MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH NATIONAL INSTITUTE OF HYGIENE AND EPIDEMIOLOGY * DO THI NHAN RESEARCH OF HIV DRUG RESISTANCE AMONG PATIENTS ON FIRST LINE ARV THERAPY IN SELECTED PROVINCES Specialization: Public Health Code: 62 72 03 01 HANOI – 2014 The dissertation was completed at the National Institute Of Hygiene And Epidemiology Supervisor: 1 Nguyen Thanh Long, Ass.Prof. PhD. 2 .Nguyen Van Trang, PhD Oppenent 1: Prof. Dao Van Dung, the Central Propaganda Department Oppenent 2: Ass.Prof. Nguyen Duc Hien, National Hospital of Tropical Disease Oppenent 3: Ass.Prof. Nguyen Vu Trung, Hanoi Medical University of Medical The dissertation will be defended before thesis committee at National Institute Of Hygiene And Epidemiology, at hour day month year 2014 The thesis information can be looked at following libraries: - National Library - Library of the National Institute of Hygiene and Epidemiology i MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH NATIONAL INSTITUTE OF HYGIENE AND EPIDEMIOLOGY * DO THI NHAN RESEARCH OF HIV DRUG RESISTANCE AMONG PATIENTS ON FIRST LINE ARV THERAPY IN SELECTED PROVINCES Specialization: Public Health Code: 62 72 03 01 HANOI – 2014 ii LIST OF ABBREVIATIONS Abbreviations English words Vietnamese meaning HIV Human immunodeficiency virus Virus gây suy giảm miễn dịch ở người AIDS Acquired Immunodeficiency Syndrome Hội chứng suy giảm miễn dịch mắc phải HAART High active antiretroviral therapy Điều trị kháng retrovirus hoạt tính cao ARV Antiretroviral Kháng retrovirus NNRTI Nonnucleoside reverse transcriptase inhibitors Nhóm thuốc ức chế men sao chép ngược không ph ả i nucleoside NRTI Nucleoside reverse transcriptase inhibitors Nhóm thuốc ức chế men sao chép ngược nucleoside PI Protease inhibitors Nhóm thuốc ức chế protease 3TC Lamivudine ABC Abacavir AZT Zidovudine EFV Efavirenz NVP Nevirapine TDF Tenofovir BN Bệnh nhân KTC confidence interval Khoảng tin cậy RT Reverse transcriptase Gen sao chép ngược TAM Thymidine analogue mutations Các đột biến tương tự thymidine WHO World Health Organization Tổ chức Y tế Thế giới TTYT Trung tâm y tế PKNT Phòng khám ngoại trú OR Odd Ratio Tỷ suất chênh PCR Polymerase Chain Reaction Phản ứng chuỗi trùng hợp TLVR Tải lượng vi rút T1 Thời điểm bắt đầu điều trị T2 Thời điểm kết thúc nghiên cứu TTPC HIV/AIDS Trung tâm phòng chống HIV/AIDS 1 INTRODUCTION The expansion of antiretroviral therapyn (ART) can lead to the emergence and spread of HIV drug-resistant due to poor adherence to treatment or supply ARV discontinuously, or monitoring of HIV drug resistance is not fulfilled enough lead to limit the effectiveness of ART. HIV Drug Resistance (HIVDR) testing is neither routinely available nor recommentded for individual patient manegement in most resource-limited countries, including Vietnam. Genotyping is expensive and complex. However, the monitoring of patient and clinic fators, early warning indicators for HIV drug resistance, associated with the emergence of preventalble HIVDR is comparatively inexpensive and can be used to identify these factors and reduce their harmful consequences. It also reflects the implementation of HIV drug-resistant prevention programs at both the clinics and program. Besides, the current situation of HIV drug resistance status in patients on ART will provide the evidence for interventions to be implemented at all levels of the OPC and program to maximize treatment effectiveness of ART. In Vietnam there still have not any studies yet which reflect the status of early warning factors for HIV drug resistance as well as no prospective research about HIV drug resistance status on patients from the time they start using ARV treatment. Therefore, we conducted a "Research of HIV drug-resistant among patients on first line ART in selected provinces" with two objectives: 1. Describe the current condition of Early Warning Indicators of HIV drug resistance at out patient clinic (OPC) in selected provinces from 2010 to 2012. 2. Identify HIV drug resistance outcomes and associated factors among patients on first line ARV therapy. New findings of the Thesis: 1. Provide the real situation of early warning indicators and their relationship with HIV Drug resistance emergence in clinic sites and program level. 2. Provide the data of HIV drug-resistance among the patients on ART, include the HIVDR prevalecne at iniating of ART, outcomes of HIVDR and HIVDR mutations after 12 months of ART initiating. These are scientific evidences in providing and deceloping policy related to expansion the ART effectively program, minimize the HIV drug-resistant situation in Vietnam. The layout of the thesis: The dissertation consists of 142 pages (excluding appendices), 4 chapters include Introduction: 2 pages; Chapter 1- Overview: 29 pages; Chapter 2 - Subjects and methods Study: 24 pages; Chapter 3 - Results: 35 pages; Chapter 4-Discussion: 32 pages; Conclusion: 2 pages; Recommendations: 1; 41 tables, 13 charts, 3 photos, 3 diagrams and 142 references, of which 22 Vietnamese and 120 documents in English. 