Today we’re looking at the pharmacology of HIV drugs – including reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, integrase inhibitors and – finally – viral DNA polymerase inhibitors. Obviously this is quite an extensive range of drugs, and so this section only serves as an introduction to what is a complex topic. We’ll address this section by going through each drug class – starting with their mechanism of action, before proceeding onto their pharmacokinetics and unwanted effects. Each class works by inhibiting the growth and replication power of the virus in some capacity – only they achieve this in different, often complementary ways.

Pharmacology of HIV Drugs

In this section, we will go through the main classes, types, and mechanisms of action of the following drugs:

  1. HIV reverse transcriptase inhibitors
  2. Protease inhibitors
  3. Entry inhibitors
  4. Integrase inhibitors
  5. Viral DNA polymerase inhibitors

The section is not intended to be exhaustive, and is only designed to introduce you – the student – to how these drugs work, and why they are used in clinical practice. Many of these drugs are used together – in combination – in the treatment of HIV.

1. HIV Reverse Transcriptase Inhibitors

There are two types of reverse transcriptase inhibitor: nucleoside and non-nucleoside.

Nucleoside RTIs include abacavir, emtricitabine, lamivudine, tenofovir, and zidovudine. They inhibit RNA viral replication by reversibly inhibiting the viral enzyme, HIV reverse transcriptase – an enzyme otherwise responsible for assisting the insertion of viral DNA into the host DNA sequence. RTIs are activated by phosphorylation inside the virus to the 5’-triphosphate form. Nucleoside RTIs are, as their name suggests, analogues of natural purines and pyrimidines.

For example, zidovudine is an analogue of thymidine, whereas emtricitabine and lamivudine are analogues of cytidine. Resistance can occur rapidly after taking RTIs – usually within weeks. They are completely absorbed from the gut. Abacavir, didanosine, and zidovudine are eliminated by hepatic metabolism, and have short half-lives between 1-2 hours. Emtricitabine and tenofovir are primarily eliminated by the kidney and half-lives between 2-16 hours.

Unwanted effects with nucleoside RTIs can be severe, often leading to discontinuation. For example, it’s not uncommon for patients to experience:

  • Neutropenia and anaemia (common)
  • Nausea, vomiting, diarrhoea
  • Muscle pain
  • Insomnia, headache
  • Hepatomegaly
  • Pancreatitis
  • Lipodystrophy

Drugs used in HIV

Non-nucleoside RTIs include drugs such as efavirenz, nevirapine, and etravirine. They work to inhibit HIV reverse transcriptase by producing a conformational change in the enzyme that prevents substrate binding. They are better tolerated and have greater activity than nucleoside RTIs, but resistance can still occur. Efavirenz and nevirapine are metabolised by hepatic CYP3A4 (while also inducing the enzyme), and have long half-lives of up to 2 days.

Nevirapine has excellent oral absorption, in contrast to efavirenz which is somewhat more variable. Up to 10 percent of patients may experience a severe rash with nevirapine, and hepatotoxicity also remains a consistent risk. Other unwanted effects with non-nucleoside RTIs include nausea, vomiting, diarrhoea, and abdominal discomfort. Some patients experience drowsiness, fatigue, and headache.

2. Protease inhibitors

The next class in our pharmacology of HIV drugs is protease inhibitors – drugs which are also used in the treatment of hepatitis C. Examples of protease inhibitors include atazanavir, lopinavir, and ritonavir. Viruses need to cleave polyproteins to their active protein counterparts, a process carried out by proteases. By inhibiting proteases, these drugs repress the infectiousness of the virus, but do not affect existing viral activity in infected host cells.

Resistance, as always, remains a problem. It can occur through mutation of the amino acid sequence of the HIV protein (the target for the enzyme). However, more than one mutation is required to establish resistance. What’s more, patients taking more than one protease inhibitor increase the likelihood of this resistance. All protease inhibitors are metabolised by CYP3A4, and have half-lives ranging from 2-10 hours.

Ritonavir is not used for any intrinsic physiological effect, rather it is used as a ‘booster’. In other words, low dose ritonavir can be administered to inhibit CYP3A4, meaning it boosts the activity of other protease inhibitors that are metabolised by this enzyme. Ritonavir also inhibits the metabolism of other drugs – such as warfarin and carbamazepine. There’s also an increased risk of myopathy in patients taking both ritonavir and simvastatin.

