African American HIV University
Wednesday, August 26, 2015
Rationale for and Goals of
ARV Treatment
Oladunni Adeyiga, MD, MS
STAR Fellow
Department of Medicine
Division of Infectious Diseases
2
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Outline
• Cases
• Learning Objectives
• HIV and AIDS classification
• ARVs: Brief History
• Before ARVs
• HIV viral dynamics and AIDS
• Effect of ARVs
• Cases and Practice Questions
• Summary
• Questions
3
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Cases
4
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Case 1
TM is a 30 year old male who without any prior known
chronic illnesses. A few months ago he developed a
cough that has persisted. He has also felt a bit tired,
but he’s a writer and has been spending long hours
working to meet his publisher’s deadline. At the urging
of a friend, he finally decides to see a doctor. His friend
noticed that he became extremely short of breath during
their usual morning run, which is unusual. The doctor
discusses his symptoms with him, performs a physical
exam, and orders a few tests. He is told that he is HIV+
and likely has pneumonia as a result of this infection.
5
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Case 2
SO is a 27 year old female who was initially brought in
by her male friend. She is back in the doctor’s office
today to go over her test results. When she initially
came in, she suspected that she was pregnant; she
also made it very clear that this was not be discussed
while her male friend was in the room. She was
somewhat evasive when probed about the nature of
their relationship. With regard to her symptoms, she
indicated that she had been fatigued, with nausea and
vomiting. Her pregnancy test was positive. At that time,
the doctor sent routine screening tests, including HIV
antibody testing, which was positive.
6
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Case 3
HK is 45 year old male who comes to the doctor’s office
in a panic. A few weekends ago he went away with
some friends for a bachelor party, the details of which
are a bit hazy at this time. There was probably alcohol
involved…he can’t remember much else. His concern
is that since then he’s developed a fever, a rash, and a
slight headache (which is improved when the lights are
dim). He’s worried that he may have caught something
from someone, though he is sure that he didn’t do
anything extremely out of the ordinary. After his
evaluation, he is told that testing for HIV and syphilis
are both positive.
7
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Learning Objectives
8
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Learning Objectives
• Understand the causal relationship between HIV
infection and the development of AIDS
• Understand the components of an ARV regimen
• Understand the effect ARVs have on the health of HIV
infected patients
• Understand the community benefits of ARV use in HIV
infection
• Understand the role between the patient and clinician in
the use of ARVs
9
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV and AIDS
Classification
10
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD
African American HIV University
Wednesday, August 26, 2015
1993 CDC Revised Classification System
HIV Infection
Clinical Categories
CD4+ T cell
categories
Absolute
CD4+ count
(A)
(B)
(C)
CD4+ %
Asymptomatic,
acute (primary)
HIV or PGL*
Symptomatic,
not (A) or (C)
conditions
AIDSindicator
conditions
of total T-cells
(1)
≥ 500/mL
(≥29)
A1
B1
C1
(2)
200 - 499/mL
(14-28)
A2
B2
C2
(3)
< 200/mL
(<14)
A3
B3
C3
*Persistent Generalized Lymphadenopathy
Castro, KG. et. al. (1993) CID; 17(4) pp 802-810
11
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
1993 CDC Revised Classification System
HIV Infection
• Clinical categories
• Category
A
• Category
B
• Category
C
• CD4+ T cell categories
• (1)
Absolute #
≥ 500/mL
• (2)
Absolute #
200 - 499/mL OR
% total # of T-cells 14-28
• (3)
Absolute #
< 200/mL
% total # of T-cells <14
OR
OR
% total # of T-cells ≥ 29
Castro, KG. et. al. (1993) CID; 17(4) pp 802-810
12
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
1993 CDC Revised Classification System
HIV Infection: Clinical Category A
• Acute (primary) HIV
• Asymptomatic HIV
• Persistent generalized lymphadenopathy
Castro, KG. et. al. (1993) CID; 17(4) pp 802-810
13
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
1993 CDC Revised Classification System
HIV Infection: Clinical Category B
• Symptomatic conditions that are NOT AIDS defining but
• Are
attributed to HIV infection or indicative of a defect in cellmediated immunity
• Are
considered by physicians to have a clinical course or require
management that is complicated by HIV
• Example conditions
• Bacillary
angiomatosis
• Candidiasis,
oropharyngeal (thrush)
• Candidiasis,
vulvovaginal; persistent, frequent, or poorly
responsive to therapy
• Cervical
dysplasia (moderate or severe)/cervical carcinoma in
situ
Castro, KG. et. al. (1993) CID; 17(4) pp 802-810
14
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
1993 CDC Revised Classification System
HIV Infection: Clinical Category B
• Example conditions cont.
