Clinical aspects of ADRs in HIV and ARV toxicity monitoring approaches - PowerPoint Presentation

Clinical aspects of ADRs in HIV and ARV toxicity monitoring approaches Workshop on management and reporting of adverse drug reactions related to ARVs 26 June 2018, Gaborone, Botswana

Presentation Outline WHO ARV recommendations Key definitions Major toxicities associated with ARVs used in clinical practiceClinical management of major ARV toxicities Management of drug-drug interactionsDTG related toxicities Clinical management of DTG toxicitiesDrug-drug interactions WHO recommended ARV toxicity monitoring approachesRoutine ARV toxicity monitoringActive ARV toxicity monitoring

WHO 2016 ARV guidelines recommend DTG as alternative 1st line regimen in adults & adolescents DTG=dolutegravir EFV=efairenz DRV/r=darunavir/ritonavir RAL=raltegravir

WHO recommendations on monitoring toxicity - Lab G uiding principles for ARV toxicity monitoring (WHO 2016 ARV guidelines) The availability of laboratory monitoring is not required for initiating ARTSymptom-directed laboratory monitoring for safety and toxicity can be used for those receiving ART At the same time several laboratory tests for monitoring ARV toxicity are advised (but not required) for specific high-risk people using certain drugs:HB test for initiating AZT Serum creatinine & eGFR for PLHIV on TDFAlanine aminotransferase for initiating NVP

Key definitions

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. Unlike an adverse event, an ADR is characterized by the suspicion of a causal relationship between the drug and the occurrence, i.e. judged as being at least possibly related to treatment by the reporting or a reviewing health professional.

Treatment limiting toxicity A serious adverse drug reaction that results in drug/regimen discontinuation or substitution.

Routine toxicity monitoring. Monitoring of treatment limiting ARV toxicities integrated into monitoring and evaluation of national HIV treatment programmes using patient monitoring tools and reporting systems.  Active toxicity monitoring. A system in which active measures are taken to detect the presence or absence of adverse drug reactions through follow-up after treatment. The adverse drug reactions may be detected by interviewing patients, preforming specific investigation or by screening patient records.

Adverse Drug Reactions Patients frequently experience ADRs or side effects when they start ARVs including: Gastrointestinal (e.g. nausea, diarrhea)Body pains HeadacheFatigue Rash Neuropsychiatric symptoms (e.g. dizziness or sleepiness) Slide courtesy of ICAP

Major toxicities associated with most used ARVs Drug Liver Renal Bone CVD MetabolicHematologicCNSSkin GI intolerance Muscular ABC   AZT      TDF   EFV    NVP   ATV/r    DRV/r LPV/rDTGRAL PIs NNRTIs NRTIs INSTIs most commonly reported adverse drug reactions CVD= cardiovascular disease CNS=central nervous system GI= gastrointestinal

Clinical management of major ADRs associated with ARVs (1) ARV drug Major types of toxicity Risk factors Suggested management               EFV Persistent central nervous system toxicity (such as dizziness, insomnia, abnormal dreams) or psychiatric symptoms (anxiety, depression, mental confusion) Depression or other mental disorder (previous or at baseline) Daytime dosing For CNS symptoms, dosing at bed time. Consider use EFV at lower dose (400mg/day or integrase inhibitor (DTG) if EFV400mg is not effective in reducing symptoms. Convulsions History of seizure Hepatotoxicity     Underlying hepatic disease HBV and HCV coinfection Concomitant use of hepatotoxic drug   For severe hepatotoxicity or hypersensitivity reactions, substitute with another therapeutic class (integrase inhibitors or boosted PIs). Severe skin and hypersensitivity reactions Risk factor(s) unknown   Gynaecomastia Risk factor(s) unknown Substitute with another therapeutic class (integrase inhibitors or boosted PIs).

