18.03.4 Drugs used to Treat HIV/AIDS

There are two main classes of drug used to treat infections with the retrovirus HIV. These are the reverse transcriptase inhibitors and the protease inhibitors. The reverse transcriptase inhibitors can be nucleoside analogs or non-nucleoside analogs.

Because of the potential for resistance to develop to the available anti-retroviral drugs, the current guidelines are that combination treatment is always used. One such combination is known as HAART or Highly Active Anti-Retroviral Therapy. The HAART combination is two of the nucleoside reverse transcriptase inhibitors with EITHER a non-nucleoside transcriptase inhibitors OR one or two protease inhibitors. Drugs that inhibit the fusion (and therefore entry) of the HIV with the host cells are used when resistance develops to the other drugs. All of the currently HIV drugs cause adverse effects that can make it likely that patients will not want to take them. This means that often the treatment regimes are changed and developed for the individual patient to minimise the adverse effects and increase the likelihood that they will take them appropriately.

The first drug developed for the treatment of HIV was AZT, which is also known as azidothymidine and zidovudine. Zidovudine is a nucleoside reverse transcriptase inhibitor. These drugs prevent the synthesis of the provirus DNA from the viral RNA (see Section 18.3.1). Nucleosides analogs are phosphorylated by host cells to give triphosphate substrates which are then incorporated into the DNA chain by reverse transcriptase action.Zidovudine is an analog of the nucleoside thymidine, and substitutes for thymidine in this process. Thus zidovudine competes with the endogenous nucleosides for the reverse transcriptase, and, once incorporated into the DNA chain, leads to the termination of the formation of the provirus DNA.

Zidovudine is active after oral administration. One of the main disadvantages with zidovudine is that it has short half-life, which means that it has to be administered every 4 hours to be effective. In addition, , zidovudine is only selective, not specific, for the reverse transcriptase. The host mitochondrial γ-DNA polymerase is also inhibited by zidovudine, and this may underlie some of the side effects observed during zidovudine treatment. In the treatment of HIV/AIDS, zidovudine has been shown to prolong life. However, resistance develops to zidovudine, and this means it not effective alone, and has to be used in combination with other drugs.

There are some serious adverse effects with zidovudine, probably because it can substitute for thymidine in many actions in the body. Zidovudine causes bone marrow suppression leading to a decreased production of red blood cells (anaemia) and of the neutrophil white blood cells (neutropenia). Blood transfusions may be required to overcome both of these. Alternatively if anaemia is the main problem, this can be overcome by stimulating erythropoiesis (red blood cell formation) with epoetin (EPO). Zidovudine can also cause headache, which can be controlled with paracetamol.

Zidovudine and another nucleoside reverse transcriptase inhibitor are one part of the HAART treatment, and the other part is either a non-nucleoside reverse transcriptase inhibitor such as nevirapine or a protease inhibitor, such as ritonavir.

Nevirapine binds to retroviral reverse transcriptase and denatures it. Thus, nevirapine, like zidovudine, prevents the formation of the provirus DNA and the HIV replication. Nevirapine differs from zidovudine in that it does not need to be converted to an active triphosphate in order to have its action. Nevirapine is active after oral administration. It induces its own metabolism. Thus, with ongoing use it is necessary to increase the doses of nevirapine to maintain therapeutic plasma concentrations. Nevirapine is contraindicated in subjects with impaired liver function, as it can worsen the liver function. Importantly, in addition to being useful in HIV infection, nevirapine is also useful in preventing mother-to-baby transmission of the HIV. Thus, nevirapine should be given to pregnant women to stop them from infecting their foetus.

An example of a protease inhibitor is ritonavir. The translation of the provirus RNA by the host ribosomes leads to the production of polypeptides. These polypeptides are then acted on by viral proteases to give the structural proteins and active enzymes for the new virion. By inhibiting the viral proteases, ritonavir inhibits this process i.e. the replication of the virus. New viral particles are released, but they are not infective.

Ritonavir is active after oral administration. One major adverse effect with ritonavir is hyperglycemia. Thus, the subject with HIV treated with ritonavir can develop new diabetes, or if they are already diabetic, have a worsening of diabetes. Another serious adverse effect with ritonavir is that it causes hypertriglyceridemia and hypercholesterolemia, and thus the subject may have to be treated with lipid lowering drugs to prevent cardiovascular disease.

There are numerous drug interactions involving ritonavir as it inhibits the CYP enzymes (CYP3A) to increase levels of other drugs. For example, ritonavir increases the levels of amiodarone, amlodipine, buprenorphine etc, and these levels may reach toxic levels. Ritonavir may also be used in combination with other protease inhibitors to inhibit the CYP enzymes and reduce the metabolism of these drugs. In this way, it acts as a “pharmacokinetic booster”.

When the resistance to HAART is such that the HIV continues to progress, other drugs have to be used. The main one of these is enfuvirtide, which inhibits the fusion of the HIV with the host cell. Normally the virus binds to the host cell, and then enters the host cell. Enfuvirtide inhibits the binding.

Enfuvirtide is administered subcutaneously. Enfuvirtide is used in HIV infection when other antiretrovirals have failed to halt the HIV. It is common to get injection site reactions with enfuvirtide. Treatment with enfuvirtide is associated with an increased risk of bacterial pneumonia.