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185 Cards in this Set
- Front
- Back
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Main cause of death in HIV?
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HIV does not produce most of the morbidity and mortality
Opportunistic infections (OIs) - caused by organsims common in the environment responsible for 90% of deaths |
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What do OIs represent?
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OIs - represent reactivation of quiescent infections and manifest with the loss of cell - mediated immunity
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how are OIs related to CD4 lymphocytes?
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The development of certain OIs is directly or indirectly related to the level of CD4 lymphocytes and can be predicted
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what happens to viral titer/CD4 count as HIV progresses?
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0-12 wks: Acute HIV syndrome, peak then decline of virus
12wks-9yrs: apparent latency of virus 8-9 yrs: constitutional sx appear 8-11 yrs: OIs, high viral load, low/no CD4, death if untreated |
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Clinically asymptomatic Phase of HIV
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May last for approximately 10 years
This is not a period of virological and immunological latency Levels of whole virus in the blood are low but levels of HIV RNA in plasma are high Viral replication and diversification are occurring at extremely high rates CD4 cell counts gradually fall over time Immune system weakens as viral load increases |
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Symptomatic AIDS
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Viral load is extremely high - possibly one million copies / ml
CD4 counts usually below 200 cells/mm3 and may fall to zero Early clinical symptoms may include lymphadenopathy, oral hairy leukoplakia and persistent thrush Symptoms of very advanced infection include Kaposi’s sarcoma, PCP, toxoplasmosis |
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protozoal OIs of interest
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PCP(now fungus)
toxoplasmosis |
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viral OIs of interest
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CMV
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what is the most common life threatening OI assoc. with AIDS?
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PCP (pneumocystic Carinii Pneumonia)
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Features of PCP
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The most common life-threatening opportunistic infections in patients with AIDS
Classified as a protozoan and fungal Genomic sequences suggest it is fungal Predilection for mammalian lung Exposure widespread - by age 2-3 y 80% population have serum antibodies Profound disturbance of T - helper function and alveolar macrophages leaves subject vulnerable The advent of effective prophylaxis for PCP has decreased the relative incidence of PCP - but not eliminated |
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Main cause of death in HIV?
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HIV does not produce most of the morbidity and mortality
Opportunistic infections (OIs) - caused by organsims common in the environment responsible for 90% of deaths |
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What do OIs represent?
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OIs - represent reactivation of quiescent infections and manifest with the loss of cell - mediated immunity
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how are OIs related to CD4 lymphocytes?
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The development of certain OIs is directly or indirectly related to the level of CD4 lymphocytes and can be predicted
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what happens to viral titer/CD4 count as HIV progresses?
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0-12 wks: Acute HIV syndrome, peak then decline of virus
12wks-9yrs: apparent latency of virus 8-9 yrs: constitutional sx appear 8-11 yrs: OIs, high viral load, low/no CD4, death if untreated |
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Clinically asymptomatic Phase of HIV
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May last for approximately 10 years
This is not a period of virological and immunological latency Levels of whole virus in the blood are low but levels of HIV RNA in plasma are high Viral replication and diversification are occurring at extremely high rates CD4 cell counts gradually fall over time Immune system weakens as viral load increases |
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clinical presentation of PCP
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Onset may be rapid but can be seen to develop over a period of weeks or even months
Earliest symptom - unproductive cough followed by dyspnea on exertion (DOE) Gradually symptoms worsen - cough becomes productive of purulent sputum, dyspnea becomes apparent at rest and systemic symptoms of fever and malaise appear |
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earliest symptom of PCP
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unproductive cough
then dyspnea on exertion |
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lab findings for PCP
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Lung Exam - may be normal or may demonstrate diffuse or localized crackles
Oxygen saturation - desaturation of arterial blood with oxygen by pulse oximetry ( especially evident with exercise) Chest X Ray - normal at start but in advanced cases it shows diffuse, perihilar alveolar-type opacity. In some cases CXR shows non-specific localized consolidation |
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definitive diagnosis of PCP
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Definitive Diagnosis - morphologic demonstration of P. jiroveci organisms in biological samples, such as expectorated sputum, bronchoalveolar lavage fluid, or lung biopsy
Sputum induction - lacks high sensitivity Bronchoscopy - diagnostic procedure of choice; broncho-alveolar lavage > 90% sensitivity Lung biopsy - invasive |
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what is the diagnostic procedure of choice for PCP
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bronchoscopy-bronchoalveolar lavage
>90% sensitivity |
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calculate DA-aO2 gradient for PCP severity
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DA-aO2 =
[150 - (PCO2/0.8)] - PO2 |
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PCP severity:
mild dx |
PO2 > 70 mm Hg
(DA-aO2 < 35 mm Hg on room air ABG) |
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PCP severity:
moderate dx |
PO2 < 70 mm Hg
(DA-aO2 = 35 - 45 mm Hg on room air ABG) |
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PCP severity:
severe dx |
DA-aO2 > 45 mm Hg on a room air ABG
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if pt. is on supplemental oxygen can you calculate severity of PCP?
