Transcript harrington_hiv

HIV: Practice and Prevention, 2013
Robert D. Harrington, M.D.
Professor of Medicine
University of Washington
HIV: Practice and Prevention, 2012
Epidemiology
Who should be tested
The initial visit/Routine testing and Prophylaxis
Starting antiretroviral therapy
Antiretroviral agents
Resistance
Side effects
Drug interactions
Adults and children estimated to be living with
HIV, 2008
Western & Eastern Europe
Central Europe & Central Asia
North America
1.4 million
[1.2 – 1.6 million]
Caribbean
240 000
[220 000 – 260 000]
850 000
[710 000 – 970 000]
1.5 million
[1.4 – 1.7 million] East Asia
Middle East & North
Africa
310 000
[250 000 – 380 000]
Sub-Saharan Africa
Latin America
2.0 million
[1.8 – 2.2 million]
22.4 million
[20.8 – 24.1 million]
850 000
[700 000 – 1.0 million]
South & South-East Asia
3.8 million
[3.4 – 4.3 million]
Oceania
59 000
[51 000 – 68 000]
Total: 33.4 million (31.1 – 35.8 million)
Awareness of HIV Status among
Persons with HIV, United States
Number HIV infected
1,039,000 -1,185,00
Number unaware of
their HIV infection
252,000 - 312,000 (24%-27%)
Estimated new infections
annually
56,000
Glynn M, Rhodes P. 2005 HIV Prevention Conference
HIV/AIDS – Washington State
as of June 30, 2012
Average HIV Rates by County, 2006-2010
New HIV Case Rates by Race/Ethnicity and
Gender, Washington State 2006-2010
HIV: Practice and Prevention, 2011
Who should be tested?
Case 1
• A 32 year old woman comes to your office for her annual
pap smear. She is G2P1 (son is 4 years old). She has a
remote history of HPV but no other medical problems.
• She is divorced from her first husband for 4 years and
recently remarried.
• Her review of symptoms and exam are normal.
Case 1
Should she be tested for HIV?
YES!
Testing Guidelines: Who to Test
• Which of the following patients should have
HIV testing?
– 30 year old heterosexual man in monogamous
relationship
– 22 year old MSM, multiple partners
– 45 year old man diagnosed with TB
– 34 year old pregnant woman
– 38 year old married woman with no identifiable
risk factors
CDC Testing Guidelines
CDC Guidelines
● HIV screening is recommended for patients in all health-care
settings after the patient is notified that testing will be performed
unless the patient declines (opt-out screening).
● Persons at high risk for HIV infection should be screened for HIV
at least annually.
● Separate written consent for HIV testing should not be required;
general consent for medical care should be considered sufficient to
encompass consent for HIV testing.
● Prevention counseling should not be required with HIV diagnostic
testing or as part of HIV screening programs in health-care
settings.
Rationale for Testing Guidelines
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Increase testing
Diagnose early before symptomatic
Decrease stigma associated with testing
Remove barriers to clinicians to implement
testing
Awareness of Serostatus Among People
with HIV and Estimates of Transmission
~25% Unaware
of Infection
Accounting for:
~55% of new
infections
~75% Aware
of Infection
~45% of new
infections
People Living with
HIV/AIDS: ~1,050,000
New Infections Each Year:
~56,000
New Washington State HIV Testing
Recommendations, 2010
• No longer linked to counseling and partner services
• Obtain informed consent separately or with general
consent for care
• Inform patient in writing or verbally that HIV testing
is included
• Offer opportunity to ask questions or decline testing
• Notify local health officer of + test results
• Pregnant women – must still document patient
refusal
HIV Care Cascade: USA
Only 28% of HIV+ persons in the US are engaged in care,
on therapy, and have suppressed HIV
(MMWR, 2011)
HIV Care Cascade: King County, WA
HIV: Practice and Prevention, 2012
The initial visit:
Routine Testing and Opportunistic Infection
Prophylaxis
Case 2
• A 23 year-old gay man tested + for HIV at a night-club. He
has several anonymous sex partners per week and regularly
uses methamphetamine.
• His past history is notable for resolved hepatitis A and
multiple STDs.
• He’s a waiter, smokes ½ ppd and drinks to excess on
weekends.
• His exam in notable for poor dentition and seborrheic
dermatitis
• You confirm that he is HIV +
Case 2
• What other history and testing do you want on
this newly diagnosed patient?
