New Thai HIV Treatment Guidelines 2010 Wichai Techasathit, MD., MPH. Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand
When is Antiretroviral Therapy Started? Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008) Since 2000, CD4+ cell count at initiation in developed countries stable at approximately 150-200 cells/mm 3, increasing in sub-saharan Africa from 50-100 cells/mm 3 187 164 102 181 200 179 123 125 86 122 100 97 97 87 163 192 157 206 103 53 95 72 134 239 Egger M, et al. CROI 2007. Abstract 62.
Development of Antiretroviral Treatment in Thailand Before 1992 Treatment of common OI without ARV 1992 AZT mono-therapy 1995 Dual therapy with AZT + ddi, AZT+3TC 1997 Triple therapy through HIV Clinical Research Network 2000 Access to Care (ATC) with 8 pre-assigned regimens 2004 National Access to Antiretroviral Program for PHA (NAPHA) 2004 ARV program by Social Security Office (SSO) 2006 National AIDS Program (NAP) by National Health Security Office (NHSO): ART Benefit Package in Universal Coverage
Thai MOPH Guideline 2007 When to Treat อาการทางคล น ก ม ความเจ บป วยของ ระยะเอดส (AIDS-defining illness)* ระด บ CD4 (เซลล / ลบ.มม.) ค าแนะน า เท าใดก ตาม เร มยาต านเอชไอว ม อาการ** เท าใดก ตาม เร มยาต านเอชไอว ไม ม อาการ < 200 เร มยาต านเอชไอว ไม ม อาการ 200 350 ย งไม เร มยาต านเอชไอว ให ต ดตามอาการและตรวจระด บ CD4 ท ก 3 เด อน ไม ม อาการ > 350 ย งไม เร มยาต านเอชไอว ให ต ดตามอาการและตรวจระด บ CD4 ท ก 6 เด อน แนวทางการด แลร กษาผ ต ดเช อเอช ไอ ว และผ ป วยเอดส ในประเทศไทยป พ.ศ. 2549/50 กรมควบค มโรค กระทรวงสาธารณส ข สมาคมโรคเอดส แห งประเทศไทย สมาคมโรคต ดเช อในเด ก
Thai Guideline for ARV 2006-2007 2 NRTIs NNRTI หร อ PI 1 st line AZT+3TC d4t+3tc 2 nd line AZT+ddI ddi+3tc TDF+3TC ABC+3TC NVP EFV IDV/RTV SQV/RTV NFV ATV+RTV LPV/RTV National Guidelines on HIV/AIDS Diagnosis and Treatment: Thailand 2006-2007
Preferred and Alternative regimens for Initiation of ART - TAS 2008 J Med Assoc Thai 2008;91(12):1925-36
ARV Regimens: NHSO vs. SSO National Health Security Office (NHSO or NAP) Effective 1 April 2007 1. Group A d4t+3tc+nvp (GPOvirS) d4t+3tc+efv AZT+3TC+NVP(GPOvirZ) AZT+3TC+EFV 2. Group B d4t+3tc+idv/r AZT+3TC+IDV/r Social Security Office (SSO) Effective 1 January 2007 1. Basic regimens d4t+3tc+nvp AZT+3TC+NVP 2. Alternative regimens d4t(azt)+3tc+efv d4t(azt)+3tc+idv/r If other regimens needed Consultation for permission 3. Group C ddi+3tc or TDF+3TC in cases of lipoatrophy (Expert approval)
National Health Security Office (NHSO or NAP) 4. Group D (After expert approval) Boosted PI+OBR -d4t+3tc - ddi+3tc - AZT+3TC - AZT+ddI - AZT+TDF - TDF+3TC Social Security Office (SSO) 3. 2 nd line regimens (After expert approval) LPV/r+OBR ATV/r+OBR (not available) - ddi+3tc - AZT+3TC - AZT+ddI - AZT+TDF - TDF+3TC Boosted PIs+NVP (or EFV) in only NRTIs resistance Boosted PIs+AZT+3TC+TDF in NNRTIs & multi NRTIs resistance: Q151M &/or T69Si &/or TAM>4
National Health Security Office (NHSO or NAP) Choices of boosted-pis 1. IDV/r 2. LPV/r 3. ATV/r AIDS Experts Regional AIDS Consultants; RAC Bangkok AIDS Consultants; BAC Social Security Office (SSO) Choices of boosted-pis 1. IDV/r 2. LPV/r 3. ATV/r (not available) AIDS Experts Group of AIDS Consultants assigned by SSO
National Health Security Office (NHSO or NAP) Monitoring 1. CD4 x 2 times/yr 2. VL x 1 time/yr 3. Drug resistance x 1 time/yr 4. CBC, FBS, Cr, TG, TC, SGPT x 2 times/yr Social Security Office (SSO) Monitoring 1. CD4 x 2 times/yr 2. VL x 2 time/yr 3. Drug resistance x 1 time/yr To do genotypic drug resistance, VL must >2,000 copies/ml To do genotypic drug resistance, VL should >1,000 copies/ml
