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D3 Retroviral Review Duffus
- 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
- 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
- 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
- 30. Face and neck Buffalo neck
- 31. Liposuction – buffalo hump
- 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.
- 35. Wasting - Face and neck Centrofacial and temporal atrophy
- 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.
- 47. 2009 DHHS Guidelines: Timing of ART Initiation in Special Patient Populations
- 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
- 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
- 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
- 71. Pneumocystis jiroveckii (carinii) pneumonia
- 72. Diagnosis of Pneumocystis carinii
- 74. Oral lesions of disseminated Histoplasma capsulatum infection
- 86. Questions
Notas do Editor
- 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.)