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Retroviral Review Wayne Duffus, MD, PhD May 25 th  2010
Human Immunodeficiency Virus Type-1 gp120 gp41 p24 Integrase Reverse Transcriptase ssRNA+ Protease
HIV Life Cycle RT Provirus Proteins RNA DNA RNA DNA DNA RT Viral protease Reverse transcriptase RNA RNA DNA DNA DNA Fusion...
FDA-Approved Antiretroviral Drugs Nucleoside Reverse Transcriptase Inhibitors (NRTIs) * Fixed-Dose Combination Products 3T...
FDA-Approved Antiretroviral Drugs Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Viramune ® NVP Nevirapine Susti...
FDA-Approved Antiretroviral Drugs Protease Inhibitors (PIs) Invirase ® SQV-hgc Saquinavir hard gel capsule Norvir ® RTV Ri...
Approved Antiretrovirals
Progress Toward Once-Daily Regimens Dosing Daily pill burden Regimen 1996 Zerit/Epivir/Crixivan 10 pills, Q8H 2002 3 pills...
HIV Treatment: Then and Now
The Choice of the NRTI Backbone <ul><li>Prediction </li></ul><ul><li>Virtually all dual-NRTI backbones prescribed for  ini...
Consideration for Initial Regimen NRTI PI NRTI <ul><li>CNS side effects </li></ul><ul><li>Hepatotoxicity/rash </li></ul><u...
Rationale For Combination Antiretroviral Therapy <ul><li>Synergistic or additive effects </li></ul><ul><li>Prevent emergen...
Patients Prefer Once-daily With Low Pill Burden 0 10 20 30 40 50 60 70 80 90 100 If you were to take a certain number of p...
HAART Patients Commonly  Miss Doses  Due to Side Effects *1 1. Munk. CPS Info Pack (suppl).  POZ . 1998. * Community Presc...
Nausea Often Results in HAART  Discontinuation *1 * Retrospective study of 345 ART-naive patients initiated on HAART and f...
Pharmacokinetic rationale for dual protease inhibitor therapy Effective Concentration Single PI Dual PI Kempf, Medcapse, 1...
Rational for Boosted or Dual PIs Incomplete Suppression Leads to Resistance More Complete Suppression Increases  Durabilit...
Boosted vs Non-Boosted ATV Viral and Immunologic Control – Mean Value (95% CI) –  52 Week Data Horberg, et al., IAS 2007; ...
Adverse Effects: NNRTIs <ul><li>All NNRTIs: </li></ul><ul><ul><li>Rash, including Stevens-Johnson syndrome </li></ul></ul>...
Adverse Effects: PIs <ul><li>All PIs:   </li></ul><ul><ul><li>Hyperlipidemia  </li></ul></ul><ul><ul><li>Insulin resistanc...
Adverse Effects: PIs (2) <ul><li>ATV </li></ul><ul><ul><li>Hyperbilirubinemia </li></ul></ul><ul><ul><li>PR prolongation <...
Adverse Effects: PIs (3) <ul><li>IDV </li></ul><ul><ul><li>Nephrolithiasis </li></ul></ul><ul><ul><li>GI intolerance </li>...
Adverse Effects: PIs (4) <ul><li>RTV   </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>Hepatitis </li></ul...
Adverse Effects: II <ul><li>RAL  </li></ul><ul><ul><li>Nausea </li></ul></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><...
Adverse Effects: NRTIs <ul><li>All NRTIs:  </li></ul><ul><ul><li>Lactic acidosis and hepatic steatosis (highest incidence ...
Adverse Effects: NRTIs (2) <ul><li>ABC </li></ul><ul><ul><li>HSR* </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><...
Adverse Effects: NRTIs (3) <ul><li>d4T   </li></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Pancreatit...
Adverse Effects: Fusion Inhibitor <ul><li>ENF  </li></ul><ul><ul><li>Injection-site reactions </li></ul></ul><ul><ul><li>H...
Adverse Effects: CCR5 Antagonist <ul><li>MVC  </li></ul><ul><ul><li>Drug-drug interactions </li></ul></ul><ul><ul><li>Abdo...
Face and neck Buffalo neck
Liposuction – buffalo hump
Lipohypertrophy <ul><li>Adiposity </li></ul><ul><ul><li>Abdominal obesity </li></ul></ul><ul><ul><li>“ Buffalo hump” </li>...
ART-Associated  Abnormalities in Body Composition Carr A, et al.  N Engl J Med.  1998;339:1296.  Warren SM, et al.  N Engl...
Lipoatrophy <ul><li>Loss of fat </li></ul><ul><ul><li>Cheeks </li></ul></ul><ul><ul><li>Limbs </li></ul></ul><ul><ul><li>“...
Wasting - Face and neck Centrofacial and temporal atrophy
Lipodystrophy May Decrease Adherence <ul><li>Adherence rate according to time since self-reported morphological alteration...
CD4 nadir association with lipoatrophy in HOPS Lichtenstein K,  et al .  JAIDS  2003;32:48–56.   30.8% (8/26) 18.2% (10/55...
Incidence of lipoatrophy Lichtenstein  et al .  JAIDS  2003; 32:48 – 56. Percentage of patients  (%) Percentage of HIV-pos...
Effect of NRTIs on Mitochondrial DNA  (in vitro) Birkus G et al.  Antimicrob Agents Chemother . 2002;46:716-723 . Effect o...
RAVE Median Change in Limb Fat DEXA arm fat + total leg fat in grams (ITT m=f analysis) Median Baseline Limb Fat  TDF 3.0k...
