Drugs to keep AIDS at bay

Point to note:
AIDS isn’t a single disease, it’s a syndrome of different symptoms seen together so frequently enough that they’re assumed to have a common cause.

 Zidovudine (t½ 1h)
This is also known as AZT (azidothymidine) and as ‘Retrovir’

HIV replicates by converting its single-stranded RNA into double stranded DNA, which then finds its way into the host’s DNA. This conversion uses the enzyme reverse transcriptase (it’s the reverse of the normal transcription of DNA to RNA). Zidovudine puts a spanner in the works by inhibiting viral reverse transcriptase. It’s converted from AZT into AZT-triphosphate (enzymes stick 3 phosphate groups on) and this gets incorporated into the viral DNA chain as it’s being made, causing premature chain termination. The drug has to be around continuously to stop the viral DNA getting into the host DNA. If the viral DNA does manage to get in, there’s nowt that zidovudine can do, I’m afraid.

Zidovudine is well absorbed from the GIT and is rapidly cleared from plasma. Concentrations in CSF are half those in plasma. It’s inactivated mainly by metabolism but 20% is excreted unchanged by the kidney.

Uses
It’s used at all the stages of HIV infection, even in early phases. 
AZT can suppress HIV production, temporarily reduce mortality and morbidity, and reduce the number and severity of opportunistic infections. CD4 cell count goes up and neurological and mental symptoms improve a lot too.

Adverse reactions
Early in treatment, it may cause anorexia, nausea, vomiting, headache – but tolerance usually develops and the dose doesn’t need to be lowered.
When the dose is high and when the disease is advanced, anaemia and neutropenia ( in neutrophils in blood) might develop. Oh, and if you use it for a long time you might get myopathy too. Some of these side effects (like the anaemia) are because AZT-triphosphate also inhibits our cells’ DNA polymerase (the enzyme that replicates DNA) as well – although not as much as it inhibits reverse transcriptase (20-30 times less).

 Other Drugs
Other reverse transcriptase inhibitors like dideoxyinosine (ddI) and dideoxycytidine (ddC) and lamivudine (3Tc) can be used, often in combination with zidovudine. Because HIV mutates so quickly, and you’re stopping the viruses that can be stopped, you’re actually generating a selection pressure for a resistant strain. Using zidovudine alone brings about resistance in about 12-18 months. With combination therapy, it’s much more difficult to come up with a strain that’s resistant to both drugs being used.

Protease inhibitors are a new class of drugs against HIV. To make more viruses, HIV produces a protein and a protease. The protease chops up the protein into component parts that can then be reassembled to make the virus particles. If you stop the protease, you stop new particles being made. These drugs have been shown to reduce viral RNA, increase CD4 counts and improve survival (compared to placebo)

Comment
In general it’s probably best to give the drugs to patients earlier in the HIV infection as well as to prevent opportunistic infection in later stages. Now that there are drugs are coming on the scene that may prolong the lives of patients more significantly, it raises another question: what about patients with cancers? In the past, AIDS patients didn’t die from the cancers. If patients were to live longer, cancer (like Kaposi’s sarcoma) would become an issue. And another thing: the drugs taken for chemotherapy may not be compatible with the HIV drugs. It would therefore be better to give treatment early to prevent the disease from developing into the stage when cancers start appearing.

Other points
•	Pneumocystis carinii pneumonia (PCP) can be treated with co-trimoxazole, which is a combination of sulphonamide and trimethoprim (if you can’t remember these, we did them in Semester 1!). An alternative drug is pentamidine, which can be squirted straight into the lungs.
•	Candida infections can be treated with nystatin. Other drugs (in no particular order) that may be useful are: amphotericin, fluconazole, ketoconazole and miconazole.
•	Kaposi’s sarcoma (KS) is more common in AIDS patients who managed to get HIV sexually than in those who were infected by blood or blood products. They’ve done some molecular microbiological techniques (yeah, it’s a long phrase to read and a pain to type in) and found a new human herpes virus (HHV8) in patients with KS.
•	Cachexia (that’s weight loss and weakness to you and me) is caused by macrophages going a bit nutty when they get infected and releasing loads of cytokines.
•	AIDS dementia complex (ADC) is probably brought about by a variety of factors. First, the microglial cells in the brain can get infected (possibly by a roving macrophage infected with HIV). HIV don’t infect neurons but it’s been shown that HIV and its component proteins are toxic to nerve cells. Another factor is that when the CD4 T cells and macrophages are themselves infected by a pathogen, they release cytokines all over the place. Cytokines have various effects on the brain (e.g. IL-1 is endogenous pyrogen and causes fever), and if infected cells are releasing this stuff all over the body, it can lead to brain “meltdown”.

References:
At War Within by William R. Clark (pp. 135-173)
Clinical Pharmacology (8th Edition) by Laurence, Bennett and Brown (p233).
Basic & Clinical Pharmacology (5th Edition) by Katzung  (p679).

“Make quick the remedy.”
-	advice an elderly chap gave to me during 
my stint as a hospital voluntary worker
(wish I’d followed it more often though!)