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Principles of HIV Therapy
Simple is Better!
Adeel A. Butt, MD
Assistant Professor of Medicine and Infectious Diseases
University of Pittsburgh
Director, VAPHS HIV-ID Clinics
Center for Health Equity Research and Promotion
Principles of HIV Therapy
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Objectives
To tell you why we should care
To tell you why the care is not optimal
To share with you how some of us feel
how this may be improved
To describe when to initiate treatment
and some initial regimens
Estimated number of adults and children
newly infected with HIV during 2002
North America
45 000
Caribbean
60 000
Latin America
150 000
Eastern Europe
Western Europe & Central Asia
30 000 250 000East Asia & Pacific
North Africa
270 000
& Middle East South
& South-East Asia
83 000
700 000
Sub-Saharan
Africa
3.5
million
Total: 5 million
00002-E-4 – 1 December 2002
Australia
& New
Zealand
500
Estimated adult and child deaths
from HIV/AIDS during 2002
North America
15 000
Caribbean
42 000
Latin America
60 000
Eastern Europe &
Western Europe Central Asia
8 000
North Africa
& Middle East
25 000 East Asia & Pacific
45 000
South
37 000
Sub-Saharan
Africa
& South-East Asia
440 000
2.4
million
Total: 3.1 million
00002-E-5 – 1 December 2002
Australia
& New
Zealand
<100
About 14 000 new HIV infections a day in
2002
- More than 95% are in developing countries
- 2000 are in children under 15 years of age
- About 12 000 are in persons aged 15 to 49
years, of whom:
almost 50% are women
about 50% are 15–24 year olds
00002-E-6 – 1 December 2002
Estimated adult and child deaths due to HIV/AIDS
from the beginning of the epidemic to end 1999
North America
450 000
Caribbean
160 000
Latin America
520 000
Eastern Europe &
Western Europe Central Asia
210 000 17 000
East Asia & Pacific
North Africa
40 000
& Middle East South
& South-East Asia
70 000
1.1 million
Sub-Saharan
Africa
13.7
million
Australia
& New
Zealand
8 000
Total: 16.3 million
Over 20 million dead by now
Projected changes in life expectancy in selected African
countries with high HIV prevalence, 1995–2000
65
Average life expectancy at birth, in years
60
55
Botswana
Zimbabwe
50
45
Zambia
Uganda
Malawi
40
35
1955 1960 1965 1970 1975 1980 1985
1990 1995 2000
Source: United Nations Population Division, 1996
Goals of Antiretroviral Therapy
Control of viral replication
Prevention or delay of
progressive immunodeficiency
Delayed progression to AIDS
Prolonged Survival
Decreased selection
of resistant virus
Treatment Impact:
CD4+ Cell Count and Plasma HIV-1 RNA Level
100
Plasma HIV-1 RNA
CD4+ Cell Count
150
50
0
-50
-100
-150
-200
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997
Years
Highly Active
Antiretroviral
Therapy
Monotherapy
Double RTI Combinations
Who Should be Treated
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HIV ELISA positive, confirmed with
Western blot
HIV RNA >55,000 copies/ml
CD4 <350 cells/mm3
Special considerations:
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Pregnant women
Acute HIV infection
Exposed healthcare workers
Highly Active Antiretroviral Therapy
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Four approved classes of drugs in
the HAART regimens
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Nucleoside and nucleotide reverse
transcriptase inhibitors
Non-nucleoside reverse transcriptase
inhibitors
Protease inhibitors
Fusion inhibitors
Currently Available Drugs
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Nucleoside analogue reverse transcriptase
inhibitors
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Zidovudine (AZT, Retrovir)
Lamivudine (3TC, Epivir)
Stavudine (D4T, Zerit)
Didanosine (DDI, Videx)
Zalcitabine (DDC)
Abacavir (Ziagen)
Nucleotide …
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Tenofovir (Viread)
Currently Available Drugs
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Non-nucleoside reverse transcriptase
inhibitors
 Nevirapine (viramune)
 Delavridine (rescriptor)
 Efavirenz (sustiva)
Fusion Inhibitors
 Enfuvirtide (T-20)
Currently Available Drugs
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Protease Inhibitors
Indinavir (crixivan)
 Nelfinavir (viracept)
 Ritonavir (norvir)
 Saquinavir soft gel (fortovase)
 Amprenavir (agenerase)
 Lopinavir/ritonavir (kaletra)
 Amprenavir/ritonavir
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What is the Best Initial Treatment
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What we know
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Two is better than one
Three is better than two
What we are trying to find out
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Is four better than three????
IS THERE A GOLD STANDARD?
