Classes of Anti-Retroviral Drugs for Treatment of HIV

PCL 12 - Alan and Bill
Amber Hartley

Treatment of HIV/AIDS
Guidelines and aims for treating doctors are:
 Monitor plasma viral load and CD4 cell count
 Start treatment before immunodeficiency becomes evident
 Aim to reduce plasma viral concentration as much as possible for as long as possible
 Use combinations of at least three drugs
 Change to a new regimen if plasma viral concentration increases

Anti-viral drugs (in general)

Most anti-virals fall into one of the following categories:
 Nucleoside analogues that inhibit reverse transcriptase
 Non-nucleoside analogues that inhibit reverse transcriptase
 Protease inhibitors
 Inhibitors of viral DNA polymerase
 Inhibitors of viral capsule disassembly
 Inhibitors of neuraminidase that prevent viral escape from infected cells
 Immunomodulators that enhance host defences
 Immunoglobulin and related preparations that contain neutralising antibodies to various viruses.

Anti-retroviral drugs (for HIV/AIDS treatment)

Two main classes of anti-retrovirals used to treat HIV:
 Reverse transcriptase inhibitors
o May be nucleoside or non-nucleoside
o Nucleoside RTIs compete with essential substrates for viral reverse transcriptase sites
o Non-nucleoside RTIs bind to reverse transcriptase enzyme near the catalytic site and denature it
 Protease inhibitors
o Inhibit cleavage of nascent viral protein into functional and structural proteins

Because these drug types have different mechanisms of action, they are used in combination – this has dramatically improved the prognosis of the disease.

Combination treatment may take the form of HAART (highly active anti-retroviral therapy). This usually involves two nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or one or two protease inhibitors. HAART can inhibit the replication of HIV, to the point of an undetectable viral load in plasma.
However, the HAART regimen is complex and has many unwanted side effects. Treatment is lifelong, because the virus is not eradicated by the therapy, but lies latent in host T cells, and will begin replication if therapy is halted.

Resistance to some anti-retrovirals has become a problem. In these cases, drugs may be changed in an effort to combat the problem, although this has limited success, and the replication of the HIV may recommence.

Treatment for pregnant/breast-feeding women
 Choice is difficult
 Main aims are to avoid damage to the foetus and prevent transmission of the disease to the newborn
 Often, zidovudine (a nucleoside reverse transcriptase inhibitor) is used alone











References:

Rang and Dale’s Pharmacology, 6e, 2007

Kumar and Clark, “Clinical Medicine”. 6e.

For explanatory videos, see http://www.youtube.com/watch?v=yYZgFndtfzc
http://www.youtube.com/watch?v=qYUnDzDO-Ic
http://www.youtube.com/watch?v=3n_MYZEfnxU
http://www.youtube.com/watch?v=2s-FKSICsz0
http://www.youtube.com/watch?v=2DzL8SQt_jo