A Textbook of Clinical Pharmacology and Therapeutics

NON-NUCLEOSIDE ANALOGUE REVERSE

TRANSCRIPTASE INHIBITORS

The non-nucleoside analogue reverse transcriptase inhibitors
(NNRTIs) are used as part of triple-therapy schedules in com-
bination with nucleoside analogue RT inhibitors (e.g. ZDV/
3-TC). Agents in this group include efavirenz,nevirapineand
delavirdine.Efavirenzis 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 devel-
opment 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

Efavirenzis well absorbed. It has a plasma t1/2of 40–60 hours,
is highly protein bound and metabolized by hepatic
CYP2B6CYP3A) to its hydroxylated metabolite, which is
glucuronidated and excreted in the urine.

Drug interactions

Efavirenzinhibits 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, nevirapineinduces CYP3A and thus
increases the clearance of drugs metabolized by this isoenzyme.

HIV PROTEASE INHIBITORS

Uses

Compounds in this class include amprenavir,ritonavir,indi-

navir, lopinavir, nelfinavir, saquinavir, atazanavir and

tipranavir(Table 46.3). They cause a rapid and marked reduc-

tion 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 aspartyl-

protease 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 matu-

ration 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).

ANTI-HIV DRUGS 355

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 (non-
  competitive) 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.

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 cross-
  resitance to others in this class.