Lipoatrophy is Associated with Insulin Resistance <ul><li>HIV-infected patients with fat redistribution have significantly...
Drug Interactions with ARVs <ul><li>Certain ARVs, particularly PIs and NNRTIs, have significant drug interactions with oth...
Drug Interactions with ARVs: Dose Modification or Cautious Use <ul><li>Lipid-lowering agents </li></ul><ul><li>Antimycobac...
Drug Interactions with ARVs: Dose Modification or Cautious Use <ul><li>Oral contraceptives (may require second method) </l...
ARV-ARV Interactions: Dose Modification or Cautious Use <ul><li>Efavirenz, nevirapine, or etravirine with PIs </li></ul><u...
Overlapping Toxicities <ul><li>Peripheral neuropathy </li></ul><ul><ul><li>didanosine, isoniazid, stavudine, zalcitabine <...
2009 DHHS Guidelines: Timing of ART Initiation in Special Patient Populations
2009 DHHS Guidelines: ART Initiation for Patients With HIVAN (1) <ul><li>HIV-associated nephropathy (HIVAN) </li></ul><ul>...
2009 DHHS Guidelines: ART Initiation for Patients With HIVAN (2) <ul><li>HIV-associated nephropathy (HIVAN) </li></ul><ul>...
2009 DHHS Guidelines: Risk of CVD and Persistent Immune Activation (1) <ul><li>Cardiovascular disease (CVD) </li></ul><ul>...
2009 DHHS Guidelines: Risk of CVD and Persistent Immune Activation (2) <ul><li>T-cell activation and inflammation </li></u...
2009 DHHS Guidelines: Treatment Recommendations for HBV/HIV Coinfected Patients  <ul><li>If neither HIV nor HBV infection ...
2009 DHHS Guidelines: Treatment Recommendations for HBV/HIV Coinfected Patients  <ul><li>If treatment becomes necessary fo...
2009 DHHS Guidelines: Treatment Considerations for HCV/HIV Coinfected Patients <ul><li>The rate of liver disease (fibrosis...
Natural History Course of HIV
Relationship Between CD 4 Count and AIDS Malignancies 50 - - - - - - - - - - - - - - -  150 - - - - - - -  250 - - - - 350...
<ul><li>HIV-infection and at least one of the following: </li></ul>AIDS Conditions <ul><ul><li>Candidiasis </li></ul></ul>...
Probability of Survival after AIDS-defining OI by Year of Diagnosis Months after OI diagnosis Proportion surviving 0 5 10 ...
Summary of OIs for Which Prevention Is Recommended <ul><li>Primary Prophylaxis </li></ul><ul><li>Pneumocystis   jiroveci  ...
Summary of OIs for Which Prevention Is Recommended <ul><li>Secondary Prophylaxis </li></ul><ul><li>Pneumocystis jiroveci  ...
OIs for Which Prevention Is Not Routinely Indicated <ul><li>Primary Prophylaxis </li></ul><ul><li>Bacteria (neutropenia) †...
Indications for Possible Discontinuation of Primary and Secondary Prophylaxis Primary: CD4 >100 cells/µL for 3 months Seco...
Prophylaxis of opportunistic infections <ul><li>CD4<200 </li></ul><ul><ul><li>PCP prophylaxis: bactrim, dapsone, pentamidi...
HIV- Complications at CD4>500mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Acute retroviral syndrome </li></ul></ul><ul><u...
HIV- Complications at CD4 200-500mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Pneumococcal pneumonia </li></ul></ul><ul><...
Oropharyngeal Candidasis <ul><li>Thrush limited to oropharynx </li></ul><ul><li>Esophagitis more serious usually CD4<100 <...
 
Candidal esophagitis
HIV- Complications at CD4 < 200mm 3 <ul><li>Infectious </li></ul><ul><ul><li>PCP </li></ul></ul><ul><ul><li>Histoplasmosis...
Pneumocystis carinii pneumonia <ul><li>Variable presentations </li></ul><ul><li>Pneumocystis   carinii  changed to  Pneumo...
Pneumocystis jiroveckii (carinii) pneumonia
Diagnosis of Pneumocystis carinii
Histoplasma <ul><li>Mississippi River Delta </li></ul><ul><li>Wide spectrum of illness from acute sepsis like syndrome to ...
Oral lesions of disseminated Histoplasma capsulatum infection
HIV- Complications at CD4 < 100mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Disseminated HSV </li></ul></ul><ul><ul><li>T...
Cryptococcal Meningitis <ul><li>C.  neoformans  is an encapsulated yeast, inhaled into the small airways where it usually ...
Cryptococcal Meningitis <ul><li>Clinical manifestations: </li></ul><ul><ul><li>headache (70-90%), fever (60-80%), malaise ...
<ul><li>Diagnosis made by CSF examination with india ink (74-88%), Crypto Ag serum/CSF (99%), CSF culture.  </li></ul><ul>...
Cryptococcus neoformans
Toxoplasmic Encephalitis <ul><li>Clinical presentation includes focal neurologic deficit (50-89%), seizures (15-20%), feve...
<ul><li>Presumptive diagnosis is considered confirmed by tissue sample or response to TOXO therapy in appropriate time fra...
Cerebral toxoplasmosis
HIV- Complications at CD4 < 50mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Disseminated CMV/Retinitis </li></ul></ul><ul>...
Disseminated MAC <ul><li>Usually a sub-acute/chronic illness characterized by fevers, weight loss, diarrhea, night sweats,...
