02.01 adult art classification,action a nd side effects gsn


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  • The virus binds to the CD4 receptor on the cell’s membrane. Interactions with co-receptors (CCR5 or CXCR4)take place- Individuals who have mutations of CCR5 are very resistant to HIV Leading to anchorage of the virus Then fusion of the virus with the membrane When fusion is complete, the virus enters the cell.
  • Fusion inhibitor already in use, T20 (Enfuvirtide), effective. Currently used mainly in salvage therapy; needs to be given SC Other entry inhibitors in development include the chemokine co-receptor inhibitors, CD4 receptors and other fusion inhibitors NRTI drugs prevent viral DNA production by incorporating themselves into the newly forming DNA. NNRTI drugs attach themselves to the viral enzyme reverse transcriptase, blocking its mechanism and making it unable to produce viral DNA To make the virus infectious it is essential that new viral proteins are cut and structured correctly. Protease inhibitors work by blocking the site where the cutting takes place, preventing the new virus from maturing and infecting any other cells.
  • The viral lifecycle is important when talking about drugs to fight HIV New drugs under development target different parts of the Lifecycle Fusion: Fusion Inhibitors – Enfuvirtide (Fuzeon) Reverse Transcriptase: Is targeted by three drug classes the NNRTI, the NRTI, the nucleotide RTI (We will talk about extensively later) Viral Integrase Viral Regulatory Proteins Viral Protease: Is targeted by Protease Inhibitors (We will talk about these extensively later) HIV proteins Made as “polyproteins” Multiple proteins attached to each other Must be cleaved to form functional proteins Protease cleaves polyproteins
  • The extent of inhibition of mitochondrial DNA polymerase gamma is as follows d4T>Zalcitabine (ddC) > Didanosine ( ddI) > Lamivudine (3TC) > Zidovudine (ZDV) > Abacavir (ABC). Generally adverse events are less common in children compared to adults Hyperbilirubinemia, haematuria and nephrolithiasis with Indivanir is more pronounced in children There is high risk of hepatoxicity with ZDV in children below 5 years. Asymptomatic retinal pigmentation with ddI is more likely in children. Be on the look out for diarrhea with NFV and manage the same. The most common adverse events are graded ( see attached table) with suggestions of interventions at each level of grading.
  • * In NNRTI containing regimens stopping all 3 drugs at once may allow for development of drug resistance. It is therefore recommended that the NRTI backbone should be continued for 2 weeks if possible to reduce the likelihood of NNRTI resistance developing. See Guidelines to ARV Treatment Minimizing Adverse Events Appropriate drug and regimen selection Dose titration Monitoring and reassuring for effects that are transient Appropriate timing of administration Pharmacological interventions Withdrawal of the offending drug(s)
  • The combination of ddI and d4T should be avoided during pregnancy because of several reports of fatal and non-fatal but serious lactic acidosis with hepatic steatosis and/or pancreatitis after prolonged use of regimens containing these two nucleoside analogues in combination [100]. This combination should be used during pregnancy only when other NRTI drug combinations have failed or have caused unacceptable toxicity or side effects.
  • 02.01 adult art classification,action a nd side effects gsn

    1. 1. Anti Retroviral Therapy in Adults and Adolescent Unit 1:Classification,Site of action and Side effects of Anti Retro Viral Drugs (ARVs)
    2. 2. Unit 1: Objectives <ul><li>At the end of the session participants should be able to </li></ul><ul><li>Describe the classification of ARVs </li></ul><ul><li>Be familiar with the site of action of the various classes of ARVs </li></ul><ul><li>Be familiar with the common toxicities seen with ARV therapy </li></ul><ul><li>Describe and diagnose common side effects associated with ARVs </li></ul>
