Antiretroviral TherapyAntiretroviral Therapy

Christopher Mathews, MDChristopher Mathews, MDUniversity of California, San DiegoUniversity of California, San Diego

Perspectives for Developing Countries

Survival Time from 1st Owen Clinic Visit, n=4854

Years1 2 3 4 5 6 7 8 9 10

0.00

0.25

0.50

0.75

1.00

yrentry 1990

yrentry 1991

yrentry 1992

yrentry 1993

yrentry 1994

yrentry 1995

yrentry 1996yrentry 1997

yrentry 1998

yrentry 1999

Time to Undetectable VL, by Year of Entry, Owen Clinic, n=701P

ropo

rtion

with

pV

L>40

0 co

pies

Follow-up time (years)0 1 2 3 4

0.00

0.25

0.50

0.75

1.00

1995-96

1997

1998

1999

(Perrin & Telenti.(Perrin & Telenti. Science 1998;280:1871-1873)Science 1998;280:1871-1873)

Licensure of Antiretroviral Agents Licensure of Antiretroviral Agents by Yearby Year

1987:1987: zidovudinezidovudine1988:1988:1989:1989:1990:1990:1991:1991: didanosinedidanosine1992:1992: zalcitabinezalcitabine1993:1993:1994:1994: stavudinestavudine1995:1995: lamivudine lamivudine

saquinavirsaquinavir

1996: 1996: ritonavir ritonavir indinavir indinavir nevirapinenevirapine

1997: 1997: nelfinavir nelfinavir delavirdine delavirdine

1998: 1998: efavirenz efavirenz abacavirabacavir

1999: 1999: amprenaviramprenavir

2000: 2000: lopinavir/ritonavirlopinavir/ritonavir

2001: 2001: tenofovirtenofovir

WHO Antiretroviral GuidelinesWHO Antiretroviral Guidelines

Primary targets are national treatment advisory Primary targets are national treatment advisory boards and senior-level policymakersboards and senior-level policymakersOutline a public health approach to enable Outline a public health approach to enable treatment of 3 million individuals in the next 3 treatment of 3 million individuals in the next 3 yearsyearsWHO placed ARVs on Essential Drug List in WHO placed ARVs on Essential Drug List in April 2002April 2002– ““they should be available at all times in adequate they should be available at all times in adequate

amounts, appropriate dosage forms, at a price amounts, appropriate dosage forms, at a price individuals and communities can afford…”individuals and communities can afford…”

(http://www.who.int/HIV_AIDS/first.html)

Feasibility and Will to Use ARVsFeasibility and Will to Use ARVs

UN General Assembly Special Session (article UN General Assembly Special Session (article 15) recognized that access to medication is 15) recognized that access to medication is integral to the human right to healthintegral to the human right to healthGlobal Fund to Fight AIDS, Tuberculosis, and Global Fund to Fight AIDS, Tuberculosis, and Malaria” – target $7-10 billion/yearMalaria” – target $7-10 billion/yearOf $174 million approved for coming year, 67% Of $174 million approved for coming year, 67% assigned to HIVassigned to HIV21 of 28 countries awarded Global Fund grants 21 of 28 countries awarded Global Fund grants specifiy purchase of ARVs as central aimspecifiy purchase of ARVs as central aim

Factors affecting successFactors affecting success

Drug acquisition costsDrug acquisition costsFacility and personnel infrastructureFacility and personnel infrastructureMinimizing side effectsMinimizing side effectsPreventing rapid evolution of drug Preventing rapid evolution of drug resistanceresistanceRecognizing indirect benefit of treatment Recognizing indirect benefit of treatment on transmission probability – “Therapy as on transmission probability – “Therapy as Prevention”Prevention”

Affordable prices

Annual cost per person for triple therapy in Africa (US$)

$12,000

$10,000

$8,000

$6,000

$4,000

$2,000

$01991 1993 1995 1997 1999 2001 2003

Drug Access Initiative

Domestic production

Accelerated access initiative

February-April 2001 offers

Clinical Stage I:

1. Asymptomatic

2. Persistent generalized lymphadenopathy (PGL).

Performance scale 1: Asymptomatic, normal activity.

