1. A double strategy to be adopted in developing countries?
DOT-TB and DOT-HAART
A double strategy to be adopted in developing countries?
Marco Antônio de Ávila Vitória, MD
Brazilian STD/AIDS Program
Ministry of Health
June of 2003

2. The Road to 3 Million on Treatment: Doubling of numbers every year
HIV AIDS Department – WHO, 2002

3. From thousands to millions?: no single approach will do
Cheap and simple
monitoring
Prevention
Robust drugs
Simple regimens
Expertise and
Manpower
Drug distribution
Financing health
care
Operational
research

4. Challenges of antiretroviral therapy in resource poor settings
Insufficient political commitment
Limited resources/cost of care (including antiretrovirals)
Lack of infrastructure
Lack of expertise
Lack of a common agenda and leadership in implementation
Complexity of ARV treatment

5. TB/HIV Co-Infection Rates in Brazil (by States and Mean), 2000
Brazil (mean): 8,1%
HIV prevalence in general population: 0,6% (MOH, 2000)

6. TB cases in patients with HIV/AIDS, according to the year of notification in health centers*. CRT-DST/AIDS,
1997/96: - 53,3%
2001/96: - 65,3%
2002/96: - 71,8%
Introduction of HAART in Brazil
*First notification and reincidences
Source: Epidemiological Surveillance. CRT-DST/Aids (data till Dec, 31, 02)

7. Outcomes from Tuberculosis Control Program in HIV+ Patients in HIV/AIDS Reference Center of São Paulo (CRT/DST-AIDS –SP), by different cohorts ( ).
Proportion of TB patients under DOTS in Brazil: ~25-30%
Mean Rates in TB pts (SP):
Cure: 70%
Abandon: 16%
Death: 6,7%
Source: E. S. CRT-DST/Aids (data until 07/2002).

8. Completed TB Treatment Considering Treatment Modalities
Treatment Strategy
Number of Studies
Completed Treatment (%)
DOT-Plus 12
90,2
DOT (“Classic”) 4
85,7
“Modified” DOT 2
80,6
Regular Treatment (without supervision) 9
61,4
Chaulk et al, 1989

9. DOT-TB and DOT-HIV Comparisons
Major Aspects
DOT-TB
DOT-HIV
Public Health Approach
Prevention of TB transmission and drug resistance
Reduction of HIV transmission and drug resistance (?)
Individual Approach
Cure
Suppression
Programmatic Approach
All doses are supervised
Generally not all doses are supervised
Duration of Treatment
6-9 months
Lifelong (?)
Target Population
All patients
Selected groups
Dosing
Once-daily to twice -weekly
Once- or twice-daily
Pill Burden
Low to moderate
Moderate to high
Tolerability
Generally good
Frequently poor
Lucas, 2001

10. Impact of Different ARV Regimen Characteristics on Patient Adherence (RESA 41071 Study)
“HELP” ADHERENCE
2 to 5 pills per day
Small- or medium-sized pills
No food or water restrictions/requirements
Once- or twice-daily dosing frequency
“HURT” ADHERENCE
10 to 16 pills per day
Large pills
3 doses per day
Food restrictions
Jordan et al, 2000

11. To Improve HAART Adherence We Must Simplify the Tretament...
Reducing tablet load
Removing food restrictions
Reducing frequency (ideally all drugs taking at the same time)
Using ARV fixed dose combinations

12. Once-Daily Dosing: Considerations and Restrictions
ADVANTAGES:
Convenience to patient
Benefits in certain settings (e.g., prisons, methadone clinic)
Potential improve adherence
Consistent timing of morning meals
DISADVANTAGES:
No demonstrated benefit in adherence in once-daily vs twice-daily dosing:
Impact of missed doses linked to differential pharmacokinetic profile
Limited availability of other once-daily drugs to support regimen
Pill burden
RESTRICTIONS:
Dietary/timing restrictions
Once-daily regimens generally must be split (“false” once-daily regimens) and with at least 3 pills per day
Once-daily regimens with unpleasant side effects
Once-daily regimens are less forgiving

