Advances in hiv treatment


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  • Date of first publication: 2/1/99 Keywords: Adherence, antiretroviral therapy, viral load Subject: Degree of adherence needed for optimal viral suppression Title: “What degree of adherence is needed?” Discussion and teaching points: How much adherence is needed for optimal viral load suppression is addressed in the graph from Paterson which shows that the best performance was achieved in patients who by self-report and MEMS-caps were found to have >95% adherence, I.e. Better than 95% of doses were taken during the 3 months of study. Sig- nificant differences were observed between >95%, 90-95%, 80-90%, 70-80%, and <70% adherence, as shown. Note that <70% adherence was associated with only 10% of patients achieving a viral load below detection. Author(s): Paterson et al. Sources: University of Pittsburgh Sponsors: NA
  • Currently, there are three commonly used resistance analyses: 1) determination of the viral genotype; 2) assessment of the viral phenotype in vitro; and 3) determination of a "virtual" phenotype based on genotypic assessment. Each of the three above-listed approaches has distinct strengths and weaknesses. Assessments based on determination of the viral genotype are readily available, provide relatively rapid results, and have low to moderate cost. Knowing the viral genotype may also permit prediction of future phenotypic resistance. Weaknesses of these approaches include requirement for expert interpretation, and the facts that they only indirectly measure resistance, do not take into account interactions among mutations, and do not include information about antiretroviral drug levels. Phenotypic resistance analysis measures susceptibility directly, and thus results are relatively easy to interpret. However, phenotypic testing is expensive and not widely available. In addition, its turnaround time is relatively long, it is insensitive to minor species, and clinically significant cutoff values may not be established for all drugs.
  • Considerations for Changing a Failing Regimen As with the initiation of antiretroviral therapy, the decision to change regimens should be approached with careful consideration of several complex factors. These factors include: recent clinical history and physical examination; plasma HIV RNA levels measured on two separate occasions; absolute CD4+ T lymphocyte count and changes in these counts; remaining treatment options in terms of potency, potential resistance patterns from prior antiretroviral therapies and potential for compliance/tolerance; assessment of adherence to medications; and preparation of the patient for the implications of the new regimen which include side effects, drug interactions, dietary requirements and possible need to alter concomitant medications. Failure of a regimen may occur for many reasons, including initial viral resistance to one or more agents, altered absorption or metabolism of the drug, multi-drug pharmacokinetics that adversely affects therapeutic drug levels, and poor patient adherence to a regimen. In this regard, it is important to carefully assess patient adherence prior to changing antiretroviral therapy; health care workers involved in the care of the patient, such as the case manager or social worker, may be of assistance in this evaluation. Clinicians should be aware of the prevalence of mental health disorders and psychoactive substance use disorders in certain HIV-infected persons; inadequate mental health treatment services may jeopardize the ability of such individuals to adhere to their medical treatment. Proper identification of and intervention in these mental health disorders can greatly enhance adherence to medical HIV treatment. It is important to distinguish between the need to change therapy due to drug failure versus drug toxicity. In the latter case, it is appropriate to substitute one or more alternative drugs of the same potency and from the same class of agents as the agent suspected to be causing the toxicity. In the case of drug failure where more than one drug had been used, a detailed history of current and past antiretroviral medications, as well as other HIV-related medications, should be obtained. Testing for antiretroviral drug resistance may also be very helpful in maximizing the number of active drugs in a regimen (see Testing ). Viral resistance to antiretroviral drugs is an important, but not the only, reason for treatment failure. Genetically distinct viral variants emerge in each HIV-infected individual over time after initial infection. Viruses with single drug resistant mutations exist even prior to therapy, but are selected for replication by antiviral regimens that are only partially suppressive. The more potent a regimen is in durably suppressing HIV replication, the less likely the emergence of resistant variants. Thus the goal of therapy should be to reduce plasma HIV RNA to below detectable limits using the most sensitive assay available (<50 copies/mL), thereby providing the strongest genetic barrier possible to the emergence of resistance.
