protocol and operation plan

Development of Active Surveillance System for the Antiretroviral Program in Karnataka State — Protocol and Operational Plan

Jude Nwokike Andy Stergachis Parthasarathi Gurumurthy September 2011

Strengthening Pharmaceutical Systems Center for Pharmaceutical Management Management Sciences for Health 4301 North Fairfax Drive, Suite 400 Arlington, VA 22203 USA Phone: 703.524.6575 Fax: 703.524.7898 E-mail: [email protected]

mailto:[email protected]

Development of Active Surveillance System for the ART Program in Karnataka — Protocol and Operation Plan

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This report is made possible by the generous support of the American people through the US Agency for International Development (USAID), under the terms of cooperative agreement number GHN-A-00-07-00002-00. The contents are the responsibility of Management Sciences for Health and do not necessarily reflect the views of USAID or the United States Government. About SPS The Strengthening Pharmaceutical Systems (SPS) Program strives to build capacity within developing countries to effectively manage all aspects of pharmaceutical systems and services. SPS focuses on improving governance in the pharmaceutical sector, strengthening pharmaceutical management systems and financing mechanisms, containing antimicrobial resistance, and enhancing access to and appropriate use of medicines. Recommended Citation This report may be reproduced if credit is given to SPS. Please use the following citation. Nwokike J., A. Stergachis, and P. Gurumurthy. 2011. Development of Active Surveillance

System for the Antiretroviral Program in Karnataka State — Protocol and Operation Plan. Submitted to the US Agency for International Development by the Strengthening Pharmaceutical Systems Program. Arlington, VA: Management Sciences for Health. Key Words Pharmacovigilance; medicine safety; antiretroviral therapy; active surveillance; adverse drug reaction; pregnancy registry; Karnataka; India

Strengthening Pharmaceutical Systems Center for Pharmaceutical Management

Management Sciences for Health 4301 North Fairfax Drive, Suite 400

Arlington, VA 22203 USA Telephone: 703.524.6575

Fax: 703.524.7898 E-mail: [email protected]

Web: www.msh.org/sps

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TABLE OF CONTENTS

Acronyms ................................................................................................................................... v

Definitions................................................................................................................................ vii

Acknowledgments..................................................................................................................... ix

Executive Summary .................................................................................................................. xi

Background ................................................................................................................................ 1

Part 1. Active Surveillance Protocol .......................................................................................... 3 Overall Goal ........................................................................................................................... 3 Specific Objectives ................................................................................................................ 3

The Need for Pharmacovigilance of Antiretroviral Medicines.............................................. 3 Active Surveillance as a Tool for Pharmacovigilance in Public Health Programs ................ 4

Types of Active Safety Surveillance ...................................................................................... 5 Generating Local Data to Inform Regulatory Actions, Treatment Guidelines, and Care Delivery.................................................................................................................................. 6

Active Surveillance Methods ..................................................................................................... 7

Overview ................................................................................................................................ 7

Data Collection and Data Management ................................................................................... 11 Data Collection Process ....................................................................................................... 12

Additional Data Required by the ASSSK Coordinating Centre .......................................... 15 Pregnancy Exposure Registry .............................................................................................. 16

Data Analysis ....................................................................................................................... 16 Sample Size Estimation ....................................................................................................... 17

Training ................................................................................................................................ 18 Data Confidentiality and Ethical Considerations ................................................................. 18

Limitations ........................................................................................................................... 19 Dissemination ...................................................................................................................... 19

Part 2. Operational Plan for Implementation of the Protocol .................................................. 21

Operational Strategic Framework ........................................................................................ 21 Stakeholders’ Engagement, Roles, and Responsibilities ..................................................... 21

Health Workers at the ART Centres .................................................................................... 22 ASSSK Advisory Committee .............................................................................................. 22

ASSSK Coordinating Centre ............................................................................................... 23 Logistics and Budget............................................................................................................ 24 Work Plan and Monitoring the Implementation of the ASSSK Activity ............................ 27 Operational Aspects of Communicating the Findings and Using Data for Decision Making.............................................................................................................................................. 29

Annex A. Suggested Minimum Data Set for the ASSSK Activity .......................................... 31

Annex B. Standard Operating Procedures ............................................................................... 35

Annex C. Illustrative Pregnancy History and Outcome Form ................................................. 37


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ACRONYMS

AAC ASSSK Advisory Committee AIDS acquired immune deficiency syndrome ADR adverse drug reaction ACC ASSSK Coordinating Centre AIIMS ANC

All India Institute of Medical Sciences antenatal care

ASSSK

Active Safety Surveillance System for the Karnataka ART Program

ART antiretroviral therapy ARV antiretroviral medicine ATC Anatomical Therapeutic Chemical Classification System BIMS Belgaum Institute of Medical Sciences CCC Community Care Centre CI confidence intervals CMIS Computerized Management Information System (NACO) HIV human immunodeficiency virus ICTC Integrated Counselling and Testing Centre IEC information, education, and communication KHPT Karnataka Health Promotion Trust KIMS Kempe Gowda Institute of Medical Sciences KSAPS Karnataka State AIDS Prevention Society M&E monitoring and evaluation MedRA Medical Dictionary for Regulatory Activities MSH Management Sciences for Health NACO National AIDS Control Organization NCC National Coordinating Centre [PvPI] OI opportunistic infection PEP post-exposure prophylaxis (of HIV) PER pregnancy exposure registry PLHA people living with HIV/AIDS PMI President’s Malaria Initiative (US) PMTCT prevention of mother-to-child-transmission (of HIV) PTR Patient Treatment Record PvPI Pharmacovigilance Programme of India for Assuring Drug Safety SOP standard operating procedure SPS Strengthening Pharmaceutical Systems Program TAHOD TREAT Asia HIV Observational Database TB tuberculosis USAID United States Agency for International Development VIMS Vijayanagar Institute of Medical Sciences WHO World Health Organization


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DEFINITIONS

Active surveillance. A system in which active measures are taken to detect the presence or absence of adverse events through follow-up after treatment. The adverse events may be detected by interviewing patients or by screening patient records.

Adverse event. Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment.

Adverse drug reaction (ADR). A response which is harmful and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.

Causality assessment. The evaluation of the likelihood that a medicine was the causative agent of an observed adverse event. Causality assessment is usually made according to established algorithms.

Pharmacovigilance. The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problem.

Risk. The probability of harm being caused; the probability (chances, odds) of an occurrence.

Serious adverse event or reaction. A serious adverse event or reaction is any untoward medical occurrence that at any dose: results in death; results in inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is life-threatening; is a congenital anomaly/birth defect.

Signal. Information reported on a possible causal relationship between an adverse event and a medicine, the relationship being unknown or previously incompletely documented. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information.

Spontaneous report. An unsolicited communication by health care professionals or consumers that describes one or more ADRs in a patient who was given one or more medicinal products.


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ACKNOWLEDGMENTS

The Strengthening Pharmaceutical Systems (SPS) Program would like to thank Mr. R.R. Jannu, Project Director of the Karnataka State AIDS Prevention Society (KSAPS) for his invaluable support, and Dr. Suresh G. Shastri, KSAPS, for his enthusiasm in working with SPS to conceptualize and implement the activity. We also thank them for their assistance in arranging stakeholder interviews and visits to ART Centres to gather information for the mapping exercise which informs the design of the active surveillance operational plan and protocol, as well as their support for the stakeholder workshop. Sincere thanks to Dr. Reynold Washington and Dr. P. Manish Kumar of the Karnataka Health Promotion Trust, and the staff of the US Agency for International Development (USAID)-funded Samastha project for their support in setting up the stakeholder workshop. SPS would also like to thank Dr. B.B. Rewari, National Program Officer (ART), National AIDS Control Organization (NACO), Dr. Y.K. Gupta, Professor and Head, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), and Dr. Po-Lin Chan, World Health Organization (WHO) Country Officer, HIV/AIDS, for the useful discussions on the active surveillance activity. Sincere thanks to the USAID India Mission for their support to SPS and to this activity. Special gratitude is offered to the staff of the ART Centres in Bangalore at Bowring and Lady Curzon Hospital, St. John’s National Academy of Health Sciences, and Kempe Gowda Institute of Medical Sciences (KIMS), K. R. Hospital, Mysore, Ashakirana Hospital, Mysore, and Vivekananda Youth Movement Hospital, Sargur, for their tireless and exceptional cooperation during the visits. SPS thanks Dr. Gurumurthy Parthasarathi, JSS College of Pharmacy and JSS Medical College Hospital, Mysore, for facilitating the mapping exercise and contributing to the development of the active surveillance operational plan and protocol.


