Evolving Realities of HIV Treatment in Resource-limited Settings Papa Salif Sow MD, MSc Department of Infectious Diseases University of Dakar, Senegal
Introduction: ARV access in RLS Scale-up of ART has been unprecedented ART initiation is too late: Low CD4 counts & clinical symptoms High early mortality Severe immunodeficiency/oi s Severe malnutrition Frequent co-infection with tuberculosis Frequent use of d4t in 1 st Line ARV Lack of virological tools for ARV monitoring: when and what to switch to Low access to 2 nd line ARV and Salvage ART
Number of people receiving ART in low- and middle-income countries, by region, 2002 2008 Souteyrand Y. IAS 2009
Botswana Rwanda Papua New Guinea Burkina Faso Zambia Haiti Gabon Kenya Malawi Swaziland Cote d'ivoire Lesotho South Africa Ethiopia Cameroon Burundi Guinea Mozambique Togo Guinea-Bissau Central African Rep Zimbabwe Congo Ghana Chad Percent Coverage ART Coverage in Resource-limited Settings 100% 80% 60% 40% 20% 0% www.unaids.org
CD4 count at start of ART, 2003 5 Comparison of the regional variation of CD4+ counts at the time ART therapy initiated Review of data from 42 countries, 176 sites; n=33,008 Median CD4+ counts at the start of therapy, by region/country North America US 187 Canada 164 South America Brazil 159 Argentina 181 Sub-Saharan Africa South Africa 87 Botswana 97 Malawi 97 Australasia India 103 Vietnam 53 Japan 192 China 163 Australia 239 Egger M, et al. 14 th CROI, Los Angeles 2007, #62
Late HIV presentation at the ARV initiation Therapy.
High frequency of Tuberculosis in patient who initiate ARV
Tuberculosis & ART in RLS Interations between Tb drugs and ARV Rifabutin not available 2009 WHO recommendations Preferred option : AZT or TDF + 3TC/FTC + EFV Initiate ART as soon as possible, within the first 8 weeks after starting TB Treatment NVP or 3 NRTI acceptable options if EFV cannot be used
1st line regimens in Resource-Limited Countries
2009 WHO ART Guidelines for Adults and Adolescents When to start: All adolescents and adults with HIV infection and CD4 counts 350 cells/mm 3, including pregnant women, should be started on antiretroviral therapy (ART) immediately, regardless of whether they have clinical symptoms. Individuals with severe or advanced clinical disease (WHO clinical stage 3 or 4) should start ART irrespective of CD4 cell count. What to use in 1 st line: First-line therapy should consist of an NNRTI + two NRTIs, one of which should be AZT or tenofovir. Countries using d4t in first-line regimens should start phasing it out because of its long term toxicity (2012 the latest) Replacing d4t by TDF in RLS
Impact of Late Treatment in Sub-Saharan African Countries Early mortality during the first three months High frequency of IRIS Presence of Resistant Viruses +++ Treatment failure of ART
Early Mortality in HIV/AIDS Immunodepression Severe Malnutrition ARV High Caloric Food
404 HIV patients longitudinal follow-up: 1998-2005 93 patients died: incidence rate of death was 6.3/100 persons-years 47 patients died during the first year after HAART Very immunodepressed patients CD4 less than 50 Most frequent causes of death: mycobacterial infection, septicemia 33% changed ARV regimen by 7 years
14,352 patients were enrolled In press Overall 13,102 patients were followed up for a median of 1.8 years (IQR:(0.8-2.8), 24620.7 persons-years of followup. During the overall study period, 521 (4.0%) patients were known to be dead 2,610 (19.9%) were lost to follow-up 9,971 (76.1%) patients were still in program and remained on ART 12 months after enrollment.
Retention rates in African ART Cohorts SOURCE: S Rosen, M P Fox, C J Gill PLoS 2007 Volume 4 1691-1698 10 2007
Patients are lost to ARV programs early on More than 20% of patients are lost to follow up Mean reasons: cost of consultations; AIDS stage High cost for transport: 50% of cost in Tanzania Poverty/logistics: ART interruption driven by stock shortages (OR 3.25), binge drinking (OR 2.87), wasting symptoms (1.23). Conclusion: Food supply programs and minimization of ARV shortage may reduce ART interruptions 1 Bull World Health Organ 2008 2. Morris K:www.thelancet.com/infection; 2008 3. Marcellin F: Tropical Medicine and Int. Health, 2008 4. Kruk M: Tropical Medicine and Int. Health, 2008
Treatment Failure and Drug Resistance in Resource Limited Settings CD4 Count Virologic failure Immunologic failure Clinical failure Drug Resistance Viral Load CARE5. Kumarasamy & P Salif Sow 2008
-Limited HIV-RNA monitoring in RLS -8376 patients from eight cohorts and two prospective studies were analysed -Resistance at virological failure at 48 weeks: infrequently versus frequently monitored - NNRTI : 88.3 % versus 61.0% (p< 0.001) - 3TC : 80.5 % versus 40.3 % (p< 0.001) - TAM : 27.8 % versus 12.1 % (p < 0.001)
Probability of death 0.14 Patients remaining on failing first-line regimen 0.12 0.10 Patients who switched Patients remaining on non-failing first-line regimen 0.08 0.06 0.04 0.02 0.00 0 2 4 6 8 10 12 Time after switching, after reaching WHO criteria or after the corresponding time since starting HAART (months)
HIV-2 Resistance mutations Multiclass drug resistance mutations (NRTI and PI) were detected in 30 % of patients (n= 23) 52 % had evidence of resistance to at least 1 ARV class 43 % had the M184V mutation 9 % had the K65R mutation 34% of patients had PI mutations
In summary :ARV Resistance in RLS Genotypic resistance at 48 weeks to 3TC and NRTI and NNRTI appears sustantially higher in less frequently monitored patients This highlights the need for cheap pointof-care viral load tests to identify early viral failures and limit the emergence of resistance.
Characteristics of a point-of-care viral-load test in RLS Simple to use & easy to read Independent of instrumentation or electronics Robust and able to withstand increased ambient temperatures without cold-chain shipment or storage Long shelf-life (longer than 12 months) Inexpensive (not > 2 $US) Harries Lancet ID: 2010 Jan;10(1):60-65.
Decentralization National VL Monitoring in RLS National Level Regional Level District Level Tertiary Laboratory : Reference Laboratory : using Nucleic Acid Testing Strategies Secondary Laboratories: Alternatives Viral Load Technologies : Non Nucleic Acid Primary Care Laboratories: sample preparation for referral
Conclusion : Perspectives RLS First line ART must be protected as long as possible (adults and children) Better management of co-infections HIV/TB : Rifabutin available HIV/HBV: HbSAg test before start ARV Reliable tools to diagnose ART failure (POC viral load) Easy-to use and relatively inexpensive second-line therapy has to be available
Demand for HIV testing still far exceeds supply