  • As everyone here knows, state of the art HIV therapy changes at lightning speed. Much of antiretroviral treatment of HIV infected is guided by outcome based studies. The story is different for post-exposure prophylaxis. Most of what we know about how to provide PEP comes from the original case control study of HCWs, anecdotes, animal data, and perinatal prophylaxis studies. Because infection is a rare event, thankfully, there is very little outcome data. This is striking contrast to the information available how to use antiretroviral therapy as treatment, as opposed to prevention where there is an relative abundence of outcome data. Many clinicians have tried to bridge this gap by extrapolating treatment data to prevention strategies. Thus, the rapid changes in antiretroviral use as treatment leads to rapid changes in antretroviral use as prevention. As a result, PEP in practice is likely to move quite rapidly. However the biology as well as the risk-benefit decision is quite different between treatment and prevention. Not all extrapolations from treatment data to prevention strategies may or may not be rational. As a result PEP in practice is likely to be different that PEP guidelines. What I would like to do today is to describe PEP in practice. I will focus mostly on PEP treatment decisions which have not been addressed by the quidelines.
  • Advances in hiv treatment

    1. 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. 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. 3. Typical CD4 Response to HAART
    4. 4. Challenges of HAART Complexity Toxicity Accessibility Incomplete efficacy Viral resistance
    5. 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. 6. New ARV Treatment Strategies and Concepts Adherence to treatment ARV resistance and resistance testing Interrupting ARV therapy Treating primary HIV infection
    7. 7. Adherence “Drugs don’t work if people don’t take them.” C. Everett Koop
    8. 8. Reasons for Non-Adherence: Clinician vs Patient Views 0 10 20 30 40 50 60 value,% No. of doses or pills Side Effects Meal Instructions Schedule complexity Other Clinican Patient Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281
    9. 9. Viral Suppression And Adherence By Refill Records 0 10 20 30 40 50 60 70 80 90 95-100% 90-95% 80-90% 70-80% < 70% Adherence, by prescription refill %Achieving<500copies/mL N = 504 pts on HAART Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056.
    10. 10. Measuring Adherence: Electronic Bottle Caps Caps harbor chips that register each time a bottle is opened or closed MEMScaps, Aardex Corp.
    11. 11. 0 20 40 60 80 100 >95 90-95 80–90 70-80 <70 PatientswithHIVRNA <400copies/mL,% PI adherence, % (electronic bottle caps) Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92. Viral Suppression And Adherence By MEMS
    12. 12. 10% adherence difference = 21% reduction in risk of AIDS Bangsberg D, et al. AIDS. 2001:15:1181 ProportionAIDS-Free Months from entry P = .0012 0 5 10 15 20 25 30 0.00 0.25 0.50 0.75 1.00 Adherence O 90–100% O 50–89% O 0–49% Adherence and AIDS-Free Survival
    13. 13. Why Does HAART Fail?
    14. 14. ARV Resistance
    15. 15. What Is Resistance? Viral replication in the presence of drug pressure
    16. 16. Basic Pharmacology Principles IC90 IC50 Cmin Cmax Time Drug Level Dosing Interval Area of Potential HIV Replication Dose Dose
    17. 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. 18. HIV-1 Quasi Species in Untreated and Treated HIV Infection: Heterogeneity vs. Selection of Resistant Strains acute chronic AIDS Time V. Simon, MD Plasmaviremia
    19. 19. Development of Drug Resistance
    20. 20. Antiretroviral Resistance Testing Goals Improve virologic control and immunologic benefit Minimize exposure to ineffective agents Options Genotype Phenotype “Virtual phenotype”
    21. 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 presence of different drug concentrations  Usually reported as the drug concentration that inhibits virus replication by 50% (IC50), or the fold increase in IC50
    22. 22. Genotype Vs Phenotype Availability Turnaround time 2 weeks Mutations may precede phenotypic resistance Lower cost GENOTYPE Requires expert interpretation Measures susceptibility indirectly Insensitive for detecting minor species Does not assess interactions among mutations Does not address drug levels Measures susceptibility directly Results are easier to interpret PHENOTYPE 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 Fast results (2 weeks) Moderate cost VIRTUAL PHENOTYPE Measures susceptibility indirectly Insensitive for detecting interactions between mutations Strengths Weaknesses