    3. 3. Classes of Anti Retro Virals <ul><li>Reverse transcriptase (RT) inhibitors </li></ul><ul><ul><li>Nucleoside RT inhibitors (NRTI) </li></ul></ul><ul><ul><li>Non-nucleoside RT inhibitors (NNRTI) </li></ul></ul><ul><ul><li>Nucleotide RT inhibitors (NtNRI) </li></ul></ul><ul><li>Protease inhibitors (PI) </li></ul><ul><li>Entry Inhibitors </li></ul><ul><ul><li>Attachment inhibitors </li></ul></ul><ul><ul><li>Chemokine receptor antagonists </li></ul></ul><ul><ul><li>Fusion inhibitors </li></ul></ul>
    4. 4. Antiretroviral Agents <ul><li>NRTI Nucleoside Reverse Transcriptase Inhibitor </li></ul><ul><ul><li>Zidovudine (AZT,ZDV Ritrovir) </li></ul></ul><ul><ul><li>Didanosine (ddI Videx) </li></ul></ul><ul><ul><li>Zalcitabine (ddC) </li></ul></ul><ul><ul><li>Stavudine (d4T Zerit ) </li></ul></ul><ul><ul><li>Lamivudine (3TC Epivir) </li></ul></ul><ul><ul><li>Abacavir (ABC Ziagen) </li></ul></ul><ul><ul><li>Emtricitabine (FTC) </li></ul></ul><ul><li>Nucleotide analogues </li></ul><ul><ul><li>Tenofovir (TDF, Viread) </li></ul></ul>
    5. 5. Antiretroviral Agents <ul><li>NNRTI Non-Nucleoside Reverse Transcriptase Inhibitor </li></ul><ul><ul><li>Nevirapine (NVP- Viramune) </li></ul></ul><ul><ul><li>Delavirdine (DLV) </li></ul></ul><ul><ul><li>Efavirenz (EFV- Stocrin, sustiva ) </li></ul></ul>
    6. 6. Antiretroviral Agents <ul><li>PI Protease Inhibitors </li></ul><ul><ul><li>Saquinavir (SQV) </li></ul></ul><ul><ul><li>Ritonavir (RIT) </li></ul></ul><ul><ul><li>Indinavir (IDV Crixivan) </li></ul></ul><ul><ul><li>Nelfinavir (NFV) </li></ul></ul><ul><ul><li>Amprenavir (APV) </li></ul></ul><ul><ul><li>Lopinavir/ ritonavir (LPV/r Kaletra, Aluvia) </li></ul></ul><ul><ul><li>Atazanavir (ATZ) </li></ul></ul><ul><li>Fusion inhibitors </li></ul><ul><ul><li>Enfuvirtide (T-20) </li></ul></ul><ul><ul><li>Entry inhibitors </li></ul></ul><ul><ul><li>-Maraviroc </li></ul></ul>
    7. 7. Some ARVs as Fixed drug combinations (FDCs) <ul><li>AZT + 3TC (combivir) </li></ul><ul><li>d4T+3TC </li></ul><ul><li>AZT + 3TC + NVP </li></ul><ul><li>d4T + 3TC + NVP </li></ul><ul><li>d4T + 3TC + NVP </li></ul><ul><li>TDF + FTC + EFV (Atripla) </li></ul><ul><li>TDF + FTC (Truvada) </li></ul>
    8. 8. <ul><li>Site of Action of ARVs </li></ul>
    9. 9. HIV Entry Mechanism 3c. Fusion Complete 1. CD4 Attachment 3b. coil-coil interaction CXCR4 CCR5 3a. Anchorage CD4 2. Co-receptor interaction Cell HIV HIV HIV gp41 gp41 HIV HIV HIV gp120
    10. 11. Targets of ARV Drugs HIV particle Injection of contents HOST CELL Binding sites RNA DNA Reverse transcription Transcription Integration of provirus DNA into host DNA Translation Cell membrane Completed HIV particle Maturation Budding Viral assembly Protein cleavage gp41 gp120 RNA s e Protease Integrase Provirus (circular structure) Protease inhibitors (e.g. Kaletra) 3 NRTI’s & NNRTI’s/ NtRTIs (e.g. AZT) 2 Entry/Fusion inhibitors work here 1 CD4 Cell HIV Particle
    11. 12. RT Provirus Proteins RNA DNA RNA DNA DNA RT Viral regulatory proteins Viral protease Reverse transcriptase Viral integrase RNA RNA Binding, fusion and entry DNA DNA DNA Viral zinc-finger nucleocapsid proteins Viral protease
    12. 13. <ul><li>Side effects of ARVs </li></ul>
    13. 14. ARV Drug Class Adverse Effects <ul><li>NRTIs </li></ul><ul><li>Peripheral neuropathy </li></ul><ul><li>Pancreatitis </li></ul><ul><li>Lipoatrophy </li></ul><ul><li>Hepatitis </li></ul><ul><li>Lactic acidosis </li></ul><ul><li>Mitochondrial toxicity </li></ul><ul><li>NNRTIs </li></ul><ul><li>Rash </li></ul><ul><li>Fever </li></ul><ul><li>Nausea </li></ul><ul><li>Diarrhea </li></ul><ul><li>Hepatoxicity </li></ul><ul><li>PIs </li></ul><ul><li>Lipodystrophy </li></ul><ul><li>GI Intolerance </li></ul><ul><li>Hyperglycaemia </li></ul><ul><li>Lipid abnormalities </li></ul><ul><li>Common Adverse Effects </li></ul><ul><li>Peripheral Neuropathy – d4T,ddI </li></ul><ul><li>Hematotoxicity - AZT </li></ul><ul><li>Hepatotoxicity - NVP </li></ul><ul><li>Diarrhea – NFV </li></ul><ul><li>Skin rash – NVP </li></ul><ul><li>Lipodystrophy – PIs, NRTIs </li></ul><ul><li>CNS disturbance – EFV </li></ul><ul><li>Hypersensitivity – ABC </li></ul><ul><li>Hyperlipidemia-PIs, d4T </li></ul>
