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Transcript of 10331
Principles of HIV Therapy
Simple is Better!
Adeel A. Butt, MDAssistant Professor of Medicine and Infectious
DiseasesUniversity of Pittsburgh
Director, VAPHS HIV-ID ClinicsCenter for Health Equity Research and Promotion
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
Principles of HIV Therapy
00002-E-4 – 1 December 2002
Estimated number of adults and childrenEstimated number of adults and childrennewly infected with HIV during 2002newly infected with HIV during 2002
Total: 5 million
Western Europe
30 00030 000North Africa & Middle East
83 00083 000Sub-Saharan
Africa
3.5 3.5 millionmillion
Eastern Europe & Central Asia
250 000250 000East Asia & Pacific
270 000270 000South & South-East Asia
700 000700 000
Australia & New Zealand
500500
North America
45 00045 000Caribbean
60 00060 000
Latin America
150 000150 000
00002-E-5 – 1 December 2002
Estimated adult and child deaths Estimated adult and child deaths from HIV/AIDS during 2002from HIV/AIDS during 2002
Total: 3.1 million
Western Europe
8 0008 000North Africa & Middle East
37 00037 000Sub-Saharan
Africa
2.4 2.4 millionmillion
Eastern Europe &Central Asia
25 00025 000East Asia & Pacific
45 00045 000South & South-East Asia
440 000440 000
Australia & New Zealand
<100<100
North America
15 00015 000Caribbean
42 00042 000
Latin America
60 00060 000
00002-E-6 – 1 December 2002
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
Estimated adult and child deaths due to Estimated adult and child deaths due to HIV/AIDSHIV/AIDS
from the beginning of the epidemic to end from the beginning of the epidemic to end 19991999
Western Europe
210 000210 000North Africa & Middle East
70 00070 000Sub-Saharan
Africa
13.7 13.7 millionmillion
Eastern Europe &Central Asia
17 00017 000East Asia & Pacific
40 00040 000South & South-East Asia
1.1 million1.1 million
Australia & New Zealand
8 0008 000
North America
450 000450 000Caribbean
160 000160 000
Latin America
520 000520 000
Total: 16.3 millionTotal: 16.3 million
Over 20 million dead by now
Projected changes in life expectancy in selected African countries with high HIV prevalence, 1995–2000
Source: United Nations Population Division, 1996
1955 1960 1965 1970 1975 1980 1985 1990 1995 2000
Average life expectancy at birth, in years65
60
55
50
45
40
35
ZimbabweZimbabwe
ZambiaZambiaUgandaUganda
BotswanaBotswana
MalawiMalawi
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
150
100
50
0
-50
-100
-150
-200
CD
4 + C
ell C
ount
Plasm
a HIV
-1 RN
A
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997
Monotherapy
Double RTI Combinations
Highly Active Antiretroviral
Therapy
Years
+
Who Should be Treated HIV ELISA positive, confirmed
with Western blot HIV RNA >55,000 copies/ml CD4 <350 cells/mm3 Special considerations:
Pregnant women Acute HIV infection Exposed healthcare workers
Highly Active Antiretroviral Therapy
Four approved classes of drugs in the HAART regimens Nucleoside and nucleotide
reverse transcriptase inhibitors Non-nucleoside reverse
transcriptase inhibitors Protease inhibitors Fusion inhibitors
Currently Available Drugs
Nucleoside analogue reverse transcriptase inhibitors Zidovudine (AZT, Retrovir) Lamivudine (3TC, Epivir) Stavudine (D4T, Zerit) Didanosine (DDI, Videx) Zalcitabine (DDC) Abacavir (Ziagen)
Nucleotide … Tenofovir (Viread)
Currently Available Drugs
Non-nucleoside reverse transcriptase inhibitors Nevirapine (viramune) Delavridine (rescriptor) Efavirenz (sustiva)
Fusion Inhibitors Enfuvirtide (T-20)
Currently Available Drugs
Protease Inhibitors Indinavir (crixivan) Nelfinavir (viracept) Ritonavir (norvir) Saquinavir soft gel (fortovase) Amprenavir (agenerase) Lopinavir/ritonavir (kaletra) Amprenavir/ritonavir
What is the Best Initial Treatment
What we know Two is better than one Three is better than two
What we are trying to find out Is four better than three????