ARV drug Major types of toxicity Risk factors Suggested management ABC Hypersensitivity reaction Presence of HLA-B*5701 gene Do not use ABC in presence of HLA-B*5701 gene. Substitute with AZT or TDF. ATV/r Electrocardiographic abnormalities (PR and QRS interval prolongation) People with pre-existing conduction system disease Concomitant use of other drugs which may prolong the PR or QRS intervals Congenital long QT syndrome Use with caution in people with pre-existing conduction disease or who are on concomitant drugs which may prolong the PR or QRS intervals. Indirect hyperbilirubinemia (clinical jaundice) Presence of UDP-Glucuronosyltransferase 1A1*28 (UGT1A1*28) gene This phenomenon is clinically benign but potentially stigmatizing. Substitute only if adherence is compromised. Nephrolithiasis History of nephrolithiasis Substitute with LPV/r or DRV/r. If boosted PIs are contraindicated and NNRTIs have failed in first-line ART, consider substitute with integrase inhibitors. Clinical management of major ADRs associated with ARVs (2)

Clinical management of major ADRs associated with ARVs (3) ARV drug Major types of toxicity Risk factors Suggested management AZT Anaemia, neutropaenia, Baseline anaemia or neutropaenia CD4 cell count of ≤200 cells/mm 3 Substitute with TDF or ABC Consider use of low dose zidovudine. () Lactic acidosis or severe hepatomegaly with steatosis lipoatrophy, lipodystrophy myopathy BMI >25 (or body weight >75 kg) Prolonged exposure to NRTIs Substitute with TDF or ABC. DRV/r Hepatotoxicity     Underlying hepatic disease HBV and HCV coinfection Concomitant use of hepatotoxic drugs Substitute with ATV/r or LPV/r. When it is used in third-line ART, limited options are available.   For hypersensitivity reactions, substitute with another therapeutic class.

Clinical management of major ADRs associated with ARVs (4) ARV drug Major types of toxicity Risk factors Suggested management LPV/r Electrocardiographic abnormalities (PR and QRS interval prolongation, torsades de pointes) People with pre-existing conduction system disease Concomitant use of other drugs which may prolong the PR or QRS intervals Congenital long QT syndrome Hypokalaemia Use with caution in people with pre-existing conduction disease or who on concomitant drugs which may prolong the PR or QRS intervals .       Hepatotoxicity         Underlying hepatic disease HBV and HCV coinfection Concomitant use of hepatotoxic drugs         If LPV/r is used in first-line ART for children, substitute with NVP or RAL for children younger than 3 years and EFV for children 3 years and older. ATV can be used for children older than 6 years. If LPV/r is used in second-line ART for adults, and the person has treatment failure with NNRTI in first-line ART, consider integrase inhibitors. Pancreatitis Advanced HIV disease, alcohol Substitute with another therapeutic class (integrase inhibitors). Dyslipidaemia, Cardiovascular risk factors as obesity and diabetes Substitute with another therapeutic class (integrase inhibitors). DiarrhoeaRisk factor(s) unknownSubstitute with atazanavir/r, darunavir/r or integrase inhibitors.

ARV drug Major types of toxicity Risk factors Suggested management NVP Hepatotoxicity Severe skin rash and hypersensitivity reaction, including Stevens-Johnson syndrome Underlying hepatic disease HBV and HCV coinfection Concomitant use of hepatotoxic drugs High baseline CD4 cell count (CD4 count > 250 cells/mm3 in women or >400 cells/mm3 for men) If hepatotoxicity is mild, consider substitution with EFV including in children 3 years and older. For severe hepatotoxicity and hypersensitivity, and in children under the age of 3 years, substitute with another therapeutic class (integrase inhibitors or boosted PIs) . RAL Rhabdomyolysis, myopathy, myalgia Concomitant use of other drugs that increase the risk of myopathy and rhabdomyolysis, including. statins     Stop ART. When symptoms are resolved, substitute with another therapeutic class (etravirine, boosted PIs) . Hepatitis and hepatic failure Severe skin rash and hypersensitivity reaction Risk factor(s) unknown Lactic acidosis or severe hepatomegaly with steatosis Prolonged exposure to nucleoside analogues Obesity, Liver disease Clinical management of major ADRs associated with ARVs (5)