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EXECUTIVE SUMMARY A pharmacovigilance system is proposed to monitor the safety and tolerability of antiretroviral medicines (ARV) at antiretroviral treatment (ART) sites in the State of Karnataka through active surveillance at sentinel sites. The goal of this activity is to develop, implement, and demonstrate the local feasibility of a practical and sustainable pharmacovigilance system that could later be scaled up to monitor the safety of ARV regimens throughout the State. The proposed system also has applicability for future active surveillance of other medicines, settings, and populations. The active surveillance activity, developed by the Strengthening Pharmaceutical Systems (SPS) Program in consultation with the Karnataka State AIDS Control Society (KSAPS) and other stakeholders, proposes to systematically document and quantify the presence or absence of ARV-related adverse events, and to determine risk factors at sentinel sites. Systematically collecting information about medicines used in a defined population helps ensure that medicines have an acceptable safety profile and are used appropriately. The active surveillance system will be a multi-center, prospective observational cohort activity designed to evaluate the incidence and identify risk factors for adverse drug events among HIV-infected patients newly placed on antiretroviral therapy. The proposed data collection strategy is based on data that the National AIDS Control Organization (NACO) of the Department of AIDS Control, Ministry of Health and Family Welfare currently requires ART Centres to collect. The system will be implemented with 10 ART sites. The initial emphasis will be to develop, implement, and operate active surveillance among adult HIV-infected patients receiving ARVs throughout the duration of their use of ARVs. Additionally, over the course of the activity period, active surveillance will also be developed and implemented with pediatric patients and with pregnant women who are receiving ARVs. Both groups are vulnerable and understudied. For patients included in this activity, all suspected adverse drug reactions will be documented and evaluated, including mild to moderate events, reactions that result in substitution, switching, and stopping of ARVs, occurrences of hospitalizations, and death. A data coordinating center will be established to provide data management and training support for the active surveillance sites. This activity will ultimately result in the development of a sustainable active surveillance system for longitudinally monitoring the safety of ARV medicines throughout the duration of the ART program. There is a clear and growing need to better understand the benefits and risks of ARVs under conditions of actual use. Most questions of drug safety may only be answered by observing and analyzing the use and outcomes of therapy in large populations during the post-approval phase.1,2 The active surveillance system presented in this proposal will contribute to the knowledge-base, and help develop infrastructure for future active surveillance approaches. Results will also help inform future revisions to ART treatment guidelines and regulatory decisions. From the perspective of patient care, knowledge of factors that may affect the risk and management of adverse reactions, including other illnesses and conditions, the patient's

1 Institute of Medicine. 2007. Committee on the Assessment of the US Drug Safety System. The Future of

Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: Institute of Medicine. 2 Lang T., D. Hughes, T. Kanyok, J. Kengeya-Kayondo, V. Marsh, et al. 2006. ―Beyond registration—

measuring the public-health potential of new treatments for malaria in Africa.‖ The Lancet Infectious Diseases 6:46-52.


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other current medications, the availability of alternative regimens, and the patient's history of medication intolerance, may lead to improved outcomes.

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BACKGROUND According to the provisional estimate of the National AIDS Control Organization (NACO) of India, approximately 2.27 million people were living with HIV at the end of 2008, with prevalence among adults at 0.29%.3 With a population 61.13 million4, Karnataka is one of the states with the highest HIV prevalence. Expanding access to antiretroviral therapy (ART) is a priority for the Karnataka State AIDS Prevention Society (KSAPS). As of April 2011, there were 44 ART Centres (up from 24 in 2008), 28 Community Care Centres, and 97 Link ART Centres functioning, with a total of 58,634 patients on ART in Karnataka. ART Centres are primarily located in teaching hospitals and district hospitals in the State. The main functions of ART Centres include: identifying eligible persons with HIV/AIDS requiring ART through laboratory services (HIV testing, CD4 count, and other required investigations); providing free antiretroviral (ARV) medicines; ensuring medication adherence through appropriate counseling; and providing a comprehensive package of services, including condoms and prevention education. So that patients do not have to travel long distances to go to the ART Centre for monthly visits, Link ART Centres have been established. The Link ART Centres: provide free ARV medicines to eligible persons with HIV/AIDS; continuously monitor patients on ART for opportunistic infections (OIs), side effects, adherence, and weight; and refer patients with symptoms suggestive of opportunistic infections, side effect of medicines, or pregnancy, and for antenatal care (ANC) back to the ART Centre. Community Care Centres (CCC) have been set up to provide treatment for minor OIs and psychosocial support through counseling. CCCs play a critical role in enabling people living with HIV/AIDS (PLHA) to access ART from the national program. They also provide monitoring, follow-up, and counseling support to patients initiated on ART, including on positive prevention, adherence, and nutrition. The US Agency for International Development (USAID) funds the Samastha project in Karnataka, a comprehensive HIV program that supports prevention, care, and treatment activities in three cities and 12 districts. In addition to reducing the risk of HIV transmission in vulnerable populations, the project aims to build the capacity of health care institutions to provide quality HIV and AIDS care, support, and treatment services. The Samastha project is led by the Karnataka Health Promotion Trust (KHPT) in partnership with Engender Health and Population Services International. The Strengthening Pharmaceutical Systems (SPS) Program has been working in India since December 2009. With field support funds from the USAID India Mission, SPS is assisting KSAPS and other local partners to address issues in the management of ART-related medicines. In the first year, SPS worked with KSAPS, the Samastha project, and other local partners to strengthen pharmacists’ capacity to appropriately manage medicines (e.g.,

avoiding stock-outs and expiries), and strengthen the appropriate use of ARVs and other ART-related pharmaceuticals. 3 Department of AIDS Control, Ministry of Health and Family Welfare, Government of India: Annual Report 2009-2010. 4 Government of India. 2011. ―Census of India 2011: Provisional Population Totals.‖

www.censusindia.gov.in/2011


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In 2010-11, SPS is assisting KSAPS to identify and initiate strategies to strengthen ART pharmacovigilance activities in the State of Karnataka. KSAPS expressed interest in expanding medicine safety activities in the ART program beyond reporting aggregate adverse drug reaction (ADR) figures to the National AIDS Control Organization (NACO), and for incorporating active surveillance methods, such as cohort studies or an ART registry, into the program. During discussions on potential SPS assistance to this endeavour, KSAPS and other local partners agreed that as a first step SPS would support KSAPS to conduct a rapid systems analysis of the pharmacovigilance system for Karnataka’s ART program

5. Based on the findings of the analysis and feedback from respondents, KSAPS and other partners, including NACO, the World Health Organization (WHO), and the National Coordinating Centre (NCC) of the Pharmacovigilance Programme of India for Assuring Drug Safety (PvPI) (based at the All India Institute of Medical Sciences [AIIMS] at the time of the study), agreed that a useful contribution by SPS would be to develop a protocol for establishing a system and platform for active safety surveillance and for longitudinal monitoring of patients on ARVs in Karnataka. Although focused on Karnataka, the protocol would benefit NACO and PvPI by contributing a methodology for active surveillance in public health programs and at ART Centres in other states. This document presents the protocol and operational plan for the active surveillance system.

5 Nwokike, J., and H. Walkowiak. 2011. Pharmacovigilance in the State of Karnataka, India: Rapid Systems

Analysis and Design of Active Surveillance Activities for the Antiretroviral Program. Submitted to the US Agency for International Development by the Strengthening Pharmaceutical Systems (SPS) Program. Arlington, VA: Management Sciences for Health.

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PART 1. ACTIVE SURVEILLANCE PROTOCOL Overall Goal The overall goal of the Active Safety Surveillance System for the Karnataka ART Program (ASSSK) is to implement an active surveillance system in the State of Karnataka’s ART program to generate local, evidence-based information to improve patient care and safety through the identification, management, and prevention of medicine-related morbidity and mortality in HIV-infected patients on ART. Pharmacovigilance may also enhance the HIV/AIDS public health program by systematically collecting information on the adverse effects of medicines, and developing early warning signs of medication-related problems that might affect the success of the program.

Specific Objectives

1. Develop and implement procedures and tools for the active surveillance of ARVs. 2. Through active surveillance, prospectively determine the incidence of and risk factors

for suspected adverse drug events in the treatment of naïve adults, children, and pregnant women receiving ART at ART Centres.

3. Identify and assess signals of ADRs that are likely to affect adherence to treatment and patient outcomes.

4. Demonstrate the feasibility of using active surveillance as a sustainable platform for assessing the safety and use of ART to help support evidence-based decision making, including feedback to clinicians and review of standard treatment guidelines.

The Need for Pharmacovigilance of Antiretroviral Medicines

Pharmacovigilance is the science and activities relating to the detection, evaluation, understanding, and prevention of adverse reactions to medicines or any other medicine-related problems.6 Despite their life-saving and quality-of-life improving effects, ARVs have safety issues ranging from minor to serious ADRs, with both short- and long-term effects. Major adverse events associated with the use of ARVs affecting patient adherence and outcomes include: lipodystrophy, anemia and neutropenia, hypersensitivity reactions, hepatic disorders, acute pancreatitis, osteopenia and osteoporosis, and lactic acidosis.7 Drug interactions are one of the major problems with these regimens. The most common opportunistic infection among patients infected with HIV is tuberculosis (TB). In many countries it is a common occurrence that patients are taking both ARVs and anti-TB medicines. Other concurrent medicines that may be important to examine in patients on ARVs include antimalarial and antifungal medicines.

