Transcript Combination Antiretroviral Threapy for HIV Infection

Combination Antiretroviral Therapy
for HIV Infection
by
Ormrat Kampeerawipakorn
Outline
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Introduction
Content
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Factors Contributing to Treatment Failure
Why does the combination therapy make
sense?
Combinations of Antiretroviral Drugs
Combinations of Nucleoside analogues
(NRTIs)
 Combinations of NRTIs and non-NRTIs
 Combinations of Protease Inhibitors and
NRTIs and/or NNRTIs
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Conclusion
Introduction
Combination Therapy
•is the use of two or more drugs at the same time
for the same disease.
•multiple agents often have additive or synergistic
effects against the disease.
•has been widely used in the treatment of some
infectious diseases and cancers.
Background of Anti-HIV drugs
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In 1987, Zidovudine (AZT) was approved as the first
drug specifically to combat HIV and AIDS by FDA.
AZT is in the family of reverse transcriptase inhibitor.
Others in this class include
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Didanosine (ddI)
Zalcitabine (ddC)
Stavudine (d4T)
Lamivudine (3TC)
Abacavir
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Nevirapine, the first non-nucleoside analogue
(NNRTIs), was approved by FDA in 1996.
Other NNRTIs include
 Delaviridine
 Efavirenz
FDA approved Saquinavir as the first protease
inhibitor in late 1995
Other agents in this class include
 Ritonavir
 Indinavir
 Nelfinavir
 Amprenivir
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In 1995, the combination of 2 NRTIs was
approved to solve the drug resistance problem
such as the combinations of AZT and ddI.
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In 1996, PIs were introduced in combination with
2 NRTIs.
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The triple antiretroviral therapy had become the
standard first-line therapy for HIV infection.
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It is called “Highly Active Antiretroviral
Therapy”(HAART).
Contents
Factors contributing to treatment failure
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Limited potency of the anti-HIV drugs
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In single NRTIs treatment, complete
suppression of HIV replicate was rarely
achieved.
AZT works best in cells actively producing new
HIV, but is not active in resting-infected cells.
Factors contributing to treatment failure (cont.)
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Poor Adherence
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Missing doses
Reducing the frequency of doses or the number
of medications taken
Side effects
The importance of regular dosing
The relationship of a number of dose and viral
load in plasma
Side Effects
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Renal colic
Diarrhea
Nausea, vomiting,dizziness and/or epigastric
discomfort
Lipodystrophy
Anxiety
Factors contributing to treatment failure (cont.)
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Pharmacologic factors
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Limited penetration of drug into sanctuary site
such as central nervous system.
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Drug-drug interaction
 Rifampin and Rifabutin reduce PIs level by
inducing cytochrome P450 3A activity.
 In contrast, Ketoconazole enhances the
increase level of PIs.
Factors contributing to treatment failure (cont.)
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Drug Resistance
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is the major factor contributing to treatment failure.
Pathogenesis
 HIV replicates at an extremely rapid rate (1-10
billion copies daily).
 Each time of replication, an average of one mutant
base pair viral genome occurs.
 There is no error-checking system to repair these
spontaneous mutations arising daily.
 These mutations can make amino acid
substitutions at active site of anti-HIV drug in
gene.
Reverse Transcriptase mutation to NRTIs
A highly drug-resistant viral strain
What does the combination therapy make
sense?
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The combination therapy can decrease HIV
progression better than monotherapy.
Rate of Decline of Plasma HIV RNA Concentration
After Initiation of Potent Combination Antiretroviral
Therapy
What does the combination therapy make
sense?
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The combination therapy can decrease HIV
progression better than monotherapy.
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Different anti-HIV drugs can attack the virus in the
different ways.
HIV Life Cycle Targets of Current and
Emerging Therapy
What does the combination therapy make
sense?
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The combination therapy can decrease HIV
progression better than monotherapy.
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Different anti-HIV drugs can attack the virus in the
different ways.
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Different drugs can attack virus in different types of
cell and in different parts of the body.
Different drugs can attack virus in different
types of cell and in different parts of the body.
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Some NRTIs and NNRTIs can get inside spinal
cords and brain such as AZT, d4T and
Nevirapine.
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AZT and d4T work best in infected cells that are
actively producing new copies of HIV.