• Constitutional
symptoms, such as fever (38.5 C) or diarrhea
lasting > 1 month
• Hairy
leukoplakia, oral
• Herpes
zoster (shingles), involving at least two distinct episodes
or more than one dermatome
• Idiopathic
thrombocytopenic purpura
• Listeriosis
• Pelvic
inflammatoryd disease, particularly if complicated by
tubo-ovarian abscess
• Peripheral
neuropathy
Castro, KG. et. al. (1993) CID; 17(4) pp 802-810
15
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
1993 CDC Revised Classification System
AIDS Surveillance Case Definition
• Candidiasis of esophagus, trachea, bronchi, or
lungs
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis with diarrhea > 1 month
• Cytomegalovirus disease of any organ other
than liver, spleen, lymph nodes
• Cytomegalovirus retinitis (with vision loss)
• HSV with mucocutaneous ulcer >1 month or
bronchitis, pneumonitis, esophagitis
• HIV-related encephalopathy
• Mycobacterium avium complex or M. kansasii,
disseminated
• Pneumocystis carinii (P jiroveci) pneumonia
• Progressive multifocal leukoencephalopathy
• Toxoplasmosis of brain
• Wasting syndrome due to HIV
•
•
•
•
•
Coccidioidomycosis, extrapulmonary
Histoplasmosis, extrapulmonary
Isosporiasis with diarrhea for >1 month
Kaposi's sarcoma
Lymphoma
•
Primary, of brain
•
Immunoblastic (or equivalent term)
•
Burkitt’s (or equivalent term)
• Mycobacterium tuberculosis, disseminated
• Salmonella septicemia (nontyphoid),
recurrent
• CD4+ count < 200 cells/mm3 OR CD4+ %<14*
• Cervical cancer, invasive*
• Mycobacterium tuberculosis, pulmonary*
• Pneumonia, recurrent*
*Requires laboratory confirmation of HIV infection
Castro, KG. et. al. (1993) CID; 17(4) pp 802-810
16
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
WHO (World Health Organization) 2005
Revised Clinical Staging of HIV/AIDS
for Adults and Adolescents
• Primary HIV Infection
•
•
Asymptomatic
Acute retroviral syndrome
• Clinical stage 3
•
• Clinical stage 1
•
•
Asymptomatic
• Persistent generalized lymphadenopathy
(PGL)
•
•
• Clinical stage 2
•
•
•
•
Moderate unexplained weight loss (<10%
of presumed or measured body weight)
• Recurrent respiratory tract infections
(RTIs,sinusitis,bronchitis, otitis media,
pharyngitis)
• Herpes zoster
• Angular cheilitis
• Recurrent oral ulcerations
• Papular pruritic eruptions
• Seborrhoeic dermatitis
• Fungal nail infections of fingers
Conditions where a presumptive
diagnosis can be made on the basis of
clinical signs or simple investigations
•
•
•
Severe weight loss (>10% of presumed or
measured body weight)
Unexplained chronic diarrhoea for longer
than one month
Unexplained persistent fever (intermittent
or constant for longer than one month)
Oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (TB) diagnosed in
last two years
Severe presumed bacterial infections (e.g.
pneumonia, empyema, pyomyositis, bone
or joint infection, meningitis, bacteraemia)
Acute necrotizing ulcerative stomatitis,
gingivitis or periodontitis
Conditions where confirmatory diagnostic
testing is necessary
•
Unexplained anemia (<8 g/dl), and or
neutropenia (<500/mm3) and/or
thrombocytopenia (<50 K/mm3) for more
than 1 month
17
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
WHO (World Health Organization) 2005
Revised Clinical Staging of HIV/AIDS
for Adults and Adolescents
• Clinical stage 4
•
Conditions where a presumptive diagnosis
can be made on the basis of clinical signs
or simple investigations
•
•
•
•
•
•
•
•
•
Unexplained severe wasting or severe
malnutrition not adequately responding to
standard therapy
Pneumocystis pneumonia
Recurrent severe presumed bacterial
infections (e.g. empyema, pyomyositis, bone
or joint infection, meningitis, but excluding
pneumonia)
Chronic herpes simplex infection; (orolabial
or cutaneous of more than one month’s
duration)
Extrapulmonary TB
Kaposi’s sarcoma
Oesophageal candidiasis
CNS toxoplasmosis (outside the neonatal
period)
HIV encephalopathy
• Clinical stage 4
•
Conditions where confirmatory diagnostic
testing is necessary
•
•
•
•
•
•
•
•
•
•
•
•
CMV infection (CMV retinitis or infection of
organs other than liver, spleen or lymph
nodes; onset at age one month or more)
Extrapulmonary cryptococcosis including
meningitis
Any disseminated endemic mycosis (e.g.
