2009 Recommendations for Antiretroviral Therapy in Adults and Adolescents. When to Start and What ART to Use in 1 st and 2 nd Line December 2009

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1 2009 Recommendations for Antiretroviral Therapy in Adults and Adolescents When to Start and What ART to Use in 1 st and 2 nd Line December 2009

2 Historic Evolution of CD4 Criteria for ART Initiation in HIV Infection: A "Cyclothymic" Process ACTG 019 and other NRTI monotherapy studies in asymptomatic individuals "Hit Hard and Early" Era (HAART) 1 st generation PIs & NNRTIs Integrase inhibitors & 2 nd generation PIs/NNRTIs CD4 count (cells/mm 3) Initial AZT studies in symptomatic individuals (ACTG 016) Concorde & Delta Trials (2 NRTIs) Lypodystrophy & other ARV associated metabolic side effects described Immune activation & Non-AIDS events 100 Potency Toxicity Potency Toxicity Potency Toxicity? Year Period M Vitoria, Dec 2009

3 Start treatment earlier Symptomatic patients (WHO Clinical Stage 3 & 4) should initiate ART irrespective of CD4 cell count (including pregnant women) Patients with CD4 350 cells/mm 3 should start treatment irrespective of clinical symptoms (including pregnant women) Patients who need TB or HBV treatment should start ART irrespective of CD4 cell count The panel placed high value on avoiding death, disease progression (including tuberculosis and HBV related cirrhosis) and reduction of HIV transmission (sexual and vertical)

4 When to Initiate ART in Adults and Adolescents (2009 WHO Guidelines) Target Population Clinical condition Recommendation Asymptomatic Individuals (including pregnant women) WHO Clinical Stage 1 Start ART if CD4 350 Symptomatic Individuals (including pregnant women) TB & Hepatitis B co-infections WHO Clinical Stage 2 WHO Clinical Stage 3 or 4 Active TB disease HBV co-infection requiring therapy Start ART if CD4 350 Start ART irrespective of CD4 cell count Start ART irrespective of CD4 cell count Start ART irrespective of CD4 cell count

5 HIV-infected indivudual Symptomatic? When to Initiate ART (2009 ART Guidelines) W HO Clinical Stage 4 Yes W HO Clinical Stage 3 WHO Clinical Stage 2 No WHO Clinical Stage 1 DRAFT Need CD4 cell count for decision to initiate ART CD4 < 350 CD4 > 350 Active TB Disease Active HBV Disease Pregnancy Other situations Initiate ART ARV for PMTCT Do not intiate ART

6 When to Start ART Target Population 2006 ART Guidelines 2009 ART Guidelines HIV+ asymptomatic ARV naive individuals (WHO clinical stage 1) HIV+ symptomatic ARV naive individuals (WHO clinical stages 2, 3 and 4) HIV+ pregnant ARV naive women HIV/TB co infection naive individuals HIV/HBV co infection naive individuals CD4 count 200 cells/mm 3 Mild or advanced clinical disease (WHO clinical stage 2 or 3) and CD4 count 200 cells/mm 3. or Advanced clinical disease (WHO clinical stage 3) if CD4 not available or Severe clinical disease (WHO clinical stage 4) irrespective of CD4 cell count or Consider treatment in advanced clinical disease (WHO clinical stage 3) and CD4 count between 200 and 350 cells/mm 3 (but initiate before drop below 200 cells/mm 3 ) Asymptomatic or mild clinical disease (WHO clinical stage 1 or 2) and CD4 200 cells/mm 3 or Advanced clinical disease (WHO clinical stage 3) and CD4 350 cells/mm 3 or Severe clinical disease (WHO clinical stage 4) irrespective of CD4 cell count Presence of active TB disease and CD4 350 cells/mm 3 No specific recommendation CD4 count 350 cells/mm 3 Mild clinical disease (WHO clinical stage 2) if CD4 cell count 350 cells/mm 3 or Advanced or severe clinical disease (WHO clinical stage 3 or 4) irrespective of CD4 cell count CD4 350 cells/mm 3 irrespective of clinical symptoms or Advanced or severe clinical disease (WHO clinical stage 3 or 4) irrespective of CD4 cell count Presence of active TB disease, irrespective of CD4 cell count Presence of chronic active hepatitis B disease, irrespective of CD4 cell count

