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Advances In HIV Treatment: HAART And Its Complications

Advances In HIV Treatment: HAART And Its Complications . Amy V. Kindrick, M.D., M.P.H. National HIV/AIDS Clinicians’ Consultation Center April 26, 2003. Overview. New concepts and strategies in HIV antiretroviral therapy Long-term toxicities of ARV therapy

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Advances In HIV Treatment: HAART And Its Complications

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  1. Advances In HIV Treatment: HAART And Its Complications Amy V. Kindrick, M.D., M.P.H. National HIV/AIDS Clinicians’ Consultation Center April 26, 2003

  2. Overview • New concepts and strategies in HIV antiretroviral therapy • Long-term toxicities of ARV therapy • New and investigational ARV agents • New strategies for OI management • Common management challenges

  3. Typical CD4 Response to HAART

  4. Challenges of HAART • Complexity • Toxicity • Accessibility • Incomplete efficacy • Viral resistance

  5. What’s a Clinician to Do? • Expanding number of agents adds complexity • Minimal clinical experience when drugs released adds toxicity risk • Shortage of outcomes data adds uncertainty

  6. New ARV Treatment Strategies and Concepts • Adherence to treatment • ARV resistance and resistance testing • Interrupting ARV therapy • Treating primary HIV infection

  7. Adherence “Drugs don’t work if people don’t take them.” C. Everett Koop

  8. Reasons for Non-Adherence: Clinician vs Patient Views Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281

  9. Viral Suppression And Adherence By Refill Records N = 504 pts on HAART % Achieving <500 copies/mL Adherence, by prescription refill Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056.

  10. Measuring Adherence: Electronic Bottle Caps • Caps harbor chips that register each time a bottle is opened or closed MEMScaps, Aardex Corp.

  11. Viral Suppression And Adherence By MEMS Patients with HIV RNA<400 copies/mL, % PI adherence, % (electronic bottle caps) Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.

  12. Adherence O 90–100% O50–89% O 0–49% Adherence and AIDS-Free Survival 10% adherence difference = 21% reduction in risk of AIDS 1.00 0.75 Proportion AIDS-Free 0.50 0.25 P = .0012 0.00 0 5 10 15 20 25 30 Months from entry Bangsberg D, et al. AIDS. 2001:15:1181

  13. Why Does HAART Fail?

  14. ARV Resistance

  15. What Is Resistance? • Viral replication in the presence of drug pressure

  16. Basic Pharmacology Principles Cmax Drug Level Cmin IC90 Area of Potential HIV Replication IC50 Dosing Interval Time Dose Dose

  17. How Does Resistance Develop? • High replication and transcription error rates generate mutant HIV variants • Spontaneously generated variants often contain mutations that confer survival advantage in the presence of antiretroviral agents • Poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’

  18. HIV-1 Quasi Species in Untreated and Treated HIV Infection:Heterogeneity vs. Selection of Resistant Strains chronic AIDS acute Plasma viremia Time V. Simon, MD

  19. Development of Drug Resistance

  20. Antiretroviral Resistance Testing • Goals • Improve virologic control and immunologic benefit • Minimize exposure to ineffective agents • Options • Genotype • Phenotype • “Virtual phenotype”

  21. Definitions • Genotype • Virus nucleotide sequence from which a protein’s amino acids can be deduced • Mutations reported as change in the deduced amino acid sequence, e.g., Met184Val • Specific mutations confer phenotypic resistance • The phenotype is always derived from the genotype • Phenotype • Relative growth of the virus in the presenceof different drug concentrations • Usually reported as the drug concentration that inhibits virus replication by 50% (IC50), or the fold increase in IC50

  22. Genotype Vs Phenotype Strengths Weaknesses

  23. HIV Drug Resistance Assays: DHHS Recommendations Recommended Optional Not Generally Recommended

  24. Resistance Testing Factors • Cost • Time • Access • Technical limitations • Thresholds • Partial resistance • Mutations yet to be identified • New drugs • Different sequence regions for old drugs • Uncertain clinical impact

  25. Complications Of HIV And ARV Therapy

  26. Long-Term Complications of HIV and ARV Therapy • Body habitus changes • Insulin resistance/hyperglycemia/diabetes • Hyperlipidemia • Lactic acidosis • Hepatic steatosis • Osteopenia • Avascular necrosis

  27. Abnormal Fat Redistribution • Syndromes • Abnormal fat accumulation • Buffalo hump • Increased abdominal girth • Increased breast size • Peripheral fat wasting • “Sunken cheeks” • Thin extremities • Prominent peripheral musculature and veins • Prevalence unknown (est. 2% to 80%) • Increased with duration of HIV infection & ARV tx • Associated with PI and NRTI use • Mechanism unknown

  28. Fat Redistribution Syndromes

  29. Cervico-dorsal Fat Pad

  30. Central Fat Accumulation

  31. Facial Lipoatrophy

  32. Abnormal Insulin and Glucose Metabolism • Associated with ARVs, especially PIs • Mechanism unclear • ?PI inhibition of glut-4 transporter • Risk factors • Older age • African American ethnicity • Clinical syndromes • Insulin resistance • Hyperglycemia • Type 2 diabetes • Treat as usual

  33. Hyperlipidemia • Mechanism unknown • Prevalence • Clinical syndromes • Hypertriglyceridemia • Hypercholesterolemia • Mixed • ? Impact on CV risk • Manage per AHA guidelines

  34. Hyperlipidemia Treatment Considerations • Risk of increased insulin resistance with niacin • Increased risk of myopathy and rhabdomyolysis • Interactions between ARVs and statins • Prefer pravastatin or atorvastatin • Avoid lovastatin and simvastatin • Interactions between statins and fibrates • May respond to ARV change

  35. Lactic Acidosis And Hepatic Steatosis • Class toxicity of NRTIs (Black Box warning) • Incidence est. 4/1000 patient-years • Risk factors • Older age • Female gender • ddI, ddC, or d4T use > 3 months • ddI+d4T in pregnancy

  36. Acute or subacute onset Varying symptoms, including Malaise a/o fatigue Abdominal pain Nausea a/o vomiting Anorexia Hepatomegaly Breathlessness Abnormal laboratory values Elevated serum lactate Anion gap Transaminitis Low serum bicarbonate Elevated amylase/lipase Lactic Acidosis: Clinical Presentation

  37. Management Of Lactic Acidosis • Be alert to symptoms • Stop ARVs if symptomatic and lactate elevated • May consider continuing ARVs if • Symptoms absent or mild • Lactate only minimally elevated (e.g., 2-4 mmol/l) • ddI, d4T can be replaced • Anecdotal treatments for mild disease • L-carnitine • Riboflavin • Thiamine

  38. Delayed Onset NRTI Toxicity • Hypothesized due to toxic effects of NRTIs on human mitochondria • NRTIs inhibit DNA polymerase γ required for mDNA synthesis • Clinical syndromes • Pancreatitis • Myopathy • Peripheral neuropathy • Bone marrow toxicity • “D” drugs especially implicated

  39. Avascular Necrosis of the Hip

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