extrapulmonary histoplasmosis,
coccidiomycosis, penicilliosis)
Cryptosporidiosis
Isosporiasis
Disseminated non-tuberculous
mycobacteria infection
Candida of trachea, bronchi or lungs
Visceral herpes simplex infection
Acquired HIV associated rectal fistula
Cerebral or B cell non-Hodgkin lymphoma
Progressive multifocal
leukoencephalopathy (PML)
HIV-associated cardiomyopathy or HIVassociated nephropathy
18
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
ARVs:
Brief History
19
1982:
1995:
1981
AIDS
PIs
1983:
HIV
1987:
AZT
1997:
NNRTIs
2006:
ATRIPLA
2007:
ISTI
2003:
PEPFAR
2003:
2015
ENTRY
INHIBITORS
• 1981:
2005:
2000:
•2005:
1987:
July:
ABC
HSR
association
with
Combivir,
Zidovudine
May:
laboratory
for
Saquinavir
PEPFAR
Generic
adults
end-points
AZT
and
5 pills
children
now 2
>6yo
pillsHLABID
(IDV)/Crixivan
approval
for
AIDS
first
reported
B*5701
allele
noted
single
or(lopinavir
combination
use
st tentative
Sept:
Oral
AZT,
FTC
Soln
April:
Jan:
July:
June:
Kaletra
Nelfinavir
1
Generic
Oral
fosamprenavir
ddI
mesylate
approval
out
of(AZT)/Retrovir
+India,
ritonavir)
(NFV)/Viracept;
soln
under
FDC
a new
Atripla
Approval
ofGeneric
Zidovudine
FDA History
Timeline*
drugs
approved
for
sale
in
FDA
(TDF/FTC/EFV),
process
3TC/AZT
with
June:
Nevirapine
approved
forapproval
children
infor
1989
*Source: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm117935.htm
Oct: Generic
Norvir
approved
1 mo
to
2
yr olds
July:
Videx
5
Generic
pills
EC
now
NVP
for
2(NVP)/Viramune
pills
combination
BID
use
Accessed August 11, 2014
the
US: AZT,
ddI,ABC
d4T,out
PEPFAR.
copackaged
Copackaged
with
Combivir
of India
approval
for
combination
use,
• 1989:
Approval
of
Dideoxyinosine
(ddI)/Videx
Nov:
Oral
generic
3TC Soln
out of India
June: Maraviroc
Aug:
Trizivir
Atazanavir
(ABC/3TC/AZT)
(MVC)/Selzentry
sulfate
(ATV)/Reyataz
st non-nuc
and
nevirapine
1
• 2009:
Many FDCs
(including
or
Aug:
Generic
NVP
outEFV/3TC
of India,
3TC/AZT
approved,
combination
•• 1995:
April:
Saquinavir
open
label
study
allowed
Dec:
Generic
oral
d4T,
generic
oral
2001:
Jan:
July:
Warning
Emtricitabine
against
(FTC)/Emtriva,
Zerit
and
Videx
Trizivir
inout
st
FDC/TDF
and
3TC/AZT/NVP)
Feb:
Caution,
of
South
avoid
Africa,
SQV/r
d4T
with
capsules
rifampin
• 1997:
Mar: out
Nelfinavir
NFV/(Viracept)
1
for
children
NVP
out
of
India
pregnant
warning
(early
women
virologic
nonNov: 3TC/d4T/NVP
Lamivudine
(3TC)/Epivir
(drug-induced
of
India
hepatitis)
PI
labeled
for
use
in
children
• 2011:
FDC
Complera
(3TC/RPV/TDF)
Oct:
response)
Tipranavir
traditional
approved
(forH
accelerated
approvaluse
(toaccelerated
be PPI,
• 2006:
Jan:
Caution,
atazanavir
with
Oct:
Tenofovir
(TDF)/Viread
and
adults
2
Oct:
Oral
ddI,
atazanavir
300
mg
capsule
Mar:
Alfuzosin
(a
blocker)
contraindicated
Rilpivirine
(RPV)/Edurant
treatment
experienced
with
PI
used
in combination
with
AZT)
blockers,
methadone,
rifampin,
ddI
Aug:
approval
Suggestion
(first
that
nucleotide
Atazanavir
analog)
should
with
norvir.
Also
norvir
interactions
April:
Delavirdine
(DLV)/Rescriptor,
Nov:
Generic
resistance)
ABC,
FDCwith
(fixed
dose
Viramune
XR
be
boosted
if
used
Tenofovir
Dec:
Saquinavir
(SQV)/Invirase
May:
for
generic
• 2002:
Feb: Tentative
Once
dailyapproval
EFV,
Boosted
APV ABC
with
fluticasone
and
trazodone
for
combination
use
combination)
d4T/3TC/NVP
Raltegravir(RAL)/Isentress
approved
approved
for combination
use
with
↑Oct:
Rate
of
bac’t
PNA
seen
w/
Fuseon
Fosamprenavir
(FPV)/Lexiva
Tentative
approval
for
another
June:
Once daily
Epivir
(3TC)
now
class D
Sept:
Combivir
(AZT
+pregnancy
3TC)
st PI)
• 2007:
Jan: Efavirenz
Tentative
approval
FDC
3TC/d4T
nucs
(1
approved
Lexiva
approved
forcobicistat,
1400
mg
• 2012:
FDC
Stribild:
elvitegravir,
general
3TC
solution
out
of
India
Aug:
Caution
on
Amprenavir
use
with
April:
daily
Kaletra
formulation
Nov: Once
Fortovase
(new
formulation
of
EFV
boosted
interaction
daily
dosing
with
in
treatment
Stavudine
(d4T)
Zerit
traditional
FTC,TDF
• 2004:
Jan: Avoid
atazanavir
with of
indinavir
Accelerated
approval
darunavir
Methadone
and
OCPs
approved
Saquinavir
(SQV)/Invirase
)
rifampin/diltiazem/azole/statins
naïve.