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no, must use room air ABG
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PCP Treatment:
Standard of Care |
Trimethoprim / sulfamethoxazole
15-20 mg/kg/day based on the trimethoprim component administered in divided doses q 6 - 8h Administered IV or PO with double strength tablets 160 mg trimethoprim and 800 mg sulfamethoxazole eg. 2 DS tablets tid Duration - 21 days results in better long term results |
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mg/kg/day dosing for Bactrim for PCP treatmen
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15-20 mg/kg/day
(divided q 6-8 hrs) PO: 2 DS TMP/SMA tablets TID(160/800) |
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PCP treatment:
alternative tx, SEVERE PCP |
Pentamidine isethionate - 4mg/kg once daily
IV over at least 60 minutes ( may also be administered by IM injection - not recommended) |
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PCP treatment:
alternative tx, mild/mod PCP |
Trimetrexate with leucovorin - Trimetrexate: 45 mg/m2 BSA or 1.2 mg/kg daily with leucovorin 20 mg/m2 BSA or 0.5 mg/kg IV or PO q6h (continue leucovorin for 3 days after trimetrexate dc’d)
Administered IV with oral leucovorin (5,10, 15 and 25 mg tablets) or... Dapsone and trimethoprim - Dapsone 100mg/day; trimethoprim 15 mg/kg/day administered orally, divided every 8h or... Clindamycin and Primaquine - clindamycin: IV = 600-900 mg q6-8h, PO = 300-450 mg q6-8h ; primaquine: PO only = 15 - 30 mg base daily clindamycin = IV or oral capsules (150 and 300 mg) primaquine = oral tablets = 15 mg of base/tablet or... Atovaquone - 750 mg (5 ml) bid with food oral suspension - 750mg/5 ml |
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which give leucovorin with trimetrexate?
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to prevent the decrease in folate that occurs with trimetrexate (to decrease bone marrow suppression)
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when are corticosteroids used for PCP treatment?
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adjunctive therapy only
moderate and severe PCP |
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adjunctive prednisone for PCP treatment
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40 mg bid for 5 days, then
20 mg bid for 5 days, then 20 mg qd for 11 days (or until therapy complete) along with 21 days treatment length |
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IV methylprednisolone dose for adjunctive PCP treatment
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75% prednisone dose
Prednison dosing: 40 mg bid for 5 days, then 20 mg bid for 5 days, then 20 mg qd for 11 days (or until therapy complete) |
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management during PCP thearpy
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Repeated ABGs
CXRs - improvement in CXR lags behind clinical improvement Therapeutic failure: deterioration or no improvement in clinical status on therapy change therapy if oral therapy - consider malabsorption or compliance patients who fail have increased mortality even with therapy changed |
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what is considered PCP treatment failure?
How to manage? |
deterioration or no improvement in clinical status on therapy
Management: 1. change therapy 2. if oral therapy - consider malabsorption or compliance 3. patients who fail have increased mortality even with therapy changed |
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Trimethoprim/sulfamethoxazole drug toxicities
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rash > 50% - resolves with dc of drug and symptomatic treatment
bone marrow suppression - monitor CBC & BUN/ Cr ( since renally cleared) |
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pentamidine drug toxicities
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acute hypoglycemia - related to infusion & may occur anytime
nephrotoxicity - monitor BUN/Cr, Mg, Ca, PO4 - replace if necessary hepatotoxicity - monitor LFTs pancreatitis - monitor patients with new abdominal pain, hypoglycemia prolongation QT interval with ventricular arrhythmias - may be related to abnormal levels Mg, Ca, PO4 |
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trimetrexate with leucovorin drug toxicities
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bone marrow suppression - especially thrombocytopenia - monitor CBC
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what can you do if bone marrow suppression occurs with trimetrexate?
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leucovorin dose can be doubled for toxicity and continue for 3 days after treatment
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dapsone and trimethoprim drug toxicities
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hemolytic anemia in G6PD deficient individuals ( rare in US)
bone marrow suppression - monitor CBC |
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clindamycin and primaquine drug toxicities
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GI intolerance and C. difficile diarrhea
allergic reactions - rash develops 7-10 days after start tx bone marrow suppression - CBC hepatotoxicity - can occurs late 3rd week of tx - LFTs nephrotoxicity - can occur late in 3rd week of tx - BUN/Crq |
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atovaquone drug toxicities
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low toxicity profile
poor enteric absorption - treatment failure for mild and moderate disease hepatotoxicity - rare - LFTs |
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Primary PCP prophylaxis indicated
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patients with CD4 < 200 cells/microliter
or presence of oral candidiasis |
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secondary PCP prophylaxis indicated
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anyone with a previous episode of acute PCP - begin within 2 weeks of acute therapy ending
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PCP prophylaxis
preferred treatment |
trimethoprim-sulfamethoxazole
1 DS tablet daily (1 SS po daily or 1 DS po TIW can be given but patient MUST be compliant or can have breakthrouh PCP) |
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Discontinuing primary prophylaxis for PCP
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in patients who have responded to HAART with increase in CD4 > 200 for at least 3 months
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discontinuing secondary prophylaxis for PCP
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in patients who have responded to HAART with increase in CD4 > 200 for at least 3 months
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organism that cuases toxoplasmosis?
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toxoplasma gondii
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features of toxoplasmosis?
