Clinical Pharmacology and Therapeutics

352 HIV AND AIDS
Host lymphocyte/macrophage
Reverse
transcriptase
Fusion inhibitors
block interaction
of viral gp41 and
cell membrane
CD4 receptor
CCR5/CXCR4
co-receptor
RNA
Integrase
Host DNA
+ vDNA
Protease
vDNA
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)
CCR5 receptor blocker
(e.g. Maraviroc)
Figure 46.1: Sites of action of anti-HIV
drugs.
gp 120
p41
individual predisposed to opportunistic infections (e.g. pneumocystis,
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.
p18
p24
Reverse
transcriptase
RNA
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.
(ELISA) techniques that identify HIV-1 antibodies and Western
blotting is then used to confirm the presence of HIV-1 structural
proteins in blood (see Figure 46.2). Massive viral replication
(3 10 9 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 CD4 cell numbers. Only after the
CD4 lymphocyte cell count has fallen to 200–500/L is the
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 intervenes.
The primary aim of treating patients with HIV infection
is maximal suppression of HIV replication for as long as possible.
This improves survival. HAART comprises two nucleoside
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 therapy
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 seropositive
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 recommended
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 monitoring
therapy and is inversely correlated with CD4 count and survival.
HIV therapy guidelines are evolving rapidly, requiring