    14. 15. Common “Mild” Side Effects <ul><li>Many patients are asymptomatic when treatment is started </li></ul><ul><li>Minor ADRs may therefore be as distressing to patients as major grade 3 or 4 ADRs </li></ul><ul><ul><li>Include </li></ul></ul><ul><ul><li>Nausea </li></ul></ul><ul><ul><li>Vomiting </li></ul></ul><ul><ul><li>Lethargy, fatigue </li></ul></ul><ul><ul><li>Headaches </li></ul></ul><ul><ul><li>Dizziness </li></ul></ul><ul><ul><li>Flu-like symptoms </li></ul></ul><ul><ul><li>Mild rash </li></ul></ul>
    15. 16. Common “Mild” Side Effects <ul><li>Occur soon after initiation of treatment; patients should be warned about them </li></ul><ul><li>Usually improve within 1-2 months </li></ul><ul><li>If necessary give supportive treatment to manage or reduce symptoms </li></ul><ul><li>Rarely necessary to change/stop treatment regimen </li></ul>
    16. 17. Rare, potentially serious ADRs <ul><li>May be acute occurring early in treatment </li></ul><ul><ul><li>Severe rash/Steven Johnson Syndrome </li></ul></ul><ul><ul><li>Hepatotoxicity </li></ul></ul><ul><ul><li>Peripheral Neuropathy </li></ul></ul><ul><ul><li>Hematological toxicity </li></ul></ul><ul><ul><li>Pancreatitis </li></ul></ul><ul><ul><li>Lactic Acidosis </li></ul></ul><ul><li>Late occurring months or years into treatment </li></ul><ul><ul><li>Metabolic complications – hyperinsulinism, dyslipidemia, lipodystrophy, cardiovascular events </li></ul></ul>
    17. 18. Toxicity: Anticipate <ul><li>Proactive assessment for predictable toxicity </li></ul><ul><li>Use of well tolerated regimens as much as possible associated with low toxicity early in treatment </li></ul><ul><li>Avoiding drug combinations likely to be associated with toxicity as much as possible </li></ul>
    18. 19. Management of Adverse Drug Effects <ul><li>Try and establish the ARV drug responsible for the adverse effect </li></ul><ul><li>Consider duration of ARV use, other disease processes, other treatments (including self administered) </li></ul><ul><li>If it is necessary to stop ART, discontinue all ARV drugs simultaneously* </li></ul><ul><li>Grade 1 or 2 reactions: continue ART under observation. </li></ul><ul><ul><li>Single drug substitution may be necessary </li></ul></ul><ul><li>Grade 3 or 4- Stop ART, manage Adverse Event and re-introduce ART. </li></ul>
    19. 20. Zidovudine (AZT,ZDV) <ul><li>ZDV-specific toxicities : </li></ul><ul><li>Bone marrow suppression (anaemia, neutropaenia). </li></ul><ul><li>Dose related,synergistic toxicity with other drugs such as TMP-SMX,ganciclovir, etc. </li></ul><ul><li>Headache, nausea,vomiting & myopathy, nail changes </li></ul><ul><li>Hepatotoxicity, fever, rash---rare </li></ul>
    20. 21. Stavudine (d4T) <ul><li>Toxicities: </li></ul><ul><li>Peripheral neuropathy - higher incidence & more severe when used with ddI (Didanosine) or ddC (Zalcitabine) </li></ul><ul><li>Elevated liver enzymes </li></ul><ul><li>Increased incidence of pancreatitis when used with ddl + hydroxyurea & fatal lactic acidosis as described earlier </li></ul><ul><li>Lipodystrophy - some association of fat redistribution syndrome & hyperlipidaemia with d4T </li></ul>
    21. 22. Didanosine (ddI) <ul><li>Toxicities : Diarrhoea (16%), pancreatitis(4-7%), peripheral neuropathy(9-15%) </li></ul><ul><li>Recent reports of increased incidence of pancreatitis & liver toxicities when used with d4T + hydroxyurea </li></ul><ul><li>5/1/2001 warning - 3 cases of fatal lactic acidosis +/- pancreatitis in HIV pregnant women receiving ddI + d4T </li></ul><ul><li>Drug interactions : </li></ul><ul><li>ddI may interfere absorption of drugs that require gastric acidity (e.g itraconazole, ketoconazole, dapsone) </li></ul><ul><li>Ca++ and Mg++ salts in ddI formulation - may chelate drugs such as tetracyclines & quinolones </li></ul><ul><li>EC formulation - eliminates these drug interactions </li></ul><ul><li>ddI + oral ganciclovir - ddI AUC increased by 100% </li></ul>
