HIV Pharmacology

HIV – or human immunodeficiency virus – is a lentivirus that causes HIV infection. Over time, this can lead to the development of AIDS, or acquired autoimmune deficiency syndrome. While there is no cure, treatment options are available.

There are two types of HIV – type 1 and type 2. Most cases of HIV are caused by the more virulent and more infective HIV type-1. Most cases of type 2 are confined to West Africa, with the strain being less virulent and less infective.

Without treatment, the average survival time from onset of HIV infection is 10 years.

HIV can be transmitted from mother to child through breast milk. It can also pass to the child during both pregnancy and childbirth – through infected blood or vaginal fluids.

Most HIV cases are caused through sexual means – via infected semen, blood, pre-ejaculate or vaginal fluids. Once in the body, HIV targets many cells that are integral to successful performance of the immune response. This includes T-helper cells, dendritic cells and macrophages, amongst others.

In 2016, there were 37 million cases of HIV/AIDS worldwide leading to 1 million deaths – most infected persons living in sub-Saharan Africa.

With these fundamental facts in mind, let’s review the major drug classes used to treat HIV/AIDS.

Pharmacology of HIV Drugs

There are five major drug classes used to treat HIV/AIDs – medicines also known as antiretroviral agents. Multiple drugs are often used as part of what’s referred to as HAART therapy – or highly active antiretroviral therapy.

For example – as part of “fixed-dose combinations”, multiple drugs are combined into a single pill. Some common fixed-dose combinations include:

    • Truvada – tenofovir disoproxil + emtricitabine
    • Atripla – tenofovir disoproxil + emtricitabine + efavirenz
    • Combivir – lamivudine + zidovudine
    • Stribild – elvitegravir + cobicistat + emtricitabine + tenofovir disoproxil
    • Epzicom – abacavir + lamivudine

The various antiretroviral drugs can be categorised into the following five classes:

    1. Nucleoside/nucleotide reverse transcriptase inhibitors – NRTIs / NtRTIs
    2. Non-nucleoside reverse transcriptase inhibitors – NNRTIs
    3. Protease inhibitors
    4. Integrase inhibitors
    5. Entry inhibitors – also known as fusion inhibitors

Below, we review the each of these antiretroviral drug classes – how they work, why they are used, and what side effects and drug interactions they are linked to. We also learn why some drugs are selected for specific fixed-dose combinations.

Let’s begin our review with one of the most well-known classes – reverse transcriptase inhibitors.

Reverse transcriptase inhibitors (RTIs)

There are three kinds of reverse transcriptase inhibitor:

    • Nucleoside – zidovudine, didanosine, stavudine, lamivudine, abacavir, emtricitabine
    • Nucleotide – tenofovir disoproxil
    • Non-nucleoside – efavirenz, nevirapine, etravirine, rilpivirine

Nucleoside and nucleotide RTIs are analogs of naturally occurring deoxynucleotides, whereas non-nucleoside RTIs are not.

Notenucleotide analog tenofovir can be recognised as “t” for tenofovir, “t” for “-tide”. All non-nucleoside drugs have “-vir-“ within their names.

Mechanism of action

Nucleoside and nucleotide RTIs compete with deoxynucleotides needed to synthesise viral DNA.

However, they have a structural difference – lacking a 3’-hydroxyl group. When incorporated into viral DNA, then, the viral deoxynucleotide cannot extend – a process known as chain termination.

Both nucleotide and nucleoside RTIs compete with host DNA as well as viral DNA, leading to their characteristic side effect profile (see below).

Nucleoside and nucleotide RTIs work very differently than non-nucleoside RTIs.

NNRTIs work by binding directly to the reverse transcriptase enzyme. Unlike NRTIs and NtRTIs, NNRTIs are not incorporated into viral DNA.

Side effects

Side effects with RTI medicines include:

    • GI effects – nausea, vomiting, upset stomach, diarrhea
    • Headache
    • Peripheral neuropathy – most common with didanosine

However, patients may experience more severe side effects, including:

    • Hepatic steatosis
    • Lipodystrophy – redistribution of body fat
    • CNS effects – depression, anxiety, dizziness
    • Reduced bone density
    • Lactic acidosis
    • Rarely, pancreatitis

Though many of these effects are rare, the student should be aware of the possibility.

Protease inhibitors

Protease inhibitors can be used to treat HIV and hepatitis C. Here though, we focus on the medicines used to treat HIV only.

Examples of protease inhibitors include:

    • Saquinavir – the first FDA-approved protease inhibitor
    • Amprenavir
    • Fosamprenavir
    • Atazanavir
    • Darunavir
    • Indinavir
    • Lopinavir
    • Nelfinavir
    • Ritonavir
    • Tipranavir

Note: All protease inhibitors end in the suffix -navir.

Protease inhibitors bind to viral proteases, such as HIV-1 protease, to stop viral replication. They also block production of essential protein precursors necessary to produce viral particles.