Mycobacterium avium-intracellulare
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D3 Retroviral Review Duffus

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D3 Retroviral Review Duffus

  1. 1. Retroviral Review Wayne Duffus, MD, PhD May 25 th 2010
  2. 2. Human Immunodeficiency Virus Type-1 gp120 gp41 p24 Integrase Reverse Transcriptase ssRNA+ Protease
  3. 3. HIV Life Cycle RT Provirus Proteins RNA DNA RNA DNA DNA RT Viral protease Reverse transcriptase RNA RNA DNA DNA DNA Fusion and entry Integrase
  4. 4. FDA-Approved Antiretroviral Drugs Nucleoside Reverse Transcriptase Inhibitors (NRTIs) * Fixed-Dose Combination Products 3TC+ZDV ABC+3TC+ZDV FTC+TDF 3TC+ZDV ABC+3TC ABC+3TC+ZDV FTC+TDF ABC+3TC+ZDV ABC+3TC Combivir ® Trizivir ® Truvada ™ Combivir ® Epizicom ® Trizivir ® Truvada ™ Trizivir ® Epzicom ® Co-Formulation* Retrovir ® AZT, ZDV Zidovudine Hivid ® ddC Zalcitabine Viread ® TDF Tenofovir Zerit ® d4T Stavudine Epivir ® 3TC Lamivudine Emtriva ™ FTC Emtricitabine Videx ® ddI Didanosine Ziagen ® ABC Abacavir Trade Name Abbreviat. Generic
  5. 5. FDA-Approved Antiretroviral Drugs Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Viramune ® NVP Nevirapine Sustiva ® EFV Efavirenz Rescriptor ® DLV Delavirdine Trade Name Abbreviat. Generic
  6. 6. FDA-Approved Antiretroviral Drugs Protease Inhibitors (PIs) Invirase ® SQV-hgc Saquinavir hard gel capsule Norvir ® RTV Ritonavir Viracept ® NFV Nelfinavir Kaletra ® LPV/r Lopinavir + ritonavir Crixivan ® IDV Indinavir Lexiva ™ F-APV Fosamprenavir Reyataz ™ ATV Atazanavir Agenerase ® APV Amprenavir Trade Name Abbreviat. Generic
  7. 7. Approved Antiretrovirals
  8. 8. Progress Toward Once-Daily Regimens Dosing Daily pill burden Regimen 1996 Zerit/Epivir/Crixivan 10 pills, Q8H 2002 3 pills, BID Combivir/Sustiva 1998 Combivir (Retrovir/Epivir)/ Sustiva 5 pills, BID 2003 3 pills, QD Viread/Emtriva/Sustiva 2004 Fixed-Dose (Viread/ Emtriva)/Sustiva 2 pills, QD
  9. 9. HIV Treatment: Then and Now
  10. 10. The Choice of the NRTI Backbone <ul><li>Prediction </li></ul><ul><li>Virtually all dual-NRTI backbones prescribed for initial therapy will consist of 1 of 3 fixed-dose coformulations: </li></ul>AZT/3TC ABC/3TC TDF/FTC Combivir Epzicom Truvada
  11. 11. Consideration for Initial Regimen NRTI PI NRTI <ul><li>CNS side effects </li></ul><ul><li>Hepatotoxicity/rash </li></ul><ul><li>K103N confers cross-resistance </li></ul><ul><li>GI side effects </li></ul><ul><li>Potential for cross-resistance </li></ul><ul><li>Differences in tolerability, potency, and safety between agents </li></ul>Cons <ul><li>Simple regimen </li></ul><ul><li>Preserves PI class </li></ul><ul><li>Multiple mutations for resistance target both RT and PI genes (except NFV) </li></ul><ul><li>Preserves NNRTIs </li></ul><ul><li>Trials with clinical endpoints </li></ul>Pros EFV + FTC +TDF LPV/r + 3TC + ZDV Example NRTI NRTI NNRTI
  12. 12. Rationale For Combination Antiretroviral Therapy <ul><li>Synergistic or additive effects </li></ul><ul><li>Prevent emergence of resistance </li></ul><ul><li>Attack the virus at different points in the lifecycle. </li></ul>
  13. 13. Patients Prefer Once-daily With Low Pill Burden 0 10 20 30 40 50 60 70 80 90 100 If you were to take a certain number of pills each day, how would you prefer them to be administered? All at once Divided and taken twice a day % patients preferring >8 pills 8 pills 6 pills 4 pills 3 pills 31% 69% 38% 62% 59% 41% 84% 16% 93% 7% Moyle G et al. Paper presented at: 6th International Congress on Drug Therapy in HIV Infection; Glasgow, Scotland; November 17-21, 2002. Poster 99.