    22. 23. Abacavir Systemic Hypersensitivity Reaction <ul><li>Mostly occurring within 6 weeks of initiation of treatment </li></ul><ul><li>Signs & Symptoms (At least 2 of the following) </li></ul><ul><li>High fever, skin rash, malaise, fatigue, nausea, vomiting, diarrhoea, myalgia, arhralgia, respiratory symptoms </li></ul><ul><li>Assessment : can be difficult, but should attempt to rule out concomitant illnesses </li></ul>
    23. 24. Abacavir Systemic Hypersensitivity Reaction <ul><li>Patient Education – Critical </li></ul><ul><li>Wallet Card - should be dispensed with each prescription </li></ul><ul><li>Education of prescribers, clinical staff, & emergency service personnel </li></ul><ul><li>Abacavir Hypersensitivity Registry </li></ul>
    24. 25. Abacavir Systemic Hypersensitivity Reaction <ul><li>Action : Stop abacavir, usually symptoms resolve within 24-48 hrs </li></ul><ul><li>DO NOT RECHALLENGE ! ! ! ! </li></ul><ul><li>Rechallenge Reactions: </li></ul><ul><ul><li>Rapid return of earlier signs and symptoms with severe hypotension </li></ul></ul><ul><li>Outcomes: Deaths & several required ICU management </li></ul>
    25. 26. NRTIs Class Adverse Reaction Lactic acidosis & Hepatic Steatosis <ul><li>Rare but serious adverse reaction </li></ul><ul><li>Intial presentation: Nonspecific GI prodome, dyspnea w/ or w/o elevation of liver enzymes </li></ul><ul><li>Can lead to fulminant hepatic failure & death </li></ul><ul><li>Can be seen with all NRTls, mostly reported in patients on ZDV or d4T </li></ul><ul><li>Potential mode of action: Mitochondrial damage </li></ul><ul><li>Risk factors: Obese,female,prolonged NRTI use </li></ul><ul><li>Outcome: Some fatalities despite aggressive interventions; </li></ul><ul><li>others resolved with discontinuation of treatment. </li></ul>
    26. 27. ARV-Associated Adverse Effects: Lactic Acidosis/ Hepatic Steatosis <ul><li>Possibly due to mitochondrial toxicity </li></ul><ul><li>Associated with NRTIs (especially d4T, ddI, ZDV) </li></ul><ul><li>Clinical presentation variable: have high index of suspicion </li></ul><ul><li>Lactate >2-5 mmol/dL plus symptoms </li></ul><ul><li>Treatment: discontinue ARVs, supportive care </li></ul>
    27. 28. ARV-Associated Adverse Effects: Lactic Acidosis/ Hepatic Steatosis (continued) <ul><li>Rare, but high mortality * </li></ul><ul><li>* Pregnant women may be at increased risk for lactic acidosis and liver damage when treated with stavudine + didanosine. This combination should be avoided in pregnant women, if possible. </li></ul>
    28. 29. ARV-Associated Adverse Effects: Hepatotoxicity <ul><li>Severity variable: usually asymptomatic, may resolve without treatment interruption </li></ul><ul><li>May occur with any NNRTI or PI: </li></ul><ul><ul><li>Nevirapine: risk of severe hepatitis in first 18 weeks of use (monitor LFT), increased risk in chronic hepatitis B/C, women, and high CD4 count (>250 cells/µL in women, >400 in men) </li></ul></ul><ul><ul><li>PI: especially RTV, RTV/SQV; increased risk in hepatitis B/C, ETOH, other hepatotoxins </li></ul></ul>
    29. 30. Non Nucleoside Reverse Transcriptase Inhibitors <ul><li>Nevirapine (NVP ) </li></ul><ul><li>Efavirenz (EFV) </li></ul>
    30. 31. Nevirapine Hepatotoxicity <ul><li>Increasing reports or serious, even life-threatening hepatic necrosis. 12 fold greater risk in women (CD4 >250, pregnancy) </li></ul><ul><li>2/3 occurred with 1st 12 weeks of treatment. </li></ul><ul><li>Clinical presentation: fatigue, malaise, anorexia, nausea, with or without elevated transminases. </li></ul><ul><li>Symptoms progressed to jaundice, hepatomegaly, high transaminases leading to hepatic failure in few days. </li></ul>