Clinical management of major ADRs associated with ARVs (6) ARV drug Major types of toxicity Risk factors Suggested management TDF Chronic kidney disease Acute kidney injury and Fanconi syndrome Underlying renal disease; Older than 50 years old; BMI <18.5 or low body weight (<50 kg) notably in females; Untreated diabetes; Untreated hypertension Concomitant use of nephrotoxic drugs or a boosted PI             Substitute with AZT or ABC Do not initiate TDF at eGFR < 50 ml/min, uncontrolled hypertension, untreated diabetes, or presence of renal failure Decreases in bone mineral density History of osteomalacia (in adults) and rickets (in children) and pathological fracture Risk factors for osteoporosis or bone mineral density loss, Vitamin D deficiency Lactic acidosis or severe hepatomegaly with steatosis Prolonged exposure to nucleoside analogues Obesity, Liver disease

Drug-drug interactions can reduce or increase the efficacy of ART and/or increase ART-related toxicities. Polypharmacy is common among PLHIV and a frequent cause of stopping or changing HIV therapy. Providers should be aware of all drugs used by the patients, including alternative medicine products such as herbal remedies, vitamins and dietary supplements - that people are taking when ART is initiated, as well as new drugs that are added during treatment maintenance. Monitoring ADRs- Interactions

Major drug interactions associated with ARVs most used in clinical practice Drug Amiodarone Astemizole/Terfenadrine Carbamazepine,/ Phenobarbital/ Phenytoin Cisapride Ergotamine/ Dihydroergotamine Halofantrine/Lumefantrine Hormonal contraceptives Itraconazole/Ketoconazole Lovastatin/Simvastatin Methadone Buprenorphine Midazolam,/Triazolam Sildenafil Simeprevir Ombitasvir/paritaprevir/ ritonavir + dasabuvir Interferon/Ribavirin Polivalent cations (Mg, Al, Fe, Ca and Zn ) Rifampicin Tenofovir EFV          NVP  ATV/rDRV/rLPV/rDTG   RAL  PIs NNRTIs INSTIs  increase interacting drug concentration  increase ARV drug concentration  decrease interacting drug concentration  decrease ARV drug concentration

Major drug interactions associated with ARVs & suggested management (1) ARV drug Key interactions Suggested management      EFV Amodiaquine Use an alternative antimalarial agent Cisapride Use alternative gastrointestinal agent Methadone Adjust the methadone dose as appropriate Hormonal contraceptives Use alternative or additional contraceptive methods Astemizole and terfenadine Use an alternative anti-histamine agent Ergotamine and dihidroi-ergotaminne Use alternative antimigraine agent Simeprevir Use alternative DAA   Midazolam and triazolam Use alternative anxiolytic agent

Major drug interactions associated with ARVs & suggested management (2) ARV drug Key interactions Suggested management        Boosted PI (ATV/r, DRV/r, LPV/r) Rifampicin Substitute rifampicin with rifabutin Adjust the dose of LPV/r or substitute with three NRTIs (for children) Halofantrine Use an alternative antimalarial agent Lovastatin and simvastatin Use an alternative dyslipidaemia agent (e.g. pravastatin) Hormonal contraceptives Use alternative or additional contraceptive methods Metformin Adjust methadone and buprenorphine doses as appropriate Astemizole and terfenadine Use alternative antihistamine agent TDF Monitor renal function Simeprevir Use alternative DAA Ombitasvir / paritaprevir /ritonavir + dasabuvir Use alternative DAA

Dolutegravir related toxicities

Dolutegravir Integrase inhibitorEffective (rapid viral load suppression)Well toleratedHigh genetic barrier to resistanceFew drug interactions Single and as fixed dose formulation (DTG)Cheap 75 USD/patient/yearPEPFAR transition

TB : double dose – 50 mg 12 hrs apart (RTC INSPIRING) IRIS: No elevation in RTC (REALITY) rapid immune reconstitution syndrome PregnancyIndication to use only if benefits outweigh risk (FDA and drug packet insert)spontaneous abortion in 13% of women living with HIV taking ART other than DTG10% in those taking DTGChildrenFDA approved for > 30 kg EMA approved for > 6 yrs and > 15 kgDolutegravir

DTG uptake by countries By May 2018, 68 LMICs (49%) informed that have included or are planning to include DTG in their national guidelines DTG introduced in national guidelines: 24DTG introduced in national guidelines and procurement initiated: 23DTG introduction in national guidelines planned : 21Approximately 500 000 PLHIV are using DTG globally Early adoption of DTG in LMIC: Botswana, Brazil, Kenya and Ukraine*Source: Global AIDS Monitoring 2018 data and WHO country correspondence * preliminary data

