Page 46 - AIDSBK23C

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TREATMENT FOR AIDS

A variety of therapies has been developed since 1984 for persons infected with HIV.
Bone marrow transplantation, lymphocyte transfusions, thymic transplantation, and therapeutic
apheresis to remove virus-bearing cells were tried without significant success against HIV
infection and are no longer employed.[253] Antiretroviral therapies are aimed at diminishing
HIV replication and subsequent destruction of the immune system with progression to AIDS. A
variety of pharmacologic agents has been developed to treat HIV infection.[254] None of these
agents can completely eliminate HIV from infected persons. Moreover, experimental in vitro
anti-viral effects do not always occur in vivo.[210] Table 3 lists drugs available to treat HIV
infection.
The first pharmacologic agent that was developed that had significant effectiveness for
treatment of HIV infection was the antiretroviral drug zidovudine (ZDV), a nucleoside analog.
Some earlier literature refers to ZDV as azidothymidine (3'-azido-3'-deoxythymidine), or AZT.
Zidovudine is a thymidine analogue, which is phosphorylated by cellular enzymes to an active
triphosphate form that, as a nucleoside analog, interferes with viral reverse transcriptase. This
drug is structurally similar to building blocks of nucleic acids, but with replacement of the
hydroxy group in the 3' position by another group unable to form the 5' to 3' phospodiester
linkage required for DNA elongation, thus competing with natural substrates and incorporating
into viral DNA to act as a chain terminator in synthesis of HIV proviral DNA.[254] Zidovudine
proved useful in prolonging the lives of treated patients by decreasing the frequency and severity
of opportunistic infections, by partially suppressing HIV replication, and by transiently
increasing CD4 lymphocyte counts.[255]
In the 1990’s, additional nucleoside analog drugs with clinically useful antiretroviral
effect against HIV were developed, including didanosine (ddI), zalcitabine (ddC), stavudine
(d4T), lamivudine (3TC), and abacavir. These drugs, known as nucleoside reverse transcriptase
inhibitors (NTRIs), have potential effectiveness in persons who cannot tolerate zidovudine or in
whom such therapy is unsuccessful, as evidenced by laboratory markers such as decreasing CD4
lymphocyte counts and increasing HIV plasma viremia. All of the NRTI’s require
phosphorylation to an active triphosphate metabolite. Didanosine is converted to
dideoxyadenosine and then phosphorylated to an active triphosphate within cells. Zalcitabine is
metabolized within cells to dideoxycytidine (ddC) in an active triphosphate form. Stavudine is
also phosphorylated intracellularly to the active form of the drug stavudine-5’-triphosphate.
Lamivudine undergoes intracellular phosphorylation to lamivudine triphosphate. Abacavir,
unlike the other NRTI’s, is a guanine analogue that, when converted to the active form carbovir
triphosphate, competes with the natural substrate dGTP.[256]
The acyclic nucleoside phosphonates include adefovir, tenofovir, and cidofovir and have
antiretroviral activity but do not require phosphorylation. This feature helps to avoid the
potential rate-limiting phosphorylation step that may limit activity in some infected cells. These
drugs also have limited cross-resistance to the nucleoside NRTI drugs. Toxicity is similar to the
NRTI’s, but may also include nephrotoxicity from toxic acute tubular necrosis.[256,257]
Another nucleotide reverse transcriptase inhibitor (NtRTI) is tenofovir (tenofovir disoproxil
fumarate) that is an acyclic phosphonate analogue and which may be useful for treatment in
cases where HIV mutations have rendered nucleoside analogue drugs ineffective.[258]