A Textbook of Clinical Pharmacology and Therapeutics

352 HIVANDAIDS

(ELISA) techniques that identify HIV-1 antibodies and Western
blotting is then used to confirm the presence of HIV-1 struc-
tural proteins in blood (see Figure 46.2). Massive viral replica-
tion (3 109 virions per day) occurs in the four to eight weeks
immediately post HIV-1 infection. Viral replication falls in 8–12
weeks, and stabilizes within 6–12 months, initiating a latent
period of good health which may last 5–12 years. During
this latent period, the viral load falls from an initial peak
and remains stable at a plateau of 10^2 –10^6 HIV RNA copy
number/mL of plasma. The HIV RNA copy number then rises
before the development of AIDS. During the latent phase, there
is a dynamic equilibrium of HIV replication, T-cell infection
and destruction and new T-cell generation with a slow
and inexorable decline in CD4cell numbers. Only after the
CD4 lymphocyte cell count has fallen to 200–500/ L is the

individual predisposed to opportunistic infections (e.g. pneu-

mocystis, tuberculosis) or malignancies (e.g. Kaposi’s sarcoma,

lymphoma). It is these infections and malignancies that define

the later stages of HIV-1 infection, known as AIDS.

GENERAL PRINCIPLES FOR TREATING

HIV-SEROPOSITIVE INDIVIDUALS

The accepted standard for HIV treatment is that combination

highly active antiretroviral therapy (HAART) should be

administered before substantial immunodeficiency inter-

venes. The primary aim of treating patients with HIV infection

is maximal suppression of HIV replication for as long as pos-

sible. This improves survival. HAART comprises two nucleo-

side analogues plus either a boosted protease inhibitor or a

non-nucleoside reverse transcriptase inhibitor and reduces

viral load to 500 copies of HIV RNA/mL in 80% of patients

after 12 months treatment. Not all patients tolerate triple ther-

apy due to toxicity, and alternate double therapy may be used.

Current British HIV Association (BHIVA) recommendations

for initiating anti-HIV therapy are as follows. All HIV seroposi-

tive patients with symptoms (or AIDS-defining disease) should

receive HAART. If the CD4 count is 350 cells per L or if there

is a rapid decline in CD4 count of 300 cells per L over 12

months, such patients should be treated. Treatment may be

deferred and the patient monitored if asymptomatic and CD4

counts are stable in the range 350–500 cells per L. The recom-

mended regimens for initial therapy are shown in Table 46.1

and are expected to reduce the HIV RNA copy number per mL

of plasma by 0.5 log by week 8 of therapy, and ultimately to

undetectable levels, and to maintain this state. The plasma HIV

RNA copy number is the accepted gold standard for monitor-

ing therapy and is inversely correlated with CD4 count and sur-

vival. HIV therapy guidelines are evolving rapidly, requiring

Host lymphocyte/macrophage

Reverse transcriptase

inhibitors prevent

transcription of viral RNA

to viral DNA (vDNA)

Integrase inhibitors prevent

vDNA being inserted

into host DNA

(e.g. Raltegravir)

Protease inhibitors prevent

viral maturation

(immature viral particles

cannot cause infection)

Protease

RNA vDNA

Reverse

transcriptase

CD 4 receptor

CCR 5 receptorblocker

(e.g.Maraviroc)

CCR 5 /CXCR 4

co-receptor

Fusioninhibitors

blockinteraction

ofviralgp 41 and

cellmembrane

Integrase

Host DNA

+ vDNA

gp 120

p41

p18

p24

Reverse

transcriptase

RNA

Figure 46.1:Sites of action of anti-HIV

drugs.

Figure 46.2:HIV structure consisting of membrane glycoprotein
gp120 and peptide protein p41 plus an outer membrane of p18
and a nuclear membrane of p24 protein containing viral RNA and
the HIV-1 reverse transcriptase and integrase.