Side effects with protease inhibitors include:

    • Lipodystrophy
    • Diarrhea
    • Elevated blood sugar levels / insulin resistance
    • Hyperlipidemia
    • Kidney stones
    • Taste disturbances
    • Hepatic dysfunction
    • Jaundice
    • Rash

Protease inhibitors interact with a wide range of medicines, including:

    • Statins – increasing their toxicity
    • Anticoagulant drugs
    • Antidepressants
    • Antiepileptic medicines
    • Antibacterial drugs
    • Diabetes medicines – because they disturb blood sugar levels / insulin resistance
    • Protease inhibitors should be avoided at the same time as other OTC medicines that reduce stomach acid production – such as PPIs.
    • John’s wort should be avoided

Not all protease inhibitors are used for their intrinsic anti-HIV activity.

For example – though ritonavir has anti-HIV activity (albeit minimal), it is not used for this purpose. Instead, it is used as an enzyme inhibitor – inhibiting enzymes such as CYP 3A4 that metabolise other anti-HIV medicines. When ritonavir is taken alongside another HIV drug, then, a lower dose of the latter may be used whilst retaining its anti-HIV effects. Through this strategy, patients experience fewer side effects.

Ritonavir is not the only medicine used as an enzyme inhibitor. Cobicistat is also used to inhibit CYP 3A enzymes, often to boost the effect of the integrase inhibitor, elvitegravir (see below), as well as several other reverse transcriptase inhibitors.

Integrase inhibitors

As their name suggests, integrase inhibitors block the effects of the enzyme, integrase.

Integrase is a viral enzyme responsible for integrating viral DNA into the host DNA of infected cells.

Examples of integrase inhibitors include:

    • Raltegravir
    • Dolutegravir
    • Elvitegravir

Note: integrase inhibitors can be identified through the “-gravir” suffix.

As we learned above, elvitegravir is not taken in isolation. It is taken along the “booster” drug cobicistat, and alongside other drugs such as tenofovir and emtricitabine.

Similarly, dolutegravir is available in combination with other medicines – such as Triumeq, a combination of dolutegravir, abacavir and lamivudine.

Though integrase inhibitors are generally well tolerated, potential side effects include:

    • Difficulty sleeping
    • Fatigue
    • High blood sugar levels
    • Headache
    • Hepatic dysfunction
    • GI effects

As integrase inhibitors are chiefly metabolised by CYP 3A enzymes, strong inducers of this enzyme should be avoided – phenytoin, rifampicin, carbamazepine and St. John’s wort, for example.

Entry inhibitors

Entry inhibitors are the final class in our study of HIV pharmacology.

As their name suggests, entry inhibitors disrupt the ability of the HIV virus to enter cells. They target the binding, fusion and entry phases of viral integration into the target host cell.

The binding-fusion-entry sequence for the HIV virus is as follows. Below, we learn where entry inhibitors block this process.

    1. A HIV surface protein, gp120, binds to the CD4 receptor – a protein receptor found on the surface of T-helper cells.
    2. A conformational change in gp120 takes effect. This has two effects – it increases its affinity for a co-receptor – either CCR5 or CXCR4 – and exposes gp41.
    3. gp120 now binds to one of those receptors.
    4. gp41 now penetrates the cell membrane, establishing the fusion phase.
    5. The HIV virion now enters the host cell

Medicines approved as entry inhibitors include:

    • Maraviroc
    • Enfuvirtide

Maraviroc binds to CCR5, preventing gp120 from binding to this co-receptor. That is why maraviroc is also referred to as a CCR5 inhibitor.

Enfuvirtide binds to gp41 – to prevent fusion of the two membranes. That is why enfuvirtide is also referred to as a fusion inhibitor.

Maraviroc is taken orally, whereas enfuvirtide is taken via the subcutaneous route (SC).

Side effects with maraviroc include:

    • Flu-like symptoms
    • Upper respiratory tract infections
    • Cough
    • Difficulty breathing
    • Headache
    • Hepatic dysfunction
    • Weakness, fatigue, dizziness
    • Rash

Side effects with enfuvirtide include:

    • Injection site reactions
    • GI effects – diarrhea, nausea, abdominal pain, dry mouth
    • Metabolic – weight loss, decreased appetite
    • Fatigue
    • Flu-like symptoms
    • Peripheral neuropathy
    • Shortness of breath / wheezing

As we have learned over the course of this HIV pharmacology guide, HIV medicines are not taken in isolation. They are mostly taken as fixed-dose combinations and as part of long-term, defined plans. Some HIV medicines are taken to “boost” the effects of other medicines.

For even more facts and pharmacology quiz questions on HIV pharmacology, register with PharmaFactz today. Check back to our pharmacy blog soon for even more great articles on HIV medicine and the many other families of antiviral drugs.