Source: MoH Botswana, Brazil & Kenya, 2018 Country Transition start PLHIV on DTG M/F ratio DTG eligibility criteria % of reported DTG adverse events Major DTG AEs reported (top 3) DTG monitoring tools Use of VL for DTG substitution ART naive NNRTI intolerance Stable on ART non EFV regimens Stable on ART EFV regimen PW TB 2 nd line 3 rd line PEP Toxicity (PV) APRHIVDRBotswanaMay 201657,00040/601%GI symptomsSkin reactionsInsomnia?BrazilJan 2017100,00070/302%GI symptomsSkin reactionsInsomniaKenyaJuly 201711,00025/75      7%HeadacheAbnormal dreams Insomnia     Botswana, Brazil and Kenya have adopted DTG as preferred 1st line option and have implemented a programmatic transition to DTG

Gaps on clinical use of dolutegravir CNS side effects: higher than expected rate of DTG discontinuation due insomnia in some cohort studies (higher rates compared with RCTs) but very low occurrence of other side effects. IRIS in PLHIV with advanced HIV disease: increased risk observed in some cohort studies but not detected in RCTs with other INSTIs (REALITY trial). Pregnant/BF women: limited safety data, very high DTG concentrations in blood cord at birth (PK and clinical studies ongoing) HIV-associated TB: need to double dose if rifampin is used (INSPIRING – 50 mg BID) Infants and children: safety and dose finding trial underway. Very limited clinical experience

DTG-related Adverse Drug Reactions Batista, et al. #494, CROI 2018

Clinical management of major ADRs associated with DTG ARV drug Major types of toxicity Risk factors Suggested management DTG Hepatotoxicity Hypersensitivity reactions Hepatitis B or C co-infection   Liver disease Substitute with another therapeutic class (EFV or boosted PIs). Insomnia Older than 60 years Female gender Consider morning dose or substitute with EFV, boosted PI or RAL.

Mary was previously taking TLE but recently changed to DTG containing regimen At her follow up appointment she complains about not being able to sleep at night What would you ask Mary?What advice could you give Mary? DTG Adverse Event: Case Study - Mary Slide courtesy of ICAP

Insomnia and DTG Symptoms may improve over time as the body adjusts Take DTG in the morning Slide courtesy of ICAP

DTG in a patient with TB Case Study - Charles Charles was referred to your clinic after testing positive for HIV at the TB clinic where he also received TB treatment. He reports feeling better after starting TB treatment and is motivated to start ART today. You decide he is ready to start ART and initiate him on DTG regimen and Cotrimoxazole. You also send labs to check his CD4You ask him to return in two weeks for follow up. What additional considerations are there for Charles starting on DTG regimen? Slide courtesy of ICAP

Immune Reconstitution Inflammatory Syndrome (IRIS) IRIS occurs when someone with severe immunosuppression has a preexisting infection that was not detected or was incompletely treated prior to starting ART. If the immune system recovers quickly it may cause worsening of symptoms. IRIS does not occur with just DTG and can happen with any other ART regimen. Slide courtesy of ICAP

Hypersensitivity Hypersensitivity is characterized by rash, constitutional findings, and sometimes organ dysfunction Whenever a patient has a severe reaction to a drug all drugs should be stopped until the patient recovers Important to find out the drug causing hypersensitivity as it should never again be used by the patient Slide courtesy of ICAP

Your patient Michael has TB. He is currently undergoing treatment for his TB and HIV simultaneously. He comes to you complaining of feeling like his legs and arms are tingling. What questions would you ask Michael? What do you suspect might be happening? Adverse Events: Case Study - Michael Slide courtesy of ICAP

Drug Interactions with DTG https://www.hiv-druginteractions.org/checker Slide courtesy of ICAP

DTG and Vitamin Supplements DTG should also not be given at the same time as supplements containing Magnesium (Mg), or Zinc (Zn) DTG may be given with calcium (Ca) and/or Iron (Fe) if it is also taken with food. If it not taken with food though DTG should not be given at the same timeThese may be in multivitamins, certain laxatives or certain antacids so it is important to know what other tablets your patients are taking. If your patients are taking any of these, advise them to take their ARVs at least 2 hours before or at least 6 hours afterwards.Slide courtesy of ICAP

