Drug resistance monitoring among Filipino HIV infected patients

Rossana A. Ditangco, MD FPCP FPSMID Head, AIDS Research Group Research Institute for Tropical Medicine Alabang Muntinlupa City

Number of HIV/AIDS Cases Reported in the Philippines by Year, January 1984 to February 2011 (N=6,326)

Management of confirmed HIV/AIDS

GOALS: prompt treatment of HIV related diseases prevention of HIV related diseases control of HIV infection restoration of immune status provision of psychosocial support

Population-level effect of HIV on adult mortality and early evidence of reversal after introduction of antiretroviral therapy in Malawi Andreas Jahna et al Reduction of AIDS related death decreased by 35%

Lancet. 2008 May 10; 371(9624): 16031611

Universal access to AIDS treatment: targets and challenges http://www.avert.org/universal-access.htm

Potential benefit of early Benefit of early treatment treatment

Protection from AIDS related death Lower risk of NONAIDS related death Lower risk of transmission

When to start treatment WHO 2006 Clinical stage IV Clinical stage 3 CD 4 not available CD4 T cell < 200 consider >200 and < 350 and clinical stage 3 WHO 2010 Clinical stage IV Clinical stage 3 CD 4 not available CD4 T cell < 350

Limitations ART Limitations ART

Not curative Short term and long term toxicities HIV drug resistance

Philippine scenario
No of persons on ARV 2006- March 2011

1400 1200 1000 800 600 400 200 0 2006 2007 2008 2009 2010 2011

Requirements for safe and effective use of ARV in roll out program
Supply Infrastructure monitoring treatment response and toxicity Human resource training (ART, adherence counseling)

Real scenario in roll out program

Need to start ART Need to start ART

Training/experience Training/experience

Strategy for safe and effective use of ARV in roll out program
- local guideline simple regimen bulk purchase lower cost less training needed preserve limited 2nd line

Cost of 1st line cART

1st line 3tc150mg/AZT 300mg Nevirapine200mg Unit cost 8.00 3.00 Cost per day 16.00 6.00 Cost per month 480 180 Cost per year

Total per months Tenofovir200mg 3tc 150mg Efavirenz600mg Total per month 17.00 3.00 7 17.00 6.00 7.00

660 510 180 270 960

7920

11520

Cost of 2nd line cART

2nd line 3tc150mg/AZT 300mg Lopinavir/rit Total per months Tenofovir200m g 3tc 150mg Lopinavir/rit Total per month 17.00 17.00 Unit cost 8.00 Cost per day 16.00 Cost per month 480 Cost per year

18.00

72.00

2160 2640 31680

510

3.00 18,00

6.00 72.00

180 2160 2850 34200

Adherence Impacts HIV-Related HIVMortality and AIDS Progression*1

For every 10% decrease in adherence

16% increase in HIV-related mortality

1.17 times higher likelihood of progression to AIDS and/or death

*Prospective, observational study of 950 ART-naive patients treated with triplecombination therapy; adherence was estimated by prescriptions dispensed.
1. Hogg et al. 7th CROI 2000. Abstract 73.
5

FIRST LINE FOREVER!!!

Philippine scenario
HIV drug resistance

HIVDR program

Prevention of HIV drug resistance through enhanced adherence and treatment monitoring program
- target: physicians and patients - launched February 2010

The goal of this project is to establish a MECHANISM for enhancing and monitoring adherence and for monitoring HIVDR within an ART scale up program. objectives: to enhance adherence among patients enrolled in the treatment program to develop a mechanism on patient enrolment and monitoring of treatment adherence to develop a mechanism for monitoring virologic failure and emergence of HIVDR among patient enrolled in the ARV treatment program

Specific activities: training of healthcare workers on treatment guideline and adherence counseling development and distribution of physician guide on adherence counseling development and distribution of IEC materials on ARV for patients establish mechanism for timely pick up of ARVs

Specific activities: utilization of patient enrollment forms utilization of adherence evaluation form SOPs on patient enrolment (especially for patients to be managed by attending physicians outside of the treatment hubs) and how to access ARVs from the treatment hubs regular CD4 and viral load testing based on established local guideline HIVDR testing among patients with virologic failure development and utilization of database of enrolled patients

Combination Antiretroviral Therapy (cART) Counseling Guide for Physicians

Guidelines on Antiretroviral Therapy (ART) Among Adults and Adolescents with Human Immunodeficiency Virus (HIV) Infection

Philippine scenario
Treatment hubs ARV -Trained (ART, adherence) -NGO -CD4 (5) -VL (2) -HIVDR (1)