approval for patients with prior
• 2013:
Dolutegravir
(DTG)/Tivicay
(DRV)/Prezista,
boosted
(for
Aug:
Epzicom
(ABC/3TC)
and
Truvada
Sept:
Caution
on
ddI
use
w/
ribavirin
and
May:
Generic
3TC,
Foscarnet
•• 1998:
Efavirenz
(EFV)/Sustiva
2008:
Jan: Etravirine
FDC
3TC/AZT/NVP
(ETR)/Intelence
prolonged
AZT
therapy
(prior
treatment
experienced)
(TDF/FTC)
TDF;↑ddI
levels
June:
Accelerated
accelerated
approval
approval
of
for
Tipranavir
patients
Dec:
Abacavir
(ABC)/Ziagen
accelerated
accelerated
approval
already)
Feb:
Entecavir
noted
to
induce
M184V
Combination
3TC/AZT/NVP,
Oct:
Traditional
approval
for
Fuzeon
Dec: Extended
release
Zerit EFV
(d4T) d4T,
(TPV)/Aptivus,
with
NNRTI
resistance
generic
approval
• 1996:
Mar:
Ritonavir
(RTV)/Norvir
and
ABC
out
of
India because
Mar:
Oral
soln
ddI,
generic
EFV
fromofIndia
st
Dec:
1
generic
antiretroviral
(ddI),
• 2003:
Mar:
Enfuvirtide
(T-20)/fuzeon
approved
July:
Feb:
Tentative
600
mg
Prezista
approval
tablets
for genetic
d4T,
1999:
Amprenavir
(APV)/Agenerase
based
on
(children
1997),
Indinavir
20
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
FDA History Timeline*
*Source: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm117935.htm
Accessed August 11, 2014
• 1981:
First cases
• 1982:
AIDS terminology used by CDC
• 1983:
Identification of HIV as virus leading to AIDS
• 1987:
First anti-retroviral (Zidovudine); class: NRTI
• 1995:
First PI, beginning of potent ART (HAART)
• 1997:
New class: NNRTI
• 2003:
PEPFAR announced by US President Bush
• 2003:
New class: Entry Inhibitors
• 2006:
Atripla (Single pill, daily medication)
• 2007:
New class: ISTI
21
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Before ARVs
22
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Clinical course of HIV Infection without therapy:
Summary
• Acute Infection
• Clinical latent period
• Long-term nonprogressors
• Elite controllers
• Early symptomatic HIV infection
• AIDS defining illness
• Advanced AIDS; death
23
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Clinical course of HIV Infection without therapy:
Summary
Elite Controllers
Acute Infection
Long-term
nonprogressors
0
Clinical latent period
6 months
Early Symptomatic
HIV Infection
Time
Advanced
HIV Infection
Years
24
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Clinical course of HIV Infection without therapy:
Clinical latent period
• Spans the time when a patient is infected to 6 months
• No symptoms
• Under examination, there may be enlarged lymph
nodes
25
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Clinical course of HIV Infection without therapy:
Early symptomatic HIV infection
• Class B (formerly called “AIDS-related complex”)
26
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Viral Dynamics and
AIDS
27
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Rapid decline in blood HIV virion levels
HIV Replication in Infection
Schacker, TW. et. al. (1998) Ann Int Med; 128(8): pp 613-620
28
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Effect on CD4+ count without therapy
Mean
CD4+
counts for 318 patients from the MACS group
N:
L:
M:
S:
Groups Represented Above
No AIDS developed during 6 years of follow-up;
AIDS developed > 6 years of follow-up;
AIDS developed 3-6 years of follow-up;
AIDS developed <3 years of follow-up;
252 patients
4 patients
28 patients
20 patients
Stein, DS. et. al. (1992) J Inf Dis; 165(2): pp 352-363
29
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Trends in AIDS Incidence, Deaths, and Prevalence—
US, 1996
Thousand Persons Infected
• 1981 – 1996: 573,800 persons age ≥13 yrs
Reported Cases
400
350
300
250
200
150
100
50
0
1981-1992
1992-1996*
*expanded AIDS surveillance case definition implemented
MMWR Morb Mortal Wkly Rep (1997);46:165-73.
30
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Trends in AIDS Incidence, Deaths, and Prevalence—
US, 1996
Thousand Persons Infected
• 1981 – 1996: 573,800 persons age ≥13 yrs
100
90
80
70
60
50
40
30
20
10
0
Yearly Reported Cases
Men
Women
1992
1993*
1994
1995
1996**
*expanded AIDS surveillance case definition implemented
**largest number of newly reported cases from Black, non-Hispanic population
MMWR Morb Mortal Wkly Rep (1997);46:165-73.
31
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Trends in AIDS Incidence, Deaths, and Prevalence—
US, 1996
• 1981 – 1996: 573,800 persons age ≥13 yrs
Race/Ethnicity of Total Reported Cases
1.8%
White, non-Hispanic
17.6%
Black, non-Hispanic
46.6%
34.6%
Hispanic
Asian/Pacific Islander
American
Indian/Alaskan Native
Unknown Ethnicity
MMWR Morb Mortal Wkly Rep (1997);46:165-73.