    31. 33. Nevirapine Hepatotoxicity Monitoring Recommendations <ul><li>Baseline deranged LFTs & pts w/ chronic Hep B or C - at higher risk </li></ul><ul><li>Do not restart after recovery from NVP associated hepatotoxicity </li></ul><ul><li>Monitor LFTs/ALT at the following schedule: </li></ul><ul><li>Baseline </li></ul><ul><li>At 2 weeks, prior to dose escalation </li></ul><ul><li>Close clinical monitoring at every visit </li></ul><ul><li>Blood ALT when suspected. </li></ul>
    32. 34. ARV-Associated Adverse Effects: Hepatotoxicity <ul><li>Severity variable: usually asymptomatic, may resolve without treatment interruption </li></ul><ul><li>May occur with any NNRTI or PI: </li></ul><ul><ul><li>Nevirapine: risk of severe hepatitis in first 18 weeks of use (monitor LFT), increased risk in chronic hepatitis B/C, women, and high CD4 count (>250 cells/µL in women, >400 in men) </li></ul></ul><ul><ul><li>PI: especially RTV, RTV/SQV; increased risk in hepatitis B/C, ETOH, other hepatotoxins </li></ul></ul>
    33. 35. Efavirenz-CNS Side Effect <ul><li>Reported in > 50% of patients </li></ul><ul><li>Occurs after 1st few doses </li></ul><ul><li>Usually resolves or stabilizes within first few weeks </li></ul><ul><li>Symptoms: Drowsiness, dizziness, dysphoria, insomnia, somnolence, abnormal dreams, altered concentration & attention span, acute psychosis, depression </li></ul><ul><li>Taking at bedtime may reduce symptoms </li></ul><ul><li>Some evidence of benefit of using drug level to predict CNS toxicities </li></ul>
    34. 36. Management of CNS Side Effects of Efavirenz <ul><li>Avoid in patients with unstable psychiatric disorders </li></ul><ul><li>Avoid concomitant CNS suppressants or stimulants </li></ul><ul><li>Patient counseling prior to initiation of therapy </li></ul><ul><li>Take at bedtime </li></ul><ul><li>Consider discontinue therapy if : </li></ul><ul><li>Debilitating impairment of functional status </li></ul><ul><li>Significant exacerbation of psychiatric disorders including suicidal tendency </li></ul>
    35. 37. Other Concerns with Efavirenz <ul><li>Elevation of liver enzymes - especially in pts w/ chronic Hepatitis B or C infection </li></ul><ul><li>Teratogenic in rhesus monkeys - major malformation seen in 3 of 20 births - anencephaly, anophthalmia, microophthalmia </li></ul><ul><li>False (+) Cannabinoid urine testing </li></ul>
    36. 39. Skin Rash - NNRTls <ul><li>Can be severe in up to 5% of patients </li></ul><ul><li>NVP >>EFV </li></ul><ul><li>Stevens-Johnson Syndrome -reported in all NNRTls, </li></ul><ul><li>highest incidence with NVP </li></ul><ul><li>NVP rash - incidence reduced with dose escalation </li></ul><ul><li>Corticosteroid - as pre-medication or treatment- does not reduce incidence or severity of rash, may even exacerbate symptoms </li></ul>
    37. 40. Management of NNRTI-associated Skin Rash
    38. 41. PI-Class Specific Adverse Effects ----------------------------------------------- <ul><li>GIT Adverse Events </li></ul><ul><li>Insulin Resistance </li></ul><ul><li>Fat Redistribution </li></ul><ul><li>Hyperlipidaemia </li></ul><ul><li>Osteopaenia </li></ul>
    39. 42. Protease Inhibitors <ul><li>Saquinavir (Invirase) hard gel cap 1995 </li></ul><ul><li> (Fortovase)soft gel cap 1997 </li></ul><ul><li>Indinavir (Crixivan) 1996 </li></ul><ul><li>Ritonavir (Norvir) 1996 </li></ul><ul><li>Nelfinavir (Viracept ) 1997 </li></ul><ul><li>Amprenavir (Agenerase ) 1999 </li></ul><ul><li>Lopinavir (ABT-378/r,Kaletra ) 2000 </li></ul>
    40. 43. Protease Inhibitor Adverse Effects Gastrointestinal Disturbances <ul><li>Diarrhoea is the most common and may result in </li></ul><ul><li>dehydration, renal failure, malnutrition, weight loss, </li></ul><ul><li>immunosuppression, poor QOL, poor adherence </li></ul><ul><li>Treatment is non-specific and includes: </li></ul><ul><li>Loperamide or other anti-motility drugs </li></ul><ul><li>Oat bran, psyllium and other bulk-forming agents </li></ul><ul><li>Calcium carbonate,pancreatic enzymes,codeine phos. </li></ul><ul><li>Other s/e include nausea, vomiting,abdominal discomfort </li></ul><ul><li>These are usually mild to moderate--symptomatic trt. </li></ul>