6 WHO. 2002. The Importance of Pharmacovigilance: Safety Monitoring of Medicinal Products. Geneva: WHO. 7 NACO. 2007. Antiretroviral Therapy Guidelines for HIV-Infected Adults and Adolescents Including Post-

exposure Prophylaxis. New Delhi: NACO.


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Little is known about the epidemiology of the toxicity profiles of ARVs in India, despite the importance of such information for regulatory and public health decision making.8 India has special factors and different conditions that may impact on the tolerability of ARVs. Medicine use and its safety may therefore vary considerably due to the presence of conditions such as: TB, malnutrition, reliance on traditional and/or alternative therapies, and the likelihood of medicine interactions.9 ADRs are one of the most important factors affecting patient adherence to ART. It is therefore important to monitor and manage adverse reactions to ARVs. Active Surveillance as a Tool for Pharmacovigilance in Public Health Programs With expanded access to ARVs, there is increasing recognition of the need to implement pharmacovigilance activities in public health programs.10 Linking and coordinating national pharmacovigilance activities with in-country public health programs supports overall systems strengthening, and may facilitate the achievement of better program outcomes. The conduct of surveillance—that is, the on-going systematic collection, analysis, and interpretation of data—is not a new concept for HIV/AIDS programs. 11 As a tool for pharmacovigilance, active surveillance involves methodically searching for exposures and health outcomes, often at sentinel site facilities.12 It consists of the systematic collection, analysis, interpretation, and dissemination of data regarding one or more medicine-related outcomes using observational methods.13 Through active surveillance, potential safety problems and risk factors may be identified for specific patient populations. Systematically collecting information about medicines used in a defined population helps ensure that medicines have an acceptable safety profile, and are safely used. Active surveillance also helps to understand, scope, and quantify adverse drug reactions. Because surveillance methods involve obtaining a denominator of persons exposed to medication(s) of interest, calculation of rates of adverse drug events is possible. The importance of active surveillance as a systematic approach to medicines safety assessment and pharmaceutical systems strengthening has been cited by many in the field.14,15,16 For instance, since 2008 the TREAT Asia HIV Observational Database

8 Modayil, R.R., et al. 2010. ―Adverse drug reactions to antiretroviral therapy (ART): an experience of

spontaneous reporting and intensive monitoring from ART centre in India.‖ Pharmacoepidemiology and Drug

Safety. 19(3):247-55. 9 Pirmohamed M., K.N. Atuah, A.N. Dodoo, P. Winstanley. 2007. ―Pharmacovigilance in developing

countries.‖ British Medical Journal. 335(7618):462. 10 WHO. 2007. The WHO Practical Handbook on the Pharmacovigilance of Antimalarial Medicines. Geneva: WHO. www.who-umc.org/graphics/19449.pdf 11 USAID Facility-Based Routine Surveillance. www.usaid.gov/our_work/global_health/id/surveillance/fbrsurveillance.html 12 Strengthening Pharmaceutical Systems (SPS). 2009. Supporting Pharmacovigilance in Developing Countries:

The Systems Perspective. Submitted to the US Agency for International Development by the SPS Program. Arlington, VA: Management Sciences for Health. 13 US Centers for Disease Control. 2001. Updated Guidelines for Evaluating Public Health Surveillance Systems. www.cdc.gov/mmwr/preview/mmwrhtml/rr5013a1.htm 14 Platt R., L. Madre, R. Reynolds. 2008. ―Active drug safety surveillance: a tool to improve public health.‖

Pharmacoepidemiology and Drug Safety. Published online DOI: 10.1002/pds.1668. 15 Wise L., J. Parkinson, J. Raine, et al. 2009. ―New approaches to drug safety: a pharmacovigilance tool kit.‖

Nature Reviews Drug Discovery. Published online DOI: 10.1038/nrd3002. 16 WHO. 2007. The WHO Practical Handbook on the Pharmacovigilance of Antimalarial Medicines. Geneva: WHO. www.who-umc.org/graphics/19449.pdf

http://www.who-umc.org/graphics/19449.pdf

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(TAHOD), a collaborative study by a cooperative network of clinicians in Asia and the Pacific, has been monitoring toxicity related to ART as one of its objectives. An increasing number of countries are establishing active surveillance methods for ARVs and other medicines important to public health programs. In 2007, the Food and Drugs Authority of the Tanzanian Ministry of Health and Social Welfare initiated a cohort event monitoring study of adverse reactions among users of ARVs in the country. Beginning in August 2007, the President’s Malaria Initiative (PMI) supported a pilot pharmacovigilance system for antimalarials in Jinja, Uganda. In South Africa, the KwaZulu-Natal Department of Health is implementing a provincial cohort event monitoring program intended to collect long-term data on safety and treatment outcomes in ART patients at eight sentinel sites. South Africa also recently received funding from the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) to support the further development of pharmacovigilance activities. In Namibia, a records-linkage active surveillance activity was conducted to investigate the association between zidovudine and the risk of anemia. Active surveillance provides accurate and timely information for program development and implementation as well as for the development and modification of guidelines. An active surveillance system increases reporting of adverse drug reactions, thereby also strengthening spontaneous reporting approaches to pharmacovigilance. Types of Active Safety Surveillance Cohort monitoring consists of prospective, observational assessment for the presence or absence of adverse effects over time in a cohort of patients following exposure to medicines of interest. Sentinel surveillance is the collection and analysis of data by designated institutions selected for their geographic location, medical specialty, and ability to report high quality data. Sentinel sites are chosen based on certain functions and criteria that are highly relevant for a planned task. Selection criteria may include considerations such as: representativeness, ease of access, infrastructure support, reasonable patient flow; interest and commitment of the potential site; any ADR-related initiative or expertise already in existence; past performance; level of computerization of ART and patient-related data management; and quality assurance measures in place. 17 Pregnancy exposure registries (PER) are used to monitor medicine safety in pregnant women. They provide reassurance on the potential risk associated with certain drugs and serve as both a signal-generating tool and means to evaluate suspected risks or risk factors. PERs use prospective approaches by identifying and following exposed women until the end of pregnancy, that is, before the outcome is known. Records-linkage is a method for assembling information contained in two or more data files, and combining the information belonging to the same individual to longitudinally assess outcomes associated with medicines exposures. Through records-linkage, existing clinical and administrative databases are used to provide a platform for the assessment of adverse drug events.

17 USAID. Sentinel Surveillance. www.usaid.gov/our_work/global_health/id/surveillance/sentinel.html


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Generating Local Data to Inform Regulatory Actions, Treatment Guidelines, and Care Delivery There is a clear and growing need to better understand the benefits and risks of medicines under conditions of actual use. Most questions of medicine safety may only be answered by observing and analyzing the use and outcomes of therapy in large populations during the post-approval phase.18,19 A local example is the paper published by Modayil et al. that assessed the nature, severity, risk factors, predictability and preventability of ADRs to ART at the ART Centre, Krishna Rajendra Hospital, in Mysore.20 This protocol for the Active Safety Surveillance System for the Karnataka ART Program (ASSSK), when implemented, will contribute to the knowledge base on safety and tolerability of ARV medicines, and help develop in-country infrastructure for future active surveillance approaches. In addition, results from this activity will help inform future revisions of in-country ART treatment guidelines and regulatory decisions. The proposed prospective, observational approach will contribute data to provide estimates of safety of ARVs as well as identify signals for evaluation of suspicions of risk to provide for better estimates of benefit-risk profiles. Also, from a patient care perspective, knowledge of factors that may affect the risk and management of adverse reactions, including other illnesses and conditions, the patient's other current medications, the availability of alternative regimens, and the patient's history of medication intolerance may lead to improved outcomes.

18 Institute of Medicine. 2007. Committee on the Assessment of the US Drug Safety System. The Future of

Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: Institute of Medicine. 19 Lang T., D. Hughes, T. Kanyok, J. Kengeya-Kayondo, V. Marsh, et al. 2006. ―Beyond registration—

measuring the public-health potential of new treatments for malaria in Africa.‖ The Lancet Infectious Diseases. 6:46-52. 20 Modayil R.R., et al. 2010. « Adverse drug reactions to antiretroviral therapy (ART): an experience of spontaneous reporting and intensive monitoring from ART centre in India.‖ Pharmacoepidemiology and Drug

Safety. 19(3):247-55.

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ACTIVE SURVEILLANCE METHODS Overview The active surveillance system will be a multi-center, prospective observational cohort activity designed to evaluate the incidence of adverse drug events among HIV-infected patients newly placed on ART. The proposed data collection strategy is based on data that NACO currently requires ART Centres to collect. The system will be implemented with 10 ART Centres that will be designated as the active surveillance sites. The initial emphasis will be to develop, implement, and operate an active surveillance system of adult HIV-infected patients receiving ARVs. Additionally, over the course of the project period, active surveillance will also be developed and implemented with pediatric patients (including infants and children who are born of a mother on ART), and with pregnant women receiving ARVs. These are both vulnerable and understudied groups. A data coordinating center will be established to provide support for data management and training for the active surveillance sites.