2 CHAPTER 1 OVERVIEW 1.1 Early warning indicators for HIV drug resistance (EWI) The early warning indicators of HIV drug resistance reflects the practice of ART at the HIV/AIDS OPC treatment which include the appropriate prescripbing, procurement and supply management of ARV drug, the relevant factors adherence to the treatment of patients, viral load suppression and retention on first line ART. These factors are associated with the HIV drug resistance emergence during ARV treatment. 1.2. HIV drug resistance situation of patients on ART 1.2.1 HIV drug resistance before ART initiation There is an increase in the prevalence of HIV drug resistance mutations before the ARV treatment, ranging from 4.8% - 6.8% from 2007 to 2010. Mainly is the surge with NNRTI group. This involves the expanded use of Nevirapine for prevention of HIV transmission from mother to child. 1.2.2. Drug-resistant HIV of patients on ART According to WHO HIV Drug Resistance report in 2012, the HIV drug resistance prevention after 12 months of ART initiating was 76.1%, HIV drug resistance was 5.1% and possible HIV drug resistance was 18.8%. In Vietnam, there have been some studies of HIV drug resistance, but they are the cross-sectional studies, the researchers monitored populations of patients on ARV treatment. There is not any study on the status of early warning indicators or cohort monitoring of emergence of HIV drug resistance since initiating of antiretroviral therapy. Chapter 2 METHOD OF STUDY Methodology is designed according to the method which recommended by World Health Organization for research/survey on HIV drug resistance. 2.1. Describe the current condition of Early Warning Indicators of HIV drug resistance at out patient clinic (OPC) in selected provinces from 2010 to 2012 2.1.1. Object, venue and time line 2.1.1.1. Study participants Participant inclusion criteria: - HIV/AIDS patients with first line ART; - Patient initiating of first line ART appropriate with requirement at the time of data collection for each early warning indicators for HIV drug resistance. Exclusion criteria: - Patients not on ART or on the second line ART. - Patients with time point of initiating of ART not consistent with the time requirements of each EWI in the collection of samples. 3 2.1.1.2. Venue and timeline of study Venue: 42 outpatient clinics (OPCs) treatment for HIV/AIDS in 23 provinces were selected according to the following criteria: - Providing ART for at least one year - Representative of central, provincial and district level - Representative of North, Central and South geographic regions Time for collecting data: May 2010 – December 2012. 2.1.2. Method of the Research 2.1.2.1. Design of the Research: Cross-sectional descriptive methods 2.1.2.2. Research index: 5 indexs are selected as follow: EWI 1: The proportion of initial ART prescribtion congruent with national guideline. EWI 2: the proportion of % patients lost to follow up at 12 months. EWI 3: The proportion of % patients still retention on first line ART at 12 months EWI 4: The proportion of patienst on-time clinical appointment keeping EWI 5: Percentage of months in a designated year in which there were no ARV drug stock-outs. 2.1.2.3. Time frame for collecting sample: For EWI 1: The time for collecting sample was selected for each year of data collecting, as follows: Year 2010: Patients initiated ARV treatment from January to December 2009. Year 2011: Patients initiated ARV treatment from January to December 2010 Year 2012: Patients initiated ARV treatment from January to December 2011. For EWI 2 and EWI 3: The time for collecting sample was selected for each year of data collecting, as follows: Year 2010: Patients initiated ARV treatment from January to December 2008. Year 2011: Patients initiated ARV treatment from January to December 2009 Year 2012: Patients initiated ARV treatment from January to December 2010. For EWI 4: All patients on ARV treatment come as per dating in the 4th quarter of the year preceding the year of data collection. For EWI 5: Reports on coming in and out status of ARV of 12 months of the year preceding the year of data collection. 2.1.2.4. Sample size The formula for calculating sample sizes of each performance index as per recommended by the WHO: N = n 0 / (1 + (n 0 -1)/n); n 0 = Z 2 *p*(1-p) / e 2 In which: Z = 1,96; p = 0,5 (estimated prevalence of each index); e = Accury = 0,07 (based on 95% with ± 7% deviation); n = number of patient with ARV treatment at OPC. However, based on actual data, the research team decided to collect all the cases eligible for the research. 