ultimately what we want to achieve is a cure for HIV and we are making considerable investments in finding the next transformative therapy that can be the answer to the end of HIV/AIDS.
Why is it so difficult to treat HIV?
In addition to the complex nature of the disease, there are other environmental factors that impact HIV treatment. Social stigma and discrimination surrounding the disease and people living or associated with the disease – and consequently low levels of awareness – are barriers to testing and treatment. This is heightened in Asia Pacific where cultures can be conservative. There is notable stigma associated with HIV and the patient populations most at risk of acquiring HIV, including men who have sex with men or injection drug users. Often, people seek treatment when symptoms have progressed and are at the last stage of AIDS. We have observed that about 30 per cent of people in the Asia Pacific region are presented to care late.
People living with HIV also suffer from other co-morbidities such as cancer, liver disease, heart disease, kidney disease and tuberculosis, and coinfection with other viruses such as hepatitis B or hepatitis C, which adds to the complexity of disease treatment and management. Additionally, as people living with HIV are living longer, they will also present other health conditions related to ageing. The drug-to-drug interactions with other medications can also pose potential risk to efficacy and tolerability of antiretroviral medications needed to treat HIV. Treatment of people living with HIV thus requires a multidisciplinary approach and healthcare professionals need to be equipped to advise patients.
Lastly it is important for governments, payors, and the industry to prioritise HIV as a public health issue, ensure that the latest drugs are made available, and that patients are able to access these therapies.
Many studies have now shown that highly effective HIV therapy that fully suppresses the virus results in a situation where it is virtually impossible for the infected person to transmit the virus to an uninfected person. A landmark study published in The Lancet earlier in May found that people whose HIV infection are fully suppressed by antiretroviral drugs carry zero risk of transmitting the virus.
This is known as “U=U”, which means “undetectable equals untransmittable”. Access to highly effective therapy is therefore also very important for public health measures aimed at preventing the spread of HIV to uninfected persons.
Are we close to finding a cure for HIV?
It took three decades of dedicated research and development to transform HIV from a fatal and debilitating disease to a condition that is chronic and manageable. I do not think finding a cure is unattainable, and we at Gilead, the industry and academic researchers are working hard to find the answer that can end HIV/AIDS.
Nevertheless, elimination might be a reality even now. The UNAIDS had set out an ambitious goal to end new cases of HIV by 2030. To achieve this, we need to diagnose at least 90 per cent of all HIV-positive persons, provide antiretroviral therapy for at least 90 per cent of those diagnosed, and achieve viral suppression for at least 90 per cent of those treated by 2020. Based on UNAIDS’ mathematical modeling, the outcome of these goals can reduce the number of transmissions, and potentially eliminate the disease in the decades ahead.
I believe that a critical step to realising this goal is treatment. If everyone with HIV is tested and treated, we would eventually one day be able to eliminate HIV because there would be no new infections. In addition, there is enormous progress when we combine treatment with the use of pre-exposure prophylaxis or “PrEP” for HIV negative persons at risk for HIV infection. The tools are available; the challenge is to overcome environmental factors, and a real, concerted collaborative effort from all stakeholders to get everyone treated on time and make elimination a reality.
- UNAIDS, 2017. Global AIDS update 2017.
- Rodger, A.J et al, The Lancet, 2019. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Accessed on 10 May 2019. www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30418-0/fulltext