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Active Surveillance Sites SPS conducted site visits to prepare a mapping of services and collect information on data recorded by ART Centres. Figure 1 depicts patient flow at the ART Centres.

Figure 1. General Overview of Patient Flow in Accordance with NACO Operational Guidelines

It is proposed that the active surveillance system be implemented in 10 outpatient ART Centres that will serve as the sentinel sites. The following criteria are recommended to develop the list of health facilities: 1. Recruits 50 or more patients into the ART program per month 2. Currently using the Computerized Management Information System (CMIS) 3. Site noted for routine and timely submission of reports to NACO 4. Prior experience documenting cohort records or with descriptive and observational studies 5. Staff at the ART Centre are motivated 6. Geographical representation 7. Availability of second line ARVs 8. Inclusion of at least one pediatric HIV care center Table 1 lists potential sentinel sites using the criteria presented above. Key characteristics relevant for the selection of the sites are presented, such as: geographic location of the facility, number of key health care staff involved in ART, and average monthly number of

Part 1. Active Surveillance Protocol

9

patients. The sites listed in table 1 are provided for illustrative purposes only. The final decision regarding selection of the actual sites will be made by KSAPS.

Active Surveillance Methods

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Table 1. Facilities That Could Serve as Active Surveillance Sites

Site No. ART Centres

Criterion 1

Criterion 2

Criterion 3

Criterion 4

Criterion 5

Criterion 6

Criterion 7

Criterion 8

Number of new patients in May

2011

1 K.R. Hospital, Mysore yes yes yes yes yes Southern Karnataka 74

2 St John’s, Bangalore yes yes yes yes yes 29

3 Indira Gandhi Inst. Child Health, Bangalore

yes yes yes yes yes 10

4 Shimoga ART Centre yes yes yes yes yes South Interior Karnataka

44

5 KIMS Hubli yes yes yes yes yes North Karnataka yes 53

6 VIMS Bellary yes yes yes yes yes Hyderabad Karnataka

52

7 BIMS, Belgaum yes yes yes yes yes North Karnataka 115

8 Udupi ART Centre yes yes yes yes yes Coastal Karnataka yes 50

9 Gulbarga ART Centre yes yes yes yes yes Hyderabad Karnataka

yes 45

10 Ashakirana Hospital, Mysore

yes yes yes yes Southern Karnataka yes 25

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DATA COLLECTION AND DATA MANAGEMENT The proposed data collection strategy is based on data that NACO currently requires ART Centres to collect. This strategy has the following advantages:

All but one of the data elements (i.e., outcome of the adverse drug event) required for the ASSSK activity is collected in the Patient Treatment Record (PTR) which is currently in use and approved by NACO. Use of the NACO form for data collection ensures that there is no additional burden on staff for the purpose of this activity.

Data collection for the ASSSK activity will improve the quality of documentation at ART Centres. Use of the required NACO form ensures that training provided for this activity will reinforce appropriate documentation at the ART Centres for the overall benefit of the ART program in Karnataka.

Additional data entry staffs are not needed for the purpose of the ASSSK activity at the ART Centres. The use of the required NACO form ensures that there will be no need to hire new data entry clerks to support the ASSSK activity.

The cost of implementing the ASSSK activity will be reduced by leveraging existing

resources and data collection processes.

Since the ASSSK activity relies on the existing components of the ART program it is sustainable. There is an opportunity for the ASSSK activity to be institutionalized into the ART program in the State of Karnataka.

It is proposed that recording of patient information at the ART sites be conducted in accordance with NACO guidelines and protocols for data collection. Figure 2 is adapted from the NACO patient flow at ART Centres. It highlights data collection points relevant to the ASSSK activity. For any pharmacovigilance system, four critical points of data collection are required: patient information (which can be ascertained through the patient demographics); exposure data (which can be ascertained through prescription and dispensing of medicines); collection of adverse events and their outcomes; and reporting.


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Source: Adapted from the patient flow at ART Centre (ART care) of the National ART Guidelines.

Figure 2. Points for Collecting Data to Support the Active Surveillance System

All patients enrolled in the active surveillance system will be followed from the start of their ART and for the duration of their ART care. Data from the participating ART Centres will be requested on a monthly basis. It is expected that active surveillance information will be integrated into usual care, with data collected every time a patient comes for follow-up, which is typically once per month for stabilized patients. The standard practice at the ART Centres includes efforts to track patients who do not come for follow-up visits. The plan is to periodically analyze the data, e.g., semi-annually. Regular monitoring visits and telephone calls will be scheduled to verify that data are reported according to protocol and standard operating procedures (SOP).

Data Collection Process Table 2 presents the suggested minimum data set for the ASSSK activity. There are 23 data elements needed for the ASSSK activity. All but one data element is currently collected by

Data Collection and Data Management

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the PTR. Included in the minimum data set is use of information from laboratory results that suggests non-symptomatic ADRs, e.g., elevation of liver enzymes. Annex A provides a detailed description of the fields and the codes that are used for completing them. The codes and entries for the fields are consistent with those required by NACO for the PTR and CMIS reporting. Table 2. Minimum Data Set for the ASSSK Activity

Type of Variable No. Name of Field Currently recorded in the

CMIS (Yes/No)

Patient demographics and baseline data

1 ART Centre code Yes

2 ART registration number Yes

3 Age/date of birth Yes

4 Gender Yes

5 Height Yes

6 Weight Yes

7 Pregnant Yes

8 Risk factor for HIV (source of transmission)

Yes

9 WHO clinical stage Yes

10 CD4 count Yes

Medicines exposure data

11 Source of first ARV exposure Yes

12 Date of starting ARV treatment Yes

13 ARV regimen Yes

14 Adherence Yes

15 Opportunistic infection medications Yes

16 Other complementary and alternative medicines

Yes

17 Other conditions Yes

18 Test results Yes

19 Other medicines Yes

20 Suspected adverse drug event Yes

Outcome data 21 Substitution, switch, and stop Yes

22 Outcome of the adverse drug event No

23 Functional status Yes

Data for item number 22, ―Outcome of the adverse drug event‖, are not currently collected. SPS recommends that the data entry clerk reviews the PTR and consults the clinician who saw the patient to obtain the necessary information. The proposed options for this item are: 1 = Resolved 2 = Resolving 3 = Resolved with sequelae 4 = Not resolved 5 = Worse 6 = Death 7 = Unknown


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Although the NACO form is currently in use at ART Centres, observations made during the mapping exercise and site visits conducted by SPS revealed that the required data are not consistently documented. The ASSSK activity will provide extensive training to ART health workers to ensure that the data are collected and consistently documented. This will potentially benefit the ART program since it will lead to improved clinical documentation in the participating sites. Table 3 is an excerpt from the PTR. It shows the data collected in the patient follow-up section of the form. As can be seen in the table, most of the data recorded is relevant to the ASSSK activity. Table 3. Patient Follow-up Section of the Patient Treatment Record

Source: National AIDS Control Organization Department of AIDS Control, Ministry of Health and Family Welfare, Government of India, September 2010.

The ASSSK activity also proposes a process for the extraction and transmission of the data from the ART Centres to the proposed ASSSK Coordinating Centre (ACC). Figure 3 depicts the proposed data collection and transmission process.


15

ART site completes the Patient Treatment

Record

CMIS data sent to ASSSK

Coordinating Center (ACC)

ACC collates, analyses, and

reports findings

Relevant fields

transcribed from the

CMIS into the

ASSSK fields and e-

Submitted to ACC

Reports submitted by

ART site once every

month

ACC provides

feedback to the

ART site

Data from PTR entered into the CMIS

Figure 3. Data Collection and Transmission Process

Additional Data Required by the ASSSK Coordinating Centre Upon review of the data described above, the ACC may require further details for a complete description of the adverse event. In some instances the ACC may need to contact the ART Centre to obtain further information. The ACC will complete the description of the event and exposure by standardizing their classifications using the following:

1. System Organ Class (Medical Dictionary for Regulatory Activities [MedDRA] terminology for the adverse reaction)

2. Anatomical Therapeutic Chemical Classification System (ATC) for classification of the medicines

3. Additional details on the ADR (e.g., how long the event lasted, challenge/rechallenge) 4. Causality assessment (for determining if the event is associated with the ARV using

scales, such as the WHO Scale and Naranjo's Algorithm) 5. Seriousness


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6. Severity grading (during the course of the ASSSK activity, additional severity grading by clinicians at the sentinel sites may be pilot tested, provided that it is acceptable and standardized instructions and training are provided).

7. Predictability 8. Preventability

Pregnancy Exposure Registry

Should a pregnancy exposure registry be phased in for patients from the ASSSK sites who are pregnant at the time of initiation of ART, or become pregnant during follow-up, a Pregnancy Outcome Form will be completed. Annex B provides a sample form which may be adapted for use by ASSSK sites. Pregnancy outcomes of interest include miscarriages, elective terminations, fetal deaths/stillbirths, and live births. Gestational age at birth and results of neonatal physical examination (e.g., weight at birth, length, infant head circumference at birth) also need to be assessed.

