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 New and investigational ARV agents New strategies for OI management Common management challenges Typical CD4 Response to HAART Challenges of HAART Complexity Toxicity Accessibility Incomplete efficacy Viral resistance 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 New ARV Treatment Strategies and Concepts Adherence to treatment ARV resistance and resistance testing Interrupting ARV therapy Treating primary HIV infection Adherence “Drugs don‟t work if people don‟t take them.” C. Everett Koop Reasons for Non-Adherence: Clinician vs Patient Views 60 50 Clinican Patient value, % 40 30 20 10 0 No. of doses or pills Side Effects Meal Instructions Schedule complexity Other Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281 Viral Suppression And Adherence By Refill Records % Achieving <500 copies/mL 90 80 70 60 50 40 30 20 10 0 95-100% 90-95% 80-90% 70-80% < 70% N = 504 pts on HAART Adherence, by prescription refill Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056. Measuring Adherence: Electronic Bottle Caps Caps harbor chips that register each time a bottle is opened or closed MEMScaps, Aardex Corp. Viral Suppression And Adherence By MEMS 100 Patients with HIV RNA <400 copies/mL, % 80 60 40 20 0 >95 90-95 80–90 70-80 <70 PI adherence, % (electronic bottle caps) Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92. Adherence and AIDS-Free Survival 10% adherence difference = 21% reduction in risk of AIDS 1.00 Proportion AIDS-Free 0.75 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 Adherence O 90–100% O 50–89% O 0–49% Why Does HAART Fail? ARV Resistance What Is Resistance? Viral replication in the presence of drug pressure Basic Pharmacology Principles Cmax Cmin IC90 IC50 Area of Potential HIV Replication Dosing Interval Time Dose Dose 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‟ HIV-1 Quasi Species in Untreated and Treated HIV Infection: Heterogeneity vs. Selection of Resistant Strains acute chronic AIDS Plasma viremia Time V. Simon, MD Development of Drug Resistance Antiretroviral Resistance Testing Goals Improve virologic control and immunologic benefit  Minimize exposure to ineffective agents  Options Genotype  Phenotype  “Virtual phenotype”  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 presence of different drug concentrations  Usually reported as the drug concentration that inhibits virus replication by 50% (IC50), or the fold increase in IC50 Genotype Vs Phenotype Strengths Availability Turnaround time 2 weeks Mutations may precede phenotypic resistance Lower cost Weaknesses Requires expert interpretation Measures susceptibility indirectly Insensitive for detecting minor species Does not assess interactions among mutations Does not address drug levels Restricted availability Turnaround time 2–4 weeks Insensitive for detecting minor species Clinically significant cutoff values may not be defined for some drugs More expensive GENOTYPE Measures susceptibility directly Results are easier to interpret PHENOTYPE Fast results (2 weeks) Moderate cost VIRTUAL PHENOTYPE Measures susceptibility indirectly Insensitive for detecting interactions between mutations HIV Drug Resistance Assays: DHHS Recommendations Clinical Situation Recommended Recommendation/Rationale Determine role of resistance in failure or suboptimal viral suppression Maximize number of active drugs Assess possibility of drug-resistant HIV transmission Treat accordingly Uncertain prevalence of resistant virus/assays may not detect minor quasispecies Assays may not detect certain quasispecies in the absence of selective pressure HIV RNA too low for reliable detection with current assays Virologic failure during ART Optional Not Generally Recommended Acute HIV infection Chronic HIV infection prior to treatment initiation After D/C ART Plasma HIV RNA <1000 copies/mL 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 Complications Of HIV And ARV Therapy Long-Term Complications of HIV and ARV Therapy Body habitus changes Insulin resistance/hyperglycemia/diabetes Hyperlipidemia Lactic acidosis Hepatic steatosis Osteopenia Avascular necrosis Abnormal Fat Redistribution Syndromes  Abnormal fat accumulation    Buffalo hump Increased abdominal girth Increased breast size “Sunken cheeks” Thin extremities Prominent peripheral musculature and veins  Peripheral fat wasting    Prevalence unknown (est. 2% to 80%)  Increased with duration of HIV infection & ARV tx Associated with PI and NRTI use Mechanism unknown Fat Redistribution Syndromes Cervico-dorsal Fat Pad Central Fat Accumulation Facial Lipoatrophy 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 Insulin resistance