Clinical Manifestations and Treatment of HIV

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Clinical Manifestations and Treatment of HIV

• Ronald Mitsuyasu, MD
• Professor of Medicine
• Director, UCLA Center for Clinical AIDS Research
  and Education (CARE Center)

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Clinical Manifestations of HIV

• Signs and symptoms
• Serologic testing and vaccination
• Oral manifestations
• Opportunistic Infections
• Neuro-psychiatric illnesses
• Malignancies
• Women and HIV

Not in todays presentation, but on course
web site
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Antiretroviral Therapy for HIV

• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• When to change therapy
• Second line therapies
• New drugs recently approved

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Signs and Symptoms
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CDC Stage of HIV Disease

• Stage I Acute HIV infection
• Stage II Asymptomatic HIV
• Stage III Early Symptomatic HIV
• Stage IV Late Symptomatic HIV
• A Constitutional Disease
• B Neurological Disease
• C Secondary Infections
• C1 AIDS defining
• C2 Other infections
• D Secondary Cancers
• E Other Conditions

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Acute Retroviral Syndrome

• Fever 96
• Lymphadenopathy 74
• Pharyngitis 70
• Rash 70
• Myalgia/Arthraligia 54
• Diarrhea 32
• Headaches 32
• Nausea/Vomiting 27
• Hepatomegaly 14
• Weight Loss 13
• Thrush 12
• Neurologic symptoms 12

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Serologic Testing and Vaccination
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Recommended Routine Serologic Tests
Disease
Test

• Toxoplasmosis
• Syphilis
• Hepatitis A Virus
• Hepatitis B Virus
• Hepatitis C Virus
• Cytomegalovirus

Anti-Toxoplasma IgG VDRL or RPR HAV total
antibody Anti-HBc, HBsAb, HBsAg Anti-HCV
IgG Anti-CMV IgG
Only in persons with relatively low risk
DHS/HIV//PP
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ACIP Recommended Vaccinations
Vaccine
Schedule
Yearly Once Repeat after 5 Years 0 6-12
months 0, 1, 6 months Every 10 Years

• Influenza Vaccine
• Pneumococcal
• Hepatitis A Vaccine
• Hepatitis B Vaccine
• Tetanus-Diphtheria

Optimal to vaccinate when CD4 counts highest
From ACIP. MMW 200251 (40)904-8.
DHS/HIV/PP
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Vaccines Other

• Give if indicated
• Cholera
• Japanese encephalitis
• Lyme disease
• Tetanus-diptheria
• Typhoid inactivated (Typhim V1)

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Vaccines Other

• Contraindicated (live virus)
• Varicella
• Yellow Fever
• Typhoid live (Ty21a)
• Measles
• Vaccinia

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Oral Manifestations of HIV
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HIV-related Oral Lesions

• Infections
• Fungal, Viral, Bacterial
• Neoplasms
• Kaposis Sarcoma, Non-Hodgkins Lymphoma
• Other
• Aphthous-like Ulcers, Lichenoid or Drug
  Reactions, Salivary Gland Disease

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Oral CandidiasisClinical Types

• Erythematous Pseudomembranous
  Angular Cheilitis

DHS/HIV/PP
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Oropharyngeal CandidiasisTreatment Options

• Topical Therapy- Clotrimazole troches 10 mg
  5x/d x 7-10d- Nystatin pastilles 1-2 pastilles
  5x/d x 7-10d
• Systemic Therapy (Oral)- Fluconazole 100 mg qd
  x 7-10d- Itraconazole solution 200 mg qd x
  7-10d- Ketoconazole 200 mg qd x 7-10d

DHS/HIV/PP
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Fluconazole-Resistant Oropharyngeal
CandidiasisTreatment Options

• Topical Therapy- Amphotericin B solution 5 ml
  (100 mg/ml) qid x 7-10d
• Systemic Therapy- Amphotericin B 0.3 mg/kg IV
  qd x 7-10d- Caspofungin 50 mg/kg IV qd x
  7-10d- Itraconazole solution 100 mg bid x 7-10d
  - Fluconazole 800 mg PO/IV qd x 7-10d-
  Voriconazole 200 mg PO/IV bid x 7-10d

Use 70 mg/kg IV qd for the first dose
DHS/HIV/PP
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Hairy Leukoplakia

• Treatment and Management
• Generally does not require treatment
• Antiviral treatment and topical podophyllum resin
  have been used to treat -- the result is
  temporary
• May wax and wane without treatment

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Oral Ulcers

• Herpes simplex infection
• Varicella zoster infection (Shingles)
• Cytomegalovirus infection
• Aphthous ulcers
• Histoplasmosis

• HPV lesions
• Lymphoma
• Necrotizing ulcerative gingivitis (NUG)
• Necrotizing ulcerative periodontitis (NUP)
• Necrotizing stomatitis (NS)

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Aphthous LesionsClinical Types

• Minor (Lip) Minor (Tongue)
  Major

DHS/ HIV/PP
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Oral Aphthous LesionsTreatment Options

• Topical Therapy- Topical Corticosteroids
• Intralesional - Triamcinolone 40 mg /ml (0.5
  ml-1.0 ml injected bid)
• Systemic Therapy- Prednisone 0.5-1.0 mg/kg qd x
  7-10d, then taper- Thalidomide 200 mg PO qd

DHS/HIV/PP
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Lesions Caused By Human Papilloma Virus (HPV)

• Appearance exophytic, papillary, oral mucosal
  lesions
• Several different types of HPV have been reported
  to cause lesions
• May be multiple
• Often difficult to treat due to a high risk of
  recurrence

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Kaposis Sarcoma

• Appearance Oral lesions appear as reddish
  purple, raised or flat
• Size ranges from small to extensive
• Behavior is unpredictable
• Definitive diagnosis biopsy and histologic
  examination
• No curative therapy--antiretroviral therapy,