A Textbook of Clinical Pharmacology and Therapeutics

OPPORTUNISTICINFECTIONS INHIV-1-SEROPOSITIVEPATIENTS 357

FUSION INHIBITORS

Uses

Currently, enfuvirtide is the only available HIV fusion
inhibitor. This agent is reserved for HIV patients who have
evidence of progressive HIV replication despite HAART ther-
apy. It is a 36 amino acid peptide analogue of part of the trans-
membrane region of gp41 that is involved in the fusion of the
virus particle with the host cell membranes. It is given subcu-
taneously on a twice daily basis.

Mechanism of action

The peptide enfuvirtideblocks the interaction between the
HIV gp41 protein and the host cell membrane by binding to a
hydrophobic groove in the N36 region of gp41. Due to this
unique mechanism of action, enfuvirtideis active against HIV
which has developed resistance to HAART. Resistance to
enfuvirtidecan arise by mutations in its gp41 binding site.

Adverse effects

These include:

• injection site reactions – pain, erythema, induration (98%
  of patients) and nodules; approximately 5% of patients
  discontinue therapy because of these local skin
  reactions;


• lymphadenopathy;


• flu-like syndrome;


• eosinophilia;


• biochemical hepatitis.

Pharmacokinetics

Enfuvirtideis well absorbed after subcutaneous administra-
tion and is distributed in the plasma volume, with 98% bound
to albumin. The plasma t1/2is three to four hours. The major
route of clearance is unknown.

Drug interactions

Enfuvirtideis not known to cause drug–drug interactions
with other anti-HIV drugs.

CHANGING ANTI-HIV THERAPY FOR TREATMENT

FAILURE AND/OR RESISTANCE

A change in anti-HIV therapy may be required because of
treatment failure, adverse effects, poor compliance, potential
drug–drug interactions or current use of a suboptimal regi-
men. Viral resistance to NRTIs and NNRTIs and protease
inhibitors may cause treatment failure. Reduced susceptibility
of HIV-1 isolates to NRTIs/NNRTIs and PIs is developing.
Genetic testing of the HIV genome for mutations leading to
drug resistance in isolates from individual patients is becom-
ing more widely available and may guide therapy. Resistance
to ZDV emerges more quickly and to a greater degree in the
later stages of the disease. Progressive stepwise reductions in

susceptibility of the HIV reverse transcripase (RT) correlate

with the acquisition of mutations in the gene for the RT protein.

In the case of ZDV, the only cross-resistance is to other nucle-

osides with the 3-azido side-chain and therefore such isolates

are still sensitive to 3-TC, d4T/ddI.

Future prospects include more potent protease inhibitors,

novel entry inhibitors e.g. maraviroc, HIV-integrase inhibitors

e.g.raltegravirand effective anti-HIV vaccines.

OPPORTUNISTIC INFECTIONS

IN HIV-1-SEROPOSITIVE PATIENTS

PNEUMOCYSTIS CARINII

In moderate to severe Pneumocystis cariniipneumonia (PCP)

(arterialPO 2

 60 mmHg), treatment consists not only of anti-

Pneumocystistherapy but, in addition, involves the use of gluco-

corticosteroids. This reduces the number of patients who require

mechanical ventilation and improves survival.

CO-TRIMOXAZOLE

High-doseco-trimoxazole(Chapter 43) is first-line therapy for

PCP in patients with HIV infection. It is given in divided doses

for 21 days. Initial treatment is intravenous; if the patient

improves after five to seven days, oral therapy may be substi-

tuted for the remainder of the course. The major adverse effects

of this therapy are nausea and vomiting (which is reduced by

the prior intravenous administration of an anti-emetic), rashes,

hepatitis, bone marrow suppression and hyperkalaemia.

Treatment may have to be discontinued in 20–55% of cases

because of side effects and one of the alternative therapies listed

below substituted. After recovery, secondary prophylaxis with

oralco-trimoxazole(one double strength tablet two or three

times daily) is preferred to nebulized pentamidine, as it reduces

the risk of extrapulmonary, as well as pulmonary relapse.

Dapsoneis also effective for secondary prophylaxis.

PENTAMIDINE

Uses

This is an aromatic amidine and is supplied for parenteral use

aspentamidine isetionate. It has activity against a range of

pathogenic protozoa, including P. carinii, African trypanoso-

miasis (Trypanosoma rhodesienseandT. congolese) and kala-azar

(Leishmania donovani).

Mechanism of action

Pentamidinehas a number of actions on protozoan cells. It

damages cellular DNA, especially extranuclear (mitochondr-

ial) DNA and prevents its replication. It also inhibits RNA

polymerase and, at high concentrations, it damages mitochon-

dria. Polyamine uptake into protozoa is also inhibited by

pentamidine.P. cariniiis killed even in the non-replicating

state.