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Cats and other felines definitive hosts
Humans and other mammals can be infected by ingestion of oocysts in cat feces tissue cysts from infected ( raw or undercooked meat) in utero Reactivation represents most common pathogenesis of disease Clinically apparent infection in CNS seen exclusively in immunocompromised hosts |
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CD4 count for toxoplasma encephalitis
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CD4 < 100 and usually < 50
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clinical presentation of toxoplasma encephalitis
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altered mental status - progress to coma
headache focal neurological deficits seizures occur in 1/3 patients SIADH |
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multifocal mass lesions of toxoplasmosis encephalitis
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may be granulomatous or necrotizing
occur at any part of CNS - most commonly in basal ganglia or the corticomedullary junction of cerebrum |
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definitive diagnosis toxoplamosis
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Definitive diagnosis - brain biopsy
tachyzoites, bradycysts may be seen with special staining |
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methods for diagnosing toxoplasmosis
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Brain imaging
MRI (preferred) or CT with contrast multiple ring - enhancing space occupying lesions Serologies serum Toxoplasma IgG IFA is positive in > 95% of TE cases - indicates current or previous infection. If negative - toxo very unlikely HIV patients screened for toxo IgG with diagnosis of HIV if positive > 45% chance of reactivating toxoplasma with decreased CD4 |
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acute treatment of toxoplasmosis
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Sulfadiazine 1000 mg (< 60 kg) or 1500 mg (>60 kg) po q6h + pyrimethamine 200mg po x1 then 50 mg (<60kg) or 75 mg (> 60 kg) po daily + leucovorin 10 – 20 mg po daily (can increase to > 50 mg) continue treatment for at least 6 weeks - until the lesions have resolved or stabilized at a reduced size
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chronic treatment of toxoplasmosis
(indefinite 2ndary prophylaxis) |
sulfadiazine 500 -1000 mg po QID + pyrimethamine 25-50 mg po daily + leucovorin 10-25 mg po daily} – first choice
clindamycin 300-450 mg po q6-8h + pyrimethamine 25-50 mg po daily + leucovorin 10-25 mg po daily – second choice atovaquone 750 mg po q6-12h with or without pyrimethamine 25 mg po daily + leucovorin 10 mg po daily - second choice |
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alternative treatment for toxoplasmosis
(if allergy) |
Clindamycin 600 mg IV/PO q6h + pyrimethamine 200 mg ( 1st day) 50-75 mg/day thereafter + leucovorin 10 – 20 mg/day
Atovaquone 1500mg po bid with meals + sulfadiazine 1000-1500 mg po q6h Atovaquone 1500 mg po bid with meals Pyrimethamine as above + leucovorin as above + azithromycin 900-1200mg po daily |
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adjunctive therapy for toxoplasmosis: steroids
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10 mg IV followed by 4mg q6h
for mass effect attributed to focal lesions or associated edema can switch to oral when patient improved to take po discontinue as soon as clinically feasible |
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adjunctive thearpy for toxoplasmosis: anticonvulsants
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Should be administered to patients with a history of seizures, or if pt. had a seizure for current infection
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sulfadiazine drug toxicities
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allergic reactions - rash, fever, occassionally SJS
GI intolerance nephrolithiasis interstitial nephritis toxic hepatitis toxic encephalopathy |
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pyrimethamine drug toxicities
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interferes with folate metabolism - megaloblastic anemia
bone-marrow suppression GI intolerance |
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clindamycin drug toxicities
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GI intolerance
C. difficile colitis fever, rash |
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primary prophylaxis for toxoplasmosis
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AIDS patients with CD4 < 100
Sulfamethoxazole / trimethoprim 1 DS tablet qd * Dapsone + pyrimethamine Atovaquone Atovaquone + pyrimethamine |
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secondary prophylaxis for toxoplasmosis
(same as chronic treatment) |
sulfadiazine 500 -1000 mg po QID + pyrimethamine 25-50 mg po daily + leucovorin 10-25 mg po daily} – first choice
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what is CMV?
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cytamegalovirus
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features of CMV?