  14. 14. HAART Patients Commonly Miss Doses Due to Side Effects *1 1. Munk. CPS Info Pack (suppl). POZ . 1998. * Community Prescription Service (CPS) phone survey of 400 people with HIV, most of whom were on triple combination therapy. 7
  15. 15. Nausea Often Results in HAART Discontinuation *1 * Retrospective study of 345 ART-naive patients initiated on HAART and followed for a median of 8.1 months. Of 211 patients who discontinued therapy, 40% did so due to AEs. 1. O’Brien et al. JAIDS . 2003;34:407-414. 9
  16. 16. Pharmacokinetic rationale for dual protease inhibitor therapy Effective Concentration Single PI Dual PI Kempf, Medcapse, 1999
  17. 17. Rational for Boosted or Dual PIs Incomplete Suppression Leads to Resistance More Complete Suppression Increases Durability of Response Current Single PI Regimens Dual PI Regimens With PK Enhancement Plasma drug levels High peak contribute to toxicity Low trough insufficient to completely block replication Drug required to block replication Low peak levels may reduce side effects High trough levels increase potency Two-drug Combination may increase potency
  18. 18. Boosted vs Non-Boosted ATV Viral and Immunologic Control – Mean Value (95% CI) – 52 Week Data Horberg, et al., IAS 2007; WEPEB025. <ul><li>Observational cohort analysis of ATV/RTV and ATV non-use at Kaiser Permanente and Group Health Cooperative from 2003-2006 </li></ul><ul><li>Differences in outcome and safety of ritonavir-boosted atazanavir (ATV/RTV) compared to non-boosted atazanavir </li></ul>+182 (+158, +206) +135 (+89, +182) Change CD4 T-cell count (#μL) through 52 weeks -1.77 (-1.90, -1.65) -1.31 (-1.75, -0.87) Change HV RNA (log ¹º /mL) through 52 weeks 78.8% 54.2% Percent HIV RNA <400 copies/mL Ritonavir Boosted Group Non-Ritonavir Boosted Group Outcome Measure
  19. 19. Adverse Effects: NNRTIs <ul><li>All NNRTIs: </li></ul><ul><ul><li>Rash, including Stevens-Johnson syndrome </li></ul></ul><ul><ul><li>Drug-drug interactions </li></ul></ul><ul><li>EFV </li></ul><ul><ul><li>Neuropsychiatric </li></ul></ul><ul><ul><li>Teratogenic in nonhuman primates + cases of neural tube defects in human infants after first trimester exposure </li></ul></ul><ul><li>NVP </li></ul><ul><ul><li>Higher rate of rash </li></ul></ul><ul><ul><li>Hepatotoxicity (may be severe and life-threatening; risk higher in patients with higher CD4 counts at the time they start NVP) </li></ul></ul>
  20. 20. Adverse Effects: PIs <ul><li>All PIs: </li></ul><ul><ul><li>Hyperlipidemia </li></ul></ul><ul><ul><li>Insulin resistance and diabetes </li></ul></ul><ul><ul><li>Lipodystrophy </li></ul></ul><ul><ul><li>Elevated LFTs </li></ul></ul><ul><ul><li>Possibility of increased bleeding risk for hemophiliacs </li></ul></ul><ul><ul><li>Drug-drug interactions </li></ul></ul>
  21. 21. Adverse Effects: PIs (2) <ul><li>ATV </li></ul><ul><ul><li>Hyperbilirubinemia </li></ul></ul><ul><ul><li>PR prolongation </li></ul></ul><ul><ul><li>Nephrolithiasis </li></ul></ul><ul><li>DRV </li></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Liver toxicity </li></ul></ul><ul><li>FPV </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Possible increased risk of MI </li></ul></ul>
  22. 22. Adverse Effects: PIs (3) <ul><li>IDV </li></ul><ul><ul><li>Nephrolithiasis </li></ul></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><li>LPV/r </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>Possible increased risk of MI </li></ul></ul><ul><ul><li>PR and QT prolongation </li></ul></ul><ul><li>NFV </li></ul><ul><ul><li>Diarrhea </li></ul></ul>
  23. 23. Adverse Effects: PIs (4) <ul><li>RTV </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>Hepatitis </li></ul></ul><ul><li>SQV </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><li>TPV </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Hyperlipidemia </li></ul></ul><ul><ul><li>Liver toxicity </li></ul></ul><ul><ul><li>Cases of intracranial hemorrhage </li></ul></ul>
  24. 24. Adverse Effects: II <ul><li>RAL </li></ul><ul><ul><li>Nausea </li></ul></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><li>Diarrhea </li></ul></ul><ul><ul><li>CPK elevation </li></ul></ul>
  25. 25. Adverse Effects: NRTIs <ul><li>All NRTIs: </li></ul><ul><ul><li>Lactic acidosis and hepatic steatosis (highest incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC) </li></ul></ul><ul><ul><li>Lipodystrophy (higher incidence with d4T) </li></ul></ul>
  26. 26. Adverse Effects: NRTIs (2) <ul><li>ABC </li></ul><ul><ul><li>HSR* </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Possible ↑ risk of MI </li></ul></ul><ul><li>ddI </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Pancreatitis </li></ul></ul><ul><ul><li>Possible noncirrhotic portal hypertension </li></ul></ul>* Screen for HLA-B*5709 before treatment with ABC; ABC should not be given to patients who test positive for HLA-B*5709.
  27. 27. Adverse Effects: NRTIs (3) <ul><li>d4T </li></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Pancreatitis </li></ul></ul><ul><li>TDF </li></ul><ul><ul><li>Renal impairment </li></ul></ul><ul><ul><li>Possible decrease in bone mineral density </li></ul></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><li>ZDV </li></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>Bone marrow suppression </li></ul></ul>
  28. 28. Adverse Effects: Fusion Inhibitor <ul><li>ENF </li></ul><ul><ul><li>Injection-site reactions </li></ul></ul><ul><ul><li>HSR </li></ul></ul><ul><ul><li>Increased risk of bacterial pneumonia </li></ul></ul>
  29. 29. Adverse Effects: CCR5 Antagonist <ul><li>MVC </li></ul><ul><ul><li>Drug-drug interactions </li></ul></ul><ul><ul><li>Abdominal pain </li></ul></ul><ul><ul><li>Upper respiratory tract infections </li></ul></ul><ul><ul><li>Cough </li></ul></ul><ul><ul><li>Hepatotoxicity </li></ul></ul><ul><ul><li>Musculoskeletal symptoms </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Orthostatic hypotension </li></ul></ul>
  30. 30. Face and neck Buffalo neck
  31. 31. Liposuction – buffalo hump
  32. 32. Lipohypertrophy <ul><li>Adiposity </li></ul><ul><ul><li>Abdominal obesity </li></ul></ul><ul><ul><li>“ Buffalo hump” </li></ul></ul><ul><ul><li>Enlarged breasts </li></ul></ul><ul><ul><li>Gynecomastia </li></ul></ul>
  33. 33. ART-Associated Abnormalities in Body Composition Carr A, et al. N Engl J Med. 1998;339:1296. Warren SM, et al. N Engl J Med. 2005;352:63.