Data Analysis The ACC will require a data collation and analysis tool for the ASSSK activity. Participating sites will send their data on a monthly basis. The ACC tool will be used to aggregate the data and conduct some analyses. The purpose of analysis is to identify the incidence rates, relative risks, and risk factors for the adverse drug events. The data analysis tool will need to have the following features:

Relevant dictionaries including MedDRA, ATC classification, International Nonproprietary Names (generic name), seriousness and severity scales, etc.

Built-in causality analysis function Built-in function for other analyses, such as incidence rates, unadjusted and adjusted

relative risk with 95% confidence intervals (CI), and risk factors Built-in function to generate the following reports: o Incidence of ADR (disaggregated by regimen, duration of treatment, gender, etc.) o Risk factors for each ADR (gender, concurrent medications, co-morbid

conditions, adherence, CD4 at initiation, etc.) o Longitudinal data on cohort of patients experiencing ADRs

The data collation and analysis tool may be adapted from existing tools developed by the SPS Program and used for active surveillance activities in Vietnam and South Africa. As data accumulate, descriptive frequency tables for demographics, medicine use, and adverse drug events will be prepared periodically. As the program matures and more data accumulate, statistical analyses will be performed to understand and present various adverse event profiles, such as incidence rates, predictors of adverse events, and relative risks. Frequencies and risks of adverse drug events will be compared by medicine category. Multivariate models will be developed to identify predictors of adverse drug events taking into account potential confounders (table 4).


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Table 4. Variables to Be Used in Analyses

Variable Name Category Type

ART regimen Primary exposure Categorical

Age Confounder Continuous

Gender Confounder Binary: male, female

Baseline CD4 Confounder Continuous

Baseline hemoglobin Confounder Continuous

Baseline co-illnesses Confounder Categorical

Co-trimoxazole use Confounder Binary: yes, no

Baseline comorbidities Confounder Categorical

Other concomitant drugs Confounder Categorical

Duration of ART Effect modifier Continuous

The incidence rate of an event will be calculated as the number of events divided by the total number of patient-months of follow-up, for ADRs by type. Estimates will be given with 95 percent confidence intervals assuming a Poisson distribution. Regression models will be used to investigate factors associated with the occurrence of the endpoint events. Sample Size Estimation The 10 ART Centres in the State of Karnataka are expected to enroll approximately 400 new patients per month on ART, resulting in approximately 5,000 new ART patients over the course of one year. Patients newly placed on ART regimens will be approached for possible enrolment in the active surveillance activity. An a priori criterion for sites participating in this activity is the ability to maintain a loss to follow-up rate below 10% annually. Although active surveillance will continue as long as a patient remains on ART, once approximately 3,000 patients are enrolled in the active surveillance system, there will be a 95 percent probability of identifying an adverse drug event that is expected to occur with an incidence of 1 per 1,000 persons (table 5). This sample size should be large enough to detect less common adverse drug reactions, as previously discussed in the section of this document on ―Adverse Events Associated with ARVs‖. Moreover, the number of people newly placed on ART is likely to increase if eligibility for ART expands as recommended by WHO. WHO guidance for a form of active surveillance, called Cohort Event Monitoring, recommends the recruitment and follow-up of sample sizes of approximately 10,000 persons to best allow for identification of rare ADRs. While sample sizes of this magnitude may be achieved at a later date, the recommendation is to begin with a smaller, targeted sample size to gain valuable experience with active safety surveillance in the State of Karnataka. The key advantage of this activity is the plan to continue the surveillance for the life of the ART program, and to follow up patients for as long as they remain in the ART program. This will ensure that the platform developed can be used for monitoring newer ARVs when introduced into the ART program and also allow for studying adverse events of delayed onset. The activity is not intended to be a study; rather, it is an on-going program. The 3,000 figure mentioned above is illustrative of the number of patients that need to be enrolled to obtain statistical power for the analysis, while 10,000 patients allow for the detection of rare events. However, the key expectation from this activity is to provide the incidence rate and relative risk that will allow for the characterization and quantification of known clinically significant adverse drug reactions.


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Table 5. Relationship Between Sample Size and Probability of Observing an Adverse Event: Percent Probability of Observing at Least One Adverse Event in the Sample by Adverse Event Expected Incidence

Expected Adverse Event Incidence: 1 Event out of ... Patients

Sample Size 100 200 500 1,000 2,000 5,000 10,000

200 86.47 63.21 32.97 18.13 9.52 3.92 1.98

300 95.02 77.69 45.12 25.92 13.93 5.82 2.96

500 99.33 91.79 63.21 39.35 22.12 9.52 4.88

700 99.91 96.98 75.34 50.34 29.53 13.06 6.76

1,000 100.00 99.33 86.47 63.21 39.35 18.13 9.52

2,000 100.00 100.00 98.17 86.47 63.21 32.97 18.13

3,000 100.00 100.00 99.75 95.02 77.69 45.12 25.92

5,000 100.00 100.00 100.00 99.33 91.79 63.21 39.35

Sources: WHO. 2009. A Practical Handbook on the Pharmacovigilance of Antiretroviral Medicines and WHO 2007. A Practical Handbook on the Pharmacovigilance of Antimalarial Medicines.

Training Personnel at all sites will be trained before the initiation of the ASSSK activity. Emphasis will be placed on SOPs, including the purpose of pharmacovigilance, the surveillance system, what ADRs and adverse events to record, and how to record them using the established system. The active surveillance procedures will be pretested and modified accordingly. To ensure credibility of results generated, quality assurance tools, such as SOPs, will be implemented. Quality assurance procedures will also include regular visits to the participating sites by designated personnel. The data manager at the ACC will be responsible for quality assurance checks. Site monitoring will include a review of a sample of source documents.

Data Confidentiality and Ethical Considerations

A data privacy protection SOP will address safeguarding the confidentiality of the data. All personnel involved in the program will be trained on this SOP. Prior to sending data to the ACC, patients’ personal information will be coded in the CMIS with unique, encrypted identification numbers. Identifiable patient information will only be available in the hard copies of patient records stored at ART Centres. A master list of coding will be developed at each ART Centre linking the unique identification numbers with the patient records. The master list will be under the access control of the medical officer at the ART Centre. A log will be maintained for accessing this master list. All computer systems used, including the CMIS database, will be access controlled with passwords at the entry level. The centralized database will have capabilities for an audit trail.

Safety monitoring of ARVs is an integral part of patient monitoring. The proposed active surveillance system will develop much-needed local data for better patient management, and build a safety network for comprehensive patient management. The proposed work may be presented to an ethics committee (independent or institutional) after necessary administrative approval from KSAPS/NACO. Approval from one ethics committee may be sent to ethics committees of all other participating institutions for the notification and approval of the institutional ethics committee. The issues may have to be addressed on a case-by-case basis


19

if any participating institution requests that the ASSSK work be approved by their ethics committees. ASSSK is not a clinical trial or research study and does not interfere with treatment in any way. It is a process of observation and data collection to guide decision making on the safety of ARV in the interests of public health. If an ethics committee determines the need to have informed consent, one alternative is to provide information publicly at the ART Centres, including information leaflets for patients. This is referred to as an ―opt out principle‖, which operates in a number of countries and, if needed, is much more practical than obtaining individual informed consent.

The active surveillance system is an observational activity that has minimal risk. Information is collected from the patient and the clinical history of the patient, and without any intervention. All patient identifiers will be encrypted. Procedures will be established and maintained to ensure the confidentiality of data. Unauthorized persons will not have access to the data. The 2009 WHO Practical Handbook on the Pharmacovigilance of Antiretroviral

Medicines (pages 85–87) states:

Because it is essential to record personal identifiers, the security, privacy and confidentiality of personal data need to be strenuously maintained…should avoid

attempting to obtain individual informed consent if at all possible because it will be time-consuming to try to explain the concepts of pharmacovigilance to each patient, will increase complexity and add to the cost, and could potentially compromise the validity of the results if many patients refuse to be enrolled. [It] is not a clinical trial or research study and does not interfere with treatment in any way. It is simply a process of observation data collection in the interests of public health.

Published data, including reports, will not contain any information that could identify patients.

Limitations The proposed activity has some limitations. The geographic coverage of the ASSSK sites is somewhat limited. Results therefore cannot be generalized to the entire country of India. Moreover, completeness of the data for the category, ―ART Side Effects‖, in the CMIS is unclear at this time.

Dissemination Results will be disseminated through several communication channels: Any emerging safety signals will be evaluated to assess which constitute a signal and next

steps to be taken.

Reports will be distributed to the relevant public health programs in the State of Karnataka as follows:

o An interim report on the ASSSK activity will be prepared every six months. o A report will be prepared annually, and a meeting with relevant stakeholders to

share results will be conducted.


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Publication in peer-reviewed scientific and professional journals is anticipated. Subject to copyright, publications will be disseminated via additional media, such as WHO journals and related websites that are open and accessible at no cost. Presentation of methods and findings at professional meetings is also likely.