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Herpes group DNA virus
Infection with CMV is ubiquitous Latent CMV infection is prevalent in > 98% homosexual men and ~ 75% heterosexuals with HIV Nearly all patients with advanced HIV and latent CMV will have at least intermittent reactivation of CMV with viral shedding in urine, semen, blood, or respiratory secretions The cummulative incidence of sight- or life-threatening CMV end-organ disease has been only 20 - 40 % in AIDS patients Approximately 90% of patients with CMV - end organ disease have retinitis, 15 - 20% have GI disease, pulmonary and neurologic disease 1- 2%. |
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organ complications for CMV
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retinitis
GI dx(esophagitis, colitis) neurological dx(polyradiculopathy, encephalitis) pulomonary dx(pneumonitis) |
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CMV retinitis clinical presentation
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painless, appearance of “floaters” that move across the visual field and result from necrotic retinal debris moving through the vitreous humor
near the macula may complain of visual-field deficits optic nerve general loss of visual acuity in involved eye begins unilaterally but may progress to both eyes untreated - leads to blindness |
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CMV GI disease clinical presentation
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Esophagitis
most common manifestations of CMV GI disease odynophagia substernal pain Colitis diarrhea hematochezia abdominal pain less common - painful gastric, rectal, anal or oral ulcers |
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CMV neurological disease clinical presentaiton
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Polyradiculopathy
Lower extremity weakness and areflexia Severe cases - anal and bladder tone reduced Encephalitis altered sensorium and fever Occurs usually in patients already with CMV retinitis or GI disease |
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CMV pneumonitis clinical presentation
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rare complication of AIDS
nonspecific signs and symptoms hypoxemia fever diffuse interstitial infiltrates on CXR more indolent than bacterial pneumonia or PCP |
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diagnosis CMV retinitis
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Presence of white opacified retinal lesions often associated with hemorrhage
Indirect opthalmoscopy permits visualization of the entire retina Must be performed by a trained opthalmologist Location important for prognosis zone 1- if lesions located within 2 disc diameters of the fovea or within 1 disc diameter of the optic nerve head zone 2 - located between zone 1 and the equator of the globe zone 3 - if located anterior to the equator |
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ZONE/location prognostic factors for CMV retinitis
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zone 1- if lesions located within 2 disc diameters of the fovea or within 1 disc diameter of the optic nerve head
zone 2 - located between zone 1 and the equator of the globe zone 3 - if located anterior to the equator 1-worst prognosis 3-peripheral, better prognosis |
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1st line CMV retinitis treatment
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valganciclovir
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valganciclovir
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Approved for CMV Retinitis in AIDS patients
Being studied for other forms of CMV disease and in other immunocompromised patient populations Prodrug of ganciclovir Significantly improved oral bioavailability (60%) compared to oral ganciclovir (6%) Plasma profile is comparable to IV ganciclovir |
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2nd line agents for CMV retinititis treatment
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ganciclovir
foscarnet |
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ganciclovir
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MOA- phosphorylated to a substrate which competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase resulting in inhibition of viral DNA synthesis
differs from acyclovir by only a single hydroxyl side chain 30 - 50 times more active than acyclovir in vitro against CMV The use of ganciclovir has been divided into 2 phases Induction therapy for 2-3 weeks Maintenance therapy for indefinite period (1st line for other CMV manifestations other than retinitis) |
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foscarnet
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For resistant CMV or intolerance to ganciclovir
( i.e. thrombocytopenia with plt < 20,000) MOA - pyrophosphate analogue which acts as a noncompetitive inhibitor of many viral RNA and DNA polymerases as well as HIV reverse transcriptase Administer in 2 phases Induction: x 2- 3 weeks Maintenance: indefinite period |
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third line option for CMV retinitis therapy
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Nucleotide analogue
converted to cidofovir diphosphate active intracellular metabolite MOA - suppresses CMV replication by selective inhibition of viral DNA synthesis Very long half-life allows for once a week administration Two phases of administration Induction 2 weeks Maintenance indefinite duration |
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local therapy for unilateral CMV retinitis
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gancyclovir implant
fomivirsen injection |
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gancyclovir implant
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intravitreal sustained - release pellet of ganciclovir
surgically implanted under the sclera efficacious for unilateral disease doesn’t protect other eye from retinitis development doesn’t protect against GI, neurological, lung disease development adverse events ~ 10% endopthalmitis early retinal detachment severe vitreal bleeding most patients - have transient decrease in visual acuity |
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fomivirsen injection
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A synthetic antisense oligonucleotide
Is complementary to messenger RNA of the immediate-early trasnscriptional unit (IE2) of human cytomegalovirus fomivirsen binding to this messenger RNA results in selective inhibition of IE2 proteins necessary for cytomegalovirus replication may also cause inhibition of adsorption of cytomegalovirus to host cells In vitro, it was significantly more potent than ganciclovir against cytomegalovirus (at least 30-fold), with a 50% inhibitory concentration of 0.4 micromol/L |
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dosing and admin fomivirsen injection
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330 micrograms by intravitreal injection; for induction, one dose should be injected every other week for 2 doses
for maintenance, one dose should be given once every 4 weeks after induction Fomivirsen is administered intravitreally with topical and/or local anesthesia A 30-gauge needle on a low-volume syringe (eg, tuberculin) is recommended |
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CMV retinitis treatment guidelines:
immediate sight threatening lesions KNOW |
zone 1
Ganciclovir intraocular implant + valganciclovir 900 mg po daily |
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CMV retinitis treatment guidelines:
peripheral lesions KNOW |
Valganciclovir 900 mg po bid for 14-21 days, then 900 mg po daily
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CMV retinitis treatment guidelines:
chronic maintenance thearpy (2ndary prophylaxis) KNOW |
