The TAP and ARTThe TAP and ARTPrograms in AfricaPrograms in Africa

Minimizing risksMinimizing risks

Maximizing benefits Maximizing benefits

November 30, 2006, A. VoetbergACTafrica, World Bank

The Risks The Risks

What are the risks?What are the risks?

Are they real and have they Are they real and have they materialized? materialized?

What are the What are the risk–mitigating options?risk–mitigating options?

The RisksThe Risks

Drug resistance development and Drug resistance development and transmission of drug resistant viral strainstransmission of drug resistant viral strains

Dis-inhibitonDis-inhibiton

No exit strategy, No exit strategy, no continuation strategyno continuation strategy

Crowding out prevention and other Crowding out prevention and other public health prioritiespublic health priorities

Sustainability in long termSustainability in long term

Risk 1: Risk 1: drug resistancedrug resistance

““If compliance and careful follow-up of If compliance and careful follow-up of patients is not achieved, we will see a patients is not achieved, we will see a

dramatic increase in multidrug-resistant dramatic increase in multidrug-resistant HIV mutants whose further spread will HIV mutants whose further spread will

only exacerbate the epidemic.”only exacerbate the epidemic.”

3-Drug Combination ART: 19963-Drug Combination ART: 19968AM 4PM 12 MID

fasting (1 hour before/2 hours after meals)1.5 liters of hydration/day

AZT +

3TC

+

IDV

3-Drug Combination ART: 20063-Drug Combination ART: 2006

At bedtime

TDF/FTC

+

EFV

Risk 1:Risk 1: drug resistancedrug resistance

Partial viral suppression leads to selection of resistant virusPartial viral suppression leads to selection of resistant virus

When HIV replication is not blocked completely…. When HIV replication is not blocked completely….

Sub-optimal therapy regimens Sub-optimal therapy regimens (e.g. partially suppressive regimens)(e.g. partially suppressive regimens)

Adherence problemsAdherence problems Pharmacokinetic problems: poor drug absorption, Pharmacokinetic problems: poor drug absorption,

inadequate dosing, drug-drug interactions, interperson inadequate dosing, drug-drug interactions, interperson differences in PKdifferences in PK

…….drug-resistant virus, is selected for and ultimately .drug-resistant virus, is selected for and ultimately dominatesdominates

Risk 1:Risk 1: drug resistancedrug resistance

Is it a real risk?Is it a real risk?

Resistance acquired while on treatment: Yes, but Resistance acquired while on treatment: Yes, but patterns clearer and problems more pronounced with the “old” patterns clearer and problems more pronounced with the “old” epidemic - a history of mono- and dual therapy regimenepidemic - a history of mono- and dual therapy regimen

Transmitted resistance: Yes, and still a cause of Transmitted resistance: Yes, and still a cause of concern, but prevalence of drug resistant strains in treatment-concern, but prevalence of drug resistant strains in treatment-naïve patients seems to stabilize around 9 to 10 percent (in naïve patients seems to stabilize around 9 to 10 percent (in Europe)Europe)

Drug resistance monitoring efforts (EWI, cohort studies) Drug resistance monitoring efforts (EWI, cohort studies) in emerging stages of implementation in SSAin emerging stages of implementation in SSA

European HIV Drug Resistance Workshop, Monte Carlo, March 2006

Risk 1:Risk 1: drug resistancedrug resistance

The good news: adherence good, becoming The good news: adherence good, becoming easier with new productseasier with new products

More products on the market, less side More products on the market, less side effects, fixed-dose combination formulas, effects, fixed-dose combination formulas,

new classes of drugs new classes of drugs (entry inhibitors, integrase inhibitors, (entry inhibitors, integrase inhibitors,

maturation inhibitors)maturation inhibitors)

The bad news: costs of new and second-line The bad news: costs of new and second-line drugs still prohibitivedrugs still prohibitive

