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Slide 1-

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
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Presentation Outline WHO ARV recommendations Key definitions Major toxicities associated with ARVs used in clinical practice Clinical management of major ARV toxicities Management of drug-drug interactions DTG related toxicities Clinical management of DTG toxicities Drug-drug interactions WHO recommended ARV toxicity monitoring approaches Routine ARV toxicity monitoring Active ARV toxicity monitoring
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WHO 2016 ARV guidelines recommend DTG as alternative 1st line regimen in adults & adolescents DTG=dolutegravir EFV=efairenz DRV/r=darunavir/ritonavir RAL=raltegravir
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WHO recommendations on monitoring toxicity - Lab Guiding principles for ARV toxicity monitoring (WHO 2016 ARV guidelines) The availability of laboratory monitoring is not required for initiating ART Symptom-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 TDF Alanine aminotransferase for initiating NVP
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Key definitions
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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.
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Treatment limiting toxicity A serious adverse drug reaction that results in drug/regimen discontinuation or substitution.
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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.
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Adverse Drug Reactions Patients frequently experience ADRs or side effects when they start ARVs including: Gastrointestinal (e.g. nausea, diarrhea) Body pains Headache Fatigue Rash Neuropsychiatric symptoms (e.g. dizziness or sleepiness) Slide courtesy of ICAP
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Major toxicities associated with most used ARVs PIs NNRTIs NRTIs INSTIs most commonly reported adverse drug reactions CVD= cardiovascular disease CNS=central nervous system GI= gastrointestinal
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Clinical management of major ADRs associated with ARVs (1)
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Clinical management of major ADRs associated with ARVs (2)
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Clinical management of major ADRs associated with ARVs (3)
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Clinical management of major ADRs associated with ARVs (4)
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Clinical management of major ADRs associated with ARVs (5)
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Clinical management of major ADRs associated with ARVs (6)
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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
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Major drug interactions associated with ARVs most used in clinical practice PIs NNRTIs INSTIs  increase interacting drug concentration  increase ARV drug concentration  decrease interacting drug concentration  decrease ARV drug concentration
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Major drug interactions associated with ARVs & suggested management (1)
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Major drug interactions associated with ARVs & suggested management (2)
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Dolutegravir related toxicities
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Dolutegravir Integrase inhibitor Effective (rapid viral load suppression) Well tolerated High genetic barrier to resistance Few drug interactions Single and as fixed dose formulation (DTG) Cheap 75 USD/patient/year PEPFAR transition
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TB : double dose – 50 mg 12 hrs apart (RTC INSPIRING) IRIS: No elevation in RTC (REALITY) rapid immune reconstitution syndrome Pregnancy Indication 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 DTG 10% in those taking DTG Children FDA approved for > 30 kg EMA approved for > 6 yrs and > 15 kg Dolutegravir
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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: 24 DTG introduced in national guidelines and procurement initiated: 23 DTG introduction in national guidelines planned : 21 Approximately 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
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Source: MoH Botswana, Brazil & Kenya, 2018 Botswana, Brazil and Kenya have adopted DTG as preferred 1st line option and have implemented a programmatic transition to DTG
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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
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DTG-related Adverse Drug Reactions Batista, et al. #494, CROI 2018
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Clinical management of major ADRs associated with DTG
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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
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Insomnia and DTG Symptoms may improve over time as the body adjusts Take DTG in the morning Slide courtesy of ICAP
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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 CD4 You 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
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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
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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
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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
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Drug Interactions with DTG https://www.hiv-druginteractions.org/checker Slide courtesy of ICAP
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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 time These 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
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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
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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
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Use of DTG and Other Medications ACTIVITY Slide courtesy of ICAP
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WHO recommended approaches for toxicity monitoring of new ARVs
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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
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Why implement ARV toxicity monitoring? Adverse drug reactions can lead to reduced quality of life treatment interruption treatment failure avoidable morbidity deaths added costs to the service (e.g. hospitalization) …
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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
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2 recommended approaches to toxicity monitoring of new ARVs
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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
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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.
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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
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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
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HIV Care & Treatment Card
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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 1st/2nd/3rd line ART ART interruptions
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HIV Care & Treatment Card (2) Front page: Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. Geneva. World Health Organization; 2017
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HIV Care & Treatment Card (3) Encounter page:
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ART Register
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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
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ARV Toxicity Prevalence Indicator
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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
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Indicator instructions (1) Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO, Geneva 2017.
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Indicator instructions (2) Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO, Geneva 2017.
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Indicator instructions (3) 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,
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Indicator instructions (4) Source: Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. WHO, Geneva 2017.
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Factors that support routine toxicity monitoring of new ARVs http://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-guidelines/en/
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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
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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
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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
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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 quality Going 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
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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
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Section 1 cont: Captures existing comorbidities, complimentary laboratory results, details of ARVs & concomitant drugs & medicines at time of ADR onset
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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
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DTG ADR Reporting Form- Section 2 cont.
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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.
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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.
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DTG ADR Reporting Form – Definitions
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Data collection & reporting process
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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.
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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.
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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.
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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
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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
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Stakeholder engagement (1)
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Stakeholder engagement (2)
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Stakeholder engagement (3)
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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
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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