Who is still taking d4t? 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% 78.6 77.8 62.7 47.6 45.8 28.4 24.0 25.9 11.10 11.2 8.6 8.9 9.1 6.1 7.3 5.2 6.0 3.5 4.7 4.6 4.6 2.1 1.8 0.1 0.002 0.1 0.2 1.3 1.3 0.1 Cote d'ivoire Mozambique South Africa Tanzania Zambia d4t-3tc-nvp d4t-3tc-efv d4t-ftc-efv d4t-ftc-nvp AZT-3TC-NVP AZT-3TC-EFV TDF-FTC-EFV TDF-FTC-NVP d4t-3tc-lpv/r Other Westreich DJ, et al, Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy, Clin Infect Dis. 2009 Jun 1;48(11):1617-23 Marlink R et al, IAC 2008 (WEAXO106)
Situation in National AIDS Program, Thailand. 160000 140000 Cumulative Patients on 1st and 2nd Line ARV 6,470 2nd line regimens 4.54% 120000 135,809 100000 80000 60000 40000 20000 1 st line regimens 2 nd line regimens 0 Dec.06 Mar.07 Jun.07 Sep.07 Dec.07 Mar.08 Jun.08 Sep.08 Dec.08 Mar.09 Jun.09 Sep.09 Dec.09 Mar.10 National Health Security Office (NHSO) Thailand Data at 7 Mar 2010
NAP Data on ARV Regimens Other regimens Not on ARV Data at 14 JAN 2008
Number of Symptomatic and Asymptomatic AIDS needing ART in Baseline Scenario (asymptomatics with CD4 < 200) 300,000 250,000 200,000 Not on ART On ART 150,000 100,000 50,000 2007 = 245,551 UC = 78,365 2008 = 255,178 UC = 110,770 2009 = 259,948 UC = 136,704 2010 = 260,388 UC = 149,590 0 1990 1995 2000 2005 2010 2015 2020 2025
Coverage ARV in Thailand Before and After Universal Coverage (UC) ARV Need Current Receiving 300,000 250,000 200,000 150,000 42.5 % 100,00032.5 % ARV-UC 51.5 % 77.8 % 67.1 % 56.4 % 50,000 0 2004 2005 2006 2007 2008 2009 Source: UNGASS 2009
When to Start Antiretroviral Therapy Late clinical stages Late clinical stages Early Clinical Stages Early Clinical Stages < 200 < 200 > 500 > 500 Any viral load Any viral load 200 200 350 350 High Viral load High Viral load CD4 Schechter, 2004 (JID 2004;190:1043-1045)
CD4+ Count Response Based on Baseline CD4+ Count 1000 Johns Hopkins HIV Clinical Cohort 1000 ATHENA National Cohort Mean CD4+ Count (cells/mm 3 ) 800 600 400 200 800 600 400 200 0 0 1 2 3 4 5 Years on HAART Magnitude of CD4+ increase greatest if therapy started at low CD4+ counts, but greater likelihood of CD4+ count normalization with earlier therapy Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530. 0 0 48 96 144 192 240 288 336 Weeks From Starting HAART
Clinical Outcome Improved by Starting Therapy at Higher CD4+ Cell Count Timing of antiretroviral initiation in treatment-naive subjects (N = 10,885) in Antiretroviral Cohort Collaboration HR for progression to AIDS or death by CD4+ cell count at initiation of therapy < 200 vs 201-350 cells/mm 3 HR: 2.93 (95% CI: 2.41-3.57) < 350 vs 351-500 cells/mm 3 HR: 1.26 (95% CI: 0.94-1.68) Results suggest a lower risk of disease progression/death when starting between 351-500 cells/mm 3 Sterne J, et al. CROI 2006. Abstract 525. Probability of AIDS or Death Cumulative Probability of AIDS/Death by CD4+ Cell Count at HAART Initiation 0.12 0.10 0.08 0.06 0.04 0.02 0.00 101-200 cells/mm 3 201-350 cells/mm 3 351-500 cells/mm 3 1 2 3 4 5 Years Since Initiation of HAART
IAS-USA Guidelines: When to Start Year Recommendation to Begin Immediate Therapy 2006 Active AIDS No history of active AIDS, but CD4+ cell count 200 cells/mm 3 2008 Active AIDS No history of active AIDS, but CD4+ cell count < 350 cells/mm 3 Recommendation to Consider Immediate Therapy No history of active AIDS, but CD4+ cell count from 200-350 cells/mm 3 CD4+ cell count > 350 cells/mm 3 but rapid CD4+ cell count decline, HIV-1 RNA > 100,000 copies/ml, CVD risk factors, other non-aids risk factors CD4+ cell count 350 cells/mm 3 but rapid CD4+ cell count decline, HIV-1 RNA > 100,000 copies/ml, CVD risk factors, other non-aids risk factors Recommendation to Delay Therapy CD4+ cell count 350 cells/mm 3 CD4+ cell count 350 cells/mm 3 Hammer SM, et al. JAMA. 2008;300:555-570.