Risk 1: Risk 1: drug resistancedrug resistance Risk mitigation options:Risk mitigation options:

Quality assurance (validation) of treatment regimen and Quality assurance (validation) of treatment regimen and prescribing practices, accreditation programsprescribing practices, accreditation programs

Adherence support programsAdherence support programs

Prevention counseling for those on ARTPrevention counseling for those on ART

Rationing: preferential treatment to those who are most likely Rationing: preferential treatment to those who are most likely to adhereto adhere

Continued Research & Development of better tolerated, more Continued Research & Development of better tolerated, more effective and cheaper ARVs with fewer side effectseffective and cheaper ARVs with fewer side effects

EWI and drug resistance monitoring inEWI and drug resistance monitoring intreatment naïve patient cohortstreatment naïve patient cohorts

Risk 1: Risk 1: drug resistancedrug resistance The unknowns:The unknowns:

The scale of transmission of drug-resistant The scale of transmission of drug-resistant viral strains in high viral strains in high

transmission environments transmission environments

And we’re still “early” in the And we’re still “early” in the process of ART scale-up process of ART scale-up

Risk 2: Risk 2: dis-inhibitiondis-inhibition

An increase in risky sexual behavior An increase in risky sexual behavior when ARVs become available and when ARVs become available and

accessibleaccessible

Risk 2: Risk 2: dis-inhibitiondis-inhibition

Is it a real risk?Is it a real risk?

Literature mixed, potential risk is there asLiterature mixed, potential risk is there asdocumented in San Francisco study but other documented in San Francisco study but other studies found studies found lessless risky behavior (Kenya and risky behavior (Kenya and

Uganda)Uganda)

Risk 2: Risk 2: dis-inhibitiondis-inhibition

Risk mitigation optionsRisk mitigation options

Scale-up of prevention programsScale-up of prevention programs

ART “literacy” programsART “literacy” programs

Prevention counseling for Prevention counseling for those on ARTthose on ART

Risk 2: Risk 2: dis-inhibitiondis-inhibition

The unknown:The unknown:

We’re still “early” in the We’re still “early” in the process of ART scale-up process of ART scale-up

Risk 3: Risk 3: no exit strategy, no no exit strategy, no

continuation strategycontinuation strategy

Long-term, predictable financing needed but non-Long-term, predictable financing needed but non-existent, exposing governments and external existent, exposing governments and external

financiers to “liabilities” that financiers to “liabilities” that they may not be able to deal with they may not be able to deal with

Leaving patients with an uncertain future about Leaving patients with an uncertain future about their continued access to ART programstheir continued access to ART programs

Large scale treatment interruptions could and Large scale treatment interruptions could and probably will result in serious risks to the patient probably will result in serious risks to the patient

as well as to the integrity and benefitsas well as to the integrity and benefitsof ART programs of ART programs

Risk 3: Risk 3: no exit strategy, no no exit strategy, no

continuation strategycontinuation strategy Is it a real risk?Is it a real risk?

Yes,Yes, and we’re all struggling and we’re all struggling (governments, GFATM, PEPFAR, WB)(governments, GFATM, PEPFAR, WB)

New approaches yet untestedNew approaches yet untested

(e.g. the GF’s “rolling continuation channel” will (e.g. the GF’s “rolling continuation channel” will sometimes permit a CCM to apply for up to six years sometimes permit a CCM to apply for up to six years of further funding for a grant that is approaching the of further funding for a grant that is approaching the end of Phase 2. or, the GF’s end of Phase 2. or, the GF’s “Continuity of Services”

policy, which ensures the provision of up to two years-worth of continued funding of treatment-based

services for people who have already been placed on treatment through grants that will shortly be ending.))