WHO Staging System for HIV WHO Staging System for HIV Infection and Disease in Adults Infection and Disease in Adults

and Adolescentsand Adolescents

WHO Staging System for HIV WHO Staging System for HIV Infection and Disease in Adults Infection and Disease in Adults

and Adolescentsand Adolescents

Clinical Stage II:

3. Weight loss, < 10 % of body weight.

4. Minor mucocutaneous manifestations (seborrheic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis).

5. Herpes Zoster, within the last 5 years.

6. Recurrent upper respiratory tract infections (i.e., bacterial sinusitis).

And/or Performance scale 2: symptomatic, normal activity.

WHO Staging System for HIV Infection and Disease in Adults and Adolescents:

Clinical Stage III7. Weight loss, > 10 % of

body weight.

8. Unexplained chronic diarrhoea, > 1 month.

9. Unexplained prolonged fever (intermittent or consant), > 1 month.

10. Oral candidiasis (thrush).

11. Oral hairy leukoplakia.

12. Pulmonary tuberculosis, within the past year.

13. Severe bacterial infections (i.e., pneumonia, pyomyositis).

And/or Performance scale 3: bed-ridden, < 50% of the day during the last month.

WHO Staging System for HIV Infection WHO Staging System for HIV Infection and Disease in Adults and Adolescents: and Disease in Adults and Adolescents:

Clinical Stage IVClinical Stage IV14.14. HIV wasting syndrome, as defined HIV wasting syndrome, as defined

by CDCby CDC11..15.15. Pneumocystis carinii pneumonia.Pneumocystis carinii pneumonia.16.16. Toxoplasmosis of the brain.Toxoplasmosis of the brain.17.17. Cryptosporidiosis with diarrhoea, > Cryptosporidiosis with diarrhoea, >

1 month.1 month.18.18. Cryptococcosis, extrapulmonaryCryptococcosis, extrapulmonary19.19. Cytomegalovirus (CMV) disease of Cytomegalovirus (CMV) disease of

an organ other than liver, spleen or an organ other than liver, spleen or lymph nodes.lymph nodes.

20.20. Herpes simplex virus (HSV) Herpes simplex virus (HSV) infection, mucocutaneous > 1 infection, mucocutaneous > 1 month, or visceral any duration.month, or visceral any duration.

21.21. Progressive multifocal Progressive multifocal leukoencephalopathy (PML).leukoencephalopathy (PML).

21.21. Any disseminated endemic mycosis Any disseminated endemic mycosis (i.e. histoplasmosis, (i.e. histoplasmosis, coccidioidomycosis).coccidioidomycosis).

23.23. Candidiasis of the oesophagus, Candidiasis of the oesophagus, trachea, bronchi or lungs.trachea, bronchi or lungs.

24.24. Atypical mycobacteriosis, Atypical mycobacteriosis, disseminated.disseminated.

25.25. Non-typhoid Salmonella Non-typhoid Salmonella septicaemia.septicaemia.

26.26. Extrapulmonary tuberculosis.Extrapulmonary tuberculosis.27.27. Lymphoma.Lymphoma.28.28. Kaposi’s sarcoma (KSKaposi’s sarcoma (KS29.29. HIV encephalopathy, as defined by HIV encephalopathy, as defined by

CDC2.CDC2.And/or Performance scale 4: bed-And/or Performance scale 4: bed-ridden, > 50 % of the day during the ridden, > 50 % of the day during the last month.last month.

CDC Classification of HIV Infection(1993)

Clinical Categories

A B C

CD4 Categories

>500 A-1 B-1 C-1

200-500 A-2 B-2 C-2

<200 A-3 B-3 C-3

Table ARecommendations for Initiating Antiretroviral Therapy in Adults and Adolescents with Documented HIV Infection

If CD4 Testing Available:

WHO Stage IV disease irrespective of CD4 cell count

WHO Stage I, II or III3 with CD4 cell counts <200/mm3 (1)

If CD4 Testing Unavailable:

WHO Stage IV disease irrespective of total lymphocyte count

WHO Stage II or III (3) disease with a total lymphocyte count <1000-1200/mm3 – (2)

1The precise CD4 level above 200/mm3 at which to start ARV treatment has not been established but the presence of symptoms and the rate of CD4 cell decline (if measurement available) should be factored into the decision making.