• What recommendations should you make at
this first visit?
Case 2
• What other history and testing do you want on this newly
diagnosed patient?
– Sexual, travel, exposures (TB, food, pets)
– CD4, HIVRNA, CBC, M-7 and U/A, LFTs, Hep A,B,C
serologies, Toxoplasma serology, G6PD, PPD or IGRA, RPR
and STD evaluation, lipids
– HSV serology?
– HIV genotypic resistance test
– If female, pregnancy test
• What recommendations should you make at this first visit?
– Safe sex practices, drug rehabilitation, partner notification
Case 2
• His CD4 count returns at 110 cells/mL and his HIV RNA
is 85,000 copies/mL
• What opportunistic infections is he at risk of getting?
• For which infections should he receive prophylaxis?
MMWR 1981
Risk of Opportunistic Infection
Normal CD4 = 750-1500
Mycobacterium tuberculosis (TB)
Bacterial Pneumonia, HSV, Zoster, Diarrhea
Oral Candidiasis (Thrush), Molluscum Contagiosum, Dermatitis, Folliculitis
Pneumocystis jirovecii Pneumonia (PCP), Kaposi’s Sarcoma
Cryptococcal Meningitis, Toxoplasmosis, Non-Hodgkin’s Lymphoma
Mycobacterium avium (MAC), CMV (Retinitis, Colitis), Progressive Multifocal
Leukoencephalopathy (PML), Microsporidiosis, Primary CNS Lymphoma (EBV)
Opportunistic Infections and Geography
North America
Common OIs
• PCP
• MAC
• Candida
Regional Effects
• Southwest:
– Coccidiodomycosis
• Midwest:
– Histoplasmosis and
Blastomycosis
• South:
– Blastomycosis and
Toxoplasmosis
Opportunistic Infections and Geography
The World
Candida
PCP
MAC
PCP
TB
Cryptococcus
Isospora
Cryptosporidiosis
Microsporidia
PCP, TB
Candida, MAC
Cryptococcus
Leishmaniasis
PCP
TB
Candida
Cryptococcus
Penicilliosis
TB
Bacteria
Malaria
Cryptococcus
Holmes, CID, 03
Putong, SEA Trop Med, 02
Margues, Med Mycol, 2000
Amornkul, CID, 03
HIV-Associated and Opportunistic
Infections
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PCP
MAC
Cryptosporidiosis
Microsporidiosis
Bacterial respiratory
infections
Bacterial enteric infections
Bartonellosis
Coccidiodomycosis
Paracoccidiomycosis
Histoplasmosis
Cryptococcus
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Toxoplasmosis
Candida
TB
Aspergillosis
CMV
HSV
VZV
PML (JCV)
HHV-8
HPV
Penicilliosis
Leshmaniasis
HIV ASSOCIATED MALIGNANCIES
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AIDS Defining Malignancies
Kaposi’s sarcoma
Primary CNS lymphoma (PCNSL)
Non-Hodgkin’s lymphoma (NHL)
Invasive cervical cancer
Prophylaxis to Prevent Opportunistic
Infections
Considerations for Prophylaxis
• Infection should be common and/or
predictable
• Infection should be clinically significant
• Treatment (prophylaxis) should be
effective, non-toxic and affordable
Prophylaxis to Prevent Opportunistic
Infections
Infection
Criteria
Treatment
PCP
CD4 < 200
TMP/SMX or dapsone or
atovaquone or aerolsolized
pentamidine
Tuberculosis
PPD > 5 mm
INH
Toxoplasmosis
IgG+ and CD4 < 100
TMP/SMX or
dapsone+pyrimethamine+leukovo
rin
MAC
CD4 < 50
Azithromycin
VZV
CD4 > 200
Vaccine
HAV
Vaccine
HBV
Vaccine
Streptococcus
pneumoniae
Vaccine
Influenza
Vaccine
HIV: Practice and Prevention, 2012
When to start?
What to use?
Case 3
• A 72 yo male has been your patient for 15 years. He first
tested + for HIV in 1985. He has never had any HIV related
problems. His CD4 count has never been below 600 and his
HIV RNA has never been > 9000. He is ARV naïve.
• His other medical problems include porphyria, mild HTN,
osteoarthritis, GERD, chronic dizziness and BPH.
• He smokes 1ppd (for 50 yrs), doesn’t drink or use illicit drugs.