Risk 3: Risk 3: no exit strategy, no no exit strategy, no

continuation strategycontinuation strategy Risk mitigation options:Risk mitigation options:

Development of long-term financing instruments and Development of long-term financing instruments and commitments: continuation strategycommitments: continuation strategy

Rationing: those who can affordRationing: those who can afford to pay or co-pay: limited entry strategy to pay or co-pay: limited entry strategy

Develop up-front agreements for take-over with other Develop up-front agreements for take-over with other financiers: handing-over strategyfinanciers: handing-over strategy

Maximize benefits, increase program effectiveness and Maximize benefits, increase program effectiveness and efficiency, mobilize additional resources: efficiency, mobilize additional resources:

marketing strategymarketing strategy

Share uncertainty about future funding with those (to be put) Share uncertainty about future funding with those (to be put) on treatment from the very start: the partnership strategyon treatment from the very start: the partnership strategy

Risk 4:Risk 4: crowding outcrowding out

ART programs may be crowding out other ART programs may be crowding out other priorities: priorities:

Prevention programsPrevention programs

Finances (especially recurrent costs)Finances (especially recurrent costs)

Human resource capacityHuman resource capacity

Policy dialogue on other Policy dialogue on other public health issues public health issues

Risk 4:Risk 4: crowding outcrowding out

Is it a real risk?Is it a real risk?

Yes, and it happens everywhere, to Yes, and it happens everywhere, to varying degrees varying degrees

But maybe justified in view of But maybe justified in view of back-log, if temporary and not back-log, if temporary and not

excessiveexcessive

Risk 4:Risk 4: crowding outcrowding out Risk mitigation options:Risk mitigation options:

Maintain or restore a sensible treatment – care – Maintain or restore a sensible treatment – care – prevention balanceprevention balance

Put the ART program in a sector-wide context (e.g. Put the ART program in a sector-wide context (e.g. through sector analysis, SWAp)through sector analysis, SWAp)

Wherever locally feasible and appropriate: integration Wherever locally feasible and appropriate: integration with other services, decentralization and delegation, with other services, decentralization and delegation,

simplify protocols as much as possible, use PPPssimplify protocols as much as possible, use PPPs

Develop instruments for long-term predictable financingDevelop instruments for long-term predictable financing

Avoid narrowly defined expected outcomes and/or results Avoid narrowly defined expected outcomes and/or results from health systems from health systems

Increase capacity of- and enrollment in nursing and Increase capacity of- and enrollment in nursing and medical schools medical schools

Risk 5: Risk 5: long term sustainabilitylong term sustainability Is it a real risk?Is it a real risk?

Maybe, maybe notMaybe, maybe not

Without the precedence of addressing a Without the precedence of addressing a global viral epidemic through treatment global viral epidemic through treatment

pronouncements on long-term sustainability pronouncements on long-term sustainability amounts to speculation: we’re making history amounts to speculation: we’re making history

An HIV/AIDS program without ART An HIV/AIDS program without ART component less likely to be sustainable component less likely to be sustainable

Antiretroviral Drug ApprovalAntiretroviral Drug ApprovalFDA, 1987 - 2005FDA, 1987 - 2005

0

5

10

15

20

25

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

AZTddI

ddCd4T

3TCSQV

RTVIDVNVP

NFVDLV

EFVABC

APVLPV/r

TDF

ENFATVFTC

TPV

Source: FDA, 2006

Risk 5: Risk 5: long term sustainabilitylong term sustainability Risk mitigation options:Risk mitigation options:

Explore and maximize approaches in which treatment and Explore and maximize approaches in which treatment and prevention are mutually reinforcingprevention are mutually reinforcing

Maximize benefits, increase program effectiveness and Maximize benefits, increase program effectiveness and efficiency, mobilize additional resourcesefficiency, mobilize additional resources

Wherever locally feasible and appropriate: integration with Wherever locally feasible and appropriate: integration with other services, decentralization and delegation, simplify protocols other services, decentralization and delegation, simplify protocols

as much as possible, use PPPsas much as possible, use PPPs

Integrate ART programs into PRSPs, MTEFs, and sector-wide Integrate ART programs into PRSPs, MTEFs, and sector-wide policies and strategiespolicies and strategies

Protect benefits realized (e.g. OVC, PMTCT, TB)Protect benefits realized (e.g. OVC, PMTCT, TB)

Benefits Benefits Which benefits are we looking at?Which benefits are we looking at?

