Clinical Pharmacology and Therapeutics

ANTI-HIV DRUGS 355
NON-NUCLEOSIDE ANALOGUE REVERSE
TRANSCRIPTASE INHIBITORS
The non-nucleoside analogue reverse transcriptase inhibitors
(NNRTIs) are used as part of triple-therapy schedules in combination
with nucleoside analogue RT inhibitors (e.g. ZDV/
3-TC). Agents in this group include efavirenz, nevirapine and
delavirdine. Efavirenz is administered orally and causes a
marked (50%) reduction in viral load during eight weeks of
therapy. They are synergistic with NRTIs. NNRTIs should
only be used in combination therapy due to the rapid development
of viral resistance.
Mechanism of action
Non-nucleoside agents inhibit HIV reverse transcriptase by
binding to an allosteric site and causing non-competitive
enzyme inhibition, reducing viral DNA production.
Adverse effects
These include the following:
• abdominal pain and nausea/vomiting/diarrhoea;
• lipodystrophy;
• arthralgia, myalgia;
• drug–drug interactions: complex effects on other CYP450
metabolized drugs (see below);
• neural tube defects in the fetus.
Pharmacokinetics
Efavirenz is well absorbed. It has a plasma t 1/2 of 40–60 hours,
is highly protein bound and metabolized by hepatic
CYP2B6 CYP3A) to its hydroxylated metabolite, which is
glucuronidated and excreted in the urine.
Drug interactions
Efavirenz inhibits CYP3A4, CYP2C9 and CYP2C19 and may
reduce the clearance of co-administered drugs metabolized by
these isoenzyme systems. Efavirenz autoinduces its own
metabolism. In contrast, nevirapine induces CYP3A and thus
increases the clearance of drugs metabolized by this isoenzyme.
Key points
Anti-HIV drugs – Non-nucleoside analogue reverse
transcriptase inhibitors (NNRTIs)
• Used in combination, because of synergy with NRTIs,
e.g. ZDV.
• Efavirenx, nevirapine and delavirdine are allosteric (noncompetitive)
inhibitors of the HIV reverse transcriptase.
• Oral absorption is good, hepatic metabolism by CYP3A
or 2B6, short–intermediate half-lives.
• Adverse effects include gastro-intestinal disturbances,
rashes and drug interactions.
• Resistance develops quickly; not to be used as
monotherapy.
HIV PROTEASE INHIBITORS
Uses
Compounds in this class include amprenavir, ritonavir, indinavir,
lopinavir, nelfinavir, saquinavir, atazanavir and
tipranavir (Table 46.3). They cause a rapid and marked reduction
of HIV-1 replication as measured by a fall of 100- to 1000-
fold over 4–12 weeks in the number of HIV RNA copies per mL
of plasma. Reductions in viral load are paralleled by increases
in CD4 count of approximately 100–150 cells/μL. Resistance is
a problem and leads to cross-resistance between protease
inhibitors (PIs), so they are used in combination therapy
(see Table 46.1).
Mechanism of action
These agents prevent HIV protease from cleaving the gag and
gag–pol protein precursors encoded by the HIV genome,
arresting maturation and blocking the infectivity of nascent
virions. The HIV protease enzyme is a dimer and has aspartylprotease
activity. Anti-HIV protease drugs contain a synthetic
analogue structure of the phenylalanine–proline sequence of
positions 167–168 of the gag–pol polyprotein. Thus they act as
competitive inhibitors of the viral protease and inhibit maturation
of viral particles to form an infectious virion.
Adverse effects
These include the following:
• nausea, vomiting and abdominal pain;
• fatigue;
• glucose intolerance (insulin resistance or frank diabetes
mellitus) and hypertriglyceridaemia;
• fat redistribution – buffalo hump, increased abdominal
girth;
• drug–drug interactions – complex effects on many other
drugs that are hepatically metabolized (see Chapter 13).
Key points
Anti-HIV protease inhibitors
• Used in combination, because of synergy with anti-HIV
RT inhibitors and reduced resistance.
• They competitively inhibit the HIV protease enzyme,
and are the most potent and rapid blockers of HIV
replication available.
• Oral absorption is variable, hepatic metabolism is
mainly by CYP3A.
• Boosted PI therapy involves combinations such as
lopinavir/ritonavir where low-dose ritonavir potentiates
the bioavailability of lopinavir by inhibiting
gastrointestinal CYP3A and P-glycoprotein (MDR1).
• Side-effects: include gastrointestinal upsets,
hyperglycaemia, fat redistribution and drug–drug
interactions.
• HIV resistance to one agent usually means crossresitance
to others in this class.