Hyperglycemia Type 2 diabetes Clinical syndromes    Treat as usual Hyperlipidemia Mechanism unknown Prevalence Clinical syndromes Hypertriglyceridemia  Hypercholesterolemia  Mixed  ? Impact on CV risk Manage per AHA guidelines 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 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  Lactic Acidosis: Clinical Presentation Acute or subacute onset Varying symptoms, including       Abnormal laboratory values     Malaise a/o fatigue Abdominal pain Nausea a/o vomiting Anorexia Hepatomegaly Breathlessness  Elevated serum lactate Anion gap Transaminitis Low serum bicarbonate Elevated amylase/lipase 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 L-carnitine Riboflavin Thiamine Anecdotal treatments for mild disease    Delayed Onset NRTI Toxicity Hypothesized due to toxic effects of NRTIs on human mitochondria  NRTIs inhibit DNA polymerase γ required for mDNA synthesis Pancreatitis Myopathy Peripheral neuropathy Bone marrow toxicity Clinical syndromes     “D” drugs especially implicated Avascular Necrosis of the Hip Osteopenia and Avascular Necrosis of the Radial Head Changing Therapy: Considerations Recent clinical history and physical examination Two plasma HIV RNA levels CD4+ T cell count Remaining treatment options Drug failure or drug toxicity? Medication adherence Pharmacology & drug interactions Resistance profile Patient preference Should “Failing” HAART Be Stopped? Better to stay on some ARV regimen than none Resistance mutations may impair viral “fitness”  Specific mutations may enhance response to specific ARV agents  CD4 count gains may be sustained despite incomplete viral suppression  Deeks, et al. NEJM 2/15/01 Antiretroviral Therapy: Persistent Uncertainties When to start What to start with When to change What to change to When to stop (if ever) ARV Treatment Interruption Treatment Interruption Rationale Enhance HIV-specific immune response In primary infection  In chronic infection  Reduce treatment-associated complications Toxicity  Cost  Treatment fatigue  Treatment Interruption Target Groups ARV treatment fully suppressive Started during acute infection  Started after infection chronic  ARV treatment not fully suppressive Structured Treatment Interruptions Treatment Interruptions: Real Risks And Theoretical Benefits Real Risks   Theoretical Benefits          Loss of viral suppression Development of resistance Repopulation of reservoirs Acute antiretroviral syndrome CD4 cell decline Loss of immune responses Pharmacokinetic issues Increased transmission Disease progression Death Reduced drug exposure    Minimize resistance Minimize toxicity Maximize tolerability Increased access to drugs  Reduced costs      Improved adherence Better QOL Enhanced immune function Long-term viral control off ARVs Structured Treatment Interruptions: Conclusions Still experimental Rapidly evolving field Stay tuned! ARVs For Acute HIV Infection Primary HIV Infection Rash Primary HIV Infection Oral Ulcers Natural History of HIV Infection The Berlin Patient Lisziewicz J et al. NEJM 1999; 340: 1683-1684. ARV Therapy for Primary Infection Pros  Cons    May prevent immune system damage May allow control of viremia without ARVs  No obvious end point Risk of cumulative ARV toxicity Risk of suboptimal adherence leading to emergence of resistance New ARV Agents New ARV Agents T-20 Atazanavir Capravirine Phos-Amprenavir Tipranivir New OI Management Strategies Stopping primary prophylaxis Stopping secondary prophylaxis Immune restoration syndromes Common Management Challenges Coinfection with viral hepatitis    More rapid hepatitis progression Increased risk of ARV-associated hepatotoxicity Increased risk of toxicity associated with hepatitis treatment Tolerability Teratogenicity Metabolic toxicity Transmission Pregnancy     Resources for HIV/AIDS Clinicians Handbooks   Sanford Guide to HIV/AIDS Therapy The Medical Management of HIV Infection HIV InSite (http://hivinsite.ucsf.edu) Medscape (www.medscape.com) HIV/AIDS Treatment Information Service (www.hivatis.org) Johns Hopkins (www.hopkins-aids.edu) National HIV/AIDS Clinicians‟ Consultation Center (www.ucsf.edu/hivcntr) Internet      Consultation Services For HIV/AIDS Clinicians Local expert clinicians Regional and local AIDS Education and Training Centers National HIV Telephone Consultation Service (Warmline)  (800) 933-3413 National Clinicians‟ Post-Exposure Prophylaxis Hotline (PEPline)  (888) HIV-4911 National HIV/AIDS Clinicians‟ Consultation Center A Joint Program of UCSF and San Francisco General Hospital Supported by HRSA and CDC http://www.ucsf.edu/hivcntr Akindrick@nccc.ucsf.edu PEPLine (888) 448-4911 Warmline (800) 933-3413