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

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

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

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

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)

TB cases in patients with HIV/AIDS, according to the year of notification in health centers*. CRT-DST/AIDS, 1994-2002. 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)

Outcomes from Tuberculosis Control Program in HIV+ Patients in HIV/AIDS Reference Center of São Paulo (CRT/DST-AIDS –SP), by different cohorts (1994-1999). 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).

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

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

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

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

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

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

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

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

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)

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?)

“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

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)