IS THERE A GOLD STANDARD?
ABC of HIV Therapy
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 NRTI 2 PI (ritonavir as booster)
Choice of Initial Regimen
NRTIs 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
NNRTIs Nevirapine
(Viramune) (2 tab) Efavirenz (Sustiva)
(3 cap) Delavradine
(Rescriptor) (6 or 12)
PIsIndinavir (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)
Complexity of Regimens
Adherence Issues: ZDV + ddI + IDV
Take ddl (2 tablets), no food
Take IDV (2 pills),drink 12 oz. water, no food
Drink 12 oz. water
Dinner +ZDV (1 pill)
Take IDV (2 pills),drink 12 oz. water, no food
Wake up, take IDV (2 pills),drink 12 oz. water, no food
Lunch
Breakfast + ZDV (1 pill) Just before bedtake ddl (2 tablets), no food
AMMidnight 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 Midnight
Noon
Source: Physicians’ Desk Reference . Medical Economics Co; 1997.®
Final Regimen
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?
Intolerance Infection with a resistant virus Malabsorption NON-ADHERENCE TOPS THE LIST
Rates of adherence have a direct correlation with success of HAART1
Near perfect viral suppression in DOT trials2
Reasons for Non-Adherence
Psychiatric issues Drug use Social circumstances Privacy issues Adverse events COMPLEXITY
Number of pills, number of doses, food restrictions, drug interactions
What Non-Adherence Can Do
81
64
50
25
60
10
20
30
40
50
60
70
80
90
% o
f pa
tien
tsw
ith V
L<
40
0 c
op
ies/
mL
>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?
COMBINE Study ZDV+Epivir+NEV vs. ZDV+Epivir+Nelfinavir
CNA3014 Combivir+abacavir vs. Combivir+indinavir
CNAF3007 Combivir+abacavir vs. combivir+nelfinavir
Adherence at Week 24* in CNA3014
0%
20%
40%
60%
80%
100%
Took all doses Took all doses ormissed < 1 dose per
week
ABCIDV
Per
cent
age
o f S
ubje
cts
56%
25%
74%
45%
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 OB Total (N=326) (N=165) (N=491)
Baseline RNA 5.2 5.2 5.2(median, log10)
Baseline CD4+ cell count 76 87 80(median, cells/mm3)
Prior ARVs (median) 12 12 12
Years ARV use (median)7.0 7.1 7.0
Prior ADEs (N, %) 273 (84%) 148 (90%) 421 (86%)
PSS at entry (mean) 1.7 1.8 1.7
TORO 1: Primary Study Endpoint HIV-1 RNA Log Change from Baseline at Week 24
-1.70
-0.76
-2
-1
0
(Delta=0.93 P<0.0001)
Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF)
OB aloneENF (T-20) + OB
N=165N=326
Ch
ang
e fr
om
BL
(lo
g1
0 c
op
ies/
ml)
76
32
0
50
100
Ch
an
ge
fro
m B
L
(Ce
lls/m
m3)
TORO 1: CD4+ Cell Count Change from Baseline at Week 24
P=0.0001
Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF)
OB aloneENF (T-20) + OB
Averting Failure — Promote Adherence
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
Initiate therapy at the optimal time
Patient factors, viral load, CD4
Simplify regimens Provide support
Social, medical, psychiatric, rehabilitation
active depression, risk factor for HIV other than
male-male sex, nonwhite race, low income, lower level of education, psychiatric disorders active alcoholism
Other Factors Associated with Poor Adherence
Summary
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
When to start treatment CD4<350 VL> 55,000
Choice of initial regimen 3 drugs
Appropriate prophylaxis Primary: PCP, MAC Secondary: PCP, MAC, Toxo,
candidiasis, CMV, etc.