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PART 2. OPERATIONAL PLAN FOR IMPLEMENTATION OF THE PROTOCOL Operational Strategic Framework The operational plan for the implementation of the ASSSK activity is based on the following strategic framework: leveraging existing monitoring and evaluation (M&E) structures; sustainability of the platform; stakeholder engagement; and use of the findings to inform treatment guidelines and regulatory decisions. The advantages of using existing M&E structures include cost efficiencies and improved documentation of clinical practices. As to sustainability, the operational framework will facilitate opportunities to institutionalize the ASSSK platform in the ART program. The active surveillance activities will yield lessons on the safety and effectiveness of ARVs from real-life experiences. The success of the active surveillance system will only be possible if all relevant stakeholders are engaged in the activity. The operational framework has several instruments which will ensure that lessons learned are used as evidence for action. Many countries experience challenges applying research findings in policy development and implementation. As shown in table 6 below, the operational framework will ensure that the opportunities are used. Table 6. Framework For Active Surveillance in Developing Countries

Approach Benefits

Leverage existing M&E structures

• Improve efficiencies by leveraging existing M&E resources

• Contribute to improved clinical documentation

• A component of quality improvement activities

Build on sustainable platform • Routine surveillance system, not a study

• Robust platform contributes to other safety surveillance objectives

Engage all relevant stakeholders • Government leadership

• Local ownership and involvement

Use surveillance data for decision making

• Use of local data to improve treatment outcomes is the direct benefit of the activity

• Use of the findings reinforces the importance of the surveillance activity

Stakeholders’ Engagement, Roles, and Responsibilities The successful implementation of the ASSSK activity will involve the identification and engagement of all relevant stakeholders. In addition to providing overall leadership for the implementation of this activity, KSAPS and NACO will identify and engage other key stakeholders who will contribute to the success of the activity. The roles and responsibilities of other key stakeholders are described below.


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Health Workers at the ART Centres Health workers at the participating ART Centres will have overall responsibility for data collection and transmission, and for educating patients on ARV medicine use and possible side effects or adverse events. Table 7 lists the health workers and their recommended roles and responsibilities. Table 7: Health Workers Roles and Responsibilities at the ART Centres

No. Title Role and responsibility

1 Nodal Officer Overall responsibility for monitoring the implementation of the ASSSK activity at the participating site; timely documentation and submission of data to the ACC.

2 Medical Officers Patient evaluation for possible adverse drug events; documentation of the suspected adverse drug event in the relevant fields in the PTR; additional description of the event.

3 Counselors Educate patients during counseling on possible side effects of ARVs; interview patients on possible ADRs; document information in the PTR and refer patient to the doctor for further evaluation.

4 Pharmacist Counsel patients on possible ADRs to ARVs during dispensing, focusing on short-term and long-term toxicities, as appropriate.

5 Staff Nurse Interview patient on possible side effects during follow-up visits; make appropriate entries in the medical record for further evaluation by the medical officer.

6 Data Entry Operator

Transcribe data from the PTR to the CMIS; ensure the completeness of data captured for the required fields; transmit data to the ACC; report on the NACO indicator: “Number of PLHIV who were diagnosed with a side-effect this month”.

ASSSK Advisory Committee Formation of an advisory committee to support the implementation of the active surveillance activity is recommended. The proposed roles and responsibilities of the ASSSK Advisory Committee (AAC) include:

Review reports, signals, and risk factors identified by the ACC. Provide on-going and timely advice on current and emerging safety issues identified by

the ASSSK activity. Develop recommendations related to clinical practice to address findings and safety

issues generated by the ASSSK program. Promote the dissemination and communication of priority public health

recommendations emerging from the ASSSK activity to KSAPS, NACO, PvPI, and other the key decision makers.

Membership of the AAC Representation on the AAC should include people with different backgrounds and experiences in HIV care and treatment as well as a mix of administrative and clinical experience. Geographic representation should also be considered. The following types of personnel are recommended:

Part 2. Operational Plan for the Implementation of the Protocol

23

1. Project Director, KSAPS, ex officio member: The key officer who guides, supports, and supervises the ART program in the state.

2. Regional Coordinator, KSAPS, ex officio member: Provides clinical and technical guidance to plan and implement ART programs that include ARV therapy, treatment of OIs, and palliative care.

3. Drugs Controller for the State of Karnataka, ex officio member: Represents the Ministry of Health and Family Welfare.

4. Nominee from NACO: Preferably the National Program Officer.

5. Two Nodal Officers from ART Centres with a minimum of 10 years of clinical and research experience in HIV care, treatment, and support. Experience treating HIV patients as both inpatients and outpatients is desirable.

6. Two Medical Officers from ART Centres with a minimum of five years of clinical and research experience in HIV care, treatment, and support. Experience treating HIV patients as both inpatients and outpatients is desirable.

7. An epidemiologist with research experience in public health programs, especially in HIV care, treatment, and support. Knowledge of bio-statistics is essential.

8. Pharmacovigilance expert with an understanding of the principles of pharmacovigilance. This individual should have hands on experience in intensive monitoring or active surveillance and spontaneous reporting studies of adverse drug reactions. Experience in ADR monitoring for ART is desirable.

9. Pediatric HIV specialist with work experience in both inpatient and outpatient settings of HIV clinics.

ASSSK Coordinating Centre The operational plan recommends the establishment of the ASSSK Coordinating Centre (ACC). The Centre will serve as the central data warehouse and will be responsible for data cleaning, aggregation, and analysis of all data. With the permission of NACO, the data will need to be transmitted to the central data warehouse managed by the ACC. To fulfill these requirements, the proposed Centre must meet the following criteria:

Availability of an existing ADR database for use in aggregate analysis. The database will be further enhanced for the purpose of the ASSSK activity.

Availability of dictionaries used for pharmacovigilance terminologies, such as WHO-Adverse Reaction Terminology (WHO-ART), WHO Drug Dictionary, and Medical Dictionary for Regulatory Activities (MedDRA).

Staff trained in pharmacovigilance who have prior work experience in the area.


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Regional site for the PvPI or affiliation with the PvPI program. This requirement is important to ensure that data collected during the implementation of this activity is routinely submitted to the national ADR data warehouse kept by the PvPI.

The center should be an academic institution with an affiliated school of medicine

or pharmacy. The proposed relationship among the key stakeholders and how results on safety signals of public health importance will be communicated is shown in figure 4.

ASSSK Coordinating Center

Communication of findings for

decision making

NACO, PvPI

ASSSK Advisory Committee

Data collection

Data entry operator

Health workers at ART facilities

Patients and caregivers

Figure 4: Translating Data Collection into Decision Making

To enable participants and stakeholders to implement the ASSSK activity in a consistent manner and for the purposes of quality assurance, SOPs are required. Annex 3 contains the proposed list of SOPs that may be used as a guide.

Logistics and Budget A budget for the implementation of the ASSSK activity should be developed and presented to policy makers so that funds may be allocated. Table 8 provides an illustrative budget which may be used as a guide.


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Table 8: Resource Needs and Budget

Category Activity Unit

Upfront Cost for First Year Maintenance Cost per Year

Rate (INR/Unit) Units Days Total


Human resources at ASSSK Coordinating Centre (ACC)

Technical staff (Research Associate)

Person 240,000 1 240,000 240,000 1 240,000

Data manager and secretarial support

Person 120,000 1 120,000 120,000 1 120,000

Advisory Committee Meetings 150,000 150,000 150,000 150,000

Sub-total 510,000 510,000 510,000

Training of Medical Officers and Counselors in Participating ART Centres

Travel Person 3,000 30 1 90,000 3,000 20 1 60,000

Accommodation Person 1,000 30 1 30,000 1,000 20 1 20,000

Hall rental Day 10,000 1 1 10,000 10,000 1 1 10,000

Training materials Person 250 30 1 7,500 250 20 1 5,000

Refreshments Person 250 35 1 8,750 250 25 1 6,250

Sub-total 146,250 101,250

Reference and IEC Materials

Printing (forms) Form 2 80,000 1 160,000 2 40,000 1 80,000

Photocopies, etc. Paper 1 40000 1 40,000 1 20000 1 20,000

Standard Texts and References

200,000 100,000

Pharmacovigilance Dictionaries and Terminologies

250,000 250,000

Sub-total 650,000 450,000

Quarterly site visits by ACC staff

Travel Person 1,000 1 60 60,000 1,000 1 30 30,000

Accommodation Person 1,000 1 60 60,000 1,000 1 30 30,000

Sub-total 120,000 60,000

Data analysis Allowance-Biostatician Person 1,000 1 60 60,000 1,000 1 60 60,000

Sub-total 60,000 60,000


26

Category Activity Unit

Upfront Cost for First Year Maintenance Cost per Year



Development of electronic data transfer system from ART Centres

Conceptualization, development & testing of central database

450,000 1 450,000 50,000 50,000

Teleconference calls 1,500 6 9,000 6 9,000

Telephone and internet expenses

24,000 1 24,000 24,000 1 24,000

Desktop computer Compu-ter

50,000 1 50,000

Heavy-duty photocopier with fax & scanner

Photo-copier

40,000 1 40,000

Maintenance cost per year 10,000 1 10,000 10,000 1 10,000

Sub-total 583,000 93,000

Total 2,069,250 1,274,250

10% contingencies

206,925 127,425

TOTAL 2,276,175 1,401,675


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Work Plan and Monitoring the Implementation of the ASSSK Activity To ensure the timely implementation of the ASSSK program, a work plan has been developed that is presented in table 9 below. The work plan defines the specific activities, products, output indicators, and timelines for the implementation of each activity. The following illustrative outcome indicators are provided for determining the success of the ASSSK activity:

1. Number of medicine safety decisions disseminated to inform clinical management 2. Number of revisions to ART treatment guidelines informed by findings of the ASSSK

activity 3. Percent improvement in data quality of the PTR 4. Percent reduction in preventable adverse drug events 5. Percent improvement in retention on treatment and adherence to ARVs 6. Percent improvement in health worker skills in prevention and management of ADRs 7. Percent improvement in patient knowledge of ART side effects

The indicators may be further reviewed to determine specific targets. It is important to have targets to facilitate monitoring and evaluation of the ASSSK program.