DHHS Dec 2009 Guidelines: When to Start Treatment Clinical Category AIDS-defining illness or severe symptoms* (AI) CD4+ Cell Count Plasma HIV-1 RNA * Severe symptoms = unexplained fever or diarrhea > 2-4 wks, oral candidiasis, or > 10% unexplained weight loss. General Guidelines Any value Any value Treat Asymptomatic (AI) < 350 Any value Treat Asymptomatic (A/B-II) 350-500 Any value 55% of panel members voted for strong recommendation (A) 45% of panel members voted for moderate recommendation (B) Asymptomatic (B/C-III) > 500 Any value 50% of panel members favor starting ART (B) 50% of panel members view treatment is optional (C) Pregnancy (AI) HIV associated nephropathy (AII) HBV co-infection when HBV treatment is indicated (AIII) Any value Any value Treat DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Dec 1, 2009
Half of DHHS Panel Recommended ART Initiation at CD4+ Cell Count > 500 c/mm 3 Arguments in Favor Cohort data showing survival benefit Untreated HIV infection may be associated with higher risk of non-aids conditions Availability of newer regimens with improved efficacy, convenience, and tolerability Growing evidence that treatment reduces HIV transmission Arguments Against Available data do not definitively establish benefit of ART in all patients with CD4+ cell count > 500 cells/mm 3 Benefits of earlier initiation may be outweighed by Risks of short- or long-term drug-related adverse events Risk of nonadherence in asymptomatic patients Potential for development of drug resistance DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf.
December 2009 DHHS Guidelines: Preferred Initial Regimens Preferred regimens: those with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use NNRTI based EFV/TDF/FTC Boosted PI ATV/RTV + TDF/FTC based DRV/RTV + TDF/FTC INSTI based RAL + TDF/FTC DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf.
ART and Lipoatrophy NRTI Choice: The Major Factor Driving Lipoatrophy Risk Highest Risk Intermediate Risk Lowest Risk Unknown d4t ZDV 3TC ddi + 3TC d4t + ddi ABC FTC TDF
Study 934 Median Total Limb Fat (Q1, Q3) Through Week 144 for Patients with Week 48 Data Kilograms 14 12 10 8 6 4 2 0 0 FTC+TDF+EFV AZT+3TC+EFV For change from week 48 within arm Data on file, Gilead Sciences. TDF+FTC AZT+3TC 7.4* 6.0* *P = 0.035 8.1 5.5 P < 0.001 48 96 144 Weeks 51 49 49 44 8.3 4.9 P < 0.001 48 38
ACTG 5142: Lipoatrophy at Week 96 Patients With Lipoatrophy (%) 60 45 30 15 0 32 17 9 Overall 33 51 d4t 40 16 ZDV LPV/RTV + 2 NRTIs EFV + 2 NRTIs EFV + LPV/RTV 12 6 TDF NRTI-Containing Regimens Lipoatrophy defined as > 20% loss of extremity fat by DEXA Haubrich R, et al. CROI 2007. Abstract 38.
ACTG 5142: Drug-Associated Risk for Lipoatrophy Drug-Associated Risk for Lipoatrophy at Week 96 (Logistic Regression)* Factor OR (95% CI) P Value EFV vs LPV/RTV 2.7 (1.5-4.6) <.001 d4t vs ZDV 1.9 (1.1-3.5).029 TDF vs ZDV 0.24 (0.12-0.50) <.001 *Excludes NRTI-sparing arm. Haubrich R, et al. CROI 2007. Abstract 38.
Study 903E: Patients Switching From d4t to TDF Mean (95% Cl) Total Limb Fat Years 2-6 Mean Limb Fat in kg 10 8 6 4 2 8.0 5.0 8.1 8.0 4.6 5.0 TDF+3TC+EFV d4t+3tc+efv P=0.04 8.8 8.2 5.5 5.8 P<0.001 0 1 2 3 4 5 6 Year n = 69 69 65 61 58 n = 74 74 74 71 68 Madruga JVR. HIV8, 2006 Glasgow, UK. Poster P120. Cassetti I. HIV8; 2006; Glasgow, UK. Poster P152. Data on file, Gilead Sciences.