    41. 44. Protease Inhibitor Adverse Effects: Insulin Resistance/ Hyperglycaemia <ul><li>Occurs in approximately 3-5% of pts </li></ul><ul><li>Hyperglycaemia,new onset DM, DKA, & exacerbation </li></ul><ul><li>of existing DM - all reported </li></ul><ul><li>Median time to onset - 63 days (2 - 390 days) </li></ul><ul><li>Management: </li></ul><ul><li>Educate pts re: signs of hyperglycemia </li></ul><ul><li>Monitor fasting blood glucose q 2-3 months </li></ul><ul><li>Dietary control or pharmacological therapy </li></ul>
    42. 45. ARV-Associated Adverse Effects: Hyperglycemia <ul><li>Insulin resistance, hyperglycemia, and diabetes associated with all PIs, especially with chronic use </li></ul><ul><li>Mechanism not well understood </li></ul><ul><ul><li>Insulin resistance, relative insulin deficiency </li></ul></ul><ul><li>Consider regular screening via fasting glucose </li></ul>
    43. 46. Diabetes <ul><li>Monitoring </li></ul><ul><li>Pre HAART baseline fasting blood glucose </li></ul><ul><li>Fasting glucose at 3- 4 month intervals for the first year of PI therapy </li></ul><ul><li>Subsequent measurements based on baseline measurements and risks </li></ul>
    44. 47. Diabetes <ul><li>Risk : PI use ; all agents in class </li></ul><ul><li>Frequency : 3-17 % at median of 60 days </li></ul><ul><li>Cause : Peripheral insulin resistant </li></ul>
    45. 48. Diabetes <ul><li>Treatment : </li></ul><ul><li>Insulin sensitizers ( metformin or glitazones) preferred over insulin or sulfonylureas based on mechanism of diabetes </li></ul><ul><li>Changes in HAART not recommended unless there is severe diabetes </li></ul>
    46. 49. Hypertriglyceridemia <ul><li>TRYGLICERIDES </li></ul><ul><li>Normal levels : <150 mg /dL </li></ul><ul><li>Elevated levels : 200 – 499 mg /dL </li></ul><ul><li>Very high levels requiring immediate intervention to prevent pancreatitis and reduce risk of cardiovascular disease : > 500 mg /dL </li></ul>
    47. 50. Hypertriglyceridemia <ul><li>Therapeutic Switch </li></ul><ul><li>PIs containing NNRTI agents appear to be associated with increases in blood lipids , including cholesterol, LDL cholesterol and triglycerides. </li></ul><ul><li>Use of non-PI containing regimens may reverse these changes . </li></ul><ul><li>Changing from PI based regimen to an NRTI / NNRTI based regimen ( NEV, EFV or AZT / 3TC / ABC ) may improve lipid profile </li></ul>
    48. 52. ARV-Associated Adverse Effects: Fat Maldistribution <ul><li>Lipodystrophy: </li></ul><ul><li>No uniform definition </li></ul><ul><li>Mechanism not understood </li></ul><ul><ul><li>peripheral fat wasting more associated with NRTIs (especially stavudine) </li></ul></ul><ul><ul><li>central fat accumulation perhaps more associated with PIs </li></ul></ul><ul><li>May be associated with dyslipidemia, insulin resistance, lactic acidosis </li></ul><ul><li>Treatment: switching to other agents may slow progression; insufficient data to guide specific therapy </li></ul>
    49. 53. PI Adverse Effects: Fat Redistribution (Changes in Body Habitus) <ul><li>Central obesity – increased abdominal girth </li></ul><ul><li>breast enlargement </li></ul><ul><li>dorsocervical fat accumulation </li></ul><ul><li>Peripheral wasting - facial thinning </li></ul><ul><li>extremity wasting with venous prominence </li></ul><ul><li>Management: </li></ul><ul><li>Change to alternative PI – usually unsuccessful </li></ul><ul><li>Change to PI sparing regimen – mixed results </li></ul><ul><li>Growth hormone & metformin – some success </li></ul><ul><li>Surgical intervention - liposuction </li></ul>
    50. 54. Lipodystrophy: Fat Redistribution <ul><li>High prevalence </li></ul><ul><li>Stigmatizing </li></ul><ul><li>Potentially Life Threatening (CAD?) </li></ul><ul><li>Probably Irreversible </li></ul>