ABC of HIV Therapy
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Here is what I am NOT going to
talk about
All previous HIV Studies
Details and comparisons of all
regimens
Choice of Initial Regimen
2 NRTI
1 PI
2 NRTI
1 NNRTI
3 NRTI
3rd NRTI is abacavir
2 NRTI
1 nucloeotide RTI
(tenofovir)
2 PI (ritonavir as
booster)
2 NRTI
Choice of Initial Regimen
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NRTIs
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AZT – 2 tab
Epivir – 2 tab
Zerit – 2 tab
Videx (DDI) – 1 tab (new EC formulation)
Hivid (DDC) – I don’t ever use it
Abacavir – 2 tab
Tenofovir – 1 tab
Combivir (AZT + Epivir) – 2 tab
Trizivir (AZT + Epivir + Abacavir) – 2 tab
Choice of Regimen
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NNRTIs
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Nevirapine (Viramune)
(2 tab)
Efavirenz (Sustiva)
(3 cap)
Delavradine
(Rescriptor) (6 or 12)
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PIs
Indinavir (6 or 12 cap)
 Nelfinavir (10 tab)
 Ritonavir (don’t even
go there)
 Saquinavir soft gel
(18 cap)
 Amprenavir (16 cap)
 Lopinavir/ritonavir
(6 cap)
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Complexity of Regimens
Adherence Issues: ZDV + ddI + IDV
Take IDV (2 pills),
drink 12 oz. water, no food
Drink 12 oz. water
Take ddl (2 tablets), no food
Lunch
Breakfast + ZDV (1 pill)
Wake up, take IDV (2 pills),
drink 12 oz. water, no food
AM
Midnight 1 2
3 4
5
6
7 8
Dinner +
Take IDV (2 pills), ZDV (1 pill)
drink 12 oz. water,
no food
9 10 11 12 1
2
Noon
Source: Physicians’ Desk Reference ®. Medical Economics Co; 1997.
3 4
5
6
7 8
Just before bed
take ddl (2 tablets),
no food
9 10 11 Midnight
Final Regimen
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Trizivir – 2 tab
Combivir + ABC – 4 tab
Combivir + NEV – 4 tab
Combivir + EFV – 5 tab/cap
D4t + EPI + EFV – 7 tab/cap
Why Does Treatment Fail?
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Intolerance
Infection with a resistant virus
Malabsorption
NON-ADHERENCE TOPS THE LIST
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Rates of adherence have a direct
correlation with success of HAART1
Near perfect viral suppression in DOT
trials2
Reasons for Non-Adherence
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Psychiatric issues
Drug use
Social circumstances
Privacy issues
Adverse events
COMPLEXITY
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Number of pills, number of doses,
food restrictions, drug interactions
What Non-Adherence Can Do
90
80
% of patients
with VL
<400 copies/mL
70
81
60
64
50
50
40
30
20
25
10
6
0
>95
90-95
80-90
70-80
<70
% of patients adherent--MEMS cap data
Paterson Ann Int Med 2000;133:21-30
Are Simple Regimens As Effective?
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COMBINE Study
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CNA3014
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ZDV+Epivir+NEV vs. ZDV+Epivir+Nelfinavir
Combivir+abacavir vs. Combivir+indinavir
CNAF3007
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Combivir+abacavir vs. combivir+nelfinavir
Adherence at Week 24* in CNA3014
100%
74%
80%
60%
40%
56%
45%
25%
20%
ABC
IDV
0%
Took all doses
Took all doses or
missed < 1 dose per
week
Enfuvirtide (ENF, T-20) in
Combination with an Optimized
Background (OB) Regimen vs. OB
Alone in Patients with Prior
Experience or America and Brazil
(TORO 1)
Resistance to Each of the Three
Classes of Approved Antiretrovirals
(ARVs) in North
TORO 1:
Demographics and Baseline Characteristics
ENF+OB
(N=326)
OB
(N=165)
Total
(N=491)
5.2
5.2
5.2
Baseline CD4+ cell count 76
(median, cells/mm3)
87
80
Prior ARVs (median)
12
12
12
Years ARV use (median) 7.0
7.1
7.0
273 (84%)
148 (90%)
421 (86%)
1.7
1.8
1.7
Baseline RNA
(median, log10)
Prior ADEs (N, %)
PSS at entry (mean)
TORO 1:
Primary Study Endpoint
HIV-1 RNA Log Change from Baseline at Week 24
ENF (T-20)
+ OB
OB alone
N=326
N=165
Change from BL
(log10 copies/ml)
0
-0.76
-1
-2
-1.70
(Delta=0.93 P<0.0001)
Least Squared Means Log Change from Baseline Intent-to-Treat Population (LOCF)
TORO 1:
CD4+ Cell Count Change from
Baseline at Week 24
Change from BL
(Cells/mm3)
100
76
50
0
P=0.0001
32
OB alone
ENF (T-20)
+ OB
Least Squared Means Change from Baseline
Intent-to-Treat Population (LOCF)
Averting Failure — Promote Adherence
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HAART has increased long-term survival of patients
with HIV
–
Before HAART, median survival: 8 to 10 years
–
After HAART, median survival: may be 36 years
Drug “holidays” or treatment interruptions result in
rapid viral rebound within 2 to 3 weeks of
treatment discontinuation
Simplification of dosing regimens to twice or once
daily may improve long-term adherence
Averting Failure
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Initiate therapy at the optimal time
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Patient factors, viral load, CD4
Simplify regimens
Provide support
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Social, medical, psychiatric, rehabilitation
Other Factors Associated with Poor
Adherence
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active depression,
risk factor for HIV other than
male-male sex,
nonwhite race,
low income,
lower level of education,
psychiatric disorders
active alcoholism
Summary
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Chose patients to treat carefully
With appropriate treatment, HIV is
quite controllable, like any other
chronic disease
Missing a couple of doses a week
may mean losing the game
Less is better, when it comes to the
number of pills
Summary
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When to start treatment
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Choice of initial regimen
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CD4<350
VL> 55,000
3 drugs
Appropriate prophylaxis
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Primary: PCP, MAC
Secondary: PCP, MAC, Toxo, candidiasis,
CMV, etc.