NRTIs: Lipid Changes From Baseline in Recent Prospective Clinical Trials Study and Drugs Compared GS 934 (144 wks) [1] TC, mg/dl TG, mg/dl EFV + TDF + FTC +24 +4 EFV + ZDV/3TC +36 +36 SWEET (24 wks) [2] TDF/FTC -13-22 ZDV/3TC -1 +22 BICOMBO (48 wks) [3] ABC/3TC +12 +0 TDF/FTC -9-16 RAVE (48 wks) [4] TDF -19.3-26.6 ABC +7.7 +8.9 Conclusion ZDV/3TC TC (P =.005) and TG (P =.047) more than TDF + FTC ZDV/3TC TC (P =.008) and TG (P <.001) more than TDF/FTC ABC/3TC TC (P =.001), HDL (P <.0001), LDL (P <.0001), and TG (P =.01) more than TDF/FTC ABC TC (P <.0001) more than TDF 1. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 2. Moyle G, et al. IAS 2007. Abstract WEPEB028. 3. Martinez E, et al. IAS 2007. Abstract WESS102. 4. Moyle GJ, et al. ICAAC. Abstract H-340.
Draft Thai ART Guidelines 2010 (Adult 1) Clinical Presentations CD4 (cells/mm 3 ) Recommendations AIDS-defining illness Any Treat HIV-related Symptomatic Any Treat Asymptomatic <350 Treat Asymptomatic >350 Pregnancy Any Special consideration for ART initiation Defer Rx, follow clinical status and CD4 every 6 months Treat, discontinue ARV after delivery if pre-treat CD4 >350 cells/mm 3 HBV or HCV co-infection: any CD4 if treatment of HBV or HCV needed Age >50: CD4 350-500 with at least one of these following conditions (DM, HT, Dyslipidemia) Bureau of AIDS,TB, and STIs and Thai AIDS Society (TAS)
Draft Thai ART Guidelines 2010 (Adult 2) NRTIs NNRTIs PIs Preferred Preferred AZT + 3TC TDF + 3TC/FTC Alternative ABC + 3TC d4t + 3TC ddi + 3TC + EFV NVP or (If can not tolerate NNRTIs) LPV/r Alternative ATV/r DRV/r SQV/r **In alphabetic order** Bureau of AIDS,TB, and STIs and Thai AIDS Society (TAS)
Draft d4t Phase-Out Plan 1. Patients on d4t or AZT with lipoatrophy d4t or AZT TDF 2. Patients on d4t without lipoatrophy d4t AZT 1 st priority: patients with the longest duration on d4t If patients could not tolerate AZT or start to develop lipoatrophy (after 6 months of AZT) then switch to TDF **Viral load <50 before switching to TDF**
Draft Thai ART Guidelines 2010 (PMTCT) CD4 (cells/mm 3 ) Regimen <350 AZT+3TC+LPV/r (all q 12 hrs) >350 AZT+3TC+LPV/r (all q 12 hrs) Start immediate After 14 wks gestation Timing After delivery Continue ARV (could be switched to NNRTI-based regimens) Discontinue ARV Bureau of AIDS,TB, and STIs and Thai AIDS Society (TAS)
Draft Thai ART Guidelines 2010 (Pediatric) Age < 1 ป Age 1-5 ป Age > 5 ป Clinical Presentations Treat CDC category B, C or WHO stage 3, 4 CDC category B, C or WHO stage 3, 4 CD4 levels %CD4 or absolute CD4 Treat %CD4 <25 CD4 <350cells/mm 3 Bureau of AIDS,TB, and STIs and Thai AIDS Society (TAS)
Case 1 40 year-old man was diagnosed with HIV in Dec 2001. No other medical history is available. CD4 VL May 2002 43 - GPOvir (30) (d4t+3tc+nvp) Jan 2003 14 - Jun 2004 55 - Nov 2004 13 - Mar 2005 29 -
CD4 Case 1 40 year-old man was diagnosed with HIV in Dec 2001. No other medical history is available. VL Sep 2005 29 25,631 Do nothing??? Mar 2006 23 - Oct 2006 17 - May 2007 3 - Jul 2007-27,000 Do nothing???
Case 1 CD4 VL Nov 2007 4 - May 2008 74 - Lipoatrophy Jun 2008-5,500 GPO (Z250) (AZT+3TC+NVP) Nov 2008 20 - Anemia from AZT (Hb 8 gm) Switched to TDF then Feb 2009-29,000 Genotypic drug resistance??? M41L, K65R, M184V, T215Y, Y181C, G190A
Case 2 34 yrs male, IVDU, Dx HIV+ May 2002 presented with Pulmonary TB CD4 VL Sep 03 134 Oct 03-82,742 Started GPOvir May 04 289 - Mar 05 351 <50 Dec 05 419 - Aug 06 357 33,700 Genotype Feb 07 415 2,784 No Mutation Jul 07 358 12,367 Genotype M41L, Q151M, M184V, T215Y, Y181C