Other Drug Interactions with DTG: Case Study - Blessing Your patient, Blessing, is ready to be initiated on DTG. When you take her medical history, you discover that she has epilepsy.She reports that she has been pretty well controlled on phenobarbital. What else would you want to learn from your patient? What would you recommend? Slide courtesy of ICAP

38 Other Drug Interactions with DTG: Case Study - Joyce Joyce is newly diagnosed with HIV and ready to initiate ART. She also is using family planning and gets shots of Depo Provera every three months. She is concerned because she heard that ART may make her contraception less effective. How would you counsel your patient? What would you tell her? Slide courtesy of ICAP

Use of DTG and Other Medications ACTIVITY Slide courtesy of ICAP

WHO recommended approaches for toxicity monitoring of new ARVs

WHO recommendation on ARV drug toxicity Monitoring With rapid treatment scale up, prolonged exposure to ARVs & transition to new ARV drugs, clear need for ARV toxicity monitoring to better understand the risks of new ARVs under conditions of programmatic use WHO recommends enhanced toxicity monitoring & surveillance to address gaps in safety data of new ARVs in the 2017 Technical update on Transition to new antiretroviral drugs in HIV programmes: clinical & programmatic considerations

Why implement ARV toxicity monitoring? Adverse drug reactions can lead to reduced quality of lifetreatment interruptiontreatment failure avoidable morbiditydeathsadded costs to the service (e.g. hospitalization) …

Why implement ARV toxicity monitoring? Expanded use of new ARVs in whom exposure to such treatment is relatively new and caregivers unfamiliar to the safety profile Early recognition and management of adverse reactions can improve adherence and treatment outcomes Adverse reactions pose a risk not only to the individual but also to the whole treatment programme. May harm public confidence in a national treatment programme or in a new medicine or regimen

Routine Active 2 recommended approaches to toxicity monitoring of new ARVs

Routine Active 2 recommended approaches to toxicity monitoring of new ARVs Integrated within national M&E system, (using existing HIV patient monitoring tools and indicators) & implemented at all ART sites

Routine Active 2 recommended approaches to toxicity monitoring of new ARVs Implemented at select ART sites, complements routine monitoring. Enables enhanced monitoring & data capture of ADRs including management & outcomes.

1. Routine ARV toxicity monitoring Countries use a standardized approach to integrate ARV toxicity monitoring within national M&E systems as part of routine patient monitoring Routine ARV toxicity monitoring provides data on the prevalence and clinical significance of serious toxicities 2013 Technical brief on surveillance of ARV drug toxicity in ART programmes

2017 Consolidated Guidelines for Person centred monitoring & case based surveillance Defines the key toxicity prevalence indicator to be collected & provides patient monitoring tools to capture treatment limiting toxicities as part of routine reporting Standardised tools: HIV care & treatment card ART register National ARV toxicity indicator Indicator Programme relevance and interpretation Toxicity prevalence: % of people receiving ART with treatment-limiting toxicity Measures how toxicity affects treatment outcomes. Helps to guide national policy on ART regimens, diagnosis, strategies for preventing toxicity, health-care worker training and retention in care

HIV Care & Treatment Card

HIV Care & Treatment Card (1) Designed to be completed for all individuals entering care at a facility and serves as the primary data source for patient monitoring. Toxicities captured using standardised toxicity codes in the following sections: Encounter page card: Treatment limiting toxicities Reasons for missed doses including toxicity Front page of card: Drug substitution within 1 st /2nd/3rd line ART ART interruptions

HIV Care & Treatment Card (2) Front page: Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. Geneva. World Health Organization; 2017

HIV Care & Treatment Card (3) Encounter page:

ART Register

Enter the above codes highlighted in red for reasons for substitution in the columns highlighted blue using the code 1 for toxicity . Record the corresponding code for treatment limiting toxicity (codes highlighted in green) beside it e.g. for GI related adverse drug reactions the code 1 would be recorded

