Antiretroviral therapy (anti-HIV drugs)

• Introduction to antiretroviral therapy
• What are antiretrovirals?
• How do they work?
• Nucleoside reverse transcriptase inhibitors (NRTIs)
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Protease inhibitors (PIs)
• New antiretrovirals
• When to start antiretroviral therapy
• What to start for antiretroviral therapy
• Limitations of HAART
• Side effects
• Conclusion

Introduction to antiretroviral therapy

Antiretrovirals (ARVs) are the cornerstone of HIV/AIDS management, as there is currently no cure nor vaccine available for HIV. If an individual with a non-resistant strain of HIV takes the appropriate antiretroviral treatment as directed, the replication of HIV will be effectively suppressed in about 80% of cases. Some individuals may have trouble tolerating ARV treatment due to side effects, or they may not work effectively for that individual, requiring them to change to a second- or third-line treatment regimen. If individuals do not take the medication as directed (for example, taking it occasionally or intermittently), it can increase the likelihood of resistance, where the HIV strain adapts to the treatment and make ARV medications ineffective.

ARVs have been consistently proven to reduce death due to HIV/AIDS and to reduce the development of AIDS-defining conditions. These AIDS-defining conditions are a range of infections, cancers and illnesses that can occur due to advanced stages of HIV infection. An ART regimen should be selected by a specialist doctor in consultation with the individual who has HIV. This ensures that ARV treatments are personalised to the individuals’ HIV strain (and any resistance it may have), as well as considering treatment effectiveness, toxicity, possible side effects, tolerability, dosing frequency, interactions with other medications or illnesses, financial cost and individual preferences.

What are antiretrovirals?

Antiretroviral medications are a group of drugs that inhibit different steps in the HIV replication process. In this way, they can suppress HIV infection but never entirely eliminate it from the body. There are four categories of ARV medications:

• Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs);
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs);
• Protease inhibitors (PIs) (often ritonavir-boosted); and
• Drugs that interfere with viral entry, such as fusion inhibitors and CCR5 antagonists.

Illnesses and deaths associated with HIV have been substantially reduced in recent decades, following the widespread introduction of ARVs. As a result, quality of life and the lifespan of people living with HIV has improved significantly. The World Health Organisation (WHO) recommends the use of certain combinations of ARV drugs for the optimal suppression of HIV infection, known as Highly Active Anti-Retroviral Therapy (HAART).

How do they work?

HIV is a RNA virus that uses a range of viral enzymes to incorporate itself into human DNA within certain types of immune cells. Once present in the DNA strand, HIV can use the cell’s own mechanisms to create more HIV viral particles, to infect more human immune cells.

HIV binds to receptors (such as CD4, CCR5 and CXCR4) on the surface of human immune cells, primarily CD4+ T-helper immune cells (called CD4+ cells) that fight infections. The HIV virus then gains entry into the cell cytoplasm, where an enzyme called viral reverse transcriptase creates viral DNA from HIV RNA. This DNA moves into the cell nucleus, where it is incorporated into the human DNA strand by way of viral integrase. As normal cellular DNA transcription takes place, the HIV DNA within the human strand is also transcribed, producing HIV-derived mRNA. This mRNA is then translated into the proteins required to generate more HIV viral particles by viral protease.

If this process is left unchecked, the HIV infection will rapidly spread amongst all CD4+ immune cells, eventually exhausting their activity and destroying them. These cells are critical to the human immune defences against a range of other pathogens – their loss renders the human body vulnerable to a number of cancers, infections and diseases.

ARV drugs work by inhibiting the various viral enzymes critical to the HIV replication cycle, specifically reverse transcriptase, integrase and protease, from which the ARV drug names are drawn.

Nucleoside reverse transcriptase inhibitors (NRTIs)

Reverse transcriptase inhibitors were the first generation of ARV drugs licensed for the treatment of HIV infection. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) block the HIV replication cycle by inhibiting viral reverse transcriptase, an essential enzyme for the generation of HIV DNA. These drugs are generally used in combination with other ARV drugs. Using these drugs alone can promote the evolution of drug resistant strains of HIV.

Examples of NRTIs are:

• Zidovudine (e.g. Retrovir);
• Didanosine (e.g. Videx EC);
• Stavudine (e.g. Zerit);
• Lamivudine (e.g. 3TC, Lamivudine RBX, Zefix, Zetlam);
• Abacavir (e.g. Ziagen);
• Emtricitabine (e.g. Emtriva); and
• Tenofovir (e.g. Viread).

For more information, see Nucleoside reverse transcriptase inhibitors (NRTIs).

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are structurally similar to NRTIs. However, they bind to a different site on the viral reverse transcriptase enzyme, inhibiting its activity.

Examples of NNRTIs include:

• Nevirapine (e.g. Viramune XR);
• Rilpivirine (e.g. Edurant);
• Efavirenz (e.g. Stocrin); and
• Etravirine (e.g. Intelence).

For more information, see Non-Nucleotide Reverse Transcriptase Inhibitors (NNRTIs).