2A total lymphocyte count of <1000-1200/mm3 can be substituted for the CD4 count when the latter is unavailable and HIV-related symptoms exist. It is less useful in the asymptomatic patient. Thus, in the absence of CD4 cell testing, asymptomatic HIV infected patients (WHO Stage I) should not be treated because there is currently no other reliable marker available in severely resource constrained settings.

3Treatment is also recommended for patients with advanced WHO Stage III disease including recurrent or persistent oral thrush and recurrent invasive bacterial infections irrespective of CD4 cell or total lymphocyte count.

When to change therapy?When to change therapy?

Intolerance leading to poor adherenceIntolerance leading to poor adherenceDrug toxicityDrug toxicityOccurrence of active tuberculosisOccurrence of active tuberculosisPregnancyPregnancyTreatment failureTreatment failure– Clinical Clinical

Disease progression on therapy, not due to immunologic reconsitution Disease progression on therapy, not due to immunologic reconsitution syndromesyndrome

– Immunologic: Immunologic: Drop >30% CD4 from peakDrop >30% CD4 from peakReturn to baseline or belowReturn to baseline or below

– VirologicVirologicContinued detectable viremiaContinued detectable viremia

Cytochrome P-450, HIV-1 Protease Cytochrome P-450, HIV-1 Protease Inhibitors and NNRTIsInhibitors and NNRTIs

Enzyme Substrates Inducers Inhibitors

1A2 Ritonavir

2C9 Ritonavir Delavirdine Efavirenz

2C19 Ritonavir Delavirdine Efavirenz

2D6 Delavirdine Ritonavir

3A4 Saquinavir Indinavir Ritonavir Nelfinavir Nevirapine Delavirdine Efavirenz Lopinavir

Nevirapine Efavirenz

Indinavir Ritonavir Nelfinavir Lopinavir Delavirdine Efavirenz

Abacavir Hypersensitivity Abacavir Hypersensitivity SyndromeSyndrome

Incidence about 5%Incidence about 5%Onset within 6 weeks of initiationOnset within 6 weeks of initiationDefinition:Definition:– A fever > 100.9 A fever > 100.9 F F andand one of the following: one of the following:

Nausea greater than baselineNausea greater than baselineMalaise greater than baselineMalaise greater than baselineWith or without rashWith or without rash

Stop the drug and do Stop the drug and do notnot re-challenge re-challenge

Metabolic Abnormalities Metabolic Abnormalities Associated with HIV Protease Associated with HIV Protease

Inhibitor TherapyInhibitor Therapy

Peripheral lipodystrophy Peripheral lipodystrophy (Carr et al. AIDS (Carr et al. AIDS 1998;12:F51-8)1998;12:F51-8)

HypertriglyceridemiaHypertriglyceridemia

Hypercholesterolemia & decreased HDLHypercholesterolemia & decreased HDL

Hyperinsulinemia & glucose intoleranceHyperinsulinemia & glucose intolerance

Accelerated atherosclerosis Accelerated atherosclerosis (Henry et al. (Henry et al. Lancet 1998;351:1328)Lancet 1998;351:1328)

Dorsal fat pads (“Buffalo humps”)Dorsal fat pads (“Buffalo humps”)

Peripheral LipodystrophyPeripheral Lipodystrophy

Variable definitions and prevalence Variable definitions and prevalence (5-60%)(5-60%)

CharacteristicsCharacteristics– Change in body habitusChange in body habitus– Increase abdominal girth with visceral fat Increase abdominal girth with visceral fat

deposition deposition (Miller et al. Lancet 1998;351:871-5)(Miller et al. Lancet 1998;351:871-5)

– Loss of appendicular fat, with thinning of legs Loss of appendicular fat, with thinning of legs and prominent veinsand prominent veins

– Breast hypertrophy in womenBreast hypertrophy in women

Treatment AdherenceTreatment Adherence(Altice & Friedland. Ann Intern Med 1998;129:503-505)(Altice & Friedland. Ann Intern Med 1998;129:503-505)

