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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

Africa

Eastern Europe &Central Asia

440 000440 000

<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

Africa

Eastern Europe &Central Asia

1.1 million1.1 million

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

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

1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997

Monotherapy

Double RTI Combinations

Highly Active Antiretroviral

Therapy

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)

Non-nucleoside reverse transcriptase inhibitors Nevirapine (viramune) Delavridine (rescriptor) Efavirenz (sustiva)

Fusion Inhibitors Enfuvirtide (T-20)

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

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

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

>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

Took all doses Took all doses ormissed < 1 dose per

ABCIDV

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

(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

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.

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