D3 Retroviral Review Duffus
description
Transcript of 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
Adverse Effects: PIs (3)
• IDV– Nephrolithiasis– GI intolerance
• LPV/r – GI intolerance– Possible increased risk of MI– PR and QT prolongation
• NFV – Diarrhea
Adverse Effects: PIs (4)
• 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
Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
50
2009 DHHS Guidelines: Risk of CVD and Persistent Immune Activation (2)
T-cell activation and inflammation– The degree of T-cell activation during untreated
disease is associated with risk of subsequent disease progression, independent of other factors such as plasma HIV RNA levels and the peripheral CD4 T-cell count
– Earlier treatment may result in less residual immunological perturbations on therapy, and hence less risk for AIDS- and non-AIDS-related complications
Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
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
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.
2009 DHHS Guidelines: Treatment Recommendations for HBV/HIV Coinfected
Patients • If treatment becomes necessary for either infection, follow the
guidelines listed in the scenarios below:– If treatment for HBV is needed
• Patients who need treatment for HBV infection should also be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses
– Management of HIV should be continued with a combination regimen to provide maximal suppression
– If treating only HBV• In instances when HIV treatment is not an option or is not
desirable, pegylated interferon-alpha may be used for the treatment of HBV infection, as it does not lead to the emergence of HIV or HBV resistance
Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
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
Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.
54
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
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 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
HIV- Complications at CD4 < 100mm3
• 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.
Cryptococcal Meningitis
• Clinical manifestations:– headache (70-90%), fever (60-80%),
malaise (76%), stiff neck (20-30%), photophobia (6-18%), seizures (5-10%) nausea.
• Average duration of symptoms is 30 days.
• Predictors of poor outcomes are altered mental status, increased opening pressure, WBC<20 cells/mm3.
• Diagnosis made by CSF examination with india ink (74-88%), Crypto Ag serum/CSF (99%), CSF culture.
• Level of Crypto Ag is not indicative of severity of disease or a marker of response to therapy. Serum Crypto Ag can rule out clinical disease in HIV positive but not negative patients.
Cryptococcal Meningitis
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
HIV- Complications at CD4 < 50mm3
• 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