    23. 23. HIV Drug Resistance Assays: DHHS Recommendations Clinical Situation Recommendation/Rationale Virologic failure during ART Determine role of resistance in failure or suboptimal viral suppression Maximize number of active drugs Acute HIV infection Assess possibility of drug-resistant HIV transmission Treat accordingly Chronic HIV infection prior to treatment initiation After D/C ART Plasma HIV RNA <1000 copies/mL Uncertain prevalence of resistant virus/assays may not detect minor quasispecies Assays may not detect certain quasi- species in the absence of selective pressure HIV RNA too low for reliable detection with current assays RecommendedOptionalNotGenerallyRecommended
    24. 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. 25. Complications Of HIV And ARV Therapy
    26. 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. 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. 28. Fat Redistribution Syndromes
    29. 29. Cervico-dorsal Fat Pad
    30. 30. Central Fat Accumulation
    31. 31. Facial Lipoatrophy
    32. 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. 33. Hyperlipidemia Mechanism unknown Prevalence Clinical syndromes Hypertriglyceridemia Hypercholesterolemia Mixed ? Impact on CV risk Manage per AHA guidelines
    34. 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. 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. 36. Lactic Acidosis: Clinical Presentation 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
    37. 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. 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. 39. Avascular Necrosis of the Hip
    40. 40. Osteopenia and Avascular Necrosis of the Radial Head
    41. 41. 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
    42. 42. 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
    43. 43. Antiretroviral Therapy: Persistent Uncertainties When to start What to start with When to change What to change to When to stop (if ever)
    44. 44. ARV Treatment Interruption
    45. 45. Treatment Interruption Rationale Enhance HIV-specific immune response In primary infection In chronic infection Reduce treatment-associated complications Toxicity Cost Treatment fatigue
    46. 46. Treatment Interruption Target Groups ARV treatment fully suppressive Started during acute infection Started after infection chronic ARV treatment not fully suppressive
    47. 47. Structured Treatment Interruptions
    48. 48. Treatment Interruptions: Real Risks And Theoretical Benefits Real Risks  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 Theoretical Benefits  Reduced drug exposure  Minimize resistance  Minimize toxicity  Maximize tolerability  Reduced costs  Increased access to drugs  Improved adherence  Better QOL  Enhanced immune function  Long-term viral control off ARVs
    49. 49. Structured Treatment Interruptions: Conclusions Still experimental Rapidly evolving field Stay tuned!
    50. 50. ARVs For Acute HIV Infection
    51. 51. Primary HIV Infection Rash
    52. 52. Primary HIV Infection Oral Ulcers
    53. 53. Natural History of HIV Infection
    54. 54. The Berlin Patient Lisziewicz J et al. NEJM 1999; 340: 1683-1684.
    55. 55. ARV Therapy for Primary Infection Pros  May prevent immune system damage  May allow control of viremia without ARVs Cons  No obvious end point  Risk of cumulative ARV toxicity  Risk of suboptimal adherence leading to emergence of resistance
    56. 56. New ARV Agents
    57. 57. New ARV Agents T-20 Atazanavir Capravirine Phos-Amprenavir Tipranivir
    58. 58. New OI Management Strategies Stopping primary prophylaxis Stopping secondary prophylaxis Immune restoration syndromes
    59. 59. 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 Pregnancy  Tolerability  Teratogenicity  Metabolic toxicity  Transmission
    60. 60. Resources for HIV/AIDS Clinicians Handbooks  Sanford Guide to HIV/AIDS Therapy  The Medical Management of HIV Infection Internet  HIV InSite (  Medscape (  HIV/AIDS Treatment Information Service (  Johns Hopkins (  National HIV/AIDS Clinicians’ Consultation Center (
    61. 61. 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
    62. 62. National HIV/AIDS Clinicians’ Consultation Center A Joint Program of UCSF and San Francisco General Hospital Supported by HRSA and CDC PEPLine (888) 448-4911 Warmline (800) 933-3413