    51. 55. <ul><li>Lipoatrophy (loss of facial & peripheral subcutaneous fat) </li></ul><ul><li>Lipohypertrophy (increase in visceral fat & dorsal neck, breast) </li></ul><ul><li>Both together </li></ul>Lipodystrophy: Fat Redistribution
    52. 56. Lipodystrophy: Fat redisribution <ul><li>Diagnosis </li></ul><ul><li>Dual Energy X-ray Absorptiometry (DEXA), Computed tomography (CT) scan, or magnetic resonance (MRI) </li></ul><ul><li>Waist- hip ratio >0.85 (Women) or >0.95 (men) </li></ul><ul><li>Patient perception </li></ul><ul><li>Intervention </li></ul><ul><li>Result with changing therapy, including use of different classes, are inconclusive </li></ul>
    53. 57. <ul><li>Indian Experience </li></ul><ul><li>Use of d4T in the subcontinent </li></ul><ul><ul><li>Low cost ( d4T+3Tc+NEV) </li></ul></ul><ul><ul><li>Can be used in advanced stage </li></ul></ul><ul><ul><li>Initially well accepted (minimal initial ADRs) </li></ul></ul>Lipodystrophy: Fat Redistribution
    54. 58. Lipodystrophy: Fat Redistribution <ul><li>Lesson </li></ul><ul><li>Compliant patients show clinical, immunological & virological success </li></ul><ul><li>BUT </li></ul><ul><li>High proportion present with lipoatrophy by the 3rd year </li></ul>
    55. 59. Lipodystrophy: Fat Redistribution <ul><li>Probable Solution </li></ul><ul><li>Initiate with d4T based ART & switch over to AZT </li></ul><ul><li>Validation by control studies needed </li></ul>
    56. 60. ARV-Associated Adverse Effects: Hyperlipidemia <ul><li>Elevations in total cholesterol, LDL, and triglycerides </li></ul><ul><li>Associated with all PIs (except ATV), d4T, EFV </li></ul><ul><li>Mechanism unknown </li></ul><ul><li>Consequences uncertain: concern for cardiovascular events, pancreatitis </li></ul><ul><li>Monitor regularly </li></ul><ul><li>Treatment: consider ARV switch; lipid-lowering agents (caution with PI + certain statins) </li></ul>
    57. 61. Protease Inhibitor Adverse Effects: Lipid Abnormalities <ul><li>Disproportionate increase in triglyceride over cholesterol </li></ul><ul><li>(most significant with RTV) </li></ul><ul><li>Long term clinical significance such as pancreatitis and </li></ul><ul><li>cardiovascular events - unclear </li></ul><ul><li>Indication for intervention: </li></ul><ul><li>Acute coronary artery disease </li></ul><ul><li>Significant cardiac risk factor </li></ul><ul><li>Recurrent or history of severe pancreatitis </li></ul><ul><li>Lipid levels based on NCEP guideline </li></ul>
    58. 62. ARV-Associated Adverse Effects: Bone Abnormalities <ul><li>Osteonecrosis (AVN) </li></ul><ul><ul><li>Mechanism unknown </li></ul></ul><ul><ul><li>Associated with PIs; increased in corticosteroid treatment, alcohol abuse, hemoglobinopathies, hyperlipidemia, hypercoagulable states </li></ul></ul><ul><ul><li>Treatment: surgical treatment for severe disease </li></ul></ul>
    59. 63. Lopinavir 133mg + ritonavir 33 mg (LPV/r, Kaletra ) Lopinavir 400mg +ritonavir 100mg (Aluvia) <ul><li>Normal dose: LPV 400mg +rtv 100mg bid with High fat meal </li></ul><ul><li>RTV + LPV --- inhibition of LPV metabolism via CYP-3A4 </li></ul><ul><li>LPV’s AUC is increased by > 100 fold, as well as C min & t 1/2 </li></ul><ul><li>Mean C trough / EC 50 ratio (inhibitory quotient) for wild type </li></ul><ul><li>HIV > 75 </li></ul><ul><li>PK Advantages: Potential to serve as barrier for viral resistance & good activities vs HIV - 1 resistant to other PIs </li></ul><ul><li>Major side effects: nausea,vomiting,diarrhoea,pancreatitis, </li></ul><ul><li>triglycerides(39-41%), cholesterol(35-46%),?cardiac,rash </li></ul><ul><li>Drug interactions due to inhibition of CYP-3A4 & CYP-2D6 </li></ul><ul><li>(chlorpheniramine, clarithromycin, flecainide, propafenone ) </li></ul>