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ddI, ddC, 3TC and nevirapine work best in
resting cell
What does the combination therapy make
sense?
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The combination therapy can decrease HIV
progression better than monotherapy.
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Different anti-HIV drugs can attack the virus in the
different ways.
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Different drugs can attack virus in different types of
cell and in different parts of the body.
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Combinations of anti-HIV drugs may overcome or
delay resistance.
Reduced mutation in AZT-experience patients
after treating with the combinations of Abacavir
and AZT
Combinations of Antiretroviral Drugs
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Combinations of Nucleosides Analogues
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Because of differences in the intracellular
activity, NRTIs working in actively infected cells
are given with those working in resting cells.
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Large studies in the US, Europe and Australia
showed that AZT plus ddI or AZT plus ddC worked
better than AZT alone.
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Combinations of Nucleosides Analogues (cont..)
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ACTG 175 trial (NIAID, United States) showed 50%
decline CD4 cell count rate increase significantly in
the combinations of AZT/ddI and AZT/ddC group,
compared with AZT monotherapy.
The 50% decline CD4 cell counts in volunteers in
ACTG 175 after treating with monotherapy and
combinations of NRTIs
50% decline CD4 counts (%)
50
38
40
30
27
26
23
22
17
14
20
10
10
0
AZT
ddI
AZT+ddI
AZT+ddC
Treatment
Treatment-naiv e v olunteers Treatment-experienced v olunteers
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Combinations of Nucleosides Analogues (cont.)
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ACTG 175 trial (NIAID, United States) showed 50%
decline CD4 cell count rate increase significantly in
the combinations of AZT/ddI and AZT/ddC group,
compared with AZT monotherapy.
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In treatment-naïve individuals, average peak HIVRNA reduction increased significantly in
combination NRTIs compared with NRTIs
monotherapy.
Average peak RNA reduction with RTIs
monotherapy and combination regimen in antiHIV-naïve individuals.
2
Av erage HIV-RNA reduction (log cell/ml)
1.7
1.6
1.5
1.5
1.4
1.3
1.2
1
1
0.8
0.5
0.5
0.8
0.5
0
AZT
ddC
ddI
3TC
d4T
AZT+ddI
AZT+3TC
ddI+3TC
d4T+3TC
AZT+ddC
AZT+d4T
Treatment
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Combinations of NRTIs and NNRTIs
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NNRTIs have same target and activity as in
NRTIs.
The incorporation of NRTIs and NNRTIs
shows synergistic effect and is active
against AZT-resistant HIV isolates.
In the study of Staszewski et al., plasma
HIV-RNA level in patients receiving
EFV/AZT/3TC decreased greater than in
ones receiving EFV/IDV
Percent with HIV-1 RNA Level of <400 copies/ml
Percentage of patients with plasma HIV-1 RNA level
of less than 400 copies/ml according to the
combinations of NRTIs/NNRTIs
100
80
60
40
20
0
0
2
4
8
12
16
20
24
36
48
Week
Ef av irenz+zidov udine and lamiv udine Ef av irenz+indinav ir
Ef av irenz+indinav ir
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Combinations of PIs and RTIs
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Saquinavir was the first protease inhibitor for
use in the combination with nucleoside
analogues.
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Several studies showed that the triple drugs
(PIs+2NRTIs) given together resulted in a
large and longer-lasting reduction in the
amount of virus in blood compared with 2
NRTIs combinations or with PIs alone.
Mean changes from baseline in serum human
immunodeficiency virus (HIV) RNA levels
Mean changes from baseline in serum human
immunodeficiency virus (HIV) RNA levels
Conclusion
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The potent antiretroviral regimen now have proven
capable of effecting a dramatic suppression of HIV
viral replication and a delay in the emergence of
drug resistance.
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Clinical end point studies showed the potential
benefit of NRTIs combination in intermediate-stage
HIV infection and in treatment-naive individual.
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The triple drugs (PIs plus RTIs) have the clinical
benefit in late-stage HIV infection.
Conclusion (Cont.)
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However, side effects, high cost, large number of
pills and complicated dosing schedules can make
poor adherence in the HAART regimen.
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Therefore, it is necessary to develop more potent
therapies that have low cost, fewer toxic effects and
are easier to administer such as vaccine, fusion
inhibitors.
The End