A Textbook of Clinical Pharmacology and Therapeutics

ANTI-HIV DRUGS 353

specialist care. Current principles emphasize combination ther-
apy, regime convenience, tolerability and lifelong therapy. Anti-
HIV therapy is a complex therapeutic arena, necessitating
specialist supervision.

reduce HIV-1 viral replication as indicated by plasma HIV

RNA load.

ZIDOVUDINE (AZIDOTHYMIDINE)

This was originally synthesized in 1964 in the hope that it

would be useful in treating malignancies. These hopes were

not fulfilled, but it was the first nucleoside analogue effective

in treating HIV-1 infection.

Use

Zidovudine (ZDV) is given orally to patients with HIV

infection.

Mechanism of action

The parent drug, ZDV, enters virally infected cells by diffusion

and undergoes phosphorylation first to its monophosphate

(ZDV-MP) then to the diphosphate (ZDV-DP), the rate-limiting

step, and finally to the triphosphate (ZDV-TP). The intracellu-

lart1/2of ZDV-TP is two to three hours. ZDV-TP is a competi-

tive inhibitor of the HIV-1 reverse transcriptase and when

incorporated into nascent viral DNA causes chain termination.

Human cells lack reverse transcriptase and human nuclear

DNA polymerases are much less sensitive (by at least 100-fold)

to inhibition by ZDV-TP, thus producing a selective effect on

viral replication. This mechanism of action is common to all

anti-HIV nucleoside analogues.

Adverse effects

These include the following:

• dose-dependent bone marrow suppression causing
  anaemia with reticulocytopenia and granulocytopenia.
  This occurred in 15% of patients in the original studies
  with high-dose ZDV. At currently recommended doses, it
  occurs in only 1–2% of patients;


• nausea and vomiting;


• fatigue and headache;


• melanonychia (blue-grey nail discoloration);


• lipodystrophy;


• mitochondrial myopathy (uncommon);


• hepatic steatosis with lactic acidosis (rarely);


• it is mutagenic and carcinogenic in animals. However,
  ZDV is used in HIV-positive pregnant women as it
  reduces HIV maternal–fetal transmission and thus
  fetal/neonatal HIV-1 infection and has not been shown to
  be teratogenic if given to women after the first trimester.

Pharmacokinetics

Zidovudine is almost totally absorbed (90%) from the

gastro-intestinal tract, it achieves cerebrospinal fluid (CSF)

concentrations that are 50% of those in plasma. The ZDV

plasma elimination t1/2is one to two hours. About 25–40% of

a dose undergoes presystemic metabolism in the liver. The

major metabolite (80%) is the glucuronide and approximately

20% of a dose appears unchanged in the urine.

Table 46.1:Examples of combinations to be used as initial anti-HIV drug
therapya

Two nucleoside analogues e.g. ZDV3-TC or

HIV protease inhibitor FTCLop/rit

Two nucleoside analogues e.g. ZDV or TDF3-TC or

non-nucleoside reverse FTCEfav or Nvp

transcriptase inhibitor

Three nucleoside reverse e.g. ABCZDV3-TC

transcriptase inhibitors

ABC, abacavir; ZDV, zidovudine; FTC, emtracitabine; 3-TC, 3-thiacytidine
(lamivudine); d4T, didehydrothymidine (stavudine); Lop, lopinavir; rit,
ritonovir; Efav, efavirenz; Nvp, nevirapine; TDF, tenofovir.
aCombinations usually include ZDV or d4T because they have better CSF
penetration than other nucleoside analogues and combinations attempt
to avoid overlapping toxicities, and to avoid using agents that are
phosphorylated by the same enzymes (combinations of ZDVd4T and
3-TCddC are avoided. ddC  2 3-dideoxycytidine, also known as
zalcitabine).

Key points

General guidelines for anti-HIV-1 therapy

• Treat before significant immunosuppression develops.


• BHIVA treatment criteria are CD4 count (if 350/ L) or
  symptoms or in USA HIV RNA 100,000 copies/mL plus
  CD4 350/ L.


• Standard therapy is highly active antiretroviral therapy
  (HAART) combination therapy.


• HAART is two nucleoside analogue inhibitors plus one
  protease inhibitor, e.g. ZDV3-TCamprenavir (or
  lopinavir/ritonavir).


• If there is drug treatment failure or resistance, change
  at least two and preferably all three drugs being used.


• The revised regimen may be guided by genotyping of
  the HIV genome for mutations associated with drug
  resistance.

ANTI-HIV DRUGS

NUCLEOSIDE ANALOGUE REVERSE

TRANSCRIPTASE INHIBITORS (NRTIs)

Of these agents, only zidovudine(ZDV) has been proved to
reduce mortality in late-stage AIDS. It reduces the incidence of
opportunistic infections and possibly also the rate of progres-
sion of HIV-1 infection to AIDS. Other members of the class
include lamivudine (3-TC), stavudine (d4T),didanosine
(ddI),emtricitabine(FTC) and abacavir(ABC). These drugs
are used in combinations and are available as combined
products, e.g. 3-TC/ZDV, ABC/3-TC, ZDV/tenofovir. They