Treatment Hub LUZON San Lazaro Hospital (SLH) Bicol Regional Training and Teaching Hospital (BRTTH) Jose B. Lingad Memorial Medical Center (JBLMMC) Cagayan Valley Medical Center (CVMC) VISAYAS Vicente Sotto Sr. Memorial Medical Center (VSSMMC) Western Visayas Medical Center (WVMC) Corazon Locsin Montelibano Memorial Regional Hospital (CLMMRH) MINDANAO Ilocos Training ang Regional Medical Center (ITRMC) Baguio General Hospital and Medical Center (BGHMC) Davao Medical Center Zamboanga City Medical Center

Research Institute for Tropical Medicine (RITM) Philippine General Hospital (PGH)

Current ARV Medications

NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV) NNRTI Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETV) Nevirapine (NVP) PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV)rit Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) Integrase Inhibitor Raltegravir (RAL)

Recommended regimen First line regimen: NNRTI-based (2 NRTI + 1 NNRTI) First line NRTIs : Zidovudine (AZT) + Lamivudine (3TC) Alternative first line NRTI : a. Tenofovir (TDF) + Lamivudine (3TC) b. Stavudine (d4T) + Lamivudine (3TC) - when TDF and AZT are contraindicated First line NNRTI: Nevirapine (NVP) Alternative first line NNRTI: Efavirenz (EFV) - for patients with hypersensitivity to nevirapine and/or taking rifampicin. EFV is contraindicated in pregnant patients.

Recommended regimen

Second line regimen: 2 NRTIs + Lopinavir/ritonavir (LPV/r) - AZT + 3TC + LPV/r if previously on TDF - TDF + 3TC + LPV/r if previously on AZT or d4T

HIV drug resistance testing

Genotyping* Phenotype HIV DR databases IAS, Stanford, WHO - subtype B, non subtype B

How are we doing so far? Is the recommended first line effective?

TREAT ASIA STUDIES TO EVALUATE DRUG RESISATNCE (TASER) 208 patients enrolled (April 2008) -202 treatment nave -6 treatment experienced

TREAT ASIA STUDIES TO EVALUATE DRUG RESISATNCE (TASER) 208 patients enrolled (April 2008) -202 treatment nave - 192 with available baseline VL median 202,915 (<46-6,099,010)RNA copies/ml plasma

TREAT ASIA STUDIES TO EVALUATE DRUG RESISATNCE (TASER)

208 patients enrolled (April 2008) -202 treatment nave 144 on 12th month follow-up 117 VL results available 113 (97%) <10,000 110 (94%) <1.000 109 (93%) <400 85 (73%) undetectable

TREAT ASIA STUDIES TO EVALUATE DRUG RESISATNCE (TASER) 208 patients enrolled (April 2008) -202 treatment nave 58 patients on 24th month follow-up 41 with viral load results 34 (83%) undetectable 37 (90%) < 400

TREAT ASIA STUDIES TO EVALUATE DRUG RESISATNCE (TASER)

208 patients enrolled (April 2008) -6 treatment experienced baseline VL 5,822-471,483 RNA copies 6 patients on 12th month follow-up VL available 5 patients 3 undetectable 2 <400 4 patients on 24th month- VL available 2 patients 2 patients VL < 400 coipies

HIV drug resistance results -based on WHO list of RAM

Treatment nave at baseline (amplified) 12/103 (12%) at least 1 HIV RAM PIs- 7/79 (9%) at least 1 PI RAM 6/79 (6%) one mutation 1/79 (1%) 3 mutations D30N, L90M (2), I84V (2), M46I (3), F52Y

HIV drug resistance results -based on WHO list of RAM

Treatment nave at baseline (amplified) 12/103 (12%) at least 1 HIV RAM NRT1 5/103 (5%) at least 1 RAM 3/103 (3%) w/ 1 RAM 1/103 (1%) w/3 RAM , 1/103 (1%) with 4 RAM T215Y, M41L(2), D67N (2), M184V (2), K219N, K65R, L210N

HIV drug resistance results -based on WHO list of RAM

Treatment nave at baseline (amplified) 12/103 (12%) at least 1 HIV RAM NNRT1 2/100 (2%) w/ 2 RAM Y181C, G190A K101P, G190A

Treatment experienced (6/7)

patient R03-066 R04-020 R04-AMB R06-RBP

pi major None None None None

nrti M184V, L210W, T215Y L74I, M184V, L210W, T215Y M41L, L74V, M184V, L210W, T215Y K65R, M184V

nnrti K103N Y181C, Y181C Y181C

R09-STA

None

D67N, K70E L74I M184V

V106M, Y181C, G190A,

Future directions:
Patient adherencecounseling, monitoring HCW- training, monitoring Stigma and discriminationself-isolation, family counseling, community education, health facilities, workplace Local data- HIVDR, affordable monitoring tools and algorithms

Maraming Salamat Po at INGAT LAGI! (first line forever)