the tap and art programs in africa minimizing risks maximizing benefits november 30, 2006, a....
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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
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
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%