d3 retroviral review duffus

Retroviral Review

Wayne Duffus, MD, PhD

May 25th 2010

Human Immunodeficiency Virus Type-1

gp120

gp41

p24Integrase

ReverseTranscriptase

ssRNA+

Protease

RTRT

ProvirusProvirus

ProteinsProteinsRNA

DNA

RNA

DNA

DNA

RTRT

Viral proteaseViral proteaseViral proteaseViral protease

ReverseReversetranscriptasetranscriptase

ReverseReversetranscriptasetranscriptase

RNA

RNA

DNADNA

DNADNA

DNADNA

Fusion and entryFusion and entry

IntegraseIntegraseIntegraseIntegrase

HIV Life Cycle

FDA-Approved Antiretroviral DrugsNucleoside Reverse Transcriptase Inhibitors

(NRTIs)

Generic Abbreviat. Trade Name Co-Formulation*

Abacavir ABC Ziagen® Trizivir® Epzicom®

ABC+3TC+ZDVABC+3TC

Didanosine ddI Videx®

Emtricitabine FTC Emtriva™ Truvada™ FTC+TDF

Lamivudine 3TC Epivir® Combivir® Epizicom® Trizivir®

3TC+ZDVABC+3TCABC+3TC+ZDV

Stavudine d4T Zerit®

Tenofovir TDF Viread® Truvada™ FTC+TDF

Zalcitabine ddC Hivid®

Zidovudine AZT, ZDV Retrovir® Combivir®

Trizivir®

3TC+ZDVABC+3TC+ZDV

* Fixed-Dose Combination Products

FDA-Approved Antiretroviral DrugsNon-Nucleoside Reverse Transcriptase

Inhibitors (NNRTIs)

Generic Abbreviat. Trade Name

Delavirdine DLV Rescriptor®

Efavirenz EFV Sustiva®

Nevirapine NVP Viramune®

FDA-Approved Antiretroviral DrugsProtease Inhibitors (PIs)

Generic Abbreviat. Trade Name

Amprenavir APV Agenerase®

Atazanavir ATV Reyataz™

Fosamprenavir F-APV Lexiva™

Indinavir IDV Crixivan®

Lopinavir + ritonavir

LPV/r Kaletra®

Nelfinavir NFV Viracept®

Ritonavir RTV Norvir®

Saquinavir hard gel capsule

SQV-hgc Invirase®

Approved Antiretrovirals

NNRTI

’’8787 ’’9191 ’’9292 ’’9494 ’’9595 ’’9696 ’’9797 ’’9898 ’’9999 ‘‘0000’’8888 ’’8989 ’’9090

RTIRTI

PIPI

Between ’87 and ’95, 4 antiretrovials were launched.Since ’95, 25 new products were introduced.

RetrovirRetrovir

NorvirNorvir

InviraseInvirase

CrixivanCrixivan

FortovaseFortovase

KaletraKaletraViraceptViracept

ZiagenZiagen

CombivirCombivir

VidexVidex

HividHivid

ZeritZerit

EpivirEpivir

TrizivirTrizivir

Rescriptor

Sustiva

Viramune

’’0101

VireadViread

EmtrivaEmtriva

FuzeonFuzeon

ReyatazReyataz

‘‘0202 ’’0303’’9393

AgeneraseAgenerase

LexivaLexiva

Entry inhibitorsEntry inhibitors

AtriplaAtripla

TruvadaTruvada

EpzicomEpzicom

AptivusAptivus

PrezistaPrezista

’’0404 ’’0505 ’’0606 ’’0707

NNRTI

’’8787 ’’9191 ’’9292 ’’9494 ’’9595 ’’9696 ’’9797 ’’9898 ’’9999 ‘‘0000’’8888 ’’8989 ’’9090

RTIRTI

PIPI

Between ’87 and ’95, 4 antiretrovials were launched.Since ’95, 25 new products were introduced.

RetrovirRetrovir

NorvirNorvir

InviraseInvirase

CrixivanCrixivan

FortovaseFortovase

KaletraKaletraViraceptViracept

ZiagenZiagen

CombivirCombivir

VidexVidex

HividHivid

ZeritZerit

EpivirEpivir

TrizivirTrizivir

Rescriptor

Sustiva

Viramune

’’0101

VireadViread

EmtrivaEmtriva

FuzeonFuzeonFuzeonFuzeon

ReyatazReyataz

‘‘0202 ’’0303’’9393

AgeneraseAgenerase

LexivaLexiva

Entry inhibitorsEntry inhibitorsEntry inhibitorsEntry inhibitors

AtriplaAtripla

TruvadaTruvada

EpzicomEpzicom

AptivusAptivus

PrezistaPrezista

’’0404 ’’0505 ’’0606 ’’0707

FuzeonFuzeonFuzeonFuzeonSelze

Progress Toward Once-Daily RegimensProgress Toward Once-Daily Regimens

DosingDosing Daily pill burdenDaily pill burdenRegimenRegimen

1996 1996 Zerit/Epivir/Crixivan Zerit/Epivir/Crixivan 10 pills, Q8H 10 pills, Q8H

2002 2002 3 pills, BID 3 pills, BID Combivir/Sustiva Combivir/Sustiva

1998 1998Combivir (Retrovir/Epivir)/ SustivaCombivir (Retrovir/Epivir)/ Sustiva

5 pills, BID5 pills, BID

20032003 3 pills, QD 3 pills, QD Viread/Emtriva/Sustiva Viread/Emtriva/Sustiva

20042004Fixed-Dose (Viread/ Emtriva)/Sustiva

Fixed-Dose (Viread/ Emtriva)/Sustiva

2 pills, QD 2 pills, QD

HIV Treatment: Then and Now

AZT/3TC ABC/3TC TDF/FTC

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:

Combivir Epzicom Truvada

Consideration for Initial Regimen

Example LPV/r + 3TC + ZDV EFV + FTC +TDF

Pros • Multiple mutations for resistance target both RT and PI genes (except NFV)

• Preserves NNRTIs

• Trials with clinical endpoints

• Simple regimen

• Preserves PI class

Cons • GI side effects

• Potential for cross-resistance

• Differences in tolerability, potency, and safety between agents

• CNS side effects

• Hepatotoxicity/rash

• K103N confers cross-resistance

NRTIPI NRTI NRTI NRTINNRTI

Rationale For Combination Antiretroviral Therapy

• Synergistic or additive effects

• Prevent emergence of resistance

• Attack the virus at different points in the lifecycle.

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

% p

atie

nts

pre

ferr

ing

>8 pills 8 pills 6 pills 4 pills 3 pills

31%

69%

38%

62% 59%

41%

84%

16%

93%

7%

Patients Prefer Once-daily With Low Pill Burden

Moyle G et al. Paper presented at: 6th International Congress on Drug Therapy in HIV Infection; Glasgow, Scotland; November 17-21, 2002. Poster 99.

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

Nausea Often Results in HAART Discontinuation*1

*Retrospective study of 345 ART-naive patients initiated on HAART and followed for amedian 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

Pharmacokinetic rationale for dual protease inhibitor therapy

Effective Concentration

Single PI Dual PI

Kempf, Medcapse, 1999

IncompleteSuppression

Leads to Resistance

More Complete Suppression Increases Durability of Response

Current SinglePI Regimens

Dual PI RegimensWith PK Enhancement

Plasma druglevels

High peakcontribute totoxicity

Low troughinsufficient to completely block replication

Drug required to block

replication

Low peak levels may reduce side effects

High trough levels increase potency

Two-drugCombination may increase potency

Rational for Boosted or Dual PIs

Boosted vs Non-Boosted ATV Viral and Immunologic Control – Mean Value (95% CI) –

52 Week Data

Horberg, et al., IAS 2007; WEPEB025.

Outcome MeasureNon-Ritonavir

Boosted GroupRitonavir Boosted

Group

Percent HIV RNA <400 copies/mL

54.2% 78.8%

Change HV RNA (log¹º/mL) through 52 weeks

-1.31 (-1.75, -0.87) -1.77 (-1.90, -1.65)

Change CD4 T-cell count (#μL) through 52 weeks

+135 (+89, +182) +182 (+158, +206)

• 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

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)

Adverse Effects: PIs

• All PIs: – Hyperlipidemia – Insulin resistance and diabetes– Lipodystrophy – Elevated LFTs– Possibility of increased bleeding risk

for hemophiliacs– Drug-drug interactions

Adverse Effects: PIs (2)

• ATV– Hyperbilirubinemia– PR prolongation– Nephrolithiasis

• DRV – Rash– Liver toxicity

• FPV– GI intolerance– Rash– Possible increased risk of MI


• IDV– Nephrolithiasis– GI intolerance

• LPV/r – GI intolerance– Possible increased risk of MI– PR and QT prolongation

• NFV – Diarrhea


• RTV

– GI intolerance– Hepatitis

• SQV – GI intolerance

• TPV – GI intolerance– Rash– Hyperlipidemia– Liver toxicity– Cases of intracranial hemorrhage

Adverse Effects: II

• RAL – Nausea– Headache– Diarrhea– CPK elevation

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)

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.

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

Adverse Effects: Fusion Inhibitor

• ENF – Injection-site reactions– HSR– Increased risk of bacterial pneumonia

Adverse Effects: CCR5 Antagonist

• MVC – Drug-drug interactions– Abdominal pain– Upper respiratory tract infections– Cough– Hepatotoxicity– Musculoskeletal symptoms– Rash– Orthostatic hypotension

Face and neck

Buffalo neck

Liposuction – buffalo hump

Lipohypertrophy

• Adiposity– Abdominal obesity– “Buffalo hump”– Enlarged breasts– Gynecomastia

ART-Associated Abnormalities in Body Composition

Carr A, et al. Carr A, et al. N Engl J Med. N Engl J Med. 1998;339:1296. 1998;339:1296.

Warren SM, et al. Warren SM, et al. N Engl J Med. N Engl J Med. 2005;352:63.2005;352:63.

Lipoatrophy

• Loss of fat– Cheeks– Limbs– “arm cabling” – Buttocks

Wasting - Face and neck

Centrofacial and temporal atrophy

Lipodystrophy May Decrease AdherenceAdherence 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

100

9282

75

08

1825

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

Ad

here

nce

rat

e (

%)

Adapted from Guaraldi G et al. HIV Clin Trials. 2003;4:99-106.

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-

HA

AR

T C

D4

ran

ge

Incidence of lipoatrophy

Lichtenstein et al. JAIDS 2003; 32:48–56.

Perc

en

tag

e o

f p

ati

en

ts (%

)

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)

02

468

10

121416

1820

<40 years 40–49 years >50 years

Birkus G et al. Antimicrob Agents Chemother. 2002;46:716-723.

Effect of NRTIs on Hep G2 Cell Mitochondrial DNA ContentM

itoch

ond

rial

DN

A c

on

ten

t (%

)

0.1 1 10 100 1000

ZDV

3TCTDF

ABC

d4T

ddIddC

140

120

100

80

60

40

20

0

Log drug concentration (µM)

Effect of NRTIs on Mitochondrial DNA (in vitro)

RAVEMedian Change in Limb Fat

DEXA arm fat + total leg fat in grams (ITT m=f analysis)

199

393

198

316

0

50

100

150

200

250

300

350

400

450

Baseline Week 24 Week 48

Lim

b f

at (

gra

ms)

TDF (n=52) ABC (n=52)

Median Baseline Limb Fat TDF 3.0kg, ABC 2.9kg

p=0.97

Moyle et al. 12th CROI, Boston, 2005. Abstract 44LB.

Lipoatrophy is Associated with Insulin Resistance

*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

Insu

lin S

ensi

tivity

(mg

gluc

ose/

kg L

BM

/min

)

n = 12 14 15

Lim

b F

at (

%)

Insulin Sensitivity (mg glucose/kg lean body mass/min)

20

60

40

06 12 18

r =0.60p=0.0001

• HIV-infected patients with fat redistribution have significantly less insulin sensitivity than controls

• Percentage peripheral fat correlates positively with insulin sensitivity

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

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

Drug Interactions with ARVs: Dose Modification or Cautious Use

• Oral contraceptives (may require second method)

• Methadone• Erectile dysfunction agents• Herbs - St. John’s wort

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

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

2009 DHHS Guidelines: Timing of ART Initiation in

Special Patient Populations

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. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.

48

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. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.

49

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



50

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



51

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


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


53

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/mm3)

• 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


54

Natural History Course of HIV

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 meningitisHerpes simplex virus (HSV) infections

Cytomegalovirus (CMV) infectionsMycobacterium-avium complex (MAC)

Time after onset of HIV infection

CD

4 ce

lls/

mm

3

Relationship Between CD4

Count and AIDS Malignancies

• HIV-infection and at least one of the following:

– 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

AIDS Conditions

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

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

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

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


Secondary: CD4 >200 cells/µL for 6 months + initial toxo treatment + asymptomatic

Toxo


Secondary: CD4 >200 cells/µL for 3 monthsPCP

Recommendation(only for patients on effective ART)

Agent

Prophylaxis of opportunistic infections

• CD4<200– PCP prophylaxis: bactrim, dapsone,

pentamidine, atovoaquone, primaquine + clindamycin

• CD4<50– MAC prophylaxis: azithromycin or

clarithromycin

HIV- Complications at CD4>500mm3

• Infectious– Acute retroviral syndrome– Candida vaginitis

• Other– Generalized LAD– Guillain-Barre (very rare)– Vague constitutional symptoms

HIV- Complications at CD4 200-500mm3

• Infectious– Pneumococcal pneumonia– TB– Herpes zoster– Kaposis sarcoma– Oral hairy leukoplakia (OHL)– Oropharyngeal candidiasis (thrush)

• Non-Infectious– Cervical Ca– Lymphomas– ITP (Immune thrombocytopenic purpura)

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)

Candidal esophagitis

HIV- Complications at CD4 < 200mm3

• Infectious– PCP– Histoplasmosis (other endemic fungi)– Miliary TB– PML

• Non-Infectious– Wasting– Peripheral neuropathy– Cardiomyopathy– Dementia

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

Pneumocystis jiroveckii (carinii) pneumonia

Diagnosis of Pneumocystis carinii

Histoplasma

• Mississippi River Delta

• Wide spectrum of illness from acute sepsis like syndrome to acute pneumonia to cutaneous involvement

Oral lesions of disseminated Histoplasma capsulatum infection


• Infectious– Disseminated HSV– Toxoplasmosis– Candida esophagitis– Cryptosporidiosis, microsporidiosis,

isospora– Cryptococcal disease

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.


• 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.

• 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.


Cryptococcus neoformans

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.

• 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

Cerebral toxoplasmosis


• Infectious– Disseminated CMV/Retinitis– Disseminated MAC

• Non-Infectious– CNS Lymphoma

Disseminated MAC

• Usually a sub-acute/chronic illness characterized by fevers, weight loss, diarrhea, night sweats, wasting

Mycobacterium avium-intracellulare

Questions

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