Crossroads Hotel 7 th January 2010

 All adolescents & adults with HIV infection & CD4 counts less than/equal to 350 cells/mm3, including pregnant women, should be started on 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

Target Population When to Start ART Malawi ART Guidelines (2008)2009 ART Guidelines HIV+ asymptomatic ARV naive individuals (WHO clinical stage 1) CD4 count ≤250 cells/mm 3 CD4 count ≤350 cells/mm 3 HIV+ symptomatic ARV naive individuals (WHO clinical stages 2, 3 and 4) Mild to moderate clinical disease (WHO clinical stage 2 ) and CD4 count ≤250 cells/mm 3 or TLC <1200mm3. or Advanced or severe clinical disease (WHO clinical stage 3 or 4) irrespective of CD4 cell count 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 HIV+ pregnant ARV naive women Asymptomatic or mild clinical disease (WHO clinical stage 1 or 2) and CD4 ≤ 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 HIV/TB co-infection naive individuals PTB pts(stage 3) with CD4<350 and Stage 4 (EPTB) irrespective of CD4 cell count Presence of active TB disease, irrespective of CD4 cell count HIV/HBV co-infection naive individuals No specific recommendation Presence of chronic active hepatitis B disease, irrespective of CD4 cell count

Proposed WHO 2009 Criteria for the ART Initiation in adults and adolescents (ART Guidelines Meeting, October/2009) Clinical SituationART initiation Recommendations Quality of Evidence Strength of Recommendation WHO clinical stage 3 or 4Start ART irrespective of CD4 Moderate to High Strong WHO clinical stage 1 or 2Need CD4 to decideVery LowStrong CD4 < 350 cells/mm 3 Start ART irrespective of WHO stage ModerateStrong Active TBStart ART irrespective of CD4 ModerateStrong PregnancyStart ART for stage 3/4 or CD4 < 350/mm 3 ModerateStrong Active chronic hepatitis BStart ART irrespective of CD4 LowStrong

 First line therapy should consist of an NNRTI + two NRTIs, one of which should be AZT or TDF.  Countries using D4T in first line regimens should start phasing it out because of its long term toxicity Recommended regimens:  AZT + 3TC + EFV  AZT + 3TC + NVP  TDF + 3TC or FTC + EFV  TDF + 3TC or FTC + NVP

1. Start ART in all pregnant women with HIV and CD4 count<350 cells/mm3, irrespective of clinical symptoms. 2. CD4 testing is required to identify if pregnant women with HIV and WHO clinical stage 1 or 2 disease need to start antiretroviral treatment or prophylaxis. 3. Start ART in all pregnant women with HIV and WHO clinical stage 3 or 4, irrespective of CD4 count.

◦ Benefits of NVP for women with CD4 cell count between 250 to 350/mm3 likely to outweigh risk of not treating. ◦ EFV regimens preferred but the low risk of NTD (<1%) means should avoid starting in first trimester. ◦ AZT regimens preferred in pregnancy but TDF acceptable.

4. Start one the following regimens in ART- naïve pregnant women eligible for treatment.  AZT + 3TC + EFV  AZT + 3TC + NVP  TDF + 3TC or FTC+ EFV  TDF + 3TC or FTC + NVP  5. Do not start EFV during the first-trimester of pregnancy.

Patients who require treatment for hepatitis B virus co-infection, should start ART immediately, regardless of CD4 cell count or WHO clinical stage. First and second line regimens for this group should contain TDF and either 3TC or FTC i.e. - TDF+3TC/FTC+ EFV or - TDF+3TC/FTC+ NVP

Regardless of their CD4-cell counts, patients co- infected with HIV and TB should be started on ART as soon as possible after starting TB treatment ◦ EFV based regimens preferred initial options. ◦ All active TB pts start ART as soon as tolerable. ◦ Rifabutin in TB regimen if using concomitant PI regimen Regimen options: - AZT+3TC+EFV or - TDF+3TC/FTC+EFV

Target Population Preferred 1 st Line ART Malawi ART Guidelines (2008) 2009 ART WHO Guidelines HIV+ ARV adults and adolescents NVP+3TC+D4TAZT/TDF+3TC+NVP/EFV HIV+ naive pregnant women NVP + 3TC + D4T AZT preferred but TDF acceptable EFV included as a preferred NNRTI option(but do not initiate EFV during 1 st trimester) NVP still acceptable where CD cells/mm 3 HIV/TB co-infection NVP+3TC+D4T AZT+3TC+EFV TDF+3TC/FTC/EFV HIV/HBV co-infection No specific recommendation 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).

 Second line ART should consist of a Ritonavir-boosted PI plus two NRTIs (one of which should be AZT or TDF, considering what was used in 1 st line)  Ritonavir-boosted Atazanavir and Lopinavir/ritonavir are the preferred PIs  Regimens: TDF + 3TC/FTC + LPV/r/ATZ/r or AZT + 3TC/FTC + LPV/r/ATZ/r

 All patients should have access to CD4 cell count testing to optimize Pre-ART and ART management. Viral load testing is recommended to confirm treatment failure.  Symptom directed or targeted use of lab tests is the preferred approach for drug toxicity monitoring

Phase of HIV ManagementRecommended TestDesirable Test At HIV diagnosisCD4 HBsAg, anti-HCV? Pre ARTCD4 At start of ARTCD4 Hb for AZT 1 Creatinine clearance for TDF 2 ALT for NVP 3 On ARTCD4 Hb for AZT 1 Creatinine clearance for TDF 2 ALT for NVP 3 At clinical failureCD4 Viral load At immunological failureViral load 1 Recommended test in patients with high risk of adverse events associated with AZT (low CD4 or low BMI). 2 Recommended test in patients with high risk of adverse events associated with TDF (underlying renal disease, older age group, low BMI, diabetes, hypertension and concomitant use of a boosted PI or nephrotoxic drugs). 3 Recommended test in patients with high risk of adverse events associated with NVP ( ART naive HIV+ women with CD4 > 250 cells/mm3, HCV co- infection)

 Pregnant women who don't need ART for their own health should start taking prophylaxis as soon as possible from 14 weeks gestation.  Either three-drug ART or infant prophylaxis should be given throughout the breastfeeding period if mothers do not need ART for their own health.

