Clinical Pharmacology and Therapeutics

ANTI-HIV DRUGS 353
Table 46.1: Examples of combinations to be used as initial anti-HIV drug
therapy a
Two nucleoside analogues
HIV protease inhibitor
Two nucleoside analogues
non-nucleoside reverse
transcriptase inhibitor
Three nucleoside reverse
transcriptase inhibitors
e.g. ZDV 3-TC or
FTC Lop/rit
e.g. ZDV or TDF 3-TC or
FTC Efav or Nvp
e.g. ABC ZDV 3-TC
ABC, abacavir; ZDV, zidovudine; FTC, emtracitabine; 3-TC, 3-thiacytidine
(lamivudine); d4T, didehydrothymidine (stavudine); Lop, lopinavir; rit,
ritonovir; Efav, efavirenz; Nvp, nevirapine; TDF, tenofovir.
a Combinations 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 ZDV d4T and
3-TC ddC are avoided. ddC 2 3-dideoxycytidine, also known as
zalcitabine).
specialist care. Current principles emphasize combination therapy,
regime convenience, tolerability and lifelong therapy. Anti-
HIV therapy is a complex therapeutic arena, necessitating
specialist supervision.
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. ZDV 3-TC amprenavir (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 progression
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
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 intracellular
t 1/2 of ZDV-TP is two to three hours. ZDV-TP is a competitive
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 t 1/2 is 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.