  34. 34. Lipoatrophy <ul><li>Loss of fat </li></ul><ul><ul><li>Cheeks </li></ul></ul><ul><ul><li>Limbs </li></ul></ul><ul><ul><li>“ arm cabling” </li></ul></ul><ul><ul><li>Buttocks </li></ul></ul>
  35. 35. Wasting - Face and neck Centrofacial and temporal atrophy
  36. 36. Lipodystrophy May Decrease Adherence <ul><li>Adherence rate according to time since self-reported morphological alterations </li></ul><ul><li>Definition of treatment adherence: Having missed one or more doses of antiretroviral drugs during the preceding week </li></ul>Adapted from Guaraldi G et al. HIV Clin Trials. 2003;4:99-106 . 100 92 82 75 0 8 18 25 0-6 months 6-12 months 12-24 months >24 months Adherent Non adherent N=83 pts Time since self-reported morphological alterations Adherence rate declining by 7% to 9% per year Adherence rate (%)
  37. 37. CD4 nadir association with lipoatrophy in HOPS Lichtenstein K, et al . JAIDS 2003;32:48–56. 30.8% (8/26) 18.2% (10/55) 17% (9/53) 13.2% (5/38) 12% (9/75) 3.3%(3/90) 0 25 50 Min CD4 Max CD4 >350 >350 200-349 >200 <200 <200 <200 <200 >500 350-499 200-349 <200 Incidence of lipoatrophy (%) Post-HAART CD4 range
  38. 38. Incidence of lipoatrophy Lichtenstein et al . JAIDS 2003; 32:48 – 56. Percentage of patients (%) Percentage of HIV-positive patients who developed moderate/severe lipoatrophy (n=337) at 20-month follow-up Overall: 13.1% (n=44) of patients developed lipoatrophy at 20 months 10.1 13.3 18.8 Overall age was a non-significant factor in the development of lipoatrophy in statistical analyses (n=135) (n=64) (n=138) 0 2 4 6 8 10 12 14 16 18 20 <40 years 40 – 49 years >50 years
  39. 39. Effect of NRTIs on Mitochondrial DNA (in vitro) Birkus G et al. Antimicrob Agents Chemother . 2002;46:716-723 . Effect of NRTIs on Hep G2 Cell Mitochondrial DNA Content Mitochondrial DNA content (%) 0.1 1 10 100 1000 ZDV 3TC TDF ABC d4T ddI ddC 140 120 100 80 60 40 20 0 Log drug concentration (µM)
  40. 40. RAVE Median Change in Limb Fat DEXA arm fat + total leg fat in grams (ITT m=f analysis) Median Baseline Limb Fat TDF 3.0kg, ABC 2.9kg p=0.97 Moyle et al. 12 th CROI, Boston, 2005. Abstract 44LB.
  41. 41. Lipoatrophy is Associated with Insulin Resistance <ul><li>HIV-infected patients with fat redistribution have significantly less insulin sensitivity than controls </li></ul><ul><li>Percentage peripheral fat correlates positively with insulin sensitivity </li></ul>* P < 0.05 compared with controls and HIV-infected groups. Mynarcik DC et al. J Acquir Immune Defic Syndr. 2000;25:312–321. * 18 12 6 Control HIV HIV-LD Insulin Sensitivity (mg glucose/kg LBM/min) n = 12 14 15 Limb Fat (%) Insulin Sensitivity (mg glucose/kg lean body mass/min) 20 60 40 0 6 12 18 r =0.60 p=0.0001
  42. 42. Drug Interactions with ARVs <ul><li>Certain ARVs, particularly PIs and NNRTIs, have significant drug interactions with other ARVs and with other medications: check for interactions before prescribing </li></ul>
  43. 43. Drug Interactions with ARVs: Dose Modification or Cautious Use <ul><li>Lipid-lowering agents </li></ul><ul><li>Antimycobacterials, especially rifampin* </li></ul><ul><li>Psychotropics - midazolam, triazolam </li></ul><ul><li>Ergot alkaloids </li></ul><ul><li>Antihistamines – astemizole </li></ul><ul><li>Anticonvulsants </li></ul>*Of NNRTIs and PIs, rifampin may be used only with full-dose ritonavir or with efavirenz
  44. 44. Drug Interactions with ARVs: Dose Modification or Cautious Use <ul><li>Oral contraceptives (may require second method) </li></ul><ul><li>Methadone </li></ul><ul><li>Erectile dysfunction agents </li></ul><ul><li>Herbs - St. John’s wort </li></ul>
  45. 45. ARV-ARV Interactions: Dose Modification or Cautious Use <ul><li>Efavirenz, nevirapine, or etravirine with PIs </li></ul><ul><li>Atazanavir + tenofovir </li></ul><ul><li>Didanosine + tenofovir </li></ul><ul><li>Didanosine + stavudine </li></ul><ul><li>Maraviroc + many PIs </li></ul><ul><li>Maraviroc + efavirenz or etravirine </li></ul>
  46. 46. Overlapping Toxicities <ul><li>Peripheral neuropathy </li></ul><ul><ul><li>didanosine, isoniazid, stavudine, zalcitabine </li></ul></ul><ul><li>Bone marrow suppression </li></ul><ul><ul><li>cidofovir, dapsone, hydroxyurea, ribavirin, TMP-SMZ, zidovudine </li></ul></ul><ul><li>Hepatotoxicity </li></ul><ul><ul><li>nevirapine, efavirenz, isoniazid, macrolides, maraviroc, NRTIs, PIs </li></ul></ul><ul><li>Pancreatitis </li></ul><ul><ul><li>didanosine, pentamidine, ritonavir, stavudine, TMP-SMZ </li></ul></ul>
  47. 47. 2009 DHHS Guidelines: Timing of ART Initiation in Special Patient Populations
  48. 48. 2009 DHHS Guidelines: ART Initiation for Patients With HIVAN (1) <ul><li>HIV-associated nephropathy (HIVAN) </li></ul><ul><ul><li>HIVAN is the most frequent cause of chronic renal failure in persons living with HIV infection </li></ul></ul><ul><ul><li>HIVAN occurs almost exclusively in black patients and can occur at any CD4 count </li></ul></ul><ul><ul><li>Ongoing viral replication appears to be directly involved in renal injury </li></ul></ul>Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
  49. 49. 2009 DHHS Guidelines: ART Initiation for Patients With HIVAN (2) <ul><li>HIV-associated nephropathy (HIVAN) </li></ul><ul><ul><li>HIVAN is extremely uncommon in virologically suppressed patients </li></ul></ul><ul><ul><li>Antiretroviral therapy for individuals with HIVAN has been associated with both preserved renal function and prolonged survival </li></ul></ul><ul><ul><li>ART should be initiated for patients with a diagnosis of HIVAN regardless of CD4 cell count </li></ul></ul>Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
  50. 50. 2009 DHHS Guidelines: Risk of CVD and Persistent Immune Activation (1) <ul><li>Cardiovascular disease (CVD) </li></ul><ul><ul><li>A major cause of mortality in HIV-infected patients </li></ul></ul><ul><ul><li>Patients with HIV have higher levels of markers of inflammation and endothelial dysfunction than HIV-uninfected controls </li></ul></ul><ul><ul><li>Early control of HIV replication with antiretroviral therapy can be used as a strategy to reduce cardiovascular disease risk </li></ul></ul>Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
  51. 51. 2009 DHHS Guidelines: Risk of CVD and Persistent Immune Activation (2) <ul><li>T-cell activation and inflammation </li></ul><ul><ul><li>The degree of T-cell activation during untreated disease is associated with risk of subsequent disease progression, independent of other factors such as plasma HIV RNA levels and the peripheral CD4 T-cell count </li></ul></ul><ul><ul><li>Earlier treatment may result in less residual immunological perturbations on therapy, and hence less risk for AIDS- and non-AIDS-related complications </li></ul></ul>Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
  52. 52. 2009 DHHS Guidelines: Treatment Recommendations for HBV/HIV Coinfected Patients <ul><li>If neither HIV nor HBV infection requires treatment: </li></ul><ul><ul><li>Monitor the progression of both infections </li></ul></ul><ul><li>If treatment becomes necessary for either infection, follow the guidelines listed in the scenarios below </li></ul><ul><ul><li>If treatment is needed for HIV but not for HBV </li></ul></ul><ul><ul><ul><li>Patients who need treatment for HIV infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses </li></ul></ul></ul><ul><ul><ul><li>To avoid development of HBV-resistant mutants, none of these agents should be used as the only agent with anti-HBV activity in an antiretroviral regimen </li></ul></ul></ul>Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
  53. 53. 2009 DHHS Guidelines: Treatment Recommendations for HBV/HIV Coinfected Patients <ul><li>If treatment becomes necessary for either infection, follow the guidelines listed in the scenarios below: </li></ul><ul><ul><li>If treatment for HBV is needed </li></ul></ul><ul><ul><ul><li>Patients who need treatment for HBV infection should also be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses </li></ul></ul></ul><ul><ul><ul><ul><li>Management of HIV should be continued with a combination regimen to provide maximal suppression </li></ul></ul></ul></ul><ul><ul><li>If treating only HBV </li></ul></ul><ul><ul><ul><li>In instances when HIV treatment is not an option or is not desirable, pegylated interferon-alpha may be used for the treatment of HBV infection, as it does not lead to the emergence of HIV or HBV resistance </li></ul></ul></ul>Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
  54. 54. 2009 DHHS Guidelines: Treatment Considerations for HCV/HIV Coinfected Patients <ul><li>The rate of liver disease (fibrosis) progression is accelerated by HIV/HCV coinfection, particularly in persons with low CD4 cell counts ( ≤ 350 cells/mm 3 ) </li></ul><ul><li>ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation </li></ul><ul><li>Concurrent treatment of both HIV and HCV is feasible but may be complicated by pill burden, drug toxicities, and drug interactions </li></ul><ul><ul><li>Caution should be used with certain antivirals </li></ul></ul><ul><li>Eradication of HCV infection may decrease the likelihood of drug-induced liver injury following ART </li></ul>Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
