Treatment

The goal of antiretroviral therapy (ART) is to suppress/inhibit the HIV and, by doing so, to make sure that people living with HIV can live long and healthy lives. On the other side of this page, the life cycle of HIV in the body is outlined.

How ARV’s Work

Now to look at how the antiretrovirals (ARVs) suppress the HIV in the body. The different kinds of ARVs are divided into different classes, according to where they act in the HIV life cycle. 2,4

1

Entry Inhbitors

Stop the virus from entering the CD4 cell (Step 2) e.g. maraviroc (MVC).
2

Nucleoside Reverse Transcriptase Inhibitors

Act as fake substrates and stop the DNA forming in Step 3 e.g. abacavir (ABC), didanosine (ddI), emtricitabine (FTC), lamivudine (3TC), stavudine (d4T), zidovudine (AZT) and tenofovir (TDF).
3

Non-Nucleoside Reverse Transcriptase Inhibitors

Stop the enzymes from working in Step 3 e.g. efavirenz (EFV), etravirine (ETV), nevirapine (NVP) and rilpivirine (RPV).
4

Integrase Strand Inhibitors

Stop the HIV from being added into the cell’s DNA (Step 4) e.g. dolutegravir (DTG) and raltegravir (RAL).
5

Protease Inhibitors

Stop the ‘cutting up’ needed to make new HIV in Step 6 e.g. atazanavir (ATV), darunavir (DRV), fosamprenavir (FPV), lopinavir/ritonavir (LPV/r), ritonavir (RTV) and saquinavir (SQV).

ART is made up of ARVs (antiretrovirals) from at least two classes which, together, act to suppress the HIV in the body.1 The ARVs can be given as separate medicines or combined into one tablet, also called FDCs (fixed dose combinations).

The Role of Protease Inhibitors in ART

Protease inhibitors (PIs) play an important role in highly active antiretroviral therapy (HAART)1,2.

HIV researchers realised early on that if they can prevent virions from reaching maturity, they may slow down the virus’ ability to replicate. This finding ultimately led to the development of the first PI.

Protease is an enzyme in the body that’s important for HIV replication

Viruses are often referred to as the ‘perfect’ parasite. A virus cannot reproduce on its own, so in order to make new copies, it must infect host cells of the immune system (CD4 cells)3.

As a new virion (an individual virus) buds out from an infected host cell, it is wrapped by the cell’s bilayer membrane and carries with it any protein that happens to be embedded in the membrane at the budding site. Enveloped viruses such as HIV are then free to begin a new cycle of infection by fusing their cell-derived envelope with the cellular membrane of an uninfected cell.

A virion’s machinery is so efficient that each cell infected by even a single virion can produce about a million new virions3.

However, before it can become infectious, virions have to undergo certain morphological structural changes. This is where protease enzymes come into play.

The virus uses these enzymes to break down polyproteins into smaller units needed to mature and assemble new viral particles2.

HIV researchers realised early on that if they can prevent virions from reaching maturity, they may slow down the virus’ ability to replicate. This finding ultimately led to the development of the first PI1,4,5.

The first PI (ritonavir [RTV or /r]) was approved by the American Food and Drug Administration (FDA) in 1996. Since then, 10 more PIs have been approved by the FDA, making them the largest class of drugs used in the fight against HIV1,4,5.

SA’s ‘test and treat all’ policy helps HIV patients to access ART faster

HAART is considered one of the biggest innovations in the fight against HIV, making it a chronic, manageable disease.

Highly active antiretroviral therapy (HAART) became the standard of HIV care in 1996. HAART comprises combination antiretroviral therapy (ART). HAART significantly reduces viremia, increases the body’s defence capacity, improves the individual’s general health condition, reduces the number of opportunistic infections, and prolongs survival. HAART is considered one of the biggest innovations in the fight against HIV, making it a chronic, manageable disease6,7.

In South Africa, all patients who are diagnosed with HIV should be initiated on ART as soon as possible. Exceptions include patients presenting with cryptococcal meningitis (CM) or active tuberculosis (TB). In his foreword to the 2020 National Consolidated Guidelines for The Management of HIV In Adults, Adolescents, Children, and Infants and Prevention Of Mother-To-Child Transmission, former Minister of Health, Dr Zweli Mkhize, stresses that government’s implementation of the ‘test and treat all’ approach implemented in 2016 has made it possible for people living with HIV to access ART timeously9.

According to the 2020 United Nations Programme on HIV/AIDS Global AIDS Update, increased access to ART has averted an estimated 12.1 million AIDS- related deaths since 2010. The estimated 690 000 lives lost due to AIDS-related illnesses worldwide in 2019, is a 39% reduction since 201010.

HIV drug classes

Seven classes of HIV drugs have been developed, each targeting a specific stage in the lifecycle of HIV. The seven classes are:

  1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  2. Nucleoside reverse transcriptase inhibitors (NRTIs)
  3. Protease inhibitors (PIs)
  4. Fusion inhibitors
  5. Cysteine-cysteine chemokine receptor 5 antagonists
  6. Integrase strand transfer inhibitors (INSTIs)
  7. Post-attachment

Goals of ART

According to the SAHCS, the goals of ART are to7:

  • Provide maximal and durable suppression of viral load (VL)
  • Restore and/or preserve immune function
  • Reduce HIV-related infectious and non- infectious morbidity
  • Prolong life expectancy and improve quality of life
  • Prevent onward transmission of HIV.
  • Minimise adverse effects of the treatment.

References

  1. Lv Z, Chu Y, and Wang HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV/Aids – Research and Palliative Care, 2015.
  2. Marin R-C, Behl T, Negrut N and Bungau S. Management of Antiretroviral Therapy with Boosted Protease Inhibitors—Darunavir/Ritonavir or Darunavir/ Cobicistat. Biomedicines,
  3. Cohen How Viruses Invade Cells. Biophysics Journal, 2016.
  4. Hardy Atazanavir vs darunavir – which reigns supreme? Protease inhibitors for second-line antiretroviral therapy. De Novo Medica, 2021.
  5. Nel J, Dlamini S, Meintjes G, et al for the South African HIV Clinicians Southern African HIV Clinicians Society guidelines for antiretroviral therapy in adults: 2020 update. Southern African Journal of HIV Medicine, 2020;21(1), a1115. https://sahivsoc.org/ARTGuidelines.
  6. Lv Z, Chu Y, and Wang HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV/AIDS – Research and Palliative Care, 2015.
  7. Nel J, Dlamini S, Meintjes G, et al for the South African HIV Clinicians Southern African HIV Clinicians Society guidelines for antiretroviral therapy in adults: 2020 update. Southern African Journal of HIV Medicine, 2020;21(1), a1115. https://sahivsoc.org/ARTGuidelines
  8. World Health Updated Recommendations on HIV Prevention, Infant Diagnosis, Antiretroviral Initiation and Monitoring, 2021.
  9. National Department of National Consolidated Guidelines for the management of HIV In Adults, Adolescents, Children And Infants And Prevention of Mother-to-Child Transmission. 2020.
  10. Seizing The Moment. Global Aids Update | 2020. https://www.unaids.org/sites/default/files/media_asset/2020_global-aids-report_executive-summa- ry_en.pdf
  11. National Department of Health. Notice: updated guidance for the use of dolutegravir in pregnancy. Reference: 2021/06/29/EDP/01.