    60. 64. Indinavir (IDV) <ul><li>Doses: </li></ul><ul><ul><li>As sole PI - 800 mg (2 caps) q8h on an empty stomach or with light meals ( C max less by 73-86% w/ high f,cl,p diet) </li></ul></ul><ul><ul><li>With RTV: (RTV 100 or 200 mg + IDV 800 mg) BD or </li></ul></ul><ul><ul><li>(RTV 400 mg + IDV 400mg) BD with or without food </li></ul></ul><ul><ul><li>Bioavailability 60-65%(empty stomach); 44% pr. Bound;CSF penetr. 2.2-76% </li></ul></ul><ul><li>Virologic efficacy associated with through levels (C min : IC 90 ) </li></ul><ul><li>Adverse Reaction: nausea, vomiting, crystalluria, haematuria, nephrolithiasis, renal impairment, hyperbilirubinaemia, rare reports of haemolytic anaemia, rash, dry skin / lips, ingrowing toe nails </li></ul><ul><li>Advise patients to drink 1.5-2 litres of fluid daily </li></ul><ul><li>Inhibits P450 CYP3A4—drug interactions </li></ul><ul><li>St John’s Wort reduces IDV plasma levels </li></ul>
    61. 65. Indinavir-Associated Nephrolithiasis Clinical Presentation - can mimick UTI <ul><li>Occurs in 10% </li></ul><ul><li>Flank pain </li></ul><ul><li>With or without haematuria </li></ul><ul><li>Presence of pyuria </li></ul><ul><li>Crystalluria </li></ul><ul><li>Passage of stone </li></ul><ul><li>Others: acute renal failure, interstitial nephritis, </li></ul><ul><li>renal atrophy, persistent crystalluria (despite d/c tx) </li></ul><ul><li>High plasma IDV concentration - reported in pts with </li></ul><ul><li>urological symptoms </li></ul>
    62. 66. Management of Indinavir-Associated Nephrolithiasis <ul><li>Preventive Measures: Adequate hydration-- > 1.5 L/day </li></ul><ul><li>(can be problematic in elderly pts & pts w/ CHF or renal failure) </li></ul><ul><li>Management of Nephrolithiasis: </li></ul><ul><li>Increase hydration - IV or PO </li></ul><ul><li>Pain control-may need narcotics,avoid NSAIDs in the elderly </li></ul><ul><li>Monitor renal function and urinalysis </li></ul><ul><li>Temporary or permanent discontinuation of IDV </li></ul><ul><li>Surgical intervention - ureteroscopy, ureteral stenting (if symptoms persist despite conservative measures) </li></ul><ul><li>?Role of therapeutic drug monitoring </li></ul>
    63. 67. Ritonavir (RTV) <ul><li>Dose: 600 mg (6 caps) BD (oral tolerance improves with meals and slow dose escalation during initiation </li></ul><ul><li>of therapy) – 12% ethanol; not well tolerated </li></ul><ul><li>Oral bioavl : O.Sol. less abs. w/ food(-23%),but cap +15% </li></ul><ul><li>98-99% bound to pl. pr. ; poor CSF penetr. </li></ul><ul><li>Adverse Reaction: Nausea, vomiting, diarrhoea(all 50%), perioral or peripheral paraesthesia, taste perversion, hypertriglyceridaemia, liver toxicities,vasodilation </li></ul><ul><li>S/E are dose-related </li></ul><ul><li>Potent inhibitor of CYP450 3A4 & 2D6 enzymes - Multiple drug-drug interactions </li></ul><ul><li>Most commonly used in “low dose” as PK enhancer for other PIs </li></ul>
    64. 68. Saquinavir (SQV) <ul><li>Invirase ( Hard Gel Capsule) - poor oral bioavailability(4%) </li></ul><ul><li>only to be used with ritonavir </li></ul><ul><li>Fortovase much improved bioavailability(12%) </li></ul><ul><li>97% plasma protein-bound; in CSF<1% </li></ul><ul><li>FTV Dose: 1200 mg (6 caps) TID with meals </li></ul><ul><li>( high fat, high calorie ) </li></ul><ul><li>Grapefruit juice -increases oral bioavailability </li></ul><ul><li>St John’s Wort reduces pl. conc. </li></ul><ul><li>More frequently used in dual PI regimen </li></ul><ul><li>(e.g RTV+SQV or NFV+FTV) </li></ul><ul><li>Adverse Reactions : Nausea,vomiting,diarrhoea,abdominal pain,dyspepsia(FTV),DKA(w/ RTV),rarely SJS </li></ul>
    65. 69. Adverse Effects: Fusion Inhibitors <ul><li>Enfuvirtide – injection-site reactions, hypersensitivity reaction, increased risk of bacterial pneumonia </li></ul>
    66. 70. Overlapping Toxicities of Anti-Retrovirals and Other Drugs Used in HIV patients(1)
    67. 71. Overlapping Toxicities of Anti-Retrovirals and Other Drugs Used in HIV patients(2) _______________________________________
    68. 72. DRUG TOXICITIES no drug is completely safe, but few live long without drugs therefore treatment is a trade-off balancing the benefits of reduced viral replication and the risk of side effects