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Table 9: ASSSK Work Plan

1 2 3 4 5 6 7 8 9 10 11 12 >>>

Establish ASSSK advisory committee (AAC)

and ASSSK coordinating center (ACC)

AAC terms of reference,

ACC staffing and

infrastructure

Inauguration of AAC, #

staff recruited for ACC,

infrastructure provided

KSAPS/NACO

Development of Protocol & SOPs Protocols and SOPs Protocol approved, #

SOPs developed

ACC

Develop and pilot test the data transfer and

management plan

Pilot test results Data management plan

functional

KSAPS/ACC

Provide trainings to health workers in

participating sites and train other

stakeholders

Training reports # of health workers

trained

ACC/KSAPS

Recruit patients as indicated in the protocol

and SOPs

Status of recruitment

report

# of patients recruited KSAPS/ART

sites/ACC

Collect data as indicated in the protocol

and SOPs

Status of data collection

report

# of reports submitted

per site

ART Sites/ACC

Conduct supportive supervisory visits and

onsite training of participating sites based

on needs

Training reports # of health workers

trained, % improvement

in data collection and

ACC

Develop and disseminate IEC materials

including patient information leaflets (PIL)

IEC materials, PIL # of IEC materials and

PIL developed

ACC/KSAPS

Disseminate progress reports, findings &

lessons learned

Reports, workshop,

abstracts, journal

articles

# of reports, workshop,

abstracts, journal articles

ACC/KSAPS/NACO

Conduct Advisory Committee Meetings Meeting reports # of AAC meetings held KSAPS/ACC

MonthsAccountable

person/institution

IndicatorActivity Products


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Operational Aspects of Communicating the Findings and Using Data for Decision Making It is recommended that findings from the ASSSK activity be routinely disseminated through a quarterly newsletter. The newsletter should be edited, published, and disseminated by the ACC in coordination with KSAPS. Recommendations derived from the findings of the activity should also be communicated to health workers and patients through other mechanisms, including patient information leaflets. Publication of scientific and professional articles in peer-reviewed journals will be done in accordance with the rules of publishing, e.g., stakeholders’ permission to publish, relevance of findings, etc. The ASSSK activity will emphasize and encourage scientific dissemination inasmuch as possible.


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31

ANNEX A: SUGGESTED MINIMUM DATA SET FOR THE ASSSK ACTIVITY

Type of Variable No. Name of Field Description Currently recorded in

the CMIS (Yes/No)

Patient demographics and baseline data

1 ART Centre code This refers to the ART Centre code in the Patient Treatment Record. Yes

2 ART Registration Number

Number assigned to the patient at the ART clinic where the patient is receiving care for ART management.

Yes

3 Age/date of birth This is the age of the patient. Alternatively, if provided, the date of birth of the patient may be used to compute the patient’s age.

Yes

4 Gender Choose from the drop down menu, if the patient is male or female. Yes

5 Height Enter the height of the patient as it appears in the medical record or take the patient's height. This should be recorded in centimeters.

Yes

6 Weight Enter the patient’s weight as it appears in the medical record or take the patient's weight. This should be recorded in kilograms.

Yes

7 Pregnant Note the pregnancy status of the patient. If the patient is pregnant note “1” If not, note “0”.

Yes

8 Risk factor for HIV Check the applicable “Risk factor for HIV” as provided in the Patient Treatment Record.

Yes

9 WHO clinical stage This field records the clinical stage of the HIV infection at every visit of the patient, as noted in the medical record. Choose the appropriate code from the drop down menu. The description of each code is provided.

Yes

10 CD4 result Note the CD4 count at the initiation of treatment. Yes


32


the CMIS (Yes/No)

Medicines exposure data

11 Source of first ARV exposure

This field records where the patient received his/her first ARV medicine. This is documented in the Patient Treatment Record as PMTCT, ART, Post Exposure Prophylaxis.

Yes

12 Date of starting ARV treatment

This data is noted in the patient follow-up table in the Patient Treatment Record as the ”Date of Visit”

Yes

13 ARV regimen This field records the ARV regimen the patient has been prescribed or the patient is following at the time of this particular visit. The regimens are coded. The detailed description of the regimen belonging to each code is provided in the Patient Treatment Record. The field “Others” in the adult and pediatric regimens is provided to enter regimens that are not on the list.

Yes

14 Adherence This should be entered in the field "Adher. to ART## (No. of doses missed)" on the Patient Treatment Record.

Yes

15 Opportunistic infection medications

This field is the same as "Drugs Prescribed for Opportunistic Infections" in the Patient Treatment Record.

Yes

16 Other complementary and alternative medicines

Any alternative medicines used. Yes

17 Other conditions Provide the name or diagnosis of other health conditions the patient may have as indicated in the medical record. Make an effort to obtain the current and correct diagnosis if the other conditions are not well indicated in the records.

Yes

For adult regimens, the codes and descriptions are: I (Zidovudine + Lamivudine + Nevirapine) I (a) (Stavudine + Lamivudine + Nevirapine) II (Zidovudine + Lamivudine + Efavirenz) II (a) (Stavudine + Lamivudine + Efavirenz) III (a) (Tenofovir + Lamivudine + Efavirenz) IV (Zidovudine + Lamivudine + Lopinavir/Ritonavir) IV (a) (Stavudine + Lamivudine + Lopinavir/Ritonavir) V (Tenofovir + Lamivudine+ Lopinavir/Ritonavir) Vi (Tenofovir + Lamivudine+atazanivir/ Ritonavir + Zidovudine) Vi (a) (Tenofovir + Lamivudine+atazanivir/ Ritonavir ) III (Tenofovir+ Lamivudine + Nevirapine) Others

For pediatric regimens, the codes and descriptions are: P I (Zidovudine + lamivudine+ Nevirapine) P I(a) (Stavudine + Lamivudine + Nevirapine) P II (Zidovudine + Lamivudine + Efavirenz) P II (a) (Stavudine + Lamivudine + Efavirenz) P III (Abacavir + Lamivudine + Nevirapine ) P III (a) (Abacavir + Lamivudine + Efavirenz) P III (b) (Abacavir + Lamivudine + Lopinavir/ Ritonavir) P IV (a) (Stavudine + Lamivudine + Lopinavir/ Ritonavir) P V (Abacavir + Lamivudine + Didanosine + Lopinavir/ Ritonavir) P IV (Zidovudine + Lamivudine + Lopinavir/Ritonavir) Others

Annex A: Suggested Minimum Data Set for the ASSSK Activity

33


the CMIS (Yes/No)

18 Test results Provide details of all laboratory results of the patient as indicated in the medical records. If the clinical records indicate that a result is still being expected, make an effort to follow-up to obtain the result once it is available, and enter it in this field.

Yes

19 Other medicines Provide details of all other medicines besides the ARVs that the patient may be taking currently or just stopped taking within the past 1 week. Since patients may be taking complementary and alternative medicines/traditional medicines, describe the names of these medicines as they are most commonly referred to in India. Provide both trade and generic names of the medicines. Also provide the dose, dose frequency, start date, and end date (if applicable) for the medicine. Obtain this data by transcribing from the medical records and interviewing the patient.

