Page 49 - AIDSBK23C

Page 49

Fusion inhibitor therapy is based upon blocking fusion of HIV with the target cell
surface. A synthetic peptide has been produced that corresponds to 36 amino acids within the C-
terminal heptad repeat region (HR1) of HIV-1 gp41 subunit of the viral envelope (Env) protein.
This prevents conformational changes to form a stable complex required for viral membrane
fusion to target cells. This drug, enfuvirtide, must be delivered by subcutaneous injection. It has
a low genetic barrier to resistance and must be used in combination.[273]
Integrase inhibitors interfere with strand transfer of viral DNA and prevent incorporation
of the completed HIV proviral DNA copy into the host cell DNA. The integrase inhibitors
raltegravir and elvitegravir are active against HIV-1 strains that demonstrate resistance to other
classes of antiretroviral drugs. Integrase inhibitors display synergism with other antiretroviral
drugs, but must be used in combination because resistance can quickly arise.[274,275]
Maturation inhibition of HIV involves blocking the assembly of virions so that they are
not released or they are non-infectious. Bevirimat is a maturation inhibitor with a mechanism of
action that involves inhibition of the final rate-limiting step in HIV gag gene function. This
requires release of a mature capsid protein, which is under the influence of the HIV gag gene.
Inhibition of gag directed processing prevents release of mature capsid protein from its precursor
(CA-SP1), resulting in the production of immature, non-infectious virus particles. The
antiretroviral agent beviramat prevents this release and inhibits HIV replication.[276]
The V3 loop amino acid sequence of the HIV-1 gp120 surface protein determines
whether HIV utilizes chemokines CCR5 or CXCR4 for host cell entry. HIV-1 can utilize CCR5,
CXCR4, or both. Entry via CCR5 is more common, particularly in earlier stages of HIV
infection. Maraviroc is a CCR5 inhibitor that binds to the CCR5 chemokine co-receptor,
producing a conformational change that prevents CCR5 interaction with the V3 loop.[274]
The significant mutation rate that occurs during reverse transcription of HIV to proviral
DNA within host cells (approximately once per 2000 incorporated nucleotides) enhances the
development of antiretroviral drug resistance. Resistance increases with the length of therapy, as
multiple amino acid changes accumulate over time to yield virus variants. Common mutations
include substitutions at position 215 for the NRTIs and 103N for the NNRTIs.[277] There are
both high and low prevalence HIV drug resistance mutations. Standard PCR assays detect high
prevalence drug resistance mutations in 8% and 16% of HIV-1 infected persons in North
America and Europe. More sensitive assays may detect low prevalence mutations in an
additional 14% of infected persons, and there is an increased risk for antiretroviral treatment
failure with these mutations as well as with high prevalence mutations.[278]
The monitoring of patients with HIV-1 RNA and CD4 lymphocyte counts is the primary
means for determination of potential resistance. Use of HIV-1 genotypic and phenotypic
susceptibility testing may direct subsequent changes in antiretroviral therapy. Such testing may
improve patient survival.[279] Loss of clones of CD4 lymphocytes through HIV-mediated
destruction may be slowed by antiretroviral therapy, but such clones will not be replaced, leaving
patients at continued risk for opportunistic infections.[267]
A study from the late 1990’s of patients receiving antiretroviral therapy showed that 76%
of individuals with >500 HIV-1 RNA copies/mL were resistant to one or more antiretroviral
drugs, of whom 13% had triple class resistance and 48% double-class resistance. Resistance was
more likely in individuals with a history of drug use, advanced disease, higher viral load and
lower CD4 cell count. A study of antiretroviral naïve patients from 2003 to 2004 in the U.S.
found that 14.5% of them had documented resistance to one or more antiretroviral drugs, with
resistance rates to NRTIs, NNRTIs, and PIs of 7.1%, 8.4%, and 2.8%, respectively. Data from