The most effective treatment for HIV/AIDS is antiretroviral therapy (ART), which involves taking a combination of antiretroviral medicines to slow down the rate of HIV multiplication (HIVinfo.nih.gov 2020a).
The Human Immunodeficiency Virus (HIV) Life Cycle
In order to understand how antiretroviral treatment works, we need to understand the life cycle of the human immunodeficiency virus (HIV).
HIV specifically targets and destroys CD4, a type of white blood cell that is important for a well-functioning immune system. As more and more CD4 cells are destroyed by the virus, the immune system weakens (Montoya & Vintez 2020).
Upon HIV entering the bloodstream, there are several steps to its life cycle:
HIV attaches itself to the receptors of a CD4 cell in the immune system.
The HIV envelope and CD4 cell membrane fuse, allowing HIV to enter the CD4 cell.
The genetic material (RNA) in HIV is converted into HIV DNA using the reverse transcriptase enzyme. The newly converted HIV DNA is able to enter the nucleus of the CD4 cell and combine with the cell’s DNA.
HIV releases the integrase enzyme inside the CD4 cell nucleus. This enzyme allows HIV to integrate its own DNA into the CD4 cell’s DNA. The HIV infection is now established in the cell.
The CD4 cell produces long chains of HIV proteins, which are the building blocks for more HIV.
HIV RNA and the new HIV proteins move to the surface of the CD4 cell. They assemble into non-infectious, immature HIV.
The immature HIV leaves the CD4 cell and releases an enzyme known as protease, which breaks up the long protein chains to form mature, infectious HIV. The mature
HIV then attacks other cells, beginning the process again.
The aim of antiretroviral therapy is to stop HIV from progressing to acquired immune deficiency syndrome (AIDS) by stopping the HIV life cycle in its tracks and preventing the virus from multiplying (HIVinfo.nih.gov 2020b).
Antiretroviral therapy cannot cure HIV, but provides the immune system with an opportunity to recover. It also aims to reduce the viral load in the body to an undetectable level, reducing the risk of transmission to others (HIVinfo.nih.gov 2020a).
ART medicines are categorised into several drug classes. Each drug class is designed to block a different stage of the HIV life cycle. Generally, a person undergoing ART will take medicines from at least two different drug classes in order to obstruct the HIV life cycle at multiple stages (HIVinfo.nih.gov 2020a).
There are six classes of antiretroviral medicines used in Australia. These are:
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
In Australia, recommended practice is to initially start patients on a regimen of two NRTIs and one INSTI (ASHM 2019a).
While ART has demonstrated its effectiveness, it is important to note that there is potential for adverse reactions or drug-to-drug interactions to occur (ASHM 2019b).
Barriers to Antiretroviral Therapy
HIV has a rapid rate of genomic evolution due to several factors:
Rapid rate of viral production
Rapid turnover of productively infected cells
The reverse transcriptase enzyme being prone to errors.
(ASHM 2019c)
This rapid genomic evolution allows new strains and mutations of HIV to arise, some of which are resistant to antiretroviral therapy (ASHM 2019c).
According to the World Health Organization (2020), up to 26% of people starting antiretroviral therapy are infected by an HIV strain that is resistant to first-line medicines.
Another identified issue is that in some cases, HIV viral load is detectable in semen despite being undetectable in the blood due to long-term ART. This suggests the presence of a persistent HIV reservoir in the male genital tract (Kariuki et al. 2020).
As with any treatment regimen, there are also patient-related factors that may increase the risk of adverse drug reactions to ART. These include:
Other medicines being taken
Comorbidities including underlying liver disease, viral hepatitis infection, liver steatosis and renal dysfunction
Psychiatric disorders (which may be exacerbated by certain antiretroviral medicines)
Genetic predisposition to hypersensitivity to certain antiretroviral medicines
Pregnancy (certain antiretroviral medicines are not recommended for pregnant women due to the potential for maternal or fetal complications)
Age (certain antiretroviral medicines are not recommended for children due to the potential for complications, or are not approved for children due to insufficient safety data).
(HIVinfo.NIH.gov 2019, 2021a, b)
Compliance with treatment is essential and requires deep understanding and cooperation from patients and their family members. Consistent counselling and follow-ups are crucial in ensuring adherence.
Whilst there are no alternatives to ART currently available, there is ongoing research into new and different HIV treatments.
One such approach being studied is , which involves modifying part of the body’s own genetic code in order to make CD4 cells resistant to HIV. It’s hoped that gene therapy may be a functional HIV cure that could negate the need for antiretroviral therapy (Alcorn 2020).
Another potential functional cure is bone marrow transplantation, however, there have only been two successful cases of this method to date (Warren 2019).
Attempts to develop a vaccine against HIV are currently in progress. While ART allows people with HIV to maintain viral suppression, lifelong adherence to the treatment is essential. The only perceived way to eradicate the virus completely is to remove its ability to be transmitted in the first place (HIV.gov 2021; HIVinfo.NIH.gov 2020c).
Conclusion
For the time being, it looks like antiretroviral therapy is the only effective treatment for HIV at our disposal.
As healthcare professionals, we need to continue to support our patients with HIV and ensure that compliance with treatment is maintained at all times.
Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine 2019b, Antiretroviral Guidelines: US DHHS Guidelines With Australian Commentary, ASHM, viewed 8 April 2021, https://arv.ashm.org.au/
Kariuki, S M, Selhorst, P, Norman, J, Cohen, K, Rebe, K, Williamson, C & Dorfman, J R 2020, ‘Detectable HIV-1 in Semen in Individuals With Very Low Blood Viral Loads’, Virology Journal, vol. 17, no. 29, viewed 8 April 2021, https://virologyj.biomedcentral.com/articles/10.1186/s12985-020-01300-6
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