4 Table 2.1. The number of medical reports and medication inventory situation was collected for each index per year. Indicators Number of medical reports/medication inventory collected per collecting data year 2010 2011 2012 EWI 1 The proportion of initial ART prescribtion congruent with national guideline 5122 4542 4678 EWI 2 The proportion of % patients lost to follow up at 12 months 5.631 4.778 4.727 EWI 3 The proportion of % patients still retention on first line ART at 12 months 5631 4778 4727 EWI 4 The proportion of patienst on- time clinical appointment keeping 4.365 5.134 5.536 EWI 5 Percentage of months in a designated year in which there were no ARV drug stock-outs 12 12 12 2.1.3. Data processing Data was collected, entried and managed by using Excel software. 2.2 Identify HIV Drug Reristance and relevant factors among patienst on ARV therapy first line 2.2.1. Target population, venues, and time line 2.2.1.1. Target pupulation - Participant inclusion criteria Patients attending the four selected OPCs who meet the following criteria: - > 16 years old, and - Individuals who consent following the written informed consent process, and - Who are eligible to initiate, and do initiate, an adult first-line ART regimen at a participating site. This includes individuals who have had previous ART elsewhere (including in the private sector). - Participant exclusion criteria Patients who meet any of the following criteria are excluded from the survey: 1. Individuals enrolled in a clinical trial or clinical research study. 2. Individuals who are part of an observational cohort for whom more follow-up efforts are made than for other ART patients treated at the site. 3. Individuals restarting ART, who have previously started and stopped ART at the sentinel survey site. 4. Individuals who on ART transferring in from another ART site. 2.2.1.2. Study sites and timeline 5 Study sites: four adult OPCs have been chosen: Hai Phong out patient clinic (OPC) in Viet Tiep hospital, Hai Duong OPC is located in Hai Duong Provincial AIDS Center (PAC), District 1 OPC in Ho Chi Minh City and District 10 OPC in Ho Chi Minh City . Time line:: 12/2009 to 12/2011. 2.2.2. Study Method 2.2.2.1. Method : Cohort study. 2.2.2.2. Sample size at each clinic Survey Sample size calculation According WHO’s guidelines, sample size at endpoint required (n) will be obtained folloings fomular: N * (p * (1 - p)) n = (N - 1) * (e 2 / z 2 ) + (p * (1 - p)) n : sample size at endpoint; N: total number of patients selected sites; p: estimated prevalence of HIV Drug Resistance; e: unknown proportion within 0.1 (i.e. 10%) of the true population proportio; Where z is the α / 2 point of the Normal distribution and ignoring the finite population correction this formula simplifies to: z 2 * (p * (1 - p)) n = e 2 n = 96 The estimated sample size required at each OPC to ensure at least 96 patients will be classifiable at the end of the 12 month study period, 96 individuals initially starting ART at the site, plus an additional number calculated for that site, reflecting the numbers who transferred out and those who died. Actual samplle size in each OPC as folloings: - OPC in Việt – Tiệp Hospital in Hai Phong City: 127 patients - OPC in Hai Duong PAC: 118 patients - OPC in District 1 in Ho Chi Minh City: 134 patients - OPC in District 10 in Ho Chi Minh City: 122 patients Total patient have recruited in 4 selected OPCs: 501 patients 2.2.2.4. Diagram of research: 6 Diagram 2.1: Diagram of research 2.2.2.3. Main result s of HIV Drug Resistance (HIVDR) in study - HIV Drug Resistance before initiating of ARV Treatment: - HIV drug resistance classification at defined endpoints: HIV drug resistance prevention: defined as HIV RNA suppression to < 1,000 copies/ml as measured using a quality assured viral load assay in patients still on first-line ART at 12 months. Possible HIVDR: defined as a detectable viral load with no detectable HIVDR mutations. Specimens from patients still on a first-line ART regimen with a viral load ≥1,000 copies/ml and no evidence of HIVDR on genotype testing are classified as having possible HIVDR. Patients who have been lost to follow-up or who stopped ART within the first 12 months of ART, and from whom no specimens are available for classification, are also classified as having possible HIVDR. Other patients for whom no endpoint viral load or HIVDR result is available, and who did not transfer out or die during their first 12 months of HIVDR, are also classified as having possible HIVDR. HIV Drug Resistance (HIVDR): defined as the presence of one or more mutations leading to low, intermediate, or high-level resistance to one or more relevant antiretroviral [...]