MotherInfant Option A: Maternal AZT & Daily infant NVP Antepartum AZT (14 weeks), sdNVP at onset of labour +AZT/3TC during labour & delivery AZT/3TC for 7 days postpartum Breastfeeding: daily NVP till 1 week after all exposure to breast milk has ended Non- breastfeeding: AZT or NVP for 6 weeks Option B: Maternal Triple ARV prophylaxis: AZT/3TC/LPV/r AZT/3TC/ABC AZT/3TC/EFV AZT/FTC/EFV Triple ART (from 14 weeks) until 1 week after all exposure to breast milk has ended Breastfeeding: daily NVP for 6 weeks Non- breastfeeding: AZT or NVP for 6 weeks

InfantFirst 6 months Beyond 6 months Mother HIV infected HIV uninfected/ unknown Exclusively breastfeed Introduce complementary foods & continue breast feeding till 12 months, then stop if adequate & safe nutrition is guaranteed without breast milk Mother HIV infected HIV infectedExclusively breast feed Continue breast feeding as recommended in the general population up to 2 years and beyond

I Thank you, Dr Zengani Chirwa – T/A Care Treatment & Support, HIV & AIDS Department - MOH

Department of HIV &AIDS

Crossroads hotel 7 th January 2010

 To reduce mortality & morbidity in adults and children due to HIV and AIDS and mitigate the impact of HIV and AIDS in Malawi

The eligibility criteria in Malawi includes:  CD4 <250 irrespective of WHO staging  TLC <1200mm3 for WHO stage 2 patients  WHO clinical stage 3 or 4 irrespective of CD4  CD4 < 350 for pregnant women irrespective of WHO clinical stage Malawi current ART regimens First line regimen: Nevirapine+Stavudine+ Lamivudine (Triomune) Alternative first line includes: AZT & EFV based regimens

 Through the scale up plan the programme had cummulatively by end September 2009:  253,154 patients ever started on ART  Out of which 183,147 are alive and on treatment representing 56% of those in immediate need  ART services are provided at 236 static sites which support over 100 mobile and outreach sites

 Access: over 60% of the patients are female, while children make up 10% (<15yrs)  Current ART regimen: 94% are still on 1 st line – NVP+3TC+D4T 5% are on one of the alternative first lines – AZT or EFV or both less than 1% are on second line While 1% are on non-standard regimens

 Human resources-HCW, lab technicians etc  Infrastructure: more sites required for service delivery and current sites require expansion/renovation  Equipment and reagents including DNA-PCR and CD4 machines  Funding to meet the extra cost of the recommendations  Sample transportation system (CD4 & DBS)

 Thank you

IssuesResourcesothers Early start: deals with mortality & morbidity Lack of CD4 capacity CD4 machines & reagents, Technicians, Quality assurance for CD4, systems strengthening Regimen change: deals more with quality of care Standardised regimen, FDC, No need for baseline tests and monitoring Cost of drugs, Supply chain management Few side effects, use in pregnancy Early start vs Regimen change May need to implement in phases i.e. priorities

Options D4T phase out plan 1. No change, but low threshold for alternative 3. Change all new patients and have a low threshold for changing old patients 2. Change all patients > 6-12 months (? Also new ones) 4. Change all patients new & old at same time (costly & wasteful of D4T) NB: changing after 6 months deals with anemia if changing to AZT A phased change will reduce wastage of D4T Forecasting and quantification will be crucial to the phase out plan

AZTTDFNVPEFV costRelatively cheaper Relatively expensive Relatively cheaper Relatively expensive FDCAvailableAvailable as atripla - expensive AvailableAvailable as atripla - expensive Use in pregnancy safeacceptablesafeTeratogenic contraindicat ed in 1 st trimester Side effectsAnaemiaRenal insufficiency Hypersensiti vity rxn especially with CD4>250 teratogenicit y

Point of care CD4 and Viral load when available will enable early initiation of ART using CD4 and VL monitoring for ART failure - Currently more feasible to roll out VL for ART failure than CD4 testing due to DBS for VL Monitoring of patients for ART failure currently will entail >200,000 viral loads per year Sample transportation systems will need to be strengthened /established

4 groups Group 1 – Earlier start & regimen change Group 2 – Phase out plan for D4T, lab monitoring, baseline, monitoring and ART failure Group 3 – ART in Pregnancy, HIV/TB, HIV/HBV Group 4 - PMTCT

 Trends: ◦ Encourage earlier diagnosis ◦ Treat earlier ◦ Promote less toxic/ more friendly regimens ◦ Monitor more strategically ◦ But Will cost more  The major operational question is not if these recommendations should be followed or not, but how to do it safely, with equity… and how to fund it!!

 Thank you  Dr Zengani Chirwa