ARV Toxicity Prevalence Indicator

Key ARV toxicity prevalence indicator Included in the minimum dataset for HIV patient monitoring in 2017 WHO patient monitoring guidelines Recommended this indicator is captured via electronic systems using electronic medical records

Indicator instructions (1) Indicator code and name ART.12 Toxicity prevalence Indicator definition Percentage of ART patients with treatment-limiting toxicity Overview This indicator measures the impact of toxicities on treatment outcomes. ARV-associated toxicities are among the most common reason reported for poor adherence to ART, treatment discontinuation or substitution of drugs. Routine monitoring will provide data on prevalence and clinical significance of serious toxicities, and their impact on patient outcomes and attrition. It is a new indicator designated for national programme monitoring in the WHO 2015 consolidated SI guidelines Priority level National, subnational, facility Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO, Geneva 2017.

Indicator instructions (2) Numerator Definition: number of people living with HIV and on ART within the past 12 months who substituted a regimen or interrupted/discontinued treatment due to toxicity Data source: HIV patient card, ART register Data elements: ART start date, ART follow-up status, ARV regimen, date substituted (within first-, second-, third-line regimen), reason substituted, toxicity/serious drug reaction, ART no. missed doses, reason for poor adherence Denominator Definition: ART 3. Numerator: number of people living with HIV who are currently receiving ART [at the end of the reporting period] Data source: ART register Data elements: ART follow-up status Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO, Geneva 2017.

Indicator instructions (3) Data collection methodology Denominator: this is the numerator for ART.3 ART coverage 1. Numerator: for all patients identified in the denominator, in the ART register, look at the last columns on the first page labelled “substitutions” within first-, second- and third-line regimens. Count patients if they have substituted within any regimen during the reporting period (see date), and the reason is “toxicity/serious drug reactions” (code=1). Similarly, go through the relevant follow-up months of the ART register (note: months columns will be different for every cohort; e.g. it could be Months 0–11 for ART cohort starting January 2015 or Months 11–22 for ART cohort starting January 2014) and count all patients who have a treatment interruption (no ARV regimen code recorded). For these patients, pull out their HIV patient cards and find out the reason for their poor adherence (ART no. missed doses/why column). Count those with reason “toxicity/side-effects” (code=1) recorded.   1. For full indicator definition see page 165 of consolidated guidelines on person-centered HIV patient monitoring and case surveillance. Geneva: World Health Organization; 2017. http://apps.who.int/iris/bitstream/10665/255702/1/9789241512633-eng.pdf?ua=1 ,

Indicator instructions (4) Frequency This indicator is best tallied at the end of the year when tallying ART.3 ART coverage Disaggregation For each patient, note the sex, age, current TB treatment on page 1 of the ART register. Also note the ARV regimen (code) the patient was on when experiencing the toxicity-related drug substitution and the associated toxicity category or categories recorded. • Sex • Age (less than 15 years old or 15 years and above) • TB/HIV coinfection • ARV regimen • Toxicity categories from minimum dataset Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO, Geneva 2017.

F actors that support routine toxicity monitoring of new ARVs Updating national patient monitoring system in adopter countries Introducing new indicator on Toxicity prevalence - % of ART patients with treatment-limiting toxicity Introducing electronic medical records to support reporting Updating for adult and children ART patient cards, ART registers and HIV card Using new coding for major toxicities and treatment substitution/interruption due to toxicities Tools are available in 2017 Guidelines Person-centred HIV patient monitoring and case surveillance + web annexes http://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-guidelines/en/

2. Active Toxicity Monitoring Provides additional approach to reporting & quantifying the frequency & seriousness of expected & unanticipated adverse drug reactions while maintaining simplicity of use, low cost and linkage to existing M&E and pharmacovigilance systems Data element Routine toxicity monitoring Active toxicity monitoring Management ADR Partially (drug substitutions due to toxicity captured) ✔ Seriousness of ADR X ✔ Outcome of ADR (resolved, requires or prolongs hospitalization, disability, death etc.) X ✔

Methodology Active toxicity monitoring of new ARVs based on consideration of the following: Leveraging existing M&E and pharmacovigilance structures Sustainability Stakeholder engagement Willingness and capacity of ART sites & health care workers to report & implement Approach brings cost efficiencies, improved documentation of clinical practices and integration within the ART programme Feasible, affordable and sustainable within settings with limited financial and human resources Active toxicity monitoring implemented in select number of ART sites