Life years saved, better quality of lifeLife years saved, better quality of life

Reduced transmission of HIV (directly through Reduced transmission of HIV (directly through lowering viral load or indirectly through increased lowering viral load or indirectly through increased

uptake of CT and PMTCT servicesuptake of CT and PMTCT services

Preservation of human capital and slower increase in Preservation of human capital and slower increase in the number of orphansthe number of orphans

Economic benefits, at household-, corporate- or Economic benefits, at household-, corporate- or macro level, keeping people out of poverty macro level, keeping people out of poverty

Benefits Benefits Maximizing benefitsMaximizing benefits

Explicit rationing or targeting: making sure, to the extent Explicit rationing or targeting: making sure, to the extent possible, that the most relevant or important benefits are realizedpossible, that the most relevant or important benefits are realized

Examples: limiting a further increase in the number of orphans Examples: limiting a further increase in the number of orphans by a CT and ART campaign targeting mothers/parents of young by a CT and ART campaign targeting mothers/parents of young

childrenchildren

Example: intensify ART program in peri-urban areas – important Example: intensify ART program in peri-urban areas – important hot spots for people who are just above the poverty linehot spots for people who are just above the poverty line

Example: preferential treatment of skilled workers (health Example: preferential treatment of skilled workers (health workers, university faculty, teachers, soldiers etc.) in order to workers, university faculty, teachers, soldiers etc.) in order to

conserve valuable human capitalconserve valuable human capital

Conclusion Conclusion Some of the ART program related risks Some of the ART program related risks

are real, we need to do much more in are real, we need to do much more in moving on the options to mitigate moving on the options to mitigate

against themagainst them

Many of the ART program related Many of the ART program related benefits are real and substantial, we benefits are real and substantial, we

need to do much more on the options to need to do much more on the options to optimize themoptimize them

Thank you!!Thank you!!

Predictors of Inadequate Predictors of Inadequate AdherenceAdherence

Regimen complexity and pill burdenRegimen complexity and pill burden Poor clinician-patient relationshipPoor clinician-patient relationship Active drug use or alcoholism Active drug use or alcoholism Unstable housingUnstable housing Mental illness (especially untreated depression)Mental illness (especially untreated depression) Lack of patient education Lack of patient education Medication adverse effects (or fear of them)Medication adverse effects (or fear of them)

Not age, race, sex, educational level, socioeconomic status, past history of alcoholism or drug use

Improving AdherenceImproving Adherence

Establish readiness to start therapyEstablish readiness to start therapy

Provide education on medication dosingProvide education on medication dosing

Review potential side effectsReview potential side effects

Anticipate and treat side effectsAnticipate and treat side effects

Utilize educational aids including pictures, pillboxes, Utilize educational aids including pictures, pillboxes, and calendarsand calendars

Individualized adherence programsIndividualized adherence programs

CDC Surveillance of Resistance Mutations CDC Surveillance of Resistance Mutations In Naive PatientsIn Naive Patients

633 newly diagnosed 633 newly diagnosed patients genotyped at patients genotyped at 89 sites in 6 states 89 sites in 6 states in 2003-2004in 2003-2004

14.5% prevalence of 14.5% prevalence of resistance mutationsresistance mutations• NRTI, 7.8% NRTI, 7.8% • NNRTI, 3.0% NNRTI, 3.0% • PI, 0.7% PI, 0.7% • Multiclass, 0.7%Multiclass, 0.7%

Bennett D et al. 12th CROI 2005; abstract 674

Pre

vale

nce

(%

)

7.8%

3.0%

0

2

4

6

NRTI NNRTI PI Multi

0.7%

8

0.7%