“…“…compared with therapies for other compared with therapies for other chronic diseases, which are often chronic diseases, which are often forgiving of lapses in adherence, HIV forgiving of lapses in adherence, HIV therapy is unforgiving.”therapy is unforgiving.”Nonadherence may mean:Nonadherence may mean:– Not taking medication at allNot taking medication at all– Taking reduced amountsTaking reduced amounts– Not taking doses at prescribed frequencies or Not taking doses at prescribed frequencies or

intervalsintervals– Not matching medication to food Not matching medication to food

requirementsrequirements

0 %

2 0 %

4 0 %

6 0 %

8 0 %

1 0 0 %

% P

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NA

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> 9 5 9 0 -9 4 .9 8 0 -8 9 .9 7 0 -7 9 .9 < 7 0

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C o r r e la t io n B e tw e e n O p t im a l T h e r a p e u t ic R e s p o n s e a n d A d h e r e n c e

to P r o te a s e In h ib i to r T h e r a p y

P a te r s o n D , e t a l. A n n In te r M e d . 2 0 0 0 ;1 3 3 :2 1 - 3 0 .

SS

DefinitionsDefinitions

GenotypeGenotypeVirus nucleotide sequence from which a Virus nucleotide sequence from which a protein’sprotein’samino acids can be deducedamino acids can be deduced– Mutations reported as change in the deduced amino Mutations reported as change in the deduced amino

acid sequence, e.g., Met184Valacid sequence, e.g., Met184Val– Specific mutations confer phenotypic resistanceSpecific mutations confer phenotypic resistance– The phenotype is The phenotype is alwaysalways derived from the genotype derived from the genotype

PhenotypePhenotypeRelative growth of the virus in the presenceRelative growth of the virus in the presenceof different drug concentrationsof different drug concentrations– Usually reported as the drug concentration that Usually reported as the drug concentration that

inhibits virus replication by 50% (IC50), or the fold inhibits virus replication by 50% (IC50), or the fold increase in IC50increase in IC50

Clinical characteristics

Primary HIV infection

Established HIV infection

First regimen failure

Multiple regimen failures

Pregnancy

Recommendation

Consider testing

Consider testing

Recommend testing

Recommend testing

Recommend testing

Rationale

Detect transmission of drug-resistant virus; modify therapy tooptimize response and maintainHIV-specific immune responses

Detect prior transmission of drug-resistant HIV although this maynot always be possible withcurrent tests

Document drug(s) to which thereis resistance

Optimize the number of activedrugs in the next regimen;exclude drugs to which responseis unlikely

Optimize maternal treatment andprophylaxis for the neonate

IAS-USA Recommendations for IAS-USA Recommendations for Use of HIV Drug Resistance AssaysUse of HIV Drug Resistance Assays

Hirsch. JAMA 2000;283:2417.

Types of Drug Resistance Assays:Types of Drug Resistance Assays:Strengths and WeaknessesStrengths and Weaknesses

AvailabilityAvailability

Turnaround time 2 weeksTurnaround time 2 weeks

Mutations may precede Mutations may precede phenotypic resistancephenotypic resistance

Lower costLower cost

GENOTYPEGENOTYPE

Requires expert interpretationRequires expert interpretation

Measures susceptibility indirectlyMeasures susceptibility indirectly

Insensitive for detecting minor speciesInsensitive for detecting minor species

Does not assess interactions among Does not assess interactions among mutationsmutations

Does not address drug levelsDoes not address drug levels

Measures susceptibility Measures susceptibility directlydirectly

Results are easier to Results are easier to interpretinterpret

PHENOTYPEPHENOTYPE

Restricted availabilityRestricted availability

Turnaround time 2Turnaround time 2––4 weeks4 weeks

Insensitive for detecting minor speciesInsensitive for detecting minor species

Clinically significant cutoff values may not Clinically significant cutoff values may not be defined for some drugsbe defined for some drugs

More expensiveMore expensive

Fast results (2 weeks)Fast results (2 weeks)

Moderate costModerate costVIRTUALVIRTUAL

PHENOTYPEPHENOTYPE

Measures susceptibility indirectlyMeasures susceptibility indirectly

Insensitive for detecting interactions Insensitive for detecting interactions between mutationsbetween mutations

Strengths Weaknesses

Phenotype Sample Report From ViroLogicPhenotype Sample Report From ViroLogic