ART Site Selection Criteria Key criteria for site selection: Number of individuals initiating DTG/new ARV drugs : ART sites with the largest no. of people initiating or transitioning to DTG or other new ARV drugs Availability of electronic medical records: to support data capture and reporting Human resource capacity: availability, willingness, commitment and capacity of health care workers to identify, capture and report treatment limiting toxicities associated with new ARVs Additional criteria that can be considered for site selection: Laboratory monitoring : for detection, identification and confirmation of adverse drug reactions as well as assessment of treatment efficacy Data management and record keeping: availability of unique identifiers, linkage to pharmacy database, longitudinal patient data including medication, clinical and adverse drug reaction data Outcome ascertainment and follow-up : Follow up of individuals receiving new ARVs including key populations, pregnant women and children. Ability to document outcomes important as patients lost to follow up are a source of selection and ascertainment bias in the evaluation of ADRs related to new ARVs

Data collection WHO has developed a generic adverse drug reaction reporting tool for DTG to enable standardised reporting of toxicities, drug-drug interactions and comorbidities that countries can use By focusing on a specific drug and particular ADRs of interest reporting is kept simple & feasible without comprising qualityGoing forward additional tools will be produced for other new ARVs and available for country use and adaptation Health care workers managing individuals initiating new ARVs should be required as well as sensitized and trained to report on treatment limiting toxicities

DTG ADR Reporting Form Section 1: captures demographic data, clinical status & details of indication of DTG use, TB and pregnancy status at onset of ADR

Section 1 cont: Captures existing comorbidities, complimentary laboratory results, details of ARVs & concomitant drugs & medicines at time of ADR onset

Collects information on ADRs focusing on CNS ADRs as most commonly reported ADRs associated with DTG. Section 2 Seriousness, management & outcome of ADRs are also reported in this section

DTG ADR Reporting Form- Section 2 cont.

DTG ADR Reporting Form Section 3: captures key information about the health care worker that completed the form to facilitate data quality review and enable data issues to be followed up and addressed. Instructions provided on frequency of reporting, date of submission of completed forms & key contact person the form should be returned to.

DTG ADR Reporting Form – Definitions A serious ADR is an adverse reaction that can cause one of the following consequences: limiting treatment death life threatening requires or prolongs hospitalization disability or permanent damage congenital anomaly/birth defect A case that leads to treatment interruption or requires changing drug or regimen because of an adverse drug reaction is also considered a serious adverse drug reaction.

DTG ADR Reporting Form – Definitions Definition of immune reconstitution inflammatory syndrome Immune reconstitution inflammatory syndrome describes a collection of infectious or inflammatory conditions associated with paradoxical clinical worsening of pre-existing infectious processes caused by the host’s regained capacity to mount an inflammatory response after people living with HIV initiate antiretroviral therapy (ART). It usually occurs in the first two months after starting ART among people living with HIV with severe immunodeficiency and quick immune recovery (rapid increase in CD4 counts and viral load suppression). Immune reconstitution inflammatory syndrome can present clinically in two types. The first is called unmasked immune reconstitution inflammatory syndrome because of occult and subclinical opportunistic infection and a generally detectable pathogen. The second is called paradoxical immune reconstitution inflammatory syndrome and is characterized by recrudescence or relapse of infection successfully treated previously and marked antigen-induced immune activation with no or few detectable pathogens.

Data collection & reporting process

Data management and analysis Data on ADRs related to the use of new ARVs, collected at the facility level onto a paper form should be entered in a specifically designed electronic database in order to facilitate data analysis. WHO has developed a data dictionary matched to the generic DTG ADR reporting form and is developing a simple data entry interface programme countries can utilise to securely enter and manage the data they collect on DTG treatment limiting toxicities Going forward this will be expanded to incorporate other new ARV drugs and made available to countries.