Protease inhibitors (PIs)

These ARV medications inhibit the activity of another viral enzyme, HIV protease, which is required to assemble more HIV particles. This prevents further virus particles from forming and infecting other cells. PIs suppress HIV replication in the majority of cases when combined with reverse transcriptase inhibitors. However, if these medications are used alone to treat HIV, resistant strains will emerge relatively quickly. They are therefore only ever used as part of a HAART combination regimen. The PI drug ritonavir also has the ability to slow down the breakdown of other PI drugs. Therefore, PI drugs are often combined with a low dose of ritonavir (called “ritonavir-boosted”) to prolong their activity.

Examples of PIs include:

• Saquinavir (e.g. Invirase);
• Indinavir (e.g. Crixivan);
• Ritonavir (e.g. Norvir);
• Amprenavir (e.g. Agenerase);
• Fosamprenavir (e.g. Telzir);
• Lopinavir (e.g. Kaletra);
• Atazanavir (e.g. Reyataz);
• Tipranavir (e.g. Aptivus); and
• Darunavir (e.g. Prezista).

For more information, see Protease Inhibitors (PIs).

New antiretrovirals

The newer ARV drugs use different mechanisms to arrest the HIV replication cycle.

These include drugs that interfere with HIV entry into human immune cells, known as entry inhibitors or fusion inhibitors. For HIV to enter cells, it binds to human cellular co-receptors, such as CCR5 and CXCR4, to allow entry. Many of these drugs are still in clinical trials and are not yet approved or recommended for human use. The first drugs in this class licensed for use were the fusion inhibitor enfuvirtide (e.g. Fuzeon), and a CCR5 antagonist, maraviroc (e.g. Celsentri). They are licensed for use in cases of HIV where other HAART regimens have failed.

Another class of antiretrovirals drugs is also in development, known as the integrase inhibitors. Examples of integrase inhibitors includes raltegravir (e.g. Isentress) and elvitegravir. Research suggests these drugs have a wide range of activity against HIV, including those with multiple resistance mutations, but trials are still ongoing.

When to start antiretroviral therapy

The World Health Organisation (WHO) recommends that all adults and adolescents with HIV commence ARV treatment when their CD4 cells counts reach or fall below 350 cells/mm³. They also strongly recommend that all patients who develop any of a predefined list of serious HIV-related illnesses or conditions should immediately start ARV treatment, regardless of their CD4+ cell count.

The goals of treatment with HAART is to not only prolong the life of HIV-infected individuals (i.e. reduce the risk of death) but also to preserve and enhance the immune system. This reduces HIV-associated or AIDS-defining conditions, such as infections and certain cancers. HAART can suppress HIV replication and therefore prevent disease progression, reducing serious HIV-related illnesses and improving quality of life.

What to start for antiretroviral therapy

The WHO recommends the use of two NRTIs with one NNRTI in ART-naïve patients who meet the criteria for treatment.

Recommended first-line HAART regimens are:

• Zidovudine plus lamivudine, plus either efavirenz or nevirapine;
• Tenofovir plus either lamivudine or emtricitabine, plus either efavirenz or nevirapine.

For some patients, these regimens will fail. Failure is determined by blood tests to assess the level of HIV replication. In these cases (or if individuals are unable to take first-line ARV treatment for another reason), the WHO recommends using a ritonavir-boosted protease inhibitor, plus two NRTIs for second-line treatment.

It is very important to only commence or change ARV medications in consultation with a specialist doctor, as certain combinations can be dangerous or lead to resistance emerging.

Some ARV medications are safe to use in pregnancy. It is important for pregnant mothers to take ARV drugs to not only improve their own health, but also to prevent transmission of HIV to the baby. If the woman is in the first trimester of pregnancy, efavirenz should not be used.

WHO recommends starting one the following regimens in ART-naïve pregnant women:

• Zidovudine plus lamivudine, plus either efavirenz or nevirapine; or
• Tenofovir plus either lamivudine or emtricitabine, plus either efavirenz or nevirapine.

Limitations of HAART

HAART is not curative and individuals with HIV will need to take it for the rest of their lives. Taking ARV drugs intermittently or occasionally will lead to the development of HIV resistance, which can then limit the number of ARV drugs that can be used in the future. ARV medications all have a number of side effects (some potentially serious), which may also make it difficult for people to take. People on HAART should be regularly followed up by a doctor, ideally within a specialist HIV/AIDS service.

Side effects

Like many medications ARVs are not without side effects. Most of the common side effects are mild and manageable, while some are severe, warranting stopping of therapy and moving to an alternate regimen. Examples of mild side effects include headache, nausea, fatigue, diarrhoea, abdominal pain, fever and rash. Examples of more severe side effects associated with ARVs include acute pancreatitis, hypersensitivity reactions, lactic acidosis, Stevens-Johnson syndrome and lypodystrophy.

Conclusion

The effectiveness of ARVs against HIV has increased tremendously in the last decade and their worldwide availability has vastly improved. Clinical trials of ARVs are still ongoing, particularly exploring new generation ARVs and the relative risks and benefits of different combinations of these.

The appropriate regimen for HIV treatment should be individualised, depending on a person’s medical history, other illnesses, prior treatments, disease stage and personal preferences. Individuals with HIV should be extensively counselled on the implications of living with HIV infection, as well as the benefits and potential side effects of ARV regimens.

References

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