Unwanted effects with protease inhibitors include:

  • Nausea, vomiting, diarrhoea, abdominal discomfort
  • Hepatic disturbances
  • Lipodystrophy
  • Pancreatitis

3. Entry inhibitors

There are two main entry inhibitors used in clinical practice: enfuvirtide and maraviroc.

As the name suggests, entry inhibitors prevent HIV entry into cells. In order for HIV to enter cells, the virus must first fuse with the host cell membrane – something which is facilitated by a conformational change in a glycoprotein. Enfuvirtide (en- for entry) binds to this glycoprotein, preventing that conformational change from taking place. The drug is not widely used, except when resistance to other HIV drugs has establishes. Unwanted effects with entry inhibitors include injection site reactions, pancreatitis, GERD, peripheral neuropathy, tremor, anxiety, and nightmares.

Maraviroc is a CCR5 co-receptor antagonist. It is a negative allosteric modulator of the CCR5 receptor, a receptor integral to the successful binding of HIV to the host cell. Maraviroc is usually used alongside other HIV drugs. It is only partly absorbed from the gut and is mostly metabolised by the liver. It has a long half-life of around 16 hours. Common side effects include gastrointestinal disturbances, cough, dizziness, and paraesthesia.

HIV Mindmap

4. Integrase inhibitors

The penultimate drug class in our pharmacology of HIV drugs is integrase inhibitors – the principal members of which include raltegravir (-teg-, -in-teg-rase) and dolutegravir. Once HIV enters a cell, it seeks to incorporate – or integrate – itself into the host DNA, something that HIV integrase helps to being about. Integrase inhibitors work by inhibiting viral integrase, and preventing DNA strand transfer.

Raltegravir is well absorbed from the gut. It is mostly eliminated via the biliary route after undergoing glucuronide conjugation, and has a half-life of around 10 hours. Common unwanted effects include nausea, diarrhoea, headache, and fever. Insomnia and headache are also quite common with dolutegravir. A small minority of patients experience allergic reactions or may experience abnormal liver function.

5. Viral DNA polymerase inhibitors

The final drug class in our HIV pharmacology study is viral DNA polymerase inhibitors. There are two sub-types of DNA polymerase inhibitors:

  • Nucleoside analogue
  • Non-nucleoside analogue

Examples of nucleoside analogues include aciclovir, ganciclovir, valaciclovir, and valganciclovir. They are guanosine analogues that inhibit the synthesis of viral DNA, but who only become active on phosphorylation. Aciclovir is mostly active against herpes viruses, and is only active against CMZ at high doses. It can be administered orally, intravenously, or topically (absorption from the gut is poor).

Valaciclovir has better oral bioavailability than aciclovir (it is an ester of aciclovir). Ganciclovir is, in contrast, given via the intravenous route for acute infections. Valganciclovir is a prodrug of ganciclovir, and has yet better absorption. Unwanted effects are mostly seen with intravenous use and include phlebitis, nausea, vomiting, rash, encephalopathy, nephrotoxicity, and bone marrow suppression (with ganciclovir).

Examples of non-nucleoside analogues include cidofovir and foscarnet sodium. Foscarnet is an inorganic pyrophosphate compound that binds to the sites of the same name on viral DNA polymerase – preventing chain elongation. Cidofovir works in a similar way to foscarnet – and neither require intracellular activation (unlike nucleoside analogues). These two drugs are also reversible inhibitors in the replication of CMV and herpes simplex.

Both drugs are highly polar, meaning they can only be administered intravenously. They are eliminated through the kidney and have half-lives of around 4 hours. Cidofovir is administered with probenecid in order to inhibit renal tubular secretion of cidofovir and reduce its nephrotoxic potential. Unwanted effects include but are not limited to nausea, vomiting, neutropenia, headache, tremor, dizziness, mood swings (foscarnet), nephrotoxicity, and uveitis (cidofovir).

That’s about it for our study of the pharmacology of HIV drugs. Why not test your knowledge of the pharmacology of HIV drugs with this quiz – ten questions covering just about everything we’ve covered in this article.

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