Evolving Strategies in
HIV Diagnosis and
Treatment
Rob Smith
September 27,2013
Current Success Rate for cART
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Undetectable viral load in 85% of
treated patients
Reasons for treatment failure:
adherence (co-morbidities), access,
drug resistance (<5% of pts)
Not all treated patients achieve
immune reconstitution (especially if
CD4 nadir <200)
NEJM Mar., 2010
HIV Stats in the US
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50,000 new cases/yr; 18,000
deaths/yr
20-30% do not know HIV status
These 20% account for ½ of new
cases
By 2015, ½ of all HIV cases will be
>50 yo
HIV in Maine
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1800 HIV positive; prevalence
0.1%
300-500 do not know their HIV
status
50 new cases per year; >50% “late
stage”
60% MSM; 10% hetero w known
positive partner; 16% hetero w/o
known at risk partner; 12% IVDU
Why Do We Still See AIDS in the
US?
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“Late testers”: 30-40% present with AIDS
or develop in one year –this is true in
Maine as well as nationally (NEJM
2006;354:438).
Retention in care, adherence to meds
(Psychiatric disease, substance use, other
barriers to ongoing treatment—CID
2007:44:1493)
CID Sept. 15, 2010
Recent MMC Case
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50 yo man seen in MMC ER w
“difficulty breathing”.
Evaluated w BMP, CXR (“interstitial
infiltrates”). Rx albuterol.
3 wks later: Admit to MMC - hypoxic.
Relevant Hx: 25 lb weight loss since
Jan; cough x 3-4 months. Single
male. Not currently sexually active.
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Exam: thrush; oral hairy leucoplakia;
circular dermatophytic rash in axilla.
CT: bilat ground glass opacities in
upper and lower lobes
BAL: Pneumocystis; CMV
HIV VL 200,000; CD4 45
Another Recent MMC Case
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55 yo married man with fatigue, weight
loss, intermittent fever x 6 months. Rx for
“chronic Lyme” with 3 months oral
doxycycline.
Refer to dermatology for Rx psoriasis with
topical steroids
Refer to surgery for rectal fissure
Develops right facial droop, arm
weakness; thalamic brain mass on CT
scan--?tumor. Admit to MMC.
HIV positive; CD4 40
Newer Testing Strategies
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CDC proposals (2006):
Routine testing on adults (13-64)
Annual testing in those at risk
Pregnancy, contemplated pregnancy
“Opt out provision”; implied consent
Rapid Diagnostic Tests: 6 approved
“Point of care”
Home testing
Confirm Positives!
(NEJM 2006;354:438;PLOS
ONE 2012 ;7(9): e44417)
Maine HIV Testing Law 2007
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Changes in state law:
No pre-test counseling required
No written informed consent…..BUT
Does require
“A patient must be informed orally or in writing
that an HIV test will be performed unless (they)
decline”
“Information must include an explanation of
what an HIV infection involves, and the meaning
of positive and negative test results”
“If a test is positive, post-test counseling must
be provided”
Barriers to Routine HIV Testing
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Lack of knowledge of CDC
recommendations
USPHT DID not endorse –DOES as of
2013
Assumptions re: patient risk
Low priority—lack of time
Uncertainty re: informed consent law
Traditional Diagnostic Tests-HIV 1
ELISA plus Western Blot
Sensitivity: 99.5% post 3 months
disease
Specificity: 99.99%
False negatives: Window period;
agammaglobulinemia; SubType O,N
False Positives: “autoantibodies”
New HIV Diagnostic Algorithm2012
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HIV 1/2 Immunoassay screen (includes
antibody screen and p24 antigen)
If positive, reflex to Multispot (HIV 1 vs 2
assay) and HIV RNA (viral load)
If initial screen is negative, no additional
testing UNLESS clinical concern of acute
HIV disease; in this event, do HIV RNA
Adapted from CLSI consensus guideline
(June 2011)
HPI
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22 y.o. female with no hx illness who experienced
HA and fever 1 week after returning from
vacation to resort in Caribbean. Symptoms
progressed to severe fatigue and fainting.
9/19 went to ER. Febrile with UA showing 3-5
WBC. Diagnosed with UTI and given
ciprofloxacin.
9/22 back to ER for worsening dizziness, fever,
HA, fatigue. WBC 4.8 with 29% bands. Monospot
negative. Given IV hydration and sent home for
unspecified viral illness.
HPI continued
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9/24 Returned to ER. Fever, fatigue, dizziness,
new right inguinal LAD, dry cough and mild
diarrhea. Febrile to 101.4, marked orthostatic
hypotension. WBC 2.6, platelets 105, CRP 3,
CMP WNL
Admitted to an outside hospital with ? PID versus
Lyme. ID and Gyn consulted and started on
empiric Piperacillin/Tazobactam and Doxycycline.
Exam unremarkable --- ultrasound with 2 cm
inguinal node. CT abd/pelvis negative except a
question of inflammation in the right inguinal
node. Cardiac echo negative. CXR LLL infiltrate
versus atelectasis.
HPI continued
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Further workup revealed:
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Erhlichia serology negative
Lyme ELISA equivocal
Rapid strep negative
HIV ELISA (antibody) test negative
VDRL negative
C-diff and cryptosporidium negative
Chlamydia swab positive
Blood, stool, and urine cultures showed no growth.
WBC and platelet count improved and sent home
9/27 to complete a 2 week course of doxycycline
for presumptive chlamydia/LGV, ? atypical PNA, ?
Lyme
Continued to feel lightheaded so saw her family
physcian on 10/2. Afebrile: WBC 5.6 (21%
reactive lymphs), HCT 37, plat 354, ALT 69.
DDx Expanded
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Hx of unprotected sexual intercourse while on
vacation. No new findings on exam. Doxycycline
discontinued.
HIV viral load >750,000 copies/mL
Repeat HIV testing showed + ELISA and Western
blot
Pan-sensitive genotype
Pt started on anti-retroviral Rx for “Acute
retroviral syndrome’ or “Primary HIV”
Acute Retroviral SyndromeSymptoms
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Fever (96%)
Lymphadenopathy
(74%)
Pharyngitis (70%)
Rash (70%)
Myalgia/arthralgia
(54%)
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Headache
Diarrhea
Nausea and
vomiting
Hepatosplenomega
ly
Weight loss
Thrush
Neurologic
symptoms
Baseline Tests –HIV Dx
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HIV viral load, CD4 count
HIV genotype
CBC, CMP, RPR, Hep B/C serologies,
RPR, Toxo IgG (if CD4,200)
PPD (>5mm) or IGRA assay
Immunizations: PCV13 (Prevnar)
followed 8 wks later by PPSV23
(Pneumovax); Hep A/B if indicated
OI Prevention Guidelines (CDC
2009)
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CD4<200 (or 14%): PCP—TM/SZ
(daily), dapsone (+/-pyrimethamine
for toxo), atovoquone ($$), aerosol
pentamidine
CD4<100: Toxoplasmosis—if
seropositive; tm/sz or dapsone plus
pyrimethamine/leucovorin
CD4<50: MAI—azithromycin weekly
or clarithromycin daily
Who to Rx: DHHS Guidelines 2012
Rx recommended for all HIV-infected
individuals. Strength of
recommendation varies on the basis
of preRx CD4 count.
 CD4 <350
AI
 CD4 350 to 500
AII
 CD4 >500
BIII
A=strong evidence;B=moderate
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Why Rx Everyone with HIV
Rx reduces HIV-related events, HIVunrelated events and malignancies
(Note that CD4 nadir and “viremia copy
years” predict adverse outcomes)
 Public health benefit with reduced HIV
transmission (HPTN 052; Nejm 2011)
 Timing may depend on presence of
opportunistic infections
(Inconclusive evidence for “elite
controllers, long-term non-progressors”)
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Preferred Regimens (DHHS-2012)
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Efavirenz/tenofovir/emtricitabine
Ritonavir-boosted atazanavir and
tenofovir/emtricitabine (“truvada”)
Ritonavir-boosted darunavir and
tenofovir/emtricitabine
Raltegravir and
tenofovir/emtricitabine
(http://www.aidsinfo.nih.gov/ContentF
iles/AdultandAdolescentGL.pdf)
Alternative Regimens
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Rilpivirine/tenofovir/emtricitabine
Eltegravir/cobicistat/tdf/ftc
Lopinavir/r (“Kaletra”)/tdf/ftc
May substitute abacavir/lamivudine
(“Epzicom”) for
tenofovir/emtricitabine in patients
with renal disease, osteoporosis
Factors to Consider
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Underlying drug resistance
Potential adverse effects of drugs, drugdrug interactions
Pregnancy or significant child bearing
potential
Co-morbid conditions (Hepatitis B/C,
psychiatric, substance abuse)
Post-menopausal women or other risk
osteoporosis
Convenience
Always check for drug resistance
first
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HIV genotype for everyone, as a
baseline and if there is viral
breakthrough (>500 copies HIV)
If treatment is failing, obtain
genotype while on their regimen to
detect resistance mutations
HIV phenotype for known or
suspected complex drug resistance
mutation patterns ($$)
Management of HIV (DHHS 2011)
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Goal is “undetectable” (<48
copies/mL) HIV viral load (Assays
vary on limit of detection from <75
to <20 copies/mL)
Monitor the HIV viral load q 3
months once goal is achieved
CD4 counts can be repeated q 6-12
months if viral load controlled
Continue to Monitor For…
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New STDs (annual RPR/syphilis
screen)
New onset Hep C (annual)
TB (Risk dependent on community
context)
Metabolic disorders—ie fasting
glucose, lipids; creatinine and
urinalysis; testosterone in
symptomatic males; ?bone density
Be Aware of….
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Increased CAD risk
Increased risk for liver disease (fatty
liver)
Increased risk for renal disease
Neuro-cognitive disorders-10x
reduction in HIV dementia with
ARVs, but ?increased risk over time
AIDS (lymphoma, cervical) and NonAIDS malignancies (anal, lung,
liver)—related to CD4
NEJM 352:1 January 6, 2005
Post-Exposure Prophylaxis
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Occupational—CDC algorithm; UCSF
PEPline (888-448-4911 or
www.nccc.ucsf.edu/Hotlines/PEPline.html)
; risk if needlestick exposure to an HIV
infected pt=0.33%; if mucosal, 0.09% risk
Needlestick risk factors: index patient
status; hollow vs solid needle; visible
blood; deep puncture; needle into vessel
Treat ASAP (within 2 hours if possible)
Risk reduction of 80%
Post-Exposure Prophylaxis: NonOccupational
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CDC recommends nPEP if:
“Substantial risk of exposure w/in 72
hrs”
Mucosal or non-intact skin exposed
to “body fluids” (not saliva, urine etc
unless visibly contaminated w blood)
from known HIV source
Case by case if HIV status unknown
Should not be used as a frequent
intervention for any one patient
PEP:Choice of Meds
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New recommendations (2013):
truvada plus raltegravir (well
tolerated—J AIDS 2012)
If source pts viral resistance pattern
is known, choose effective
alternatives
Do not use abacavir/3TC
28d course of treatment
Pre-Exposure Prophylaxis
(“PrePEP”)?
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Effectiveness demonstrated in MSM trial:
44% overall, 73% if adherent; 66% in
heterosexual females
Cost effective (<$100K per QALY)—but
could result in annual expenditures of $4
billion (Ann Intern Med 2012; 156: 541)
Concerns: How to stratify risk; who pays;
drug resistance; long term risks of Rx
CDC interim guidelines for MSM (2011),
heterosexuals at high risk (2012); IVDU
Real or Functional Cures?
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Berlin patient: stem cell transplant;
donor was CCR5 mutation
homozygous—off ARV x 5yrs
Activate resting memory cells with
latent infection and Rx? Use of
vorinostat (Nature 2012; 487: 482)
Resources
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Primary Care Guidelines (IDSA-2009)
CID 2009; 49: 651-681.
Pregnancy:
http://aidsinfo.nih.gov/guidelines
Opportunistic Infections:
http://aidsinfo.nih.gov/guidelines
Occupational Exposure
http://www.cdc.gov/mmwr
PEPline: 1-888-448-4911
How to Treat HIV
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Preferred Regimens—Treatment
Naïve
(DHHS 01/10/2011)
Efavirenz plus tenofovir/emtricitabine
Atazanavir/r plus same
Darunavir/r plus same
Raltegravir plus same
HIV in Refugee Populations
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Less likely to start ARV therapy
Similar CD4 at time of presentation
Higher likelihood co-infection with latent TB,
Hepatitis B
Higher prevalence of a mental health disorder
(especially PTSD)
Acquisition by heterosexual exposure rather than
IVDU or MSM
Beckwith et al; 2009;13:186. Internat J Inf Dis.
Science Vol. 332 May 13, 2011
Science Vol. 333 July 1, 2011
Prevention of HIV Infection
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Reduce high risk behaviors:
education re: safer sex, clean
needles (needle exchange programs)
Pre and post-exposure chemoprophylaxis
“Test and treat”—lower the
“community viral load”
“It has also become clear that
finding the cause of an infectious
disease is the alpha but not the
omega of its eradication.”
R.C. Gallo MD and Luc Montagnier MD
(“The Discovery of HIV as the Cause of
AIDS”, NEJM 2003; 349: 24)
“Test and Treat”?
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More effective identification of HIV
positives—can be targeted to higher
risk groups
Lower “community viral load” leads
to lower high transmission
Models: San Fran--MSM (CID 2011);
DC--community (“modest impact on
HIV transmission”-CID 2010)
Rapid HIV Testing in the ER
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N=849 adults –oral test –Oraquick
Brigham and Women’s Hospital ER
39 with positive results: 5 positive on
confirmation…26 non-infected (8 declined)
8-30 fold increased odds of HIV with
positive test, but specificity less than
predicted
(Ann Int Med 2008;
149: 153-160)
Increased false positives as kits near
expiration date (PLOS ONE; 2009)
NEJM Mar. 18, 2010
NEJM April 10, 2008
Timing of HIV Rx in Pts with
Opportunistic Infections
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Medication reactions and interactions
(ie 2/3 pts with PCP may develop
rash with TM/SZ)
“IRIS” reactions:
In general, start within 2 wks in pts
with AIDS…exceptions include TB in
patients with CD4>200; cryptococcal
or TB meningitis
Interpreting HIV Serology
HIV Indeterminate
Seroconversion
suspected
HIV-2
suspected
Low risk
patient
Obtain
viral load
Obtain
HIV-2 WB
Retest in
3-4 months
New Responses to Old Questions
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How is HIV diagnosed in 2012 (ie
there is a new algorithm)
Who should be treated?
What medications should be used
and what adverse effects might we
expect?
How is timing of treatment affected
by presence of opportunistic
infections?