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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. Member of Academic Research Council

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principles of hiv therapy simple is better

Principles of HIV TherapySimple 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

Member of Academic Research Council

A non-profit organization dedicated to improving

medical education and fostering research

principles of hiv therapy
Principles of HIV Therapy

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
Estimated number of adults and childrennewly infected with HIV during 2002

Eastern Europe & Central Asia

250 000

Western Europe

30 000

North America

45 000

East Asia & Pacific

270 000

North Africa

& Middle East

83 000

South

& South-East Asia

700 000

Caribbean

60 000

Sub-Saharan Africa

3.5 million

Latin America

150 000

Australia

& New Zealand

500

Total: 5 million

estimated adult and child deaths from hiv aids during 2002
Estimated adult and child deaths from HIV/AIDS during 2002

Eastern Europe &

Central Asia

25 000

Western Europe

8 000

North America

15 000

East Asia & Pacific

45 000

North Africa

& Middle East

37 000

South

& South-East Asia

440 000

Caribbean

42 000

Sub-Saharan Africa

2.4 million

Latin America

60 000

Australia

& New Zealand

<100

Total: 3.1 million

about 14 000 new hiv infections a day in 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 hiv aids from the beginning of the epidemic to end 1999
Estimated adult and child deaths due to HIV/AIDSfrom the beginning of the epidemic to end 1999

Eastern Europe &

Central Asia

17 000

Western Europe

210 000

North America

450 000

East Asia & Pacific

40 000

North Africa

& Middle East

70 000

South

& South-East Asia

1.1 million

Caribbean

160 000

Sub-Saharan Africa

13.7 million

Latin America

520 000

Australia

& New Zealand

8 000

Total: 16.3 million

Over 20 million dead by now

slide8
Projected changes in life expectancy in selected African countries with high HIV prevalence, 1995–2000

65

60

55

50

45

40

35

Average life expectancy at birth, in years

Botswana

Zimbabwe

Zambia

Uganda

Malawi

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Source: United Nations Population Division, 1996

goals of antiretroviral therapy
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

slide10

Treatment Impact:

+

CD4

Cell Count and Plasma HIV-1 RNA Level

150

100

50

Cell Count

0

Plasma HIV-1 RNA

-50

+

CD4

-100

-150

-200

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

Years

Highly Active

Antiretroviral

Monotherapy

Therapy

Double RTI Combinations

who should be treated
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
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
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 drugs1
Currently Available Drugs
  • Non-nucleoside reverse transcriptase inhibitors
    • Nevirapine (viramune)
    • Delavridine (rescriptor)
    • Efavirenz (sustiva)
  • Fusion Inhibitors
    • Enfuvirtide (T-20)
currently available drugs2
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 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
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 regimen1
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)

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)

Choice of Regimen
final regimen
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
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
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
What Non-Adherence Can Do

Paterson Ann Int Med 2000;133:21-30

are simple regimens as effective
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
slide27

Adherence at Week 24* in CNA3014

74%

56%

Percentage of Subjects

45%

25%

slide28

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
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
TORO 1: Primary Study Endpoint HIV-1 RNA Log Change from Baseline at Week 24

ENF (T-20)

+ OB

OB alone

0

N=326

N=165

Change from BL(log10 copies/ml)

-0.76

-1

-1.70

-2

(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
TORO 1: CD4+ Cell Count Change from Baseline at Week 24

100

76

P=0.0001

Change from BL (Cells/mm3)

50

32

0

ENF (T-20)

+ OB

OB alone

Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF)

averting failure promote adherence
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
Averting Failure
  • Initiate therapy at the optimal time
      • Patient factors, viral load, CD4
  • Simplify regimens
  • Provide support
      • Social, medical, psychiatric, rehabilitation
other factors associated with poor adherence
Other Factors Associated with Poor Adherence
  • active depression,
  • risk factor for HIV other than male-male sex,
  • nonwhite race,
  • low income,
  • lower level of education,
  • psychiatric disorders
  • active alcoholism
summary
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
summary1
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.
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