32
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Estimated AIDS-opportunistic illness (OI) incidence and estimated deaths among persons
with AIDS (AIDS deaths)*, adjusted for delays in reporting, by quarter year of
diagnosis/death — United States, 1984–June 1996†
AZT
PIs
MMWR Morb Mortal Wkly Rep (1997);46:165-73.
33
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Number of prevalent AIDS cases among persons aged ≥13 years, adjusted
for delays in reporting, by quarter year — United States, 1988–June 1996*
MMWR Morb Mortal Wkly Rep (1997);46:165-73.
34
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Kaplan-Meier estimates of the cumulative probability of dying according to the
number of years from seroconversion. HIV indicates human immunodeficiency virus.
*Number of patients remaining at each time point who were at risk
Phillips et. al. JAMA (1992);268(19): pp. 2662-2666.
35
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Mother to Child Transmission
John, GC and Kreiss, J. Epi Reviews (1996); 18(2): pp 149-157.
36
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
HIV/AIDS Outcomes Prior to ART
Summary
African American HIV University
Wednesday, August 26, 2015
• Ongoing HIV viral replication
• Destruction of CD4+ T cells
• Resulting cell-mediated immunity defect
• Transmission of HIV
• To
• In
sexual contacts
utero
• Development of
• Recurrent
Infections
• Malignancy
• Death
37
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Infection
Ongoing HIV viral replication
AIDS
38
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Infection
ARVs
Ongoing HIV viral replication
AIDS
39
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
OVERALL RATIONALE
to
from
to the development of
40
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Effect of ARVs
41
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
ARVs: 1986-1997
• 1986: First clinical trial with Zidovudine1
• 1993: Two drug therapy2
• 1996: Saquinavir, 1st PI used in combination therapy3
• 1997: Indinavir (also a PI) used in combination therapy4,5
1Fischl,
MA et. al. (1987) NEJM; 317(4): pp. 185-91
AC et. al. (1993) Ann Intern Med.; 119(8): pp. 786-793
3Collier, AC et. al. (1996) NEJM; 334(16): pp. 1011-7
4Hammer, SM et. al. (1997) NEJM; 337(11): pp. 725-733
5Guilick, RM et. al. (1997) NEJM; 337(11): pp. 734-739
2Collier,
42
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
ARVs: 1986-1997
What did we learn?
African American HIV University
Wednesday, August 26, 2015
• Multiple drugs needed
• Potent drugs needed
• Antimicrobial prophylaxis for opportunistic infections
Corey, L and Holmes, KK. (1996) NEJM; 336(16): pp. 1142 – 1143
Girard, PM et. al., (1989) Lancet; 333(8651): pp 1348-53
Ruskin, J and LaRiviere, M. (1991) Lancet; 337(8739): pp. 468-71
43
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
• In general:
• base
= INSTI, Maraviroc, NNRTI, PI
PLUS
• backbone = 2 N[t]RTIs (nucleoside/nucleotide reverse transcriptase inhibitors)
TWO
Nucleoside/
Nucleotide
Reverse transcriptase
Inhibitors
Base
Integrase Inhibitor OR
CCR5 Antagonist OR
Non-nucleoside Reverse Transcriptase Inhibitor
OR
Protease Inhibitor
44
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Life Cycle
1. Cell entry
ENTRY INHIBITORS
(CCR5 ANTAGONISTS)
FUSION INHIBITORS
3. Integration
INTEGRASE
2. Reverse Transcription
NON-NUCLEOSIDE REVERSE
INHIBITORS
4. Protein assembly
PROTEASE INHIBITORS
TRANSCRIPTASE INHIBITORS
NUCLEOSIDE/NUCLEOTIDE REVERSE
TRANSCRIPTASE INHIBITORS
5. Budding
Tsibris, AMN and Hirsch, MS. (2010). Chapter 128. Antiretroviral Therapy for Human Immunodeficiency Virus Infection Mandell,
Douglas, and Bennett’s Principles and Practice of Infectious Diseases (7th Ed.). Philadelphia, PA: Churchill Livingstone/Elsevier
45
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Life Cycle
• Cell entry
• Fusion
• Entry
Inhibitors
Inhibitors (CCR5 antagonists)
• Reverse Transcription
• Nucleoside/Nucleotide
• Non-nucleoside
Reverse Transcriptase Inhibitors
Reverse Transcriptase Inhibitors
• Integration
• Integrase
Inhibitors
• Protein production and virion assembly
• Protease
Inhibitors
• Budding
Tsibris, AMN and Hirsch, MS. (2010). Chapter 128. Antiretroviral Therapy for Human Immunodeficiency Virus Infection Mandell,
Douglas, and Bennett’s Principles and Practice of Infectious Diseases (7th Ed.). Philadelphia, PA: Churchill Livingstone/Elsevier
46
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Rationale #1: In general, three active drugs
from two different classes are needed to
suppress viral replication.
47
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Tuesday, September 2, 2014
ARVs: 1997-2006
• Highly active antiretroviral therapy = HAART
• Establishment of target viral load
• Risk vs. Benefit
• Benefits
CD4+ counts, decreased viral load
• Increased
• Delay
in progression to AIDS, reduction in perinatal transmission
• Risk
• Metabolic
• Drug
complications
interactions
• Cost
• Treatment
failure
48
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Effect of ARVs:
↓ in HIV Viral Replication; ↑ in CD4+ counts
Evolution of viremia and CD4+ counts under different treatment regimens. Mean changes from baseline of HIV RNA and of CD 4+ counts are given.
Vertical bars represent standard deviations. Monotherapy = 1 RTI; RTI Combination = 2 RTI; HAART = 1 RTI + 2 PI OR 2 RTI + 1 PI
*RTI = NRTI
Erb, P. et al., JAMA (1996); 18(2): pp 149-157.
49
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Patients with Virologic Failure, %
Effect of ARVs: Patient Adherence
Adherence to antiretroviral therapy and
virologic failure
100
80
60
40
54.6
20
66.7
71.4
82.1
21.7
0
≥95
90 - 94.9
80 - 89.9
70 - 79.9
Adherence, %
<70
Paterson, DL. et al., Ann Intern Med (2000); 133(1): pp 21-30.
50
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Rationale #2: Compliance with medications
is CRITICAL for suppression of HIV viral
replication.
51
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Effect of ARVs: PMTCT
Prevention of Mother to Child Transmission
n = 250 (22%)
n = 396 (25.7%)
n = 186 (16%)
n = 710 (62%)
Cooper, ER., et. al. JAIDS (2002); 29(5): pp 484-494.
52
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Effect of ARVs: PMTCT
Prevention of Mother to Child Transmission
Number of children acquiring HIV infection in lowand middle-income countries, 1996-2012
Global Update on HIV Treatment 2013: Results,
Impact, and Opportunities. WHO Report. June 2013
53
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Effect of ARVs: Transmission
Donnell, D., et. al. Lancet (2010); 375(5): pp 2092-98.
54
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
Effect of ARVs:
Decline in AIDS and death rates
African American HIV University
Wednesday, August 26, 2015
• ACTG 1751
• EuroSIDA study 20032
• Swiss HIV Cohort Study 20053
1Katzenstein,
DA. et. al. (1996) NEJM; 335(15): 1091-8
et. al. (2003) Lancet; 362(9377): pp. 22-29
3Sterne, JAC et. al. (2005) Lancet; 366(9483): pp. 378-384
2Mocroft, A.
55
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
ARVs: 2006-2015
*Era of Single Pill, Once a day Regimen
• Atripla®
• Efavirenz
+ Tenofovir + Emtricitabine
• Gilead Sciences and Bristol-Myers Squibb
• Complera®
• Rilpivirine
+ Tenofovir + Emtricitabine
• Janssen Therapeutics and Gilead Sciences
• Stribild®
• Elvitegravir
+ Cobicistat** + Tenofovir + Emtricitabine
• Gilead Sciences
• Triumeq®
• Dolutegravir
+ Abacavir + Lamivudine
• ViiV Healthcare
*For those patients who are appropriate candidates
**Cobicistat is NOT an ARV, it is used to maintain appropriate blood levels of Elvitegravir
56
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
2015 ARV Recommendations:
Who should be treated?
• International Antiviral Society-USA Panel (IAS—USA)1
should be offered treatment regardless of CD4+ count
(Rating: AIa-BIII)
• Everyone
• Reasons:
lack of demonstrated harm from early therapy, costeffective in resource –rich and –poor nations, more than 20 drugs
are expected to become generic in the next 4 years.
• US Department of Health and Human Services (DHHS)2
should be offered treatment regardless of CD4+ count
(Rating: AI-BIII)
• Everyone
• Reasons:
reduce risk of disease progression, to prevent HIV
transmission.
1Gϋnthard,
HF. et. al. (2014) JAMA; 312(4) pp 410-425
2http://aidsinfo.nih.gov/guidelines
57
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
World Health Organization (WHO) 2013 Consolidated ARV Guidelines
Population
Adults and
adolescents
(≥10 years)
Children ≥ 5
years old
Children 1-5
years old*
Infants < 1 year
old*
Recommendation
Initiate ARV if CD4+ cell count ≤500 cells/mm3
•As a priority, initiate ARV in all individuals with severe/advanced HIV disease (WHO clinical stage
3 or 4) or CD4+ count ≤350 cells/mm3
Initiate ARV regardless of WHO clinical stage and CD4+ cell count
•Active TB disease
•HBV coinfection with severe chronic liver disease
•Pregnant and breastfeeding women with HIV
•HIV-positive individual in serodiscordant partnership (to reduce HIV transmission risk)
Initiate ARV if CD4+ cell count ≤500 cells/mm3
•As a priority, initiate ARV in all children with severe/advanced HIV disease (WHO clinical stage 3
or 4) or CD4+ count ≤350 cells/mm3
Initiate ARV regardless of CD4+ cell count
•WHO clinical stage 3 or 4
•Active TB disease
Initiate ARV in all regardless of WHO clinical stage and CD4+ cell count
•As a priority, initiate ART in all HIV-infected children 1-2 years old or with severe/advanced HIV
disease (WHO clinical stage 3 or 4) or with CD4+ cell count ≤750 cells/mm3 or <25%, whichever is
lower
Initiate ARV in all infants regardless of WHO clinical stage and CD4+ cell count
*Initiate ARV in all HIV-exposed children below 18 months of age with presumptive clinical diagnosis of HIV infection
http://www.who.int/hiv/pub/guidelines/arv2013/download/en/
58
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Rationale #3: In general, in the US everyone
who has been infected with HIV should be
offered ARV treatment.
59
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Evidence of rebound viremia after stopping
ARVs
Felipe, G., et. al. AIDS (1999); 13(11): pp F79 – F86.
60
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Cumulative Probability of the Primary End Point (Panel A); Death from
Any Cause (Panel B); Major Cardiovascular, Renal, or Hepatic Disease
(Panel C); and Grade 4 Adverse Events (Panel D)
The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med
2006;355:2283-2296
The Strategies for Management of Antiretroviral Therapy
(SMART) Study Group. N Engl J Med (2006);355:2283-2296
61
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Rationale #4: ARV Treatment should be
LIFELONG.
62
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Summary: Rationale for ARV Treatment
Suppress viral replication
• In general, three active drugs from two different
classes are needed to suppress viral replication.
• Compliance with medications is critical for
suppression of HIV viral replication.
• In general, in the US, everyone who has been
infected with HIV should be offered ARV treatment.
• ARV Treatment is LIFELONG.
1Bartlett,
JG. The stages and natural history of HIV Infection. (2012) ww.uptodate.com
2http://aidsinfo.nih.gov/guidelines
63
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Goals of ARV Treatment
• Laboratory goals
• Reduce
viral replication
• Increase
CD4+ counts; restore and preserve immunologic function
• Clinical goals
• Reduction
is AIDS defining events
• Reduction
in opportunistic infections
• Reduction
in AIDS associated malignancies
• Reduction
in hospitalizations
• Reduction
in mortality; prolong duration and quality of survival
• Reduction
in transmission (including Pre & Post Exposure
Prophylaxis)
• Improvement
in non-AIDS associated malignancies, TB, HIVAN +
ESRD, cardiovascular health, TB
1Bartlett,
JG. The stages and natural history of HIV Infection. (2012) ww.uptodate.com
2http://aidsinfo.nih.gov/guidelines
64
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Early HIV Infection: Treatment
*Clinical trial outcome data is limited
Possible benefits:
Risks:
• Decreased severity of acute
disease
 Drug-related toxicity
• Lower viral “set point”
• Reduced viral reservoir
• Reduced rate of mutation
 Earlier emergence of drug
resistance
 Adverse effects on
quality of life
• Preserved immune function
• Lower risk of HIV transmission
www.aidsetc.org
April 2015
66
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Treatment Cascade/HIV Care Continuum1,2
• HIV testing and diagnosis
• Linkage to care
• Retention in care
• Initiation of effective ARVs
• Adherence to treatment
1http://aids.gov/federal-resources/policies/care-continuum/
2Gardner,
EM, et. al. CID (2011); 52(6): pp 793-800.
66
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Care Continuum: Best Case Scenario—
Everyone is successfully diagnosed and treated!
HIV Care Continuum: Best Case Scenario
Percent of all People with HIV
100
100
100
100
100
100
Diagnosed
Linked to
Care
Retained in
Care
Prescribed
ARVs
Virally
Suppressed
80
60
40
20
0
67
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
HIV Care Continuum1:
Regarding HIV transmission, hose not retained
in care are more likely to transmit2
1http://aids.gov/federal-resources/policies/care-continuum/
2JAMA
Accessed August 14, 2015
Intern Med. 2015;175(4):588-596.
68
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
OVERALL GOAL
To build a thriving long term
between the
so that HIV can be managed
.
69
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Practice Questions!
70
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
OVERALL RATIONALE
to
from
to the development of
71
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
In general, __ active drug(s) from at least __ class(es)
are needed to suppress HIV virus replication
A. In general, 1 active drug from at least 1 class is
needed to suppress HIV virus replication
B. In general, 2 active drugs from at least 2 classes
are needed to suppress HIV virus replication
C. In general, 3 active drugs from at least 2 classes
are needed to suppress HIV virus replication
D. In general, 3 active drugs from at least 3 classes
are needed to suppress HIV virus replication
E. In general, 4 active drugs from at least 4 classes
are needed to suppress HIV virus replication
72
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
How often must a patient take ARVs to ensure
success?
A. Never
B. At least 3 times a week
C. Only when feeling sick
D. Everyday
E. I’m ready for a coffee break
73
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
True or False
A. After taking ARVs for an extended period of time, it’s
generally okay for a patient to decide to stop therapy,
since their viral load is not detectable.