... target: 94.5% of patients at 12 months of ART with HIV viral load < 1000 copies/ml 2.2 Percentage of HIV drug resistance prevention at 12 months of ART was high: 84,8% patients with HIV drug resistance prevention at 12 months of first line ART 2.3 Percentage of patients with HIV drug resistance who receiving first line ART in 4 OPC at base line and at 12 months of ART was low Specify: - 3.5% patients with... and on time clinic appointment did not meet WHO target One clinic with one of 3 above indications did not meet WHO target for 2 consecutive years This presented a potential risk of increase in HIV drug resistance among patients on ART 2 Identify HIV drug resistance among patients receiving first line ART in 4 outpatient clinics: 2.1 Percentage of patients archiving viral load suppression (< 1000 copies/ml)... EWIs in 4 OPCs implementing of monitoring of HIV Drug resistance among patients on first line ARV: These OPCs were OPC in Hai Duong Provincial AIDS Center, OPC in Viet Tiep Hospital in Hai Phong city, 2 OPCs in Health Center in District 1 and in District 10 in Ho Chi Minh City EWI 2, EWI 3 and EWI 5 met WHO’s target With EWI 1, the proportion of patients got prescribing of ART congruent with national... indicators of retention on appropriate 1st line and on- time clinics appointment lower than WHO’s targets The retention on first line ART regimens depended on lost to follow up, stop to treatment, death or switching to second line ART In fact, the second line switching in clinics was very low Especially, in Khanh Hoa provincial HIV/ AIDS prevention center, the percentage of retention on 1st line regiment... 4.2.2.1 HIV drug resistance prevention and HIV drug resistance at T2 All 4 clinics met WHO target of HIV drug resistance prevention The prevalence of HIV drug resistance prevention for 4 clinics was as high as 84.8% The prevalence of HIV drug resistance at 12 months of ART was as low as 2,9%, but the prevalence of possible HIV drug resistance was as high as 12.3% The prevalence of HIV drug resistance. .. first line ART at 12 months: 82,5%, 82,1% and 83,6% - Percentage of patients who kept on time clinic appointment: 90,2%, 86,8% and 88,8% - ARV drug supply continuity indicators: 100% over years The ARV drugs were supplied continuously without stock out 1.2 However, there were 15/42 (35,7%) outpatients clinics with at least one out of 3 indicators of ART discontinuation, retain on first line ART and on. .. 3.5% patients with at least one HIV drug resistance mutation at baseline - 2.9% patients with at least one HIV drug resistance mutation at 12 months of ART 2.4 However, percentage of possible HIV drug resistance at 12 months of ART was quite high in 4 OPC: 12.3% patients with possible HIV drug resistance mutation Therefore the prevalence of HIV drug resistance may be higher in real life than the results... trend on HIV drug resistance and HIV drug resistance mutations in population of HIV patients receiving ART 4 Perform HIV viral load testing routinely in patients on ART to early detect virological failure manifestation 5 HIV drug resistance genotyping before switching to second line ART should be performed to reduce the unnecessary switching 21 LIST OF PUBLISHED ARTICLES 1 Do Thi Nhan, Nguyen Thanh Long,... Description of HIV drug resistance early warning indicators in HIV/ AIDS clinics: 1.1 HIV drug resistance early warning indicators for 42 outpatient clinics during 3 years met WHO targets as following: - Percentage of patients with standard ART prescriptions: 99.9%, 100%, 100% - Percentage of patients who lost to follow up within 12 months of ART: 5,4%, 5,8% and 5,9% - Percentage of patients retained on first. .. lowest prevalence at district 1 clinic and highest at district 10 clinic The HIV drug resistance at ART initiation could reflex the prior infection of drug resistance HIV or past ART This result was in accordance with low transmitted HIV drug resistance in Vietnam 4.2.1.2 ARV drug resistance and resistance categorization of HIV drug resistance mutation at T1 HIV drug resistances which were detected at . " ;Research of HIV drug- resistant among patients on first line ART in selected provinces& quot; with two objectives: 1. Describe the current condition of Early Warning Indicators of HIV drug resistance. supply continuity): 100% of OPCs met WHO’s target of 100% ARV supply continuity. 3.1.3. EWIs in 4 OPCs implementing of monitoring of HIV Drug resistance among patients on first line ARV: These. s of HIV Drug Resistance (HIVDR) in study - HIV Drug Resistance before initiating of ARV Treatment: - HIV drug resistance classification at defined endpoints: HIV drug resistance prevention: