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  • This slide identifies in simplified form the stages in the HIV life cycle that are demonstrated as potential targets for inhibition. All currently available agents act on viral reverse transcriptase and protease, working inside the infected cell. Mechanisms necessary for cell entry are a new target in pharmaceutical development; it is anticipated that clinical management of patients who harbor virus resistant to RTIs and PIs will benefit from new agents such as FUZEON ™ .
  • This cartoon illustrates the pharmacokinetic rationale for dual protease inhibitor therapy. Single protease inhibitors may result in trough levels below the IC50 of the virus. Dual protease inhibitors increases the trough level but because the dose is lower, the peak concentration is lower. The net effect is low peaks equals less side effects while high troughs increases potency.
  • Papada:acumul submental i submandibular.
  • Slide: ART-Associated Abnormalities in Body Composition This slide illustrates typical clinical presentations of lipoatrophy and lipohypertrophy associated with ART toxicity. 1,2 References Carr A, Cooper DA. Images in clinical medicine. Lipodystrophy associated with an HIV-protease inhibitor. N Engl J Med . 1998;339:1296. Warren SM, May JW Jr. Lipodystrophy induced by antiretroviral therapy. N Engl J Med. 2005;352:63.
  • Another important factor is a patient’s CD4 count. In this cut of patients in the HOPS cohort you can see patients with CD4s > 350 at therapy initiation and who have maintained this level or above only have a 3% incidence of LA. Again if you are weighing the risk/benefits of therapy you should take into account the patient’s CD4, race and age before switching.
  • Rifamycins are essential drugs for the treatment oftuberculosis, but are also associated with frequent drinteractions with PIs and NNRTIs due to their effe as inducers of the hepatic cytochrome P-450 enzymesystem. Despite these interactions, rifamycin shouincluded in the p Among the rifamycins, rifampin is the most potent inducer. Unfortunately, of all available NNRTIs and PIs, rifampin may be used only with full dose ritonavir or with efavirenz. Rifampin cannot be used safely with ritonavir-boosted PI regimens. Rifabutin is recommended when used in combination with appropriate dose adjustments.
  • Drug Interactions Potential drug-drug and/or drug-food interactions should be taken into consideration when selecting an antiretroviral regimen. A thorough review of current medications can help in designing a regimen that minimizes undesirable interactions. Moreover, review of drug interaction potential should be undertaken when any new drug, including over-the-counter agents, is added to an existing antiretroviral combination. Tables 20-22b list significant drug interactions with different antiretroviral agents and suggested recommendations on contraindication, dose modification, and alternative agents. PI and NNRTI Drug Interactions Most drug interactions with antiretrovirals are mediated through inhibition or induction of hepatic drug metabolism [205] . All PIs and NNRTIs are metabolized in the liver by the cytochrome P450 (CYP) system, particularly by the CYP3A4 isoenzyme. The list of drugs that may have significant interactions with PIs or NNRTIs is extensive and continuously expanding. Some examples of these drugs include medications that are commonly prescribed in HIV patients for non-HIV medical conditions, such as lipid-lowering agents (statins), benzodiazepines, calcium channel blockers, immunosuppressants (such as cyclosporine and tacrolimus), anticonvulsants, rifamycins, erectile dysfunction agents (such as sildenafil), ergot derivatives, azole antifungals, macrolides, oral contraceptives, and methadone. Unapproved therapies, such as St. John’s Wort, can also cause negative interactions. All PIs are substrates of CYP3A4, so their metabolic rate may be altered in the presence of CYP inducers or inhibitors. Some PIs may also be inducers or inhibitors of other CYP isoenzymes and of P-glycoprotein. Tipranavir, for example, is a potent inducer of P-glycoprotein. The net effect of tipranavir/ritonavir on CYP3A in vivo appears to be enzyme inhibition. Thus, concentrations of drugs that are substrates for only CYP3A are likely to be increased if given with tipranavir/ritonavir. The net effect of tipranavir/ritonavir on a drug that is a substrate for both CYP3A and P-glycoprotein cannot be confidently predicted; significant decreases in saquinavir, amprenavir, and lopinavir concentrations have been observed in vivo when given with tipranavir/ritonavir. The NNRTIs are also substrates of CYP3A4 and can act as an inducer (nevirapine), an inhibitor (delavirdine), or a mixed inducer and inhibitor (efavirenz). Thus, these antiretroviral agents can interact with each other in multiple ways and with other drugs commonly prescribed for other concomitant diseases. For example, the use of a CYP3A4 substrate that has a narrow margin of safety in the presence of a potent CYP3A4 inhibitor may lead to markedly prolonged elimination half-life (t1/2) and toxic drug accumulation. Avoidance of concomitant use or dose reduction of the affected drug, with close monitoring for dose-related toxicities, may be warranted. The inhibitory effect of ritonavir (or delavirdine), however, can be beneficial when added to a PI, such as amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, or saquinavir [206] . Lower than therapeutic doses of ritonavir are commonly used in clinical practice as a pharmacokinetic enhancer to increase the trough concentration (Cmin) and prolong the half-life of the active PIs [207] . The higher Cmin allows for a greater Cmin: IC50 ratio, reducing the chance for development of drug resistance as a result of suboptimal drug exposure; the longer half-life allows for less frequent dosing, which may enhance medication adherence. Coadministration of PIs or NNRTIs with a potent CYP3A4 inducer, on the other hand, may lead to suboptimal drug concentrations and reduced therapeutic effects of the antiretroviral agents. These drug combinations should be avoided. If this is not possible, close monitoring of plasma HIV RNA, with or without antiretroviral dosage adjustment and therapeutic drug monitoring, may be warranted. For example, the rifamycins (rifampin, and, to a lesser extent rifabutin) are CYP3A4 inducers that can significantly reduce plasma concentrations of most PIs and NNRTIs [208, 209] . As rifabutin is a less potent inducer, it is generally considered a reasonable alternative to rifampin for the treatment of tuberculosis when it is used with a PI- or NNRTIbased regimen, despite wider experience with rifampin use [210] . Table 21 lists dosage recommendations for concomitant use of rifamycins and other CYP3A4 inducers and PIs and NNRTIs. NRTI Drug Interactions Unlike PIs and NNRTIs, NRTIs do not undergo hepatic transformation through the CYP metabolic pathway. Some, however, do have other routes of hepatic metabolism. Significant pharmacodynamic interactions of NRTIs and other drugs have been reported. They include increases in intracellular drug levels and toxicities when didanosine is used in combination with hydroxyurea [211, 212] or ribavirin [204] ; additive bone marrow suppressive effects of zidovudine and ganciclovir [213] ; and antagonism of intracellular phosphorylation with the combination of zidovudine and stavudine [179] . Pharmacokinetic interactions have also been reported. However, the mechanisms of some of these interactions are still unclear. Some such interactions include increases of didanosine concentrations in the presence of oral ganciclovir or tenofovir [214, 215] , and decreases in atazanavir concentration when it is co-administered with tenofovir [216, 217] . Table 21 lists significant interactions with NRTIs. CCR5 Antagonist Drug Interaction Maraviroc, the first FDA-approved CCR5 antagonist, is a substrate of CYP3A enzymes. As a consequence, the concentrations of maraviroc can be significantly increased in the presence of strong CYP3A inhibitors (such as ritonavir and other PIs, except for ritonavir boosted tipranavir) and are reduced when used with CYP3A inducers, such as efavirenz or rifampin. Dose adjustment is necessary when used in combination with these agents. (See Table 14a for dosage recommendations) Maraviroc is neither an inducer nor an inhibitor of CYP3A system. It does not alter the pharmacokinetic of the drugs evaluated in interaction studies to date. Fusion Inhibitor Drug Interaction The fusion inhibitor enfuvirtide is a 36 amino-acid peptide that does not enter human cells. It is expected to undergo catabolism to its constituent amino acids with subsequent recycling of the amino acids in the body pool. No clinically significant drug-drug interaction has been identified with enfuvirtide to date. Integrase Inhibitor Drug Interaction Raltegravir, an HIV integrase strand transfer inhibitor, is primarily eliminated by glucuronidation mediated by the enzyme UDP-glucuronosyltransferases (UGT1A1). Strong inducers of UGT1A1 enzymes (such as rifampin) can significantly reduce the concentration of raltegravir. The significance of this interaction is unknown; thus this combination should be used with caution or an alternative therapy should be considered. Other inducers of UGT1A1, such as efavirenz, tipranavir/ritonavir, or rifabutin, can also reduce raltegravir concentration. A pharmacokinetic interaction should be considered if optimal virologic response is not achieved when these drugs are used in combination. Efavirenz lowers indinavir levels by 31%, saquinavir levels by 62%, and amprenavir levels by 36%; dose alterations are required when these agents are combined. In the presence of boosted PIs, eg indinavir 800 BID + ritonavir 200 BID, the ritonavir effect is dominant, and no dose alteration is needed. Lopinavir + ritonavir levels are decreased by 28-35% in the presence of efavirenz and nevirapine; thus a dose escalation to 4 tablets BID of lopinavir/r (533/133 mg) is recommended. For drugs primarily or partly excreted by the kidneys, such as stavudine, lamivudine, zidovudine, didanosine, and zalcitabine, dose reduction is required in renal failure.
  • Candidal esophagitis. Manifestations of HIV infection extend throughout the gastrointestinal tract. Candidal infection of the oral cavity or thrush may be one of the first manifestations of immune compromise in an HIV-infected patient. Ahpthous ulcers of unclear etiology also occur. Some of these can be persistent, painful, and refractory to therapy, although some response to thalidomide has been seen. Esophagitis caused by Candida albicans is a frequent complication in AIDS patients and may develop as an extension of untreated oral thrush. The use of the effective oral prophylactic antifungal agent, fluconazole, has decreased the incidence of this opportunistic infection. Severe disease may also be treated by a short course of intravenous amphotericin B. The appearance of severe candidal esophagitis is distinctive as seen in this figure, but confirmation of the diagnosis depends on scrapings demonstrating the classic gram-positive candidal forms.
  • Pneumocystis jiroveckii (carinii ) pneumonia (PCP). P.carinii pneumonia is one of the opportunistic infections listed in the Centers for Disease Control and Prevention clinical definition of AIDS and the most frequently reported. However, it has also been recently described as developing during symptomatic, primary HIV-1 infection. These cases all occurred within 2 weeks of the onset of symptoms of primary HIV infection, and were associated with profound CD4 lymphopenia. All regained normal CD4 + counts and percentages within 4 months and had been followed for between 29 and 48 months after the episodes of PCP with no signs or symptoms of progression to AIDS.
  • Diagnosis of Pneumocystis carinii . Diagnosis of pneumocystosis is made by histologic demonstration of the organism. Stains such as methenamine silver, cresyl echt violet, and toluidine blue O selectively stain P. carinii cysts. Stains such as Giemsa stain the nuclei of all P. carinii developmental stages. Immunofluorescence and immunoperoxidase techniques also have been used. Induced sputum has been used to obtain specimens for analysis, but its success rate is highly variable. Bronchoalveolar lavage (BAL) has been the widely used diagnostic procedure, with a success rate of more than 90%. If BAL is unsuccessful, more invasive procedures ( eg , transbronchial biopsy, open lung biopsy) can be used. A , Methenamine silver stain of BAL fluid shows cysts of P. carinii , which often are characterized by the presence of parenthesis- or comma-shaped collapsed cell wall material. (×1000.)
  • Oral lesions of disseminated Histoplasma capsulatum infection. Disseminated H. capsulatum infection can present as discrete painful ulcers of the gastrointestinal tract mucosa , particularly on the tongue and buccal mucosa. This patient presented with fever and a painful ulcer on the lateral margin of the tongue. Biopsy of the lesion showed yeast forms compatible with histoplasmosis, and cultures grew H. capsulatum .
  • Cryptococcus neoformans . A , Bronchoalveolar lavage (BAL) fluid shows dense clusters of encapsulated yeast cells of C. neoformans . (Giemsa stain, × 1000.) The diagnosis of pulmonary cryptococcosis may be advanced by assaying for cryptococcal capsular polysaccharide antigen in BAL fluid, in which fluid is reacted to an endpoint titration with latex particles coated with anticryptococcal antibody. Confirmation of C. neoformans infection rests on isolation of the mycotic agent. B , Bronchoalveolar lavage fluid shows encapsulated yeast cells of C. neoformans within a pulmonary macrophage. This microscopic presentation may mimic that seen with Histoplasma capsulatum . However, C. neoformans is larger and more spherical than the ovoid yeast cells of H. capsulatum , and budding is less frequently observed. (Giemsa stain, × 1000.) C , Bronchoalveolar lavage fluid shows irregularly stained, sparsely encapsulated yeast cells of C. neoformans within pulmonary macrophages. (Gram stain, × 1000.) D , Gram-stained smear of a blood culture positive for C. neoformans showing markedly stippled, oval yeast cells. In the Gram staining technique, the capsule of C. neoformans may prevent the entry of crystal violet to the interior part of the yeast cell, thereby reducing complete gram-positive staining. Irregular staining and absence of a clearly stained yeast cell wall give the appearance of discrete clusters of gram-positive cocci. Assessment of blood culture medium for cryptococcal antigen and isolation of mycotic agent will confirm the diagnosis. (Gram stain, × 1000.) E , Scraping of gelatinous perisplenic exudate shows innumerable encapsulated yeast cells of C. neoformans . Note the presence of oval yeast cells of varying sizes, including sparsely encapsulated, infrequently budding cells. (Papanicolaou stain, × 1000.) Many C. neoformans cells were enmeshed in a viscous, glistening exudate covering the spleen. C. neoformans was also observed in lungs, brain, liver, and cerebrospinal fluid. F , Histologic section of lung shows dense clusters of oval yeast cells of C. neoformans . The cellular component of tissue has been almost completely supplanted by cryptococcal yeast cells. (Mucicarmine stain, × 1000.) G , A BAL specimen shows yeast cells with capsules delineated by cellular constituents in the specimen. (Phase contrast microscopy, × 1000.) India ink preparation of BAL fluid confirmed the presence of encapsulated yeast cells. H , In cerebrospinal fluid, C. neoformans is distinguished by a rim of deep pink-staining capsular material surrounding the yeast cells. The internal aspect of the yeast cells may show linear invaginations, which distinguish cryptococcal yeast cells from those of Candida species. Single, more densely stained bodies near the periphery of the cell may also be discerned. (Giemsa stain, × 1000.) I , Methenamine silver staining of a lung biopsy specimen shows yeast cells of C. neoformans within a pulmonary macrophage. Rounded yeast cells with a suggestion of central folding and deep-staining oval bodies aid distinction from H. capsulatum . (Methenamine silver stain, × 1000.)
  • Cerebral toxoplasmosis. Coronal brain magnetic resonance imaging reveals multiple subtentorial and supratentorial contrast-enhancing toxoplasma lesions. Central nervous system toxoplasmosis is the most common brain mass lesion in AIDS and generally represent the reactivation of latent infection . Empirical therapy with sulfadiazine, pyrimethamine, or clindamycin generally results in rapid clinical and radiologic improvement.
  • Myocbacterium avium-intracellulare . A , Histologic section of liver from a patient with disseminated M. avium-intracellulare infection shows dense clumps of acid-fast bacilli. (Kinyoun stain, × 1000.)
  • Transcript

    • 1. Retroviral Review Wayne Duffus, MD, PhD May 25 th 2010
    • 2. Human Immunodeficiency Virus Type-1 gp120 gp41 p24 Integrase Reverse Transcriptase ssRNA+ Protease
    • 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. 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. FDA-Approved Antiretroviral Drugs Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Viramune ® NVP Nevirapine Sustiva ® EFV Efavirenz Rescriptor ® DLV Delavirdine Trade Name Abbreviat. Generic
    • 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. Approved Antiretrovirals
    • 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. HIV Treatment: Then and Now
    • 10. The Choice of the NRTI Backbone
      • Prediction
      • Virtually all dual-NRTI backbones prescribed for initial therapy will consist of 1 of 3 fixed-dose coformulations:
      AZT/3TC ABC/3TC TDF/FTC Combivir Epzicom Truvada
    • 11. Consideration for Initial Regimen NRTI PI NRTI
      • CNS side effects
      • Hepatotoxicity/rash
      • K103N confers cross-resistance
      • GI side effects
      • Potential for cross-resistance
      • Differences in tolerability, potency, and safety between agents
      • Simple regimen
      • Preserves PI class
      • Multiple mutations for resistance target both RT and PI genes (except NFV)
      • Preserves NNRTIs
      • Trials with clinical endpoints
      Pros EFV + FTC +TDF LPV/r + 3TC + ZDV Example NRTI NRTI NNRTI
    • 12. Rationale For Combination Antiretroviral Therapy
      • Synergistic or additive effects
      • Prevent emergence of resistance
      • Attack the virus at different points in the lifecycle.
    • 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. 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. 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. Pharmacokinetic rationale for dual protease inhibitor therapy Effective Concentration Single PI Dual PI Kempf, Medcapse, 1999
    • 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. Boosted vs Non-Boosted ATV Viral and Immunologic Control – Mean Value (95% CI) – 52 Week Data Horberg, et al., IAS 2007; WEPEB025.
      • Observational cohort analysis of ATV/RTV and ATV non-use at Kaiser Permanente and Group Health Cooperative from 2003-2006
      • Differences in outcome and safety of ritonavir-boosted atazanavir (ATV/RTV) compared to non-boosted atazanavir
      +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. Adverse Effects: NNRTIs
      • All NNRTIs:
        • Rash, including Stevens-Johnson syndrome
        • Drug-drug interactions
      • EFV
        • Neuropsychiatric
        • Teratogenic in nonhuman primates + cases of neural tube defects in human infants after first trimester exposure
      • NVP
        • Higher rate of rash
        • Hepatotoxicity (may be severe and life-threatening; risk higher in patients with higher CD4 counts at the time they start NVP)
    • 20. Adverse Effects: PIs
      • All PIs:
        • Hyperlipidemia
        • Insulin resistance and diabetes
        • Lipodystrophy
        • Elevated LFTs
        • Possibility of increased bleeding risk for hemophiliacs
        • Drug-drug interactions
    • 21. Adverse Effects: PIs (2)
      • ATV
        • Hyperbilirubinemia
        • PR prolongation
        • Nephrolithiasis
      • DRV
        • Rash
        • Liver toxicity
      • FPV
        • GI intolerance
        • Rash
        • Possible increased risk of MI
    • 22. Adverse Effects: PIs (3)
      • IDV
        • Nephrolithiasis
        • GI intolerance
      • LPV/r
        • GI intolerance
        • Possible increased risk of MI
        • PR and QT prolongation
      • NFV
        • Diarrhea
    • 23. Adverse Effects: PIs (4)
      • RTV
        • GI intolerance
        • Hepatitis
      • SQV
        • GI intolerance
      • TPV
        • GI intolerance
        • Rash
        • Hyperlipidemia
        • Liver toxicity
        • Cases of intracranial hemorrhage
    • 24. Adverse Effects: II
      • RAL
        • Nausea
        • Headache
        • Diarrhea
        • CPK elevation
    • 25. Adverse Effects: NRTIs
      • All NRTIs:
        • Lactic acidosis and hepatic steatosis (highest incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC)
        • Lipodystrophy (higher incidence with d4T)
    • 26. Adverse Effects: NRTIs (2)
      • ABC
        • HSR*
        • Rash
        • Possible ↑ risk of MI
      • ddI
        • GI intolerance
        • Peripheral neuropathy
        • Pancreatitis
        • Possible noncirrhotic portal hypertension
      * Screen for HLA-B*5709 before treatment with ABC; ABC should not be given to patients who test positive for HLA-B*5709.
    • 27. Adverse Effects: NRTIs (3)
      • d4T
        • Peripheral neuropathy
        • Pancreatitis
      • TDF
        • Renal impairment
        • Possible decrease in bone mineral density
        • Headache
        • GI intolerance
      • ZDV
        • Headache
        • GI intolerance
        • Bone marrow suppression
    • 28. Adverse Effects: Fusion Inhibitor
      • ENF
        • Injection-site reactions
        • HSR
        • Increased risk of bacterial pneumonia
    • 29. Adverse Effects: CCR5 Antagonist
      • MVC
        • Drug-drug interactions
        • Abdominal pain
        • Upper respiratory tract infections
        • Cough
        • Hepatotoxicity
        • Musculoskeletal symptoms
        • Rash
        • Orthostatic hypotension
    • 30. Face and neck Buffalo neck
    • 31. Liposuction – buffalo hump
    • 32. Lipohypertrophy
      • Adiposity
        • Abdominal obesity
        • “ Buffalo hump”
        • Enlarged breasts
        • Gynecomastia
    • 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. Lipoatrophy
      • Loss of fat
        • Cheeks
        • Limbs
        • “ arm cabling”
        • Buttocks
    • 35. Wasting - Face and neck Centrofacial and temporal atrophy
    • 36. Lipodystrophy May Decrease Adherence
      • Adherence rate according to time since self-reported morphological alterations
      • Definition of treatment adherence: Having missed one or more doses of antiretroviral drugs during the preceding week
      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. 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. 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. 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. 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. Lipoatrophy is Associated with Insulin Resistance
      • HIV-infected patients with fat redistribution have significantly less insulin sensitivity than controls
      • Percentage peripheral fat correlates positively with insulin sensitivity
      * 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. Drug Interactions with ARVs
      • Certain ARVs, particularly PIs and NNRTIs, have significant drug interactions with other ARVs and with other medications: check for interactions before prescribing
    • 43. Drug Interactions with ARVs: Dose Modification or Cautious Use
      • Lipid-lowering agents
      • Antimycobacterials, especially rifampin*
      • Psychotropics - midazolam, triazolam
      • Ergot alkaloids
      • Antihistamines – astemizole
      • Anticonvulsants
      *Of NNRTIs and PIs, rifampin may be used only with full-dose ritonavir or with efavirenz
    • 44. Drug Interactions with ARVs: Dose Modification or Cautious Use
      • Oral contraceptives (may require second method)
      • Methadone
      • Erectile dysfunction agents
      • Herbs - St. John’s wort
    • 45. ARV-ARV Interactions: Dose Modification or Cautious Use
      • Efavirenz, nevirapine, or etravirine with PIs
      • Atazanavir + tenofovir
      • Didanosine + tenofovir
      • Didanosine + stavudine
      • Maraviroc + many PIs
      • Maraviroc + efavirenz or etravirine
    • 46. Overlapping Toxicities
      • Peripheral neuropathy
        • didanosine, isoniazid, stavudine, zalcitabine
      • Bone marrow suppression
        • cidofovir, dapsone, hydroxyurea, ribavirin, TMP-SMZ, zidovudine
      • Hepatotoxicity
        • nevirapine, efavirenz, isoniazid, macrolides, maraviroc, NRTIs, PIs
      • Pancreatitis
        • didanosine, pentamidine, ritonavir, stavudine, TMP-SMZ
    • 47. 2009 DHHS Guidelines: Timing of ART Initiation in Special Patient Populations
    • 48. 2009 DHHS Guidelines: ART Initiation for Patients With HIVAN (1)
      • HIV-associated nephropathy (HIVAN)
        • HIVAN is the most frequent cause of chronic renal failure in persons living with HIV infection
        • HIVAN occurs almost exclusively in black patients and can occur at any CD4 count
        • Ongoing viral replication appears to be directly involved in renal injury
      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. Accessed December 1, 2009.
    • 49. 2009 DHHS Guidelines: ART Initiation for Patients With HIVAN (2)
      • HIV-associated nephropathy (HIVAN)
        • HIVAN is extremely uncommon in virologically suppressed patients
        • Antiretroviral therapy for individuals with HIVAN has been associated with both preserved renal function and prolonged survival
        • ART should be initiated for patients with a diagnosis of HIVAN regardless of CD4 cell count
      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. Accessed December 1, 2009.
    • 50. 2009 DHHS Guidelines: Risk of CVD and Persistent Immune Activation (1)
      • Cardiovascular disease (CVD)
        • A major cause of mortality in HIV-infected patients
        • Patients with HIV have higher levels of markers of inflammation and endothelial dysfunction than HIV-uninfected controls
        • Early control of HIV replication with antiretroviral therapy can be used as a strategy to reduce cardiovascular disease risk
      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. Accessed December 1, 2009.
    • 51. 2009 DHHS Guidelines: Risk of CVD and Persistent Immune Activation (2)
      • T-cell activation and inflammation
        • 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
        • Earlier treatment may result in less residual immunological perturbations on therapy, and hence less risk for AIDS- and non-AIDS-related complications
      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. Accessed December 1, 2009.
    • 52. 2009 DHHS Guidelines: Treatment Recommendations for HBV/HIV Coinfected Patients
      • If neither HIV nor HBV infection requires treatment:
        • Monitor the progression of both infections
      • If treatment becomes necessary for either infection, follow the guidelines listed in the scenarios below
        • If treatment is needed for HIV but not for HBV
          • Patients who need treatment for HIV infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses
          • 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
      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. Accessed December 1, 2009.
    • 53. 2009 DHHS Guidelines: Treatment Recommendations for HBV/HIV Coinfected Patients
      • If treatment becomes necessary for either infection, follow the guidelines listed in the scenarios below:
        • If treatment for HBV is needed
          • 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
            • Management of HIV should be continued with a combination regimen to provide maximal suppression
        • If treating only HBV
          • 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
      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. Accessed December 1, 2009.
    • 54. 2009 DHHS Guidelines: Treatment Considerations for HCV/HIV Coinfected Patients
      • 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 )
      • ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation
      • Concurrent treatment of both HIV and HCV is feasible but may be complicated by pill burden, drug toxicities, and drug interactions
        • Caution should be used with certain antivirals
      • Eradication of HCV infection may decrease the likelihood of drug-induced liver injury following ART
      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. Accessed December 1, 2009.
    • 55. Natural History Course of HIV
    • 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.
      • HIV-infection and at least one of the following:
      AIDS Conditions
        • Candidiasis
        • Coccidioidomycosis
        • Cryptococcosis
        • Cryptosporidiosis
        • Cytomegalovirus
        • HIV-encephalopathy
        • Herpes simplex
        • Histoplasmosis
        • Isosporiasis
        • Kaposi’s sarcoma
        • Lymphoma
        • Mycobacterium
        • Pneumocystis
        • Recurrent pneumonia
        • Progressive multifocal leukoencephalopathy
        • Toxoplasma
        • Wasting syndrome
    • 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. Summary of OIs for Which Prevention Is Recommended
      • Primary Prophylaxis
      • Pneumocystis jiroveci pneumonia (PCP)*
      • Tuberculosis*
      • Toxoplasmosis*
      • Mycobacterium avium complex (MAC)*
      • Varicella-zoster*
      • S pneumoniae infections †
      • Hepatitis A and B †
      • Influenza †
      * Standard of care † Generally recommended
    • 60. Summary of OIs for Which Prevention Is Recommended
      • Secondary Prophylaxis
      • Pneumocystis jiroveci pneumonia (PCP)*
      • Toxoplasmosis*
      • Mycobacterium avium complex (MAC)*
      • Cryptococcosis*
      • Histoplasmosis*
      • Coccidioidomycosis*
      • Cytomegalovirus*
      • Salmonella bacteremia †
      * Standard of care † Generally recommended
    • 61. OIs for Which Prevention Is Not Routinely Indicated
      • Primary Prophylaxis
      • Bacteria (neutropenia) †
      • Cryptococcosis †
      • Histoplasmosis †
      • Cytomegalovirus †
      • Secondary Prophylaxis
      • Herpes simplex virus §
      • Candida §
      † Evidence for efficacy but not routinely indicated § Recommended only if subsequent episodes are frequent or severe
    • 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. Prophylaxis of opportunistic infections
      • CD4<200
        • PCP prophylaxis: bactrim, dapsone, pentamidine, atovoaquone, primaquine + clindamycin
      • CD4<50
        • MAC prophylaxis: azithromycin or clarithromycin
    • 64. HIV- Complications at CD4>500mm 3
      • Infectious
        • Acute retroviral syndrome
        • Candida vaginitis
      • Other
        • Generalized LAD
        • Guillain-Barre (very rare)
        • Vague constitutional symptoms
    • 65. HIV- Complications at CD4 200-500mm 3
      • Infectious
        • Pneumococcal pneumonia
        • TB
        • Herpes zoster
        • Kaposis sarcoma
        • Oral hairy leukoplakia (OHL)
        • Oropharyngeal candidiasis (thrush)
      • Non-Infectious
        • Cervical Ca
        • Lymphomas
        • ITP (Immune thrombocytopenic purpura)
    • 66. Oropharyngeal Candidasis
      • Thrush limited to oropharynx
      • Esophagitis more serious usually CD4<100
        • Odynophagia
        • Chest pain
      • Other causes of esophagitis
        • CMV (usually CD4<50)
        • Idiopathic ulceration (CD4<50)
    • 67.  
    • 68. Candidal esophagitis
    • 69. HIV- Complications at CD4 < 200mm 3
      • Infectious
        • PCP
        • Histoplasmosis (other endemic fungi)
        • Miliary TB
        • PML
      • Non-Infectious
        • Wasting
        • Peripheral neuropathy
        • Cardiomyopathy
        • Dementia
    • 70. Pneumocystis carinii pneumonia
      • Variable presentations
      • Pneumocystis carinii changed to Pneumocystis jiroveci
      • 20-40% in patients not on HIV rx
        • Usually subacute presentation of dry cough, dyspnea
        • CXR typically reveals interstitial infiltrates
          • May have lobar consolidation
          • Pneumothorax in severe cases
        • Treatment/ prophylaxis
    • 71. Pneumocystis jiroveckii (carinii) pneumonia
    • 72. Diagnosis of Pneumocystis carinii
    • 73. Histoplasma
      • Mississippi River Delta
      • Wide spectrum of illness from acute sepsis like syndrome to acute pneumonia to cutaneous involvement
    • 74. Oral lesions of disseminated Histoplasma capsulatum infection
    • 75. HIV- Complications at CD4 < 100mm 3
      • Infectious
        • Disseminated HSV
        • Toxoplasmosis
        • Candida esophagitis
        • Cryptosporidiosis, microsporidiosis, isospora
        • Cryptococcal disease
    • 76. Cryptococcal Meningitis
      • 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.
      • C. neoformans produces no toxins and evokes little inflammatory response. The main virulence factor is the capsule.
    • 77. Cryptococcal Meningitis
      • Clinical manifestations:
        • headache (70-90%), fever (60-80%), malaise (76%), stiff neck (20-30%), photophobia (6-18%), seizures (5-10%) nausea.
      • Average duration of symptoms is 30 days.
      • Predictors of poor outcomes are altered mental status, increased opening pressure, WBC<20 cells/mm3.
    • 78.
      • Diagnosis made by CSF examination with india ink (74-88%), Crypto Ag serum/CSF (99%), CSF culture.
      • 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.
      Cryptococcal Meningitis
    • 79. Cryptococcus neoformans
    • 80. Toxoplasmic Encephalitis
      • Clinical presentation includes focal neurologic deficit (50-89%), seizures (15-20%), fever (56%), generalized cerebral dysfunction, neuropsychiatric abnormalities.
      • Diagnosis is often presumptive based on characteristic lesions, clinical course, risk strata and positive serology.
    • 81.
      • Presumptive diagnosis is considered confirmed by tissue sample or response to TOXO therapy in appropriate time frame.
      • 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.
      Toxoplasmic Encephalitis
    • 82. Cerebral toxoplasmosis
    • 83. HIV- Complications at CD4 < 50mm 3
      • Infectious
        • Disseminated CMV/Retinitis
        • Disseminated MAC
      • Non-Infectious
        • CNS Lymphoma
    • 84. Disseminated MAC
      • Usually a sub-acute/chronic illness characterized by fevers, weight loss, diarrhea, night sweats, wasting
    • 85. Mycobacterium avium-intracellulare
    • 86. Questions