7 What country guidelines are recommending? (survey in 26 country guidelines)

8 What country guidelines are recommending?(survey in 26 country guidelines) When to Start ART N= 26 WHO, 2009

9 What country guidelines are recommending? (survey in 26 country guidelines) "Consider" to Start ART N= 26 WHO 2009

10 Increase in ART needs according CD4 criteria (based in the eart-linc data and Cascade Collaboration, considering a linear ART scale up projection) Kenya ART total estimates for ART Zambiia Total ART needs in adults Total need for ART adults > 15 Thousands CD4<200 CD4<250 CD4<350 CD4<500 Todal ART needs > 15 Thousands CD4<200 CD4<250 CD4<350 CD4<500 years Years Cameroon Total ART needs Adults 2007_2012 Vietnam: total ART needs Adults ART Needs (Thaousands) CD4<200 CD4<250 CD4<350 CD4<500 Todal number needs ART > 15, thousands CD4<200 CD4<250 CD4<350 CD4<500 years years T Calleja, 2009

11 Impact of CD4 treshold on ART needs Kenya: % Increase on ART needs according to CD4 criteria per year Year CD4<250 CD4<350 CD4< % 63.9% 121.9% Changing CD4 criteria will increase ART total needs in adults from 20-25% if CD4 <250, 50-60% if CD4< 350, and over 100% if CD4<500 threshold is applied % 57.3% 110.0% 16.7% 50.9% 98.6% 15.1% 45.8% 89.1% 13.5% 41.2% 80.4% 11.7% 36.0% 71.0% Increasing ART needs differences will decrease over time Other main factors affecting overall needs if CD4 criteria is changed is overall ART coverage on first year and increasing coverage over time

12 Use simpler 1 st and 2 nd line regimens Preferred 1 st Line Options AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC or FTC + EFV TDF + 3TC or FTC + NVP Preferred 2 nd Line Options TDF + 3TC or FTC + ATV/r TDF + 3TC or FTC + LPV/r AZT + 3TC + ATV/r AZT + 3TC + LPV/r The panel placed high value on the benefits of using fixed dose combinations and on avoiding d4t toxicity

13 What to use in 1 st Line ART (2009 ART Guidelines) HIV-infected individual elegible for ART AZT+3TC+NVP AZT+3TC+EFV TDF+3TC or FTC+EFV TDF+3TC or FTC+NVP Preferred in Pregnancy Preferred in active TB Preferred in HIV/HBV

14 Preferred 1 st Line ART in Adults and Adolescents (2009 WHO Guidelines) Target Population Preferred Options Comments Adults and Adolescents Pregnant Women TB/HIV co-infection Hepatitis B co-infection AZT or TDF + 3TC or FTC + EFV or NVP AZT + 3TC + EFV or NVP AZT or TDF + 3TC or FTC + EFV TDF + 3TC or FTC + EFV or NVP Select the preferred regimen's applicable to the majority of PLHIV Use fixed dose combinations Do not initiate EFV during the 1 st trimester TDF acceptable option Initiate ART as soon as possible (within the first 8 weeks) after starting TB treatment NVP or triple nukes acceptable options if EFV cannot be used HbSAg test recommended for all HIV+ individuals before start ART Use 2 ARVs with anti-hbv activity required

15 Target Population Preferred 1 st Line ART 2006 ART Guidelines 2009 ART Guidelines HIV+ ARV adults and adolescents HIV+ naive pregnant women HIV/TB co infection HIV/HBV co infection AZT or TDF + 3TC or FTC + EFV or NVP AZT + 3TC + NVP AZT or TDF + 3TC or FTC + EFV TDF + 3TC or FTC + EFV No change 1 AZT preferred but TDF acceptable EFV included as a preferred NNRTI option(but do not initiate EFV during 1 st trimester) NVP acceptable where CD cells/mm 3 No change 2 NNRTI regimens that contain both TDF + 3TC or FTC required (1) d4t phase out plan towards AZT or TDF is recommended in settings where d4t regimens are used as the principal option to start ART. (2) ART should be initiated as soon as possible in all HIV/TB coinfected patients with active TB (within 8 weeks after start TB treatment).