Valganciclovir 900 mg po daily
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CMV retinitis alternative therapy
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Ganciclovir 5 mg/kg IV q12h for 14-21 days, then 5 mg/kg IV q24h
Ganciclovir 5 mg/kg IV q12h for 14-21 days, then valganciclovir 900 mg po daily Foscarnet 90 mg/kg IV q12h for 14-21 days, then 90-120mg/kg IV q24h Cidofovir 5mg/kg IV qweek for 2 weeks, then 5 mg/kg IV every other week – each dose should be administered with IV saline hydration and oral probenecid Repeated intravitreal injections with fomivirsen (for relapses only, not as initial therapy) |
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CMV end organ dx
salvage therapy combo therapy |
Ganciclovir + Foscarnet
can prolong the time to retinitis progression twofold in patients who have already had progression on standard antiviral monotherapy maintenance dose of primary agent and add induction doses of second agent |
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CCMV end organ dx:
primary prophylaxis |
New guidelines do not recommend this anymor
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CMV end organ dx:
2ndary prophylaxis (chronic maintenance) |
May be safely discontinued among patients with inactive disease and sustained CD4 > 100-150 for > 6 months – consultation with opthalmologist is advised
Patients with CMV retinitis who discontinue maintenance therapy should undergo regular eye examination for early detection of relapse |
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galanciclovir drug toxicities
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myelosuppression - dose limiting
neutropenia ( ANC < 500) 15-20% patients can be reversed with GCSF or GMCSF thrombocytopenia dose limiting in 5% of patients azospermia and ovarian failure may be irreversible nephrotoxicity - rare altered mental status - rare |
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foscarnet drug toxicities
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nephrotoxicity - dose limiting
10 - 23% patients with increased Scr ARF has been reported keep patients well hydrated- IV sodium loading with 1L NS predose ionized hypocalcemia foscarnet appears to complex with free, unbound serum calcium responsible for arrhythmias, seizures, nausea, mental status changes, neurotoxicity renal losses of total body calcium, phosphate, magnesium or potassium can be managed by replacement fatal cases of hypocalcemia have been reported in individuals receiving pentamidine concomitantly |
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cidofovir drug toxicities
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nephrotoxicity
prolonged renal tubular toxicity - begins with proteinuria and subsequently leads to azotemia and RTA concomitant administration of probenecid and saline hydration myelosuppression alopecia anterior uveitis hypotony peripheral neuropathy |
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fomivirsen inj. drug toxicities
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INCREASED INTRAOCULAR PRESSURE (19% of patients)
INTRAOCULAR INFLAMMATION, including iritis and vitritis (15% to 25%) Topical corticosteroids may be useful for treating inflammatory changes BULL'S EYE MACULOPATHY, a perifoveal hypopigmented ring surrounded by a hyperpigmented Vision was not affected. The maculopathy resolved in cases within 3 to 4 months of stopping treatment with fomivirsen DECREASED VISUAL ACUITY - very rare |
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ART initiation during acute OI:
Benefits |
Improvement in immune function that would potentially contribute to faster resolution of the OI
OIs for which limited or no effective therapies are available cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy (PML), Kaposi sarcoma Reduction in risk for a second OI |
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ART initiation during acute OI:
cons |
Drug toxicities including additive toxicities
Drug interactions Immune reconstitution syndromes (IRS) |
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what is immune reconstituation syndrome (IRS)?
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characterized by fever and worsening of the clinical manifestations of the OI
new manifestations weeks after the initiation of ART If the syndrome does represent an immune reactivation syndrome, adding nonsteroidal anti-inflammatory agents or corticosteroids to alleviate the inflammatory reaction is appropriate The inflammation might take weeks or months to subside |
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OIs with new ART within 12 wks:
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subclinical infections that have been unmasked by early immune reconstitution and are not considered to be early failure of ART
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OIs >12 wks after ART initiation
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among patients with suppressed HIV-1 RNA levels and sustained CD4+ T lymphocyte counts >200 cells/μL
Determining whether these represent a form of immune reconstitution syndrome as opposed to incomplete immunity with the occurrence of a new OI is difficult The presence of organisms by stain and culture suggests that, in either situation, specific therapy is indicated |
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OIs developing among pts. experienceing virologic/immunologic failure while on potent ARTs
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These represent clinical failure of ART
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when to initiate ART in the setting of an OI???
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No consensus has been reached about the optimal time to start ART in the presence of a recently diagnosed OI
The decision to start potent ART should take into consideration the availability of effective therapy for the OI risk for drug interactions, overlapping drug toxicities, the risk for and consequences of the development of IRS, and the willingness and ability of patients to take and adhere to their regimens. TB disease, MAC, PCP, and cryptococcal meningitis awaiting a response to OI therapy is usually warranted before initiating ART When an OI occurs within 12 weeks of starting ART, treatment for the OI should be started, and ART should be continued When an OI occurs despite complete virologic suppression (i.e., late OI), therapy for the OI should be initiated, potent ART should be continued, and if the CD4+ T cell response to ART has been suboptimal, modification of the ART regimen may be considered When an OI occurs in the setting of virologic failure, OI therapy should be started, antiretroviral resistance testing should be performed, and the ART regimen should be modified if possible to achieve better virologic control |
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1st recognition of transmissible immunodeficiency
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Pneumocystis Pneumonia – Los AngelesMMWR 1981;30:252-52 (June 5, 1981)
Citation: From October 1980 – May 1981, 5 young men, all homosexuals, were treated for biopsy confirmed Pneumocystis carinii pneumonia at 3 different hospitals in Los Angeles, CA. Two of the patients died. All 5 patients had previous or current CMV and candidal mucosal infection… The fact that these patients were all homosexuals suggests an association between some aspect of a homosexual lifestyle or disease acquired through sexual contact and Pneumocystis pneumonia in this population… All the above observations suggest the possibility of a cellular-immune dysfunction related to a common exposure that predisposes individuals to opportunistic infection… |
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Epidemiology 1st gen. HIV
1981-1991 |
179,136 AIDS cases reported in U.S.
Second leading cause of death Men 25-44 years of age 8 to 10 million infections worldwide MSM and IDU are the leading risk factors |
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predictions for 2000 from 1981 for HIV epidemiology
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40 million infections by 2000
90% predicted to be in developing countries 10 million AIDS orphans worldwide |
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rates of adults/adolescents w/ diagnosis of HIV infection 2007
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highly concentrated in SE,
CO also highest concentration atleast 200/100,000 |
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How is epidemiology of HIV changing?
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MSM still #1, but heterosexual incidence transmission is now #2 above IDU
Women have the most rapid increase in incidence/transmission HIV people of color have highest transmission rates SE region of US is highest HIV incidence |
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HIV in the world
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It’s currently estimated that 40,000,000 people are living with HIV and/or AIDS in the world
It’s estimated that 25,000,000 people have died from HIV/AIDS There are more than 10,000,000 AIDS orphans in sub-Saharan Africa alone Approximately 4 million new HIV-infections occurred in 2005 Approximately 2.5 million people died from HIV/AIDS in 2005 The extent of epidemics in India, China, and Eastern Europe are just beginning to be understood |
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where are 90% of HIV located?
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resource limited areas/developing countries
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2006 data people living w/ HIV in Aisa
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8 million
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2006 data people living with HIV subsaharan africa
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25 million
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seroprevalance HIV in world
S. Africa |
S. Africa
15-28% |
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what has happend to life expectancy in Africa?
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from 1970-2010
it has decreased a lot in the last 40 years ex: Botswana gone from 65 yrs in 1990 to 35 in 2010 |
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AIDS orphaans 2007
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incrased a lot 12 million in 2007
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what is HIV?
type of virus |
HIV is a retrovirus (family retroviridae, genus lentivirus)
An enveloped ssRNA virus Retroviruses rely on the enzyme reverse transcriptase to make DNA from RNA DNA is integrated into the host's genome with an integrase enzyme |
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what type of cell does HIV infect?
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HIV primarily infects a type of lymphocyte known as CD4+ lymphocytes (T Helper Cells)
Also infects monocytes, dendritic cells, and others |
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what happens during HIV replication?
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During HIV replication the host CD4 lymphocyte is destroyed (by several mechanisms)
Leads to progressive cellular immune dysfunction |
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what are the 3 gene groups in HIV
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GAG
POL ENV |
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what is GAG?
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HIV GAG genes - encode capsid proteins
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what is POL?
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HIV POL genes - encode enzymes critical to virus development
->reverse transcriptase ->integrase ->protease |
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what three enzymes are critical to HIV development?
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reverse transcriptase
integrase protease |
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what is ENV?
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HIV ENV genes - encode envelope glycoproteins
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HIV virion structure
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envelope: outer layer of proteins that allow for host cell attachment
protein nucleocapside: surrounds RNA and replication proteins |
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how many times has HIV corssed species lines in last 100 yrs?
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at least 3 times,
mostly with monkeys |
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what is the most common HIV type?
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HIV 1
Groups M (A through K) Clade B (U.S.) O N |
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where is HIV 2 primarily located? how prevalent is it?
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Minority of strains that originate in West Africa
<100 cases of HIV-2 diagnosed in U.S. to date |
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ListTypical HIV replication cycle steps
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binding and entry
reverse transcription integration(possible latency) transcription/translation assembly virus budding |
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desc. HIV binding and entry
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HIV proteins gp41 and gp120 bding to CD4 receptors on host cells and also host coreceptors CCR5/CXCR4 and allows entry of HIV into the host cell
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what happens to gp120 when binds to CD4?
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gp120 conformational change and co-receptor binding
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what happens to gp41 when it binds to CD4?
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gp41 conformational change and fusion/insertion occurs
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desc. reverse transcription
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After insertion, the nucleocapsid “uncoats” and the RNA genome is reverse transcribed into a duplex DNA copy
This is performed by the viral enzyme Reverse Transcriptase |
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what is the enzyme responsible for uncoating HIV nucleocapsid and the RNA genome is reverse transcribed into a duplex DNA copy?
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reverse transriptase
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desc. integration of HIV
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• The DNA migrates to the nucleus and is integrated into the host chromosome by the enzyme Integrase
At this point the cell can become latently infected or can become productively infected |
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desc. transcription and translation of HIV
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The integrated DNA is transcribed by host RNA polymerase into viral mRNA
• The viral mRNA is translated into envelope proteins, capsid proteins, and enzymes • The viral mRNA also serves as a plus-sense viral genome |
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can drug therapy be used to target HIV transcription/translation?
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no b/c it is the host machinery doing the work and so there are no drug targets
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desc. HIV assembly
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Nucleocapsid assembly occurs in the cytoplasm
Protease is the key enzyme involved in regulating assembly The nucleocapsid matures and migrates to the cell membrane, joining with the envelope proteins on the cellular membrane |
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what HIV enzyme facilitates HIV assembly?
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protease
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desc. HIV viral budding
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Infectious virions bud off and infect other susceptible cells
10 Billion virus particles are produced daily in the average human host who is not on therapy |
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what is cellular latency in HIV?
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After integration (Step 3), the virus can complete replication or can establish latency
CD4+ lymphocytes usually replicate when they are activated Activated T-cells produce large amounts of virus resulting in death of the host cell Common activating factors include concomitant infections (viral, bacterial, fungal, etc.) or receipt of immunizations In non-activated T-cells, the viral DNA remains integrated in the host DNA but is dormant, this is called cellular latency These resting cells provide a reservoir of virus that cannot be eliminated by antiretroviral therapy |
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what happens after integration in activated T cells?
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CD4+ lymphocytes usually replicate when they are activated
Activated T-cells produce large amounts of virus resulting in death of the host cell Common activating factors include concomitant infections (viral, bacterial, fungal, etc.) or receipt of immunizations |
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what happens after integratino in nonactivated T cells?
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In non-activated T-cells, the viral DNA remains integrated in the host DNA but is dormant, this is called cellular latency
These resting cells provide a reservoir of virus that cannot be eliminated by antiretroviral therapy |
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why cant HIV be cured?
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latent CD4 cells are a reservoir for the virus and can't be eliminated with ART
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New HIV infection occurrence
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>12,000 infected worldwide each day
About 1 person every 7 seconds >95% in low and middle income countries ≈1500 (each day) are in children under 15 years of age Remainder in adults (>15 years) of whom: 50% are women 40% are adolescents |
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modes of HIV transmission
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sexual
paarenteral perinatal |
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sexual mode HIV transmission
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male:male (MSM = men who have sex with men)
male:female (more than female:male) female:female – uncommon (but has been reported) |
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parentaral mode HIV transmission
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Injection drug use
Blood transfusion Needle stick |
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perinatal mode HIV transmission
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Usually at delivery (in utero less common)
Breast feeding |
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what are the acts with the highest risk of acquisition of HIV with no ART?
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blood transfusion 90%
childbirth 25% |
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factors that influence HIV transmission
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Viral load (HIV-RNA) of source (Each 10-fold increment of plasma HIV-RNA is associated with an 81% increased rate of HIV transmission)
Acute infection (increased risk) AIDS (increased risk) HIV treatment decreases HIV-RNA (decreased risk) Presence of genital ulcer diseases increases transmission Non-ulcerative sexually transmitted infections increases transmission Condoms reduce transmission Susceptibility of exposed individual CCR5∆32 mutation lowers acquisition rate |
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what is the most common factor that influences HIV transmission?
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Viral load (HIV-RNA) of source (Each 10-fold increment of plasma HIV-RNA is associated with an 81% increased rate of HIV transmission)
Acute infection (increased risk) AIDS (increased risk) HIV treatment decreases HIV-RNA (decreased risk) |
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HIV vaccine study
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Overall – disappointing
One study yielded positive(?) results Randomized, double-blind, placebo controlled Vaccination with canarypox vaccine and GP120 booster x 2 > 16,000 subjects followed for about 3 years Vaccine Group = 56 seroconversions Placebo Group = 76 seroconversions Vaccine Efficacy ≈ 30% Adverse effects mild in nature |
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when is benefit seen for HIV vaccine?
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within first few months see the largest prevention of seroconversion
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efficacy seen with the HIV vaccine?
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30%
low for a vaccine, most are 80-100% effective for other illness |
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most cases of occupational HIV seroconversation due to?
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mostly needlestick injuries
Needlestick: 20 of 6135 needlesticks (0.33 percent) Mucosal exposure: 1 of 1143 exposures (0.09 percent) Intact skin exposure: 0 of 2712 exposures |
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factors assoc. with incrased risk HIV from needlestick?
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Deep injury (odds ratio [OR] 15)
A device visibly contaminated with the patient's blood (OR 6.2) Needle placement in a vein or artery of source patient (OR 4.3) Terminal illness in the source patient (OR 5.6) |
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PEP HIV regimen
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High risk: Protease inhibitor + two NRTIs
Moderate risk: two NRTIs duration 28 days recommended |
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nonoccupational PEP
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Non-occupational post-exposure prophylaxis (NPEP)
Same idea as PEP Fear of repeated exposures Who pays? expensive and pts. cant afford it |
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Pre-PEP
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Pre-Exposure Prophylaxis (PrEP)
One randomized Phase II Safety trial in 936 HIV negative women at risk for HIV in 3 African Nations Treated with Tenofovir 300 mg daily No safety issues raised 2 seroconversion with TDF, 6 with placebo RR 0.35 (95% CI 0.03 – 1.93) |
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circumcision and HIV prevention
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Randomized Controlled Trials
South Africa – 60% reduction in HIV incidence in men randomized to circumcision PLoS Med 2007;2(11): e298 Kenya – 53% reduction in HIV incidence Lancet 2007;369:643-656 Uganda – 51% reduction in HIV incidence |
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circumcision benefit to female partners in HIV prevention?
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No benefit seen
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is circumcision an effective HIV prevention method?
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yes, especially in places with high HIV prevalence like Africa, it is more effective than vaccine (~50-60%)
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HIV testing
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Antibody tests
Newer 2nd and 3rd generation tests positive within 3-4 weeks of infection Rapid tests Oral fluid/cell tests Sensitivity and Specificity both > 99% Need confirmation with western blot P24 antigen – rarely used HIV-RNA – not recommended for screening Useful in neonates of HIV-infected mothers Useful in acute HIV infection HIV culture – not used except in research |
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what is the most commonly used HIV test?
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antibody tests
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antibody test effectiveness?
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Sensitivity and Specificity both > 99%
Need confirmation with western blot |
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% US population unknowingly infected with HIV?
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21%
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% pts. already have AIDS when diagnosed for HIV?
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30-50%
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barriers to HIV testing?
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****Stigma
Culture Cost Avoidance and fear Providers Availability Language |
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WHO should be tested for HIV?
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Routine, voluntary HIV testing for all persons 13-64 years in primary health care settings
NOT BASED ON RISK Repeat HIV screening of persons with known risk at least annually Prevention counseling in conjunctions with HIV screening in health care settings is not required |
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HIV testing in pregnant women?
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ALL pregnant women should be screened but...
Universal opt-out HIV screening Include HIV in routine panel of prenatal screening tests Consent for prenatal care includes HIV testing Notification and option to decline Second test in 3rd trimester for pregnant women: Known to be at risk for HIV In jurisdictions with elevated HIV incidence In high HIV prevalence health care facilities |
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why should higher risk pregnant women be rescreened in 3rd trimester?
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b/c most mom->child HIV transmissino occurs due to NEW HIV infection during pregnancy
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natural history of untreated HIV infection
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viral transmission 2-3 wks
acute retroviral syndrom 2-3wk recovery/seroconversion 2-4wk asymptomatic chronic infection 8-10 yrs symptomatic HIV/AIDS 1.3yrs death |
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symptoms of acute retroviral syndrom (ARS)
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Fever, sore throat, fatigue, weight loss, myalgia
40-80% exhibit rash usually involving the trunk Diarrhea, nausea, vomiting Lymphadenopathy, night sweats Aseptic meningitis (fever, headache, photophobia, and stiff neck) Other: High viral loads are common CD4 lymphopenia Opportunistic Illnesses have been reported during acute HIV infection |
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most common ARS symptoms?
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rash (fine erythematous)
lymphadenopathy |
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asymptomatic chronic HIV infection
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Strong immune defenses significantly decrease HIV viremia
patient enters clinical latency Viruses are found in circulating lymphocytes and within lymphoid tissue Typical viral loads are 10,000 – 100,000 Initially, the number of blood CD4+ cells is only slightly decreased, but the virus persists in other tissues On average, CD4 cell counts drop by about 50 per year Rate depends on viral ‘set-point’ |
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Why can't human immune system clear HIV on its own?
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over 1 billino HIV replications per day
new (~3) mutations occur with each replication immune system always playing "catch up" but eventually it loses |
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TRAIN:
clinical course of HIV |
viral load = how quickly pt. is traveling towards AIDS/death
CD4 count= how far away patient is from developing AIDS/death ART reverses viral load and increases CD4 count |
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Early symptomatic infection
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Occurs prior to clinical AIDS (formerly called ARC – AIDS Related Complex)
Also called stage B by 1993 CDC definition CD4 counts are generally in the 200 – 400 range Conditions include: Oral and vaginal candidiasis Oral hairy leukoplakia (EBV infection) Herpes-Zoster Idiopathic thrombocytopenic purpura Peripheral Neuropathy Bacillary Angiomatosis Listeriosis Cervical dysplasia or carcinoma-in-situ Diarrhea > 1 month Fever > 1 month |
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when does a patient have AIDS by defn?
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CD4 < 200 cells/mm3
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conditions assoc. with early symptomatic infection of HIV
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Oral and vaginal candidiasis
Oral hairy leukoplakia (EBV infection) Herpes-Zoster Idiopathic thrombocytopenic purpura Peripheral Neuropathy Bacillary Angiomatosis Listeriosis Cervical dysplasia or carcinoma-in-situ Diarrhea > 1 month Fever > 1 month |
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conditions indicative of AIDS
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P. carinii pneumonia 42.6 %
Esophageal candidiasis15.0 % Wasting 10.7 % Kaposi's sarcoma 10.7 % Disseminated M. avium infection 4.8 % Tuberculosis 4.5 % Cytomegalovirus disease3.7 % HIV-associated dementia3.6 % Recurrent bacterial pneumonia 3.0 % Toxoplasmosis 2.6 % Immunoblastic lymphoma 1.9 % Chronic cryptosporidiosis 1.5 % Burkitt’s lymphoma 1.5 % Disseminated histoplasmosis 1.0 % Invasive cervical cancer 0.9 % Chronic Herpes simplex0.5 % |
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main condition/OI indicative of AIDS
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PCP
pneumocystic carnii pneumonia (actually P. jiroveci) |
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when do most OIs occur in AIDS
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CD4 typically < 200
but majority occur CD4 <50 |
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Advanced AIDS
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CD4 cell count below 50 cells/ul
Median survival is 12 to 18 months without antiretroviral therapy Virtually all patients who die of HIV-related complications have CD4 cell counts in this range |
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CD4 advanced age
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<50
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median sruvival advanced age?
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12-18 mos
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targets for ART?
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entry inhibitors(fusion, CCR5)
integrase inhibitors RT inhibitors (NNRTI, NRTI) protease inhibitors |