13. Selected Once-Daily HAART Studies: Patient and Treatment Characteristics
Clinical Trial
Country
Year
No. Patients
HAART Regimens
Adherence Rate(%)
Maggiolo
Italy
2001 75
ddI/3TC/EFV 98
Mole US 10
ddI/3TC/IDV/r
> 90
Molina
France
2000 40
ddI/FTC/EFV 97
Skoworn 11
ddI/3TC/EFV/ADF 89
Jordan 15
ddI/NVP/EFV NR
Landman 90
Magiollo (*)
2002
102
ddI/3TC/EFV vs ZDV/3TC/EFV vs ZDV/3TC/NFV
Saag (*)
571
ddI/FTC/EFV vs ddI/d4T/EFV
Senegal
95%
Virological Efficacy: 70-95% (mean  CD4: + 114/mm3)
Ena & Pasquau, 2003
(*) Randomized controlled

14. Large Observational Study in India (Pujari et al.*)
Safety and Immunological Effectiveness of Simplified ARV Fixed Dose Combination
Large Observational Study in India (Pujari et al.*)
Pune and Ahmehabad HIV clinics
ARV naive HIV+ patients (n= 994) initiating NVP fixed dose combination HAART
AZT/3TC/NVP ( n=659)
d4T/3TC/NVP (n=335)
Significant immunologic improvement after 24 months (> 3 x increase in mean CD4 counts)
Adherence rate: > 95%
Adverse events in first 3 months: ~ 23% (mainly in female gender)
(*) to be presented in 2nd IAS Conference , Paris, July 2003

16. Once-Daily ARV that can be used in DOT-HAART regimens
APPROVED
EFAVIRENZ
NEVIRAPINE
DIDANOSINE
TENOFOVIR
AMPRENAVIR/r
LAMIVUDINE
UNDER INVESTIGATION
ABACAVIR
SAQUINAVIR/r
INDINAVIR/r
LOPINAVIR/r
STAVUDINE (ER)
ATAZANAVIR
EMTRICITABINE (FTC)
T-1249

17. POTENTIAL ADVANTAGES OF DOT-HAART
Improve Adherence
Improve Tolerability (?)
Cost Reductions (direct and indirect)
Improvement of clinical and laboratorial monitoring (prevention and health promotion)
Permits and Integrated Health Approach (other associated needs and health problems)
Impact in Public Health issues (DOT-TB model)

18. POTENTIAL CHALLANGES OF DOT-HAART
IMPACT (LACK) OF INFRASTRUCUTURE AND HUMAN RESOURCES IN DIFFERENT EPIDEMIC SCENARIOS
DISPITE HAART SIMPLIFICATION, HIV TREATMENT CONTINUE TO BE A COMPLEX ISSUE
EVALUATION AND VALIDATION OF THIS POLICY NEED TO BE ELABORATED
SOCIAL DIMENSION OF AIDS IS WIDER THAN ITS EPIDEMIOLOGICAL DIMENSION (will DOT-HAART promote additional stigmatization?)

19. “DOT-HAART”:HOW TO IMPLEMENT?
USE OF GOOD EXERIENCES WITH DOT-TB AS A FRAME MODEL (BUT HOW IT CAN BE USEFULL?)
MUST INITIALLY BE LIMITED TO SPECIFIC SITUATIONS (PILOT STUDIES? SPECIFIC PROTOCOLS IN REFERENCE SITES?)
POSSIBLE CRITERIA:
HARD TO REACH POPULATIONS (Prisoners, IDU, long term care facilities, marginalized populations ?)
PLACES WITH SIGNIFICANT BURDEN OF BOTH INFECTIONS (CONSIDER INFRA-STRUCTURE, SPECIFIC NON-ADHERENCE MARKERS)?
PLACES WHERE DOT-TB STRATEGIES ARE WELL IMPLEMENTED

20. CONCLUSIONS
SIMPLIFIED REGIMENS (ONCE- OR TWICE-DAILY) COULD BE THE FIRST CHOICE INITIAL HAART REGIMEN FOR MAJORITY OF PATIENTS FOR SCALING UP PURPOSES.
DOT-HAART MUST BE CONSIDERED IN SELECTED GROUPS WITH HIGH RISK OF NON-ADHERENCE OR POOR OUTCOME
REASONS WHY TB/HIV CO-INFECTION MUST BE CONSIDERED A TARGET FOR DOT-HAART/DOT-TB STRATEGIES:
ELEVATED RISK FOR DEATH, ABANDON AND TB TREATMENT FAILURE
HIGH PREVALENCE IN IVDU, MARGINALIZED POPULATIONS
HIGH PILL BURDEN (TB + HAART DRUGS)
OVERLAPPING DRUG TOXICITY
ARV/TB DRUG INTERACTIONS
RISK OF IMMUNE RECONSTITUTION SYNDROME (POST-HAART)