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Toxicities Linked to ARVs PowerPoint Presentation

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Description : This medical presentation titled ""Anti-HIV Drugs"" is about targets for Antiretroviral Drugs in HIV life cycle, Non-Nucleoside Reverse Transcriptase Inhibitors (NNTRIs) and Protease Inhibitors (PIs).

Tags : Human Immunodeficiency Virus, HIV, infection, cells, immune system, AIDS, Acquired Immune Deficiency Syndrome, HIV Positive, Anti-HIV Drug, antiretroviral drugs, AIDS drugs, HIV Protease, Alternative Therapies, therapy, Non-Nucleoside Reverse Transcriptase Inhibitors, NNTRIs, Protease Inhibitors, PIs,

Published on : Apr 22, 2021 | Views : 1225 | Downloads : 1

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Slide 1-

Toxicities Linked to ARVs Non-Nucleoside Reverse Transcriptase Inhibitors (NNTRIs) Protease Inhibitors (PIs)
Slide 2-

Acknowledgements sources of slide material Published data Lynne Moffenson WHO – progress report 2009 DART study group
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Targets for Antiretroviral Drugs in HIV Life Cycle Reeves & Piefer, 2005
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NNRTI s
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NNRTI Toxicity Hypersenstivity reactions (all NNRTIs) (nevirapine > efavirenz > etravirine) Hepatotoxicity (Nevirapine) Neuropsychiatric side effects (Efavirenz) Concern in women of child bearing age (Efavirenz) Drug interactions & Resistance
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Nevirapine hypersensitivity
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7 Occurrence of SARs in NORA study DART Trial Team. TIMH 13 (1), 6-16
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Efavirenz hypersensitivity
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Other therapeutic issues with NNRTIs PK interaction - rifamycins; oral contraceptives Low genetic barrier to resistance Prolonged plasma half life (Nevirapine) - nevirapine “tail cover” or “staggered stop”
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19 subjects analysed in a PK study 5 male, 14 female; median 35 years ; median CD4 341 cells/mm3 All had received 52 weeks of prior cART : Combivir + Nevirapine 1 patient had substituted stavudine for zidovudine at week 16 - anaemia After 1 week : 15 /18 (83%) had detectable plasma NVP 11 (61%) were above 100 ng/ml but only 5 (28%) were >200 ng/ml By 2 weeks, only 5/ 19 had detectable NVP Median time to decay to LLQ thresholds Data suggest that the optimum period of staggered therapy for patients who discontinue NVP (at steady state) is 7– 10 days 10 days when covered with NRTI s or with currently licensed (ritonavir-boosted) protease inhibitors. Kikaire B et al. AIDS 2007, Vol 21 No 6 Rate of decay of NVP plasma levels in Ugandan patients after discontinuing NVP containing cART
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Issues with Efavirenz in women of reproductive age Neural tube defects in neonates Meningomyelocele
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Efavirenz Drug Label Information – Pregnancy Category D Can be used if benefit justifies potential fetal risk
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Issues with Efavirenz and Reproductive-Aged Women Highest risk to use is in women who become pregnant while receiving EFV; contraception/family planning critical part of care of HIV-infected women. APR prospective and retrospective data indicate possible signal for neural tube defects with 1st trimester EFV exposure, with defects similar to animal data. Overall birth defects not increased with EFV, but incidence of neural tube defects is only ~0.1%. With available 1st trimester data (~500 patients) can likely rule out 10-fold increase in risk of neural tube defects with EFV (eg, incidence of 1%). To rule out lesser increase in risk, need several thousand 1st trimester exposures. Based on available data, if risk is present, seems would be likely <1% with 1st trimester EFV exposure.
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Issues with Efavirenz and Reproductive-Aged Women The risk/benefit of EFV use in reproductive-aged women varies depending on reason for use and availability of alternatives (e.g., benefits of use for treatment vs other alternative available if used solely for PMTCT; benefit of use for treatment with co-existing TB). It is probable that EFV can safely be used in pregnant women 2nd-3rd trimester (and probably late 1st trimester). The real concern is use in non-pregnant women who conceive while on EFV. Women need to better understand the risks (eg, that they are relatively low) to be able to make educated decisions regarding starting EFV-based treatment.
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Efavirenz Neuropyschiatric side effects
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Commonly described in patients taking Efavirenz insomnia, dizziness, lightheadedness, nervousness, irritability, impaired concentration, abnormal / vivid dreams, hallucinations Last a median of 13 days Usually decrease within 2 – 4 weeks Also reported in patients taking Efavirenz Severe depression Suicidal ideation Aggressive behaviour Paranoid reactions Manic reactions But also correlated with: injecting drug use history of psychiatric disorders previous psychiatric medication association with Efavirenz ??? Take EFV on an empty stomach / at bedtime Eliminate or diminish alchohol Care with pyschoactive drugs
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PROTEASE INHIBITORS
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* Revised Guidelines
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Class wide side effects of PIs associated with some ↑ risk GI disturbances Hepatotoxicity Metabolic changes ↑ tryglycerides lypodystrophy ↑ cholesterol hyperglycaemia Insulin resistance CV Risk bleeding disorders (haemophilia) 4 most common GI disturbances (nausea, vomiting, diarrhoea) Lipid abnormalities Hyperglycaemia Lipoaccumulation *Atazanavir is comparatively less likely to cause GI disturbances or metabolic abnormalities
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Protease inhibitors Management of ADRs Diarrhoea often early and transient Symptomatic treatment Metabollic Changes Life style and risk changes Statins Hepatotoxicity Other risk factors – e.g Hepatitis Symptom directed treatment Safety monitoring Baseline serum lipid profiles Baseline blood glucose (?) Baseline liver enzymes Symptom driven testing
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Other therapeutic issue with PIs PK interaction with Rifamycins ↑ Access to Rifabutin
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Estimated HIV prevalence (%) among people newly infected with TB, 2007
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Incidence of TB during ART in cohort of 404 patients National ART Programme - Senegal A Diouf, A Akoivugui, P de Beaudrap, R Ecochard, PS Sow, E Delaporte, JF Etard. 15th ICASA. December 2008
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TB / HIV co-treatment Timing of ART / TB treatment Common toxicities Neuropathy (INH – NRTIs) Hepatic Toxicity ( INH - Rifampicin – NNRTIs - PIs) Pharmacokinetic interactions Rifamycins – PIs / NNRTIs
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Hepatitis Virus Infections
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Hepatitis B Estimated 370-400 million with chronic HBV globally – co-infection with HIV common / common epidemiology Limited access to diagnostic testing for HBV – true prevalence may be underestimated Effects mortality from liver disease susceptibility to hepatic toxicity differential diagnosis of drug induced hepatic toxicity Selection & maintenance of ARVs Tenofovir , FTC & 3TC are active against HBV
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Hepatitis C Estimated 180 million globally with chronic HBCV infection Special accelerated risk in people who use injected drugs 92% of injecting drug users in India Hepatitis C virus 10 x as infectious as HIV and infection is often asymptomatic Co-infection: HIV increases morbidity /mortality from severe HCV liver disease Pharmacologic interactions: Ribavirin vs Abacavir/ Atazanavir/Zidovudine/ ddI Challenges Awareness & Prevention programmes Access to testing & Access to drugs Data to inform guidance on co-treatment