Data quality review and control (1) Personnel involved in data collection & collation should have these functions included in their ToR & be allocated time to complete these activities. Data flow chart describing how & when different information is collected & reported, people responsible, formats used, & timing of each step provides clarity to the data collection process. Personnel involved in data collection, including supervisors, should receive instructions & training & be evaluated in using the formats & record keeping. Supervisors should regularly review the ADR reporting forms to ensure that they are correctly & completely filled out. Quality assurance & use of toxicity monitoring data should be included as part of routine supervisory assessments & as an aspect of service quality at the ART site.

Data quality review and control (2) Whenever possible, ADRs related to new ARVs should be recorded at the time of the patient encounter rather than recorded later from memory. Electronic medical records & database should be used to capture & manage data. The ADR reporting forms should be archived systematically to allow for verification or record review to confirm aggregated results, as needed. ARV toxicity data have inherent value & should be available for use & analysis locally (e.g. at site level) to improve the management of ADRs instead of being reported up for higher level or central level use only.

Data dissemination and use (1) Site-level data should be forwarded to the national level (ART programme/PV unit, MoH) and aggregated, de-identified and analysed with reports generated on a regular basis (e.g. quarterly) and disseminated Data should be fedback to ART sites to guide and provide information on the management of ADRs related to new ARVs to improve patient outcomes. If issues where ADRs could have been prevented are identified non punitive feedback should be provided to the ART site and care giver

Data dissemination and use (2) Communication between reporting levels should be bi-directional; just as systems for reporting data to higher reporting levels are established, so should feedback and data analysis flow regularly back down  In order for data on the toxicity of new ARV drugs to be used effectively it needs to be available in real time when decisions are made

Stakeholder engagement (1) Stakeholder Role and responsibility ART site Health care workers (Completion & submission of data forms) Overall responsibility for monitoring ADRs related to new ARVs and timely documentation using standardised data reporting forms and submission Required elements: Standardized ADR reporting forms available Training and feedback to health care workers on management of ADRs and reporting Data entry clerk/operator (Input of data) Enter and submit data from paper data collection forms into the electronic database and ensure data security Required elements: Standardised data entry interface programme Training, supervision and feedback on data quality

Stakeholder engagement (2) Stakeholder Role and responsibility National ART Programme, MOH M&E focal point (Data analysis & dissemination) Review data reports on ADRs of new ARVs and risk factors and asses and support data quality Aggregate data and generate regular quarterly/annual reports Disseminate and feedback information to relevant stakeholders including reporting ART sites Required elements: National database with data aggregation and report generation features Training Standard operating procedures for data quality assurance ART programme manager (Data use) Review reports of ADRs related to new ARVs Develop recommendations to address findings and toxicity issues identified by toxicity monitoring of new ARVs Promote the dissemination and communication of priority public health recommendations including changes to the ART programme emerging from the toxicity monitoring data as required Required elements: Timely reports summarising available data on new ARV related ADRs and risk factors Effective communication channels

Stakeholder engagement (3) Stakeholder Role and responsibility Other stakeholders Partners (Technical & financial support) Provide technical and financial assistance to support countries with the implementation of toxicity monitoring of new ARVs WHO (Coordination and technical support) Provide normative guidance, tools, training materials and technical support to key countries Convene partners to support implementation of active toxicity monitoring

WHO technical support for active toxicity monitoring and safe introduction of DTG and other new ARVs 2. Strengthening routine toxicity monitoring via HIV patient monitoring system 1. WHO ARV toxicity monitoring implementation tool and training materials Global ARV toxicity database Surveillance of drug safety in pregnancy General population inc. children Pregnant women Pregnancy & birth defect registry

83 Contacts and resources 2017 WHO Technical update: Transition to new antiretroviral drugs in HIV programmes: clinical and programmatic considerations http://www.who.int/hiv/pub/toolkits/transition-to-new-arv-technical-update/en/ 2017 WHO Consolidated guidelines on person centred HIV patient monitoring and case surveillance: http://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-guidelines/en/ 2015 WHO consolidated HIV strategic information guidelines: http://www.who.int/hiv/pub/guidelines/strategic-information-guidelines/en/ May 2018 WHO statement on DTG: http://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdf?ua=1 Contact HIV/SIP team: Françoise Renaud renaudf@who.int Contact HIV/SIP: Hiwot Haile-Selassie haileselassieh@who.int