Yes

20 Suspected adverse drug event

Enter the side effects reported by the patient during the visit in the Patient Treatment Record in the field "ART side effects - code". The following codes are provided: Side effects: S=Skin rash; Nau-nausea; V=Vomiting; D=Diarrhoea; N=Neuropathy;J=Jaundice; A=Anemia; F=Fatigue; H=Headache; Fev=Fever; Hyp=Hypersensitivity; Dep=Depression; P=Pancreatitis; L=Lipodystrophy; Drows=Drowsiness; Lipodystrophy (L);Lactic Acidosis(LA); Skin Reaction (SR); Myalgia(M); IRIS (I); GI Side Effects (GI); Drug induced Hyperglycemia (DIH); Renal abnormalities (RA); O=Other− Specify

Yes

Outcome data 21 Substitution, Switch, and Stop

This field allows for the entry of the reason for any of the following outcomes: ARV substitution, switch, or stop

Yes

22 Outcome of the adverse drug event

Provide a description of the outcome of the adverse event. Enter the appropriate code describing the outcome of the adverse event: 1 = Resolved 2 = Resolving 3 = Resolved with sequelae 4 = Not resolved 5 = Worse 6 = Death 7 = Unknown

No


34


the CMIS (Yes/No)

23 Functional status In this field, provide the functional state of the patient. The Patient Treatment Record provides a field and the codes for "Functional Status WAB" including: W – Working = able to perform usual work in or out of the house, harvest, go to school or, for children, normal activities or playing A – Ambulatory = Able to perform activities of daily living but not able to work/go to school/play B – Bedridden = Not able to perform activities of daily living

Yes

35

ANNEX B. STANDARD OPERATING PROCEDURES

List of Standard Operating Procedures for Intensive Monitoring of ART Safety

Sl. No. Standard Operating Procedure To Be Used By

1 Completion of Patient Treatment Record ART Centres

2 Interviewing and Counseling Patients on Medication Safety ART Centres

3 Data Entry in Electronic Format ART Centres

4 Follow-up of Patients with ADRs and Providing Additional Information to the ACC

ART Centres

5 Transmission of Data from ART Centres to the ACC ART Centres

6 Data Privacy Protection ART Centres and ACC

7 Causality Assessment of ADRs ACC

8 Transmission of ADR Reports from ACC to National Pharmacovigilance Programme

ACC

9 Follow-up of Treated Pregnant Patients ART Centres

10 ART Product Quality Complaints and Associated ADRs ART Centres and ACC


36

37

ANNEX C. ILLUSTRATIVE PREGNANCY HISTORY AND OUTCOME FORM

Pregnancy History and Outcome Form Date of visit: [_][_]/[_][_][_]/[_][_] (DD/MMM/YY)

Name of

Patient:_________________________________________________ ID number: [_][_][_][_][_][_] [_] [_][_][_] Obstetric History *Record Items 1 through 20 at the first contact with a pregnant woman included in the active surveillance

1. Is this your first pregnancy? [_] 1=Yes 2=No IF YES go to question 9

2. How many pregnancies have you had where the baby was born alive? (including those babies not alive today)

Number [_][_]

3. Have you ever had a still birth? (baby which was born dead; no crying and no breathing after delivery) Number [_][_] Have you ever lost a pregnancy before 7 months of pregnancy?

4. Number of miscarriages [_][_] 5. Number of induced abortions [_][_]

6. Number of previous multiple pregnancies? (e.g., twin, triplets) [_][_]

7. Calculate the total number of previous pregnancies [_][_]

8. Did any of the babies born alive have major malformations or other abnormalities at birth? [_] 1=Yes 2=No If yes, describe the abnormality:……………………………………………………………………......................................

9. Was anyone in the family born with an abnormality? [_] 1=Yes, 2=No, 10. If yes, who? [_]1=Mother of participant, 2= Father of participant, 3=Sibling/self, 4=Baby’s father,

5=Other, Specify who:........................................... 11. If yes, describe the abnormality:……………………………………………………………………......................................

Record from Antenatal Care (ANC) Card

Ask the women if you can see her ANC card

12. ANC Card available

[_] 1=Yes, 2=No

13. IPTp

Number

of doses[_]

14. Record if the patient received any of the following according to the ANC Card: [_] Ferrous Sulphate tabs [_] Folate tabs [_]Cotrimoxazole [_]Tetanus vaccination


38

15. VDRL results [_] 1=Positive, 2=Negative, 3=Not tested, 9=Doesn’t know

16. Hb [_][_].[_] g/dl [_] Not done

17. Tuberculosis [_] 1=Yes ,2=No, 3=Not tested, 9=Unknown

18. Diabetes [_] 1=Yes, 2=No, 3=Not tested, 9=Unknown

19. Hypertension [_] 1=Yes, 2=No, 3=Not tested, 9=Unknown

20. Other [_] Describe:_________________________

Pregnancy Outcome and Delivery

21. End of pregnancy date [_][_]/[_][_][_]/[_][_] (DD/MMM/YY)

22. Place of delivery: [_] 1=Home, 2= TBA’s home, 3=Health facility, 4=On the way; Health Facility, specify……………………………; 8=Other, specify………………………

23. Who attended the delivery? [_] 1=None, 2=An untrained family member, friend or neighbour, 3=A traditional birth attendant, 4=A professionally trained provider (doctor, nurse,

midwife), 8=other, specify……………………………………….. 24. Number of babies: [_] 1=Singleton, 2=Twins, 3=Triplets If multiple births, fill in a newborn details form for each baby

25. Pregnancy Outcome [_]* 1=Alive, 2=Intra-uterine death/stillbirth (≥28 weeks) NS, 3= Macerated stillbirth (skin not intact), 4= Fresh stillbirth (normal in appearance and skin not intact), 5=Miscarriage/spontaneous abortion (<28 weeks), 6=Induced abortions, 7=Pregnancy loss NS, 8=Neonatal death (after 1 breath); *In case of a miscarriage or abortion, fill in the miscarriage form

26. Method for gestational age assessment: [_] 1=Ultrasound, 2=LMP, 3=Fundal height, 4=Ballard/Dubowitz score, 9=Unknown

27. Gestational age at end of pregnancy [_][_] weeks [_] days

28. Type of delivery : [_] 1=Normal vaginal, 2=Forceps, 3=C-section, 4=Vacuum, 5= Breech, 6= Medical abortion, 9=Unknown

29. Was the labour induced? [_] 1=Yes, 2=No, 3=Augmented, 9=Unknown

30. How did the baby come out? [_] 1= Head first, 2=Feet first, 9=Unknown , 8=Other, specify ………………………………………..

31. Any complication at delivery? [_] 1=Haemorrhage, 2=Pre-eclampsia, 9=Unknown, 8=Other, specify …………………………………

Annex C. Suggested Pregnancy History and Outcome Form

39

Newborn Details

32. Baby’s name: ................................ 33. ID number:

[_][_][_][_][_][_] [_][_][_][_]

34. Age of baby at examination (days): [_][_] 35. Baby’s gender [_] 1=Female, 2=Male, 3=Ambiguous

36. Supine length (cm) [_][_] 37. Head

circumfer

ence (cm)

[_][_]

38. Weight (g) [_][_][_][_]

NEWBORN SURFACE EXAMINATION

Location Examination findings Were any of the following observed or suspected?

39. Skull bones & fontanelles/ sutures

[_] Normal

[_] Suspect abnormality

[_] Craniosynostosis [_] Hydrocephaly [_] Microcephaly [_] Macrocephaly [_] Anencephaly [_] Encephalocele [_] Other (describe)_______________________________________

40. Face [_] Normal


[_] Small chin [_] Other (describe)____________________________________________

41. Eyes [_] Normal


[_] Hypotelorism [_]Hypertelorism [_]Cataracts [_] Other (describe)_______________________________________

42. Mouth and lips [_] Normal


[_] Cleft lip [_] Cleft palate [_] Smooth Philtrum [_] Other (describe)_______________________________________

43. Nose [_] Normal


[_] Choanal atresia [_] Other (describe)__________________________________________

44. Ear [_] Normal


[_] Microtia [_] Ear tag [_] Ear pit [_] Low-set ear [_] Other (describe)__________________________________________________________

45. Chest [_] Normal


[_] Indrawing [_] Nasal flaring [_] Tracheal tug [_] Head bobbing [_] Other (describe)_______________________________________


40

46. Abdomen [_] Normal


[_] Umbilical Hernia [_] Gastroschisis [_] Omphalocele [_] Other (describe)________________________________________________________

47. Limbs [_] Normal


[_] Arm Limb reduction [_] Leg limb reduction [_] Bent limbs [_] Other (describe)________________________________________________________

48. Hands [_] Normal


[_] Extra finger (hanging off 5th finger) [_] Extra finger other [_] Fused finger [_] Missing finger [_] Single palmar crease [_] Other (describe)________________________________________________________

49. Feet [_] Normal


[_] Missing toe [_] Extra toe [_] Fused toe [_] Club foot [_] Other (describe)________________________________________________________

50. Genitourinary [_] Normal


[_] Hypospadias [_] Undescended testicles [_]Ambiguous [_] Other (describe)________________________________________________________

51. Anus [_] Normal


[_] Imperforate anus [_] Other (describe)________________________________________________________

52. Spine/sacrum [_] Normal


[_] Spina bifida [_] Sacral skin tag [_] Sacral dimple [_] Tuffs of hair [_] Saccrococcygeal teratoma [_] Other (describe)________________________________________________________

53. Skin [_] Normal


[_] Other (describe)________________________________________________________

54. If there was any abnormality diagnosed at birth or unusual finding please describe it here:

Annex C. Suggested Pregnancy History and Outcome Form

41

55. Remarks and Comments

Acronym Key: Hb = haemoglobin IPTp = intermittent preventive treatment of malaria in pregnancy NS = Not specified LMP = last menstrual period VDRL = Venereal Disease Research Laboratory (test)

protocol and operation plan

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