  55. 55. Natural History Course of HIV
  56. 56. Relationship Between CD 4 Count and AIDS Malignancies 50 - - - - - - - - - - - - - - - 150 - - - - - - - 250 - - - - 350 - - Bacterial skin infections Varicella zoster virus (VZV), Kaposi’s sarcoma (KS) Oral Candidiasis Pneumocystis carinii pneumonia (PCP) Non-Hodgkin’s lymphoma (NHL) Cryptococcal meningitis Herpes simplex virus (HSV) infections Cytomegalovirus (CMV) infections Mycobacterium-avium complex (MAC) Time after onset of HIV infection CD 4 cells/mm 3
  57. 57. <ul><li>HIV-infection and at least one of the following: </li></ul>AIDS Conditions <ul><ul><li>Candidiasis </li></ul></ul><ul><ul><li>Coccidioidomycosis </li></ul></ul><ul><ul><li>Cryptococcosis </li></ul></ul><ul><ul><li>Cryptosporidiosis </li></ul></ul><ul><ul><li>Cytomegalovirus </li></ul></ul><ul><ul><li>HIV-encephalopathy </li></ul></ul><ul><ul><li>Herpes simplex </li></ul></ul><ul><ul><li>Histoplasmosis </li></ul></ul><ul><ul><li>Isosporiasis </li></ul></ul><ul><ul><li>Kaposi’s sarcoma </li></ul></ul><ul><ul><li>Lymphoma </li></ul></ul><ul><ul><li>Mycobacterium </li></ul></ul><ul><ul><li>Pneumocystis </li></ul></ul><ul><ul><li>Recurrent pneumonia </li></ul></ul><ul><ul><li>Progressive multifocal leukoencephalopathy </li></ul></ul><ul><ul><li>Toxoplasma </li></ul></ul><ul><ul><li>Wasting syndrome </li></ul></ul>
  58. 58. Probability of Survival after AIDS-defining OI by Year of Diagnosis Months after OI diagnosis Proportion surviving 0 5 10 15 20 25 30 35 40 45 50 55 60 1.0 0.8 0.6 0.4 0.2 0 1997 1996 1995 1994 1993 1992 1984–1991 JAMA 2001; 285: 1308-1315
  59. 59. Summary of OIs for Which Prevention Is Recommended <ul><li>Primary Prophylaxis </li></ul><ul><li>Pneumocystis jiroveci pneumonia (PCP)* </li></ul><ul><li>Tuberculosis* </li></ul><ul><li>Toxoplasmosis* </li></ul><ul><li>Mycobacterium avium complex (MAC)* </li></ul><ul><li>Varicella-zoster* </li></ul><ul><li>S pneumoniae infections † </li></ul><ul><li>Hepatitis A and B † </li></ul><ul><li>Influenza † </li></ul>* Standard of care † Generally recommended
  60. 60. Summary of OIs for Which Prevention Is Recommended <ul><li>Secondary Prophylaxis </li></ul><ul><li>Pneumocystis jiroveci pneumonia (PCP)* </li></ul><ul><li>Toxoplasmosis* </li></ul><ul><li>Mycobacterium avium complex (MAC)* </li></ul><ul><li>Cryptococcosis* </li></ul><ul><li>Histoplasmosis* </li></ul><ul><li>Coccidioidomycosis* </li></ul><ul><li>Cytomegalovirus* </li></ul><ul><li>Salmonella bacteremia † </li></ul>* Standard of care † Generally recommended
  61. 61. OIs for Which Prevention Is Not Routinely Indicated <ul><li>Primary Prophylaxis </li></ul><ul><li>Bacteria (neutropenia) † </li></ul><ul><li>Cryptococcosis † </li></ul><ul><li>Histoplasmosis † </li></ul><ul><li>Cytomegalovirus † </li></ul><ul><li>Secondary Prophylaxis </li></ul><ul><li>Herpes simplex virus § </li></ul><ul><li>Candida § </li></ul>† Evidence for efficacy but not routinely indicated § Recommended only if subsequent episodes are frequent or severe
  62. 62. Indications for Possible Discontinuation of Primary and Secondary Prophylaxis Primary: CD4 >100 cells/µL for 3 months Secondary: CD4 >100 cells/µL for 6 months + 12 months MAC treatment + asymptomatic MAC Primary: CD4 >200 cells/µL for 3 months Secondary: CD4 >200 cells/µL for 6 months + initial toxo treatment + asymptomatic Toxo Primary: CD4 >200 cells/µL for 3 months Secondary: CD4 >200 cells/µL for 3 months PCP Recommendation (only for patients on effective ART) Agent
  63. 63. Prophylaxis of opportunistic infections <ul><li>CD4<200 </li></ul><ul><ul><li>PCP prophylaxis: bactrim, dapsone, pentamidine, atovoaquone, primaquine + clindamycin </li></ul></ul><ul><li>CD4<50 </li></ul><ul><ul><li>MAC prophylaxis: azithromycin or clarithromycin </li></ul></ul>
  64. 64. HIV- Complications at CD4>500mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Acute retroviral syndrome </li></ul></ul><ul><ul><li>Candida vaginitis </li></ul></ul><ul><li>Other </li></ul><ul><ul><li>Generalized LAD </li></ul></ul><ul><ul><li>Guillain-Barre (very rare) </li></ul></ul><ul><ul><li>Vague constitutional symptoms </li></ul></ul>
  65. 65. HIV- Complications at CD4 200-500mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Pneumococcal pneumonia </li></ul></ul><ul><ul><li>TB </li></ul></ul><ul><ul><li>Herpes zoster </li></ul></ul><ul><ul><li>Kaposis sarcoma </li></ul></ul><ul><ul><li>Oral hairy leukoplakia (OHL) </li></ul></ul><ul><ul><li>Oropharyngeal candidiasis (thrush) </li></ul></ul><ul><li>Non-Infectious </li></ul><ul><ul><li>Cervical Ca </li></ul></ul><ul><ul><li>Lymphomas </li></ul></ul><ul><ul><li>ITP (Immune thrombocytopenic purpura) </li></ul></ul>