FALSE
B. Taking ARVs can stop the progression from HIV
infection to AIDS. TRUE
C. A pregnant woman should not be offered ARV
Treatment because
ARVs may harm the baby.
FALSE
D. A patient taking ARVs has been cured and no longer
has HIV.
FALSE
E. Key to successful treatment is a partnership built on
trust between the patient
and clinician.
TRUE
74
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
The HIV Care Continuum
A. is a model that is used by federal, state and local
agencies to identify issues and opportunities related to
improving the delivery of services to people living with
HIV across the entire continuum of care.
B. tells us that 30% of the 1.2 million Americans living with
HIV are virally suppressed, based on analysis of the
latest CDC data using this model.
C. Those who are not retained in care are more likely to
transmit HIV, based on analysis of the latest CDC data
using this model.
D. All of the above
75
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Cases
76
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Tuesday, September 2, 2014
Case 1
TM is a 30 year old male who is without any prior known
chronic illnesses. A few months ago he developed a
cough that has persisted. He has also felt a bit tired,
but he’s a writer and has been spending long hours
working to meet his publisher’s deadline. At the urging
of a friend, he finally decides to see a doctor. His friend
noticed that he became extremely short of breath during
their usual morning run, which is unusual. The doctor
discusses his symptoms with him, performs a physical
exam, and orders a few tests. He is told that he is HIV+
and likely has pneumonia as a result of this infection.
77
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Tuesday, September 2, 2014
Case 2
SO is a 27 year old female who was initially brought in
by her male friend. She is back in the doctor’s office
today to go over her test results. When she initially
came in, she suspected that she was pregnant; she
also made it very clear that this was not be discussed
while her male friend was in the room. She was
somewhat evasive when probed about the nature of
their relationship. With regard to her symptoms, she
indicated that she had been fatigued, with nausea and
vomiting. Her pregnancy test was positive. At that time,
the doctor sent routine screening tests, including HIV
antibody testing, which was positive.
78
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Tuesday, September 2, 2014
Case 3
HK is 45 year old male who comes to the doctor’s office
in a panic. A few weekends ago he went away with
some friends for a bachelor party, the details of which
are a bit hazy at this time. There was probably alcohol
involved…he can’t remember much else. His concern
is that since then he’s developed a fever, a rash, and a
slight headache (which is improved when the lights are
dim). He’s worried that he may have caught something
from someone, though he is sure that he didn’t do
anything extremely out of the ordinary. After his
evaluation, he is told that testing for HIV and syphilis
are both positive.
79
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Cases: Discussion
80
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
What are some issues that may prevent
someone from accessing care or taking
medications?
81
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD
African American HIV University
Wednesday, August 26, 2015
Using what you’ve learned, how might you get
this person to agree to therapy?
82
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Summary
83
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Summary
• We have experience with a broad range of ARVs that
have been shown to be effective with regard to
suppressing HIV viral replication.
• ARV treatment is currently the only way we are able to
stop the progression from HIV infection to AIDS that will
occur in the majority of patients who are not treated
over time.
• A successful ARV treatment strategy includes building a
trusting relationship between the clinician and the
patient.
84
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Questions?
85
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Thank You!
oadeyiga@mednet.ucla.edu
86
Rationale for and Goals of ARV Treatment
Oladunni Adeyiga, MD, MS
African American HIV University
Wednesday, August 26, 2015
Additional References
• Update: trends in AIDS incidence, deaths, and prevalence — United States, 1996. MMWR Morb
Mortal Wkly Rep 1997;46:165-73.
• Phillips AN, Elford J, Sabin C, et al. Immunodeficiency and the risk of death in HIV infection.
JAMA 1992; 268:2662
• Valdiserri, R. (2012, July 19). HIV/AIDS Treatment Cascade Helps Identify Gaps in Care,
Retention. Retrieved August 31, 2014, from http://blog.aids.gov/2012/07/hivaids-treatmentcascade-helps-identify-gaps-in-care-retention.html
• Gardner, EM et al. The Spectrum of Engagement in HIV Care and its Relevance to Test-andTreat Strategies for Prevention of HIV Infection. Clinical Infectious Diseases 2011; 52(6):793800
• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human
Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
Initiating Antiretroviral Therapy in Treatment-Naïve Patients [insert date] pp. E1-E2
• World Health Organization. Interim WHO Clinical Staging of HIV/AIDS and HIV/AIDS Case
Definitions for Surveillance. Geneva, Switzerland: World Health Organization; 2005
• Bartlett, JG. The stages and natural history of HIV infection. UpToDate. June 2012.
• Pedersen, C. et. al. Clinical course of primary HIV infection: consequences for subsequent
course of infection. BMJ 1989; 299: 154-7
• Weekly Epidemiological Record.1994; 69 (37): pp.273-275. World Health Organization, Geneva.
• Bartlet, JG. Ten years of HAART: Foundation for the Future. Medscape. February 2006.
• A Timeline of AIDS. Accessed August 28, 2014. http://www.aids.gov/hiv-aids-basics/hiv-aids101/aids-timeline/
87