His meds include HCTZ, omeprazole, ibuprofen, sildenafil
and tamsulosin.
• His family history is notable for longevity – both parents are
still alive as are 2 siblings.
Case 3
• At his most recent visit he is cantankerous but without
worrisome complaints. He has a new partner with whom he is
sexually active. His partner is HIV negative.
• His most recent CD4 is 598 and his HIV RNA is 8500.
• Who wants to start him on anti-retroviral therapy?
HIV Infection: Pathogenesis
Anti-HIV
T-cell response
Sero-conversion
Antibody response
Typical Course
10,000,000
AIDS
Plasma HIV RNA
1,000,000
100,000
Plasma RNA Copies
10,000
Viral set point
1,000
CD4 Cell Count
Intermediate Stage
1,000
100
CD4 Cells
10
500
1
4-8 Weeks
Up to 12 Years
A lot of important stuff happens here
2-3 Years
Long Term Non-progression
HIV-CTL Sero-conversion
10,000,000
CD4 Cell Count
Plasma HIV RNA
1,000,000
100,000
10,000
CD4 Cells
1,000
1,000
100
Plasma RNA
Copies
10
500
1
4-8 Weeks
Up to 12 Years
2-3 Years
Some CD4 death, good HIV-CTL, good HIV control
Rapid Progression
CTL
response
Seroconversion
10,000,000
CD4 Cell Count
AIDS
Plasma HIV RNA
1,000,000
Plasma RNA Copies
100,000
10,000
1,000
1,000
100
500
CD4 Cells
10
1
4-8 Weeks
Up to 12 Years
2-3 Years
Lots of CD4 death, poor HIV-CTL, poor HIV control
Early Vs Standard HAART in Haiti
(Severe, et.al NEJM, 2010;263:257-65)
• Randomized, open label study ARV (AZT+3TC+EFV)
given when
– CD4 cells were > 200 and < 350 cells/uL and no h/o
AIDS Vs
– CD4 cells were < 200 cells/uL or when patients had a
clinical AIDS diagnosis
• N = 816 (408 in each group)
• Baseline CD4 ~ 280 in each group
• All patients received TMP/SMX, daily MVI and food
supplements and those who were PPD + received INH
Early Vs Standard HAART in Haiti
(Severe, et.al NEJM, 2010;263:257-65)
23 deaths in the standard Rx group Vs 6 in the early Rx group
36 incident cases of TB in the standard Rx group Vs 18 in the early Rx group
Survival
Incident TB
Impact of Age on Risk of HIV
Progression
Predicted Risk (%)
Predicted 6-Month Risk of Progression to
AIDS in Patient With HIV RNA of 30,000 c/mL
CD4 Cell Count (cells/mm3)
Phillips A et al. AIDS. 2004;18:51-58.
When to Initiate ARV Therapy:
Starting at a Higher CD4 Count?
Johns Hopkins HIV Clinical Cohort
– >350 cells/mm3:
CD4 counts significantly increased
and returned
to near-normal levels
– 201–350 and <200 cells/mm3: CD4
counts significantly increased and
plateaued after 4 years below normal
levels
• Differences in CD4 counts associated
with differences in morbidity and
mortality
Moore RD, Keruly JC. Clin Infect Dis. 2007;44(3):441-446.
CD4 Count (cells/mm3)
• Analysis of CD4-count recovery in
ARV-treated patients (n=655) with
sustained HIV RNA suppression
(<400 c/mL) up to 6 years, stratified
by BL CD4 counts
Median CD4 Counts Over 6 Years
Stratified by Baseline CD4 Count
900
800
700
600
500
400
300
200
100
0
201–350
<200
0
1
2
3
4
>350
5
Years After Starting HAART
6
Early Vs Deferred HAART
(Kitahata, et.al NEJM, 2009)
NA-ACCORD study
• Observational study of 17,517 asymptomatic
patients in US and Canada
• Two analyses:
– 1: Start HAART b/n 350-500 Vs deferred.
• N= 8362, 2084 (25%) started at 350-500, 6278 deferred
• RR of death for deferred group 1.69 (P<0.001)
– 2: Start HAART at > 500 Vs deferred
• N=9155, 2220 (24%) started at > 500, 6935 deferred
• RR of death for deferred group 1.94 (P<0.001)
Early Vs Delayed HAART, 2011
CASCADE Study (Arch Int Med, 2011, 171:1560)
• Observational cohort study of 9455 ARV naïve patients
with known date of HIV infection
CD4 count
AHR for AIDS or Death
AHR for Death
0-49
0.32 (0.17-0.59)
0.23 (0.14-0.95)
50-199
0.48 (0.31-0.74)
0.55 (0.28-1.07)
200-349
0.59 (0.43-0.81)
0.71 (0.44-1.15)
350-499
0.75 (0.49-1.14)
0.51 (0.33-0.80)
500-799
1.10 (0.67-1.79)
1.02 (0.49-2.12)
HAART, 2012: Simple Regimens
Simple Regimens
Drugs
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RLP/TDF/FTC
R-ATZ - TDF/FTC
R-LPV - TDF/FTC
R-DRV – TDF/FTC
R-FAMP - TDF/FTC
EFV/TDF/FTC
R-LPV - AZT/3TC
EFV - AZT/3TC
RAL – TDF/FTC
ELV/COB/TDF/FTC
Number of pills
1 pills
3 pills
5 pills
Schedule
QD
QD
QD
3 pills
5 pills
1 pill
6 pills
QD
QD
QD
BID
3 pills
3 pills
1 pill
BID
BID
QD
HAART, 2012: Effect on Transmission
What about his new partner?
HPTN 052: Immediate vs Delayed ART for HIV
Prevention in Sero-discordant Couples
HIV-infected, heterosexual
sero-discordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
Immediate HAART*
Initiate HAART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed HAART
Initiate HAART at CD4+ cell count ≤ 250 cells/mm3†
(n = 877 couples)
• Primary efficacy endpoint: virologically linked HIV transmission
• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe
bacterial infection and/or death
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
HAART, 2012: Effect on Transmission
HPTN 052: HIV Transmission Reduced by
96% in Sero-discordant Couples
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .001)
Linked Transmissions:
28
Immediate
Arm: 1
Delayed
Arm: 27
P < .001
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
Unlinked or TBD
Transmissions: 11
Early Vs Delayed HAART, 2011
CASCADE Study (Lodi, CID, 2011, 53:817)
• Observational cohort study of 9455 ARV naïve patients
with known date of HIV infection
• Analyzed time from seroconversion to CD4 threshholds
Median time to < 500: 1.2 yrs
Median time to < 350: 4.2 yrs
Median time to < 200: 7.9 yrs
When to Treat?
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Prevent Immune system destruction •
More effective when started early •
Mortality benefit even at high CD4 •
Prevent clinical “events”
•
Prevent transmission & truncate the
epidemic
Early
Toxicities of treatment
Increased risk of resistance
Low rate of disease progression?
Cost
Later
DHHS Guidelines 2012: When To Treat
ART is recommend for all HIV infected patients: only the strength of
the recommendation varies by CD4 count
CD4+ Cell Count
Recommendation
 < 350 cells/mm³
 Start ART (AI)
 350-500 cells/mm³
 Start ART (AII)
 > 500 cells/mm³
 Start ART (BIII)
Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count
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History of AIDS-defining illness (AI)
Pregnancy (AI)
HIV-associated nephropathy (AII)
HBV co-infection (AII)
Patients at risk of transmitting HIV to sexual partners (AI, heterosexuals; AIII, others)
HCV co-infection* (BII)
Patients > 50 years of age (BIII)
DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, 2012.
HIV: Practice and Prevention, 2012
When to start?
What to use?
Antiretroviral Therapy
Five Drug Classes
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•
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Protease Inhibitors (PI)
Integrase Inhibitors
Cell Entry Inhibitors
HIV Life Cycle
Antiretroviral Therapy
NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS (NRTIs)
AZT (zidovudine; Retrovir)
3TC (lamivudine; Epivir)
d4T (stavudine; Zerit)
ddI (didanosine; Videx)
Abacavir (Ziagen)
ddC (zalcitabine; Hivid)
Tenofovir (Viread)*
Emtricitabine (Emtriva)
Antiretroviral Therapy
NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS (NNRTIs)
Efavirenz (Sustiva)
Nevirapine (Viramune)
Delavirdine (Rescriptor)
Etravirine (Intelence)
Rilpivirine (Endurant)
Efavirenz + Tenofovir + FTC (Atripla)
Rilpivirine + Tenofovir + FTC (Complera)
Antiretroviral Therapy
PROTEASE INHIBITORS
Ritonavir (Norvir)
Saquinavir (Fortavase; Invirase)
Nelfinavir (Viracept)
Indinavir (Crixivan)
Fosamprenavir (Lexiva)
Lopinavir/ritonavir (Kaletra)
Atazanavir (Reyataz)
Tipranavir (Aptivus)
Darunavir (Prezista)
Antiretroviral Therapy
INTEGRASE INHIBITORS
Raltegravir (Isentress)
• Only member of its class, twice a day medicine
• Initially approved for salvage therapy, now
recommended as a preferred drug for initial
treatment
Stribild
• Elvitegravir + Cobicistat + TDF + FTC: 1 pill QD
Antiretroviral Therapy
CELL ENTRY INHIBITORS
T-20 (Enfuvirtide)
•
•
•
•
•
•
Synthetic peptide – blocks gp41 mediated fusion
Subcutaneous injection twice/day
Indicated for “salvage therapy” (use with at least one other active drug or in
patients with high risk of disease progression/death)
Maraviroc (Selzentry)
Only effective against HIV isolates that utilize CCR5 co-receptor
Must screen patients for the absence of CXCR4 using virus
Not clear where to use it since “salvage patients” more likely to have CXCR4
virus
NNRTI or PI or Integrase Inhibitor?
NNRTIs
• High efficacy
• Simplicity—lowest pill
burden
• Relatively well tolerated
• Limited toxicity
• Low genetic barrier to
resistance
• Drug-drug interactions
PIs
• High efficacy
• Getting simpler, but
regimen ≥3 pills per day
• High genetic barrier to
resistance
• Relatively well tolerated
except for GI
• Fat accumulation and lipid
problems persist
• Drug-drug interactions,
especially with RTV
GI = gastrointestinal; RTV = ritonavir.
Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at:
http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.
NNRTI or PI or Raltegravir?
Raltegravir
• High efficacy
• Very well tolerated (maybe increased
depression?)
• No Drug-drug interations
• Low genetic barrier to resistance
• BID dosing
Initiating Antiretroviral Therapy
DHHS Recommendations (2012)
Preferred Regimens
NNRTI-Based
EFV QD
+ TDF/FTC
PI-Based
Atazanavir/R QD
Darunavir/R QD
+ TDF/FTC
+ TDF/FTC
Integrase-Based
Raltegravir BID
+ TDF/FTC
Conclusions
• A patient’s CD4 T-cell count is used to stage disease and
determine the need for ART. The current threshold for
initiating treatment is < 500 cells
– Factors to consider include viral load, rate of CD4 decline,
co-morbidities, transmission risk, age, patient readiness and
the likelihood of adherence - may want to start at CD4 >
500
• TDF/FTC in once-daily fixed-dose combination plus an EFV
or ATZ/r or DRV/r or RAL are proven and preferred initial
choice
HIV: Practice and Prevention, 2012
Failure and Drug Resistance
Case 4
• A 38 year old man with AIDS was started on HAART
(EFV, TDF, FTC) a year ago with an excellent response:
his HIV RNA dropped from 248,000 copies to < 30 copies
and his CD4 increased from 87 to 360 cells.
• Unfortunately, he’s missed several recent appointments
and when he finally does make it to the office you find he
has thrush and seborrheic dermatitis. His CD4 count has
decreased to 240 cells and his HIV RNA is now detectable
at 37,000 copies.
• What is going on?
• What, in particular, are you worried about?
HIV: Practice and Prevention, 2012
Social/personal issues
Regimen issues
Toxicities
Poor potency
Wrong dose
Host genetics
Poor adherence
Poor absorption
Insufficient drug level
Rapid clearance
Viral replication in the
presence of drug
Poor activation
Drug interactions
Resistant virus
Adherence and Drug Resistance Relationship
When to Use Resistance Testing
IAS-USA1
DHHS2
European3
Recommend
Recommend‡
Recommend
—
—
Recommend
Consider*
Recommend‡
Strongly
consider*
Failure
Recommend
Recommend
Recommend
Pregnancy
Recommend†
Recommend
Recommend†
—
—
Recommend†
Patient Status
Primary/acute
Post-exposure prophylaxis
Chronic, treatment naïve
Pediatric
*Especially if exposure to someone receiving antiretroviral drugs is likely or if prevalence of drug
resistance in untreated patients ≥5% (European: ≥10%); †When viral load is detectable; ‡December 1,
2007: The panel recommends performing genotypic drug resistance testing for all treatment-naïve
patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated. This
recommendation is based on the fact that transmitted resistance mutation may be detected at a time
point more proximal to the time of infection than later. Repeat testing may be considered at the time
when therapy is to be initiated.
1. Hirsch MS et al. Clin Infect Dis. 2003;37(1):113-128; 2. Adapted from US Department of Health and Human Services
Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf.
Accessed March 13, 2008; 3. Vandamme AM et al. Antivir Ther. 2004;9(6):829-848.
Overview of Antiretroviral
Resistance Testing
How do we test for resistance?
Genotype: most common, least
expensive
Phenotype: useful for viruses
with multiple PI mutations
Virtual Phenotype: less expensive
than a phenotype
Genotypic Resistance Assay
• Sequences relevant portions of the HIV genome coding for
Reverse Transcriptase and Protease enzymes
• Detects and reports variations in the sequences of these
genes that are known or suspected to confer antiretroviral
resistance
pol
LTR
LTR
gag
env
RT
Codon
PR
INT
Mutation
AAA GAC AGT
AAA AAC AGC
Lys Asp Ser
Lys Asn Ser
Adapted from Winters. Reviewed in Wilson. AIDS Read 2000;10:469.
Silent Mutation
Antiretroviral Drug Resistance Testing
Some Key Mutations
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AZT
D4T
TNF
ABC
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NVP
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DDI
3TC/FTC
The class
EFV
ETR
210, 215
70
65
65, 74,
115, 184
65, 74
184
151, 69
103 181,188,
190,230
103, 188,190
100, 181, 188,
190
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•
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•
NLF
30, 90
SQV 48, 90
IDV
46, 82
RTV 82
APV 50
LPV
82
ATZ
50, 84, 88
DRV 32,33,47,50,54,76,84
TPV
33, 82, 84
• RTV 143,148,155
• MRV
R5 only virus
• Website: http://hivdb.stanford.edu/
Phenotypic
Resistance
Testing
• Tests viability of a chimeric
version of the patient’s HIV
in the presence of
antiretroviral agents
• Similar to traditional
bacterial antibiotic
susceptibility assays
• Results reported as foldchange in susceptibility to
antiretroviral agents
HIV: Practice and Prevention, 2012
Drug Side effects
Case 5
• A 23 year old woman with HIV is switched from a
failing HAART regimen to abacavir, lamivudine
and atazanavir.
• She does well for a week and then starts to feel
poorly with muscle aches, fever, nausea and then a
rash.
• What’s going on?
Abacavir hypersensitivity
Case 5
Abacavir Hypersensitivity
• Multiple organs involved
• Four most common symptoms:
– Fever, rash, GI, malaise/fatigue
• Less common symptoms:
– Edema, musculoskeletal, respiratory, mucous membrane,
headache, paresthesia
• Resolves upon stopping ABC
• Reappears on re-challenge and can be fatal (DO NOT
RECHALLENGE)
Hetherington S et al. 7th CROI 2000: Abst. 60.
Time to Onset of ABC Hypersensitivity
60
Median time to onset 11 days
50
No. of Cases
40
93% of reported cases
occurred within the first 6
weeks of initiating abacavir
30
20
10
0
1
8
15
22 29
36 43
50 57
64 71
78
85 92
Days
N = 636 cases
99 106 113 120 127 134 141 148 155 162 169 176
* One additional ABC hypersensitivity
reaction reported at 318 days
Hetherington S et al. 7th CROI 2000: Abst. 60.
HLA-B*5701 Screening for ABC HSR
PREDICT Study Results1
9
8
Control arm
Prospective HLA-B*5701
screening arm
7
Incidence (%)
HLA-B*5701 Screening2
OR 0.40 (0.25, 0.62)
P<.0001
6
Skin testing
5
OR 0.03 90, 0.18)
P<.0001
4
3
2
1
7.8
(66/847)
3.4
(27/803)
0
Clinically Suspected
HSR
2.7
0.0
(23/842) (0/802)
• Screen before starting patients on an
ABC-containing regimen
• HLA-B*5701(+) patients should not
receive ABC
– Record as an ABC allergy
• HLA-B*5701(–) does not absolutely
rule out ABC HSR
– Screening is not a substitute for
clinical judgment or vigilance
• If screening is not available, initiate
ABC with appropriate clinical
counseling and monitoring for any
signs of HSR
Immunol Confirmed
HSR
OR = odds ratio; ABC = abacavir; HSR = hypersensitivity reaction.
1. Molina JM et al. 11th European AIDS Conference/EACS; October 24-27, 2007; Madrid, Spain. Abstract PS5/1;
2. Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available
at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.
Case 6
• A 45 year old woman with HIV has been on a stable
regimen of FTC, TDF and lopinavir/ritonavir for years
with excellent HIV control (plasma HIV level < 30
copies/mL) and a steady increase in CD4 cells to 800
cells/uL.
• At a regular follow-up visit she complains of “getting
really fat” plus a change in her face such that the DMV
officer didn’t think it was her when she renewed her
drivers license.
• What has developed?
Lypodystrophy syndrome
Antiretroviral Toxicity
METABOLIC COMPLICATIONS OF HIV
AND HAART
•
•
•
•
•
•
Lipodystrophy Syndrome (LDS)
Dyslipidemia
Lactic acidosis
Hyperglycemia
Osteopenia
Avasular necrosis
Antiretroviral Toxicity
LYPODYSTROPHY SYNDROME
• Reported in 40-50% of HIV outpatients
• Lipoatrophy (loss of fat in the buttocks, face and limbs) >
Lipoaccumulation (development of central fat: buffalo
hump, visceral fat, breast hypertrophy)
• Pathogenesis:
– PIs inhibit adipocyte differentiation, increase lipolysis
and may also induce an insulin resistant state
– NRTIs associated with lipolysis
• Risk factors: older age, female sex, duration of HAART
facial lipoatrophy
breast enlargement
central adiposity
peripheral lipoatrophy
Facial lipoatrophy
peripheral lipoatrophy
Dorso-cervical Fat Pad
Lipoatrophy and Fat Accumulation in HIV-Infected Adults
Grinspoon, S. et al. N Engl J Med 2005;352:48-62
Antiretroviral Toxicity
LDS: TREATMENT
• Lipoatrophy
– Switch D4T/AZT to other NTRTI (abacavir/tenofovir)
– Cosmetic surgery (polylactic acid implants)
• Lipoaccumulation
–
–
–
–
–
Diet and exercise
Recombinant HGH - incomplete and reversible
Metformin/rosiglitazone
Cosmetic surgery (buffalo hump)
TH9507: synthetic GHRF: Decreases visceral fat and
improves lipids (Falutz, CROI, 2007)
HIV: Practice and Prevention, 2012
Drug interactions
Case 7
• A 25 year old woman is recently diagnosed with advanced
HIV. Her CD4 count is 10, her plasma HIV RNA level is
> 1,000,000.
• Her PMH is notable for GERD, anxiety, opiate addiction,
hyperlipidemia, primary pulmonary hypertension, hepatitis
C, hepatitis B and a seizure disorder.
• Current medications are omeprazole, diazepam,
methadone, lovastatin, sildenafil, dilantin, pegylated
interferon, ribavirin and estridiol.
• Besides bactrim and azithromycin you prescribe HAART
selecting ddI, 3TC and atazanavir/ritonavir.
• The clinic pharmacist approaches you shaking her head in
disgust. What is the problem?
Case 7
Drug Interactions
•
•
•
•
NNRTIs (EFV and NVP) induce the cytochrome P450 system
Protease inhibitors (esp RTV) inhibit the cytochrome P450 system
Ribavirin increases the toxicity due to ddI
NNRTIs decrease estradiol concentrations and, paradoxically, so do
protease inhibitors
• Methadone metabolism is increased by NNRTIs and variably affected
by protease inhibitors
• Atazanavir absorption is decreased with co-administration of PPI
• Watch out for significant drug interactions with all antiretrovirals,
especially those metabolized through the cytochrome P450 system
Case 7
For this patient:
•
•
•
•
•
•
•
•
•
Change omeprazole to ranitidine
Change diazepam to lorazepam
Watch for methadone withdrawl
Change lovastatin to pravistatin
Talk to pulmonologist about sildenafil dose
Transition from dilantin to other anticonvulsant (Keppra)
Don’t use ddI with ribavirin
Don’t use 3TC alone in patient with hepatitis B
Don’t rely on OCPs alone for birth control in patient on
HAART
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www.madisonclinic.org