  66. 66. Oropharyngeal Candidasis <ul><li>Thrush limited to oropharynx </li></ul><ul><li>Esophagitis more serious usually CD4<100 </li></ul><ul><ul><li>Odynophagia </li></ul></ul><ul><ul><li>Chest pain </li></ul></ul><ul><li>Other causes of esophagitis </li></ul><ul><ul><li>CMV (usually CD4<50) </li></ul></ul><ul><ul><li>Idiopathic ulceration (CD4<50) </li></ul></ul>
  67. 68. Candidal esophagitis
  68. 69. HIV- Complications at CD4 < 200mm 3 <ul><li>Infectious </li></ul><ul><ul><li>PCP </li></ul></ul><ul><ul><li>Histoplasmosis (other endemic fungi) </li></ul></ul><ul><ul><li>Miliary TB </li></ul></ul><ul><ul><li>PML </li></ul></ul><ul><li>Non-Infectious </li></ul><ul><ul><li>Wasting </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Cardiomyopathy </li></ul></ul><ul><ul><li>Dementia </li></ul></ul>
  69. 70. Pneumocystis carinii pneumonia <ul><li>Variable presentations </li></ul><ul><li>Pneumocystis carinii changed to Pneumocystis jiroveci </li></ul><ul><li>20-40% in patients not on HIV rx </li></ul><ul><ul><li>Usually subacute presentation of dry cough, dyspnea </li></ul></ul><ul><ul><li>CXR typically reveals interstitial infiltrates </li></ul></ul><ul><ul><ul><li>May have lobar consolidation </li></ul></ul></ul><ul><ul><ul><li>Pneumothorax in severe cases </li></ul></ul></ul><ul><ul><li>Treatment/ prophylaxis </li></ul></ul>
  70. 71. Pneumocystis jiroveckii (carinii) pneumonia
  71. 72. Diagnosis of Pneumocystis carinii
  72. 73. Histoplasma <ul><li>Mississippi River Delta </li></ul><ul><li>Wide spectrum of illness from acute sepsis like syndrome to acute pneumonia to cutaneous involvement </li></ul>
  73. 74. Oral lesions of disseminated Histoplasma capsulatum infection
  74. 75. HIV- Complications at CD4 < 100mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Disseminated HSV </li></ul></ul><ul><ul><li>Toxoplasmosis </li></ul></ul><ul><ul><li>Candida esophagitis </li></ul></ul><ul><ul><li>Cryptosporidiosis, microsporidiosis, isospora </li></ul></ul><ul><ul><li>Cryptococcal disease </li></ul></ul>
  75. 76. Cryptococcal Meningitis <ul><li>C. neoformans is an encapsulated yeast, inhaled into the small airways where it usually causes sub-clinical disease; dissemination to the CNS is not related to pulmonary response. </li></ul><ul><li>C. neoformans produces no toxins and evokes little inflammatory response. The main virulence factor is the capsule. </li></ul>
  76. 77. Cryptococcal Meningitis <ul><li>Clinical manifestations: </li></ul><ul><ul><li>headache (70-90%), fever (60-80%), malaise (76%), stiff neck (20-30%), photophobia (6-18%), seizures (5-10%) nausea. </li></ul></ul><ul><li>Average duration of symptoms is 30 days. </li></ul><ul><li>Predictors of poor outcomes are altered mental status, increased opening pressure, WBC<20 cells/mm3. </li></ul>
  77. 78. <ul><li>Diagnosis made by CSF examination with india ink (74-88%), Crypto Ag serum/CSF (99%), CSF culture. </li></ul><ul><li>Level of Crypto Ag is not indicative of severity of disease or a marker of response to therapy. Serum Crypto Ag can rule out clinical disease in HIV positive but not negative patients. </li></ul>Cryptococcal Meningitis
  78. 79. Cryptococcus neoformans
  79. 80. Toxoplasmic Encephalitis <ul><li>Clinical presentation includes focal neurologic deficit (50-89%), seizures (15-20%), fever (56%), generalized cerebral dysfunction, neuropsychiatric abnormalities. </li></ul><ul><li>Diagnosis is often presumptive based on characteristic lesions, clinical course, risk strata and positive serology. </li></ul>
  80. 81. <ul><li>Presumptive diagnosis is considered confirmed by tissue sample or response to TOXO therapy in appropriate time frame. </li></ul><ul><li>Patients should show clinical response -- neuro deficits, not necessarily fever or headache -- by day 5 (50%), day 7 (70%), and day 14 (90%). In contrast, patients with CNS lymphoma all had worsening of signs or symptoms by day 10 of therapy. </li></ul>Toxoplasmic Encephalitis
  81. 82. Cerebral toxoplasmosis
  82. 83. HIV- Complications at CD4 < 50mm 3 <ul><li>Infectious </li></ul><ul><ul><li>Disseminated CMV/Retinitis </li></ul></ul><ul><ul><li>Disseminated MAC </li></ul></ul><ul><li>Non-Infectious </li></ul><ul><ul><li>CNS Lymphoma </li></ul></ul>
  83. 84. Disseminated MAC <ul><li>Usually a sub-acute/chronic illness characterized by fevers, weight loss, diarrhea, night sweats, wasting </li></ul>
  84. 85. Mycobacterium avium-intracellulare
  85. 86. Questions

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