16 Major ART Toxicities ARV Drug Major Toxicity Risk situations* d4t AZT TDF EFV NVP Lipodystrophy Neuropathy Lactic acidosis Anemia Neutropenia Renal dysfunction Teratogenicity Hepatotoxicity Skin Rash Age > 40 years-old CD4 count < 200 cells/mm 3 BMI > 27 (or body weight >75kg) Concomitant use with INH or ddi CD4 count < 200 cells/mm 3 BMI < 22 (or body weight <50 kg) Anemia at baseline Underlying renal disease Age > 40 years-old BMI < 22 (or body weight <50 kg) Diabetes Mellitus Hypertension Concomitant use of a boosted PI or nephrotoxic drugs Use during 1 st trimester of pregnancy depression or psychiatric disease (previous or at baseline) Women with CD4 cell count > 250 cells/mm 3 (?) HCV and HBV co-infection * Situations where the ARV drug should be avoided or used with close clinical and/or laboratory monitoring.

17 d4t phase out and risk assessment Components of d4t phase out plan: 1) Assessment of the cost and feasibility of phasing out d4t use Market Trends: Distribution of 1 st Line N(t)RTIs in LMIC ( ) 80% 2) Risk assessment of continuing to use d4t 3) Implementation of systems to prevent, monitor & manage toxicities during the phase out period or if decide to continue to use d4t containg regimens 4) Do not use d4t 40 mg formulations % of 1st Line Re 60% 40% 20% 0% Year d4t AZT TDF 8 High value placed on need for less toxic alternatives, avoiding the stigma associated with long term d4t side effects and low acceptability of d4t by PLHIV/clinicians

18 How fast this d4t phase out can occur? 1) Homogeneous rapid phase out process at global level rapid substitution both new patients and old patients 2) Heterogeneous phase out process Slow in key countries with high use of d4t (eg; India, South Africa, Thailand, Malawi) and moderate to high phase-out process in other settings 3) Homogeneous slow phase out process at global level Phase out concentrated in new patients and/or patients on long term use/high risk groups for toxicity Despite a progressive reduction on use already occuring, d4t probably will still stay as an important ARV option by 2012

19 Evidence on d4t 20 mg BID (or less) Study Country Quality Design n Regimen Arms for pts >/< 60kg Adverse events in reduced dose (RD) compared to standard dose (SD) Ribera et al. [21] Hanvanich et al. [ 22] Spain High Randomized, open-label 54 40/30 or 30/20 RD had reduced lipoatrophy Thailand Moderate Prospective 80 30/20 RD had reduced lipoatrophy McComsey et al. [23] USA Low Randomized, open-label 24 40/30 or 20/15 RD better fat mtdna and less bone mineral Siangphoe et al. [24] Thailand Low Randomized, open-label /15 or 40/30 Lactic acidosis in three pts on SD Wolf et al. [26] Gerrmany Low Retro /30 30/20 More peripheral neuropathy in SD Anderson et al. [18] USA Low Randomized, double-blind /20 mg or 30/15 More peripheral neuropathy in SD Pedrol et al. [28] Shalit et al. [30] Urbina et al. [31] Pedrol et al. [32] Spain Low Retro /20 No difference USA Very Low Retro USA Very Low Retro /20 Peripheral neuropathy more common with low CD4 count 29% developed lipodystrophy 12.2% peripheral neuropathy Spain Very Low Retro /20 One peripheral neuropathy and one lactic acidosis

20 Preferred 2 nd Line ART in Adults and Adolescents (2009 WHO Guidelines) Target Population Preferred Options 1 Comments Adults and Adolescents (including pregnant women) TB/HIV coinfection If d4t or AZT used in 1 st line If TDF used in 1 st line If Rifabutin available If Rifabutin not available Hepatitis B co-infection TDF + 3TC or FTC + ATV/r or LPVr AZT + 3TC + ATV/r or LPVr Same regimens recommended for adults and adolescents Same NRTI backbones recommended for adults and adolescents plus LPVr or SQV/r with adjusted dose of RTV (i.e., LPV/RTV or SQV/RTV) 2 AZT + TDF + 3TC or FTC + ATV/r or LPVr 1 ABC and ddi can be considered as backup options in case of toxicity or contraindication to AZT or TDF. 2 LPV 400 mg + RTV 400 mg or SQV 400 mg + RTV 400 mg NRTI sequencing based on availability of FDCs and potential for retained antiviral activity, considering early and late switch scenarios. ATV/r and LPVr are comparable and available as heat stable FDC or copackage formulations. No difference in efficacy between rifabutin and rifampicin. RFB causes significant less drug interaction with PIs, which permit maintenance of usual ARV doses. Rifampicin significantly reduce the levels of PIs, limiting the effective options. Use of extra doses of ritonavir with selected bpis (LPV and SQV) can overcome this effect but with increased rates of toxicity. In case of ART failure, TDF+3TC or FTC should be maintained for anti- HBV activity and the 2 nd line regimen should include other drugs with anti- HIV activity.

21 Preferred 2 nd Line ART Target Population 2006 ART Guidelines 2009 ART Guidelines HIV+ ARV adults and adolescents HIV+ pregnant women HIV/TB co infection HIV/HBV co infection ABC + ddi or TDF+ ABC or ddi +3TC or TDF + 3TC (± AZT) +ATV/r or FPV/r or IDV/r or LPVr or SQVr ABC + ddi or TDF+ ABC or ddi +3TC or TDF + 3TC (± AZT) plus LPVr or NFV or SQVr ABC + ddi or TDF+ ABC or ddi +3TC or TDF + 3TC (± AZT) +LPVror SQV/r with adjusted dose of RTV (LPV/RTV + SQV/RTV*) 3TC and/or TDF containing regimens If d4t or AZT used in 1 st line If TDF used in 1 st line If Rifabutin available If Rifabutin not available TDF + 3TC or FTC + ATV/r or LPVr AZT + 3TC + ATV/r or LPVr Same regimens recommended for adults and adolescents Same regimens recommended for adults and adolescents Same NRTI backbones recommended for adults and adolescents plus LPVr or SQV/r with adjusted dose of RTV (i.e., LPV/RTV or SQV/RTV*) AZT + TDF + 3TC or FTC + ATV/r or LPVr * LPV 400 mg + RTV 400 mg or SQV 400 mg + RTV 400 mg

22 What is the impact of early ART therapy? 1. Overall the provision of early therapy (<350 CD4+) and high coverage (to 85%) would produce: Increase the number of people in need (50%) Increase the financial requirements by US$ 11.5 billion or 57% Reduce deaths (20%) Avert 1.2 million infections between 2010 and An early start strategy would require: Increase in testing, estimated in US$ 5.2 billion

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24 Other investment Equipment Other recurrent Laboratory supplies The Importance of Moving Forward Responsibly In depth ART costing studies ART Costs per Annum for Different Scenarios in Malawi Personnel ARVs Uganda '08 (PEPFAR) Vietnam '08 (PEPFAR) Nigeria '08 (PEPFAR) Cost per patient per year (US$) S. Africa, 2004 (Cleary) Ethiopia '08 (PEPFAR) Nigeria '04 (Abt Ass.) Haiti (Koenig) Cote d'ivoire '08 (Abt Ass.) Zambia '03 (Abt Ass.) Cote d'ivoire '06 Botswana '08 (PEPFAR) Bottom up costings, , economic costs, provider perspective Slide courtesy E Korenromp GFTAM The realities of global scale up 02 December GOM contribution to health current scale up early start early start (AZT NVP) early start (TFD EFV) US$ (million)

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26 Projected number of PLHIV in different countries considering South Africa HIV prevalence Country Estimated Population* (2009) Estimated Number of PLHIV if HIV country prevalence rate would be equal to South Africa (18.8%) Brazil 192,140,000 36,170,000 USA 308,100,000 57,925,000 Switzerland 7,700,000 1,450,000 UK 61,135,000 11,495,000 EU (27 countries) 499,725,000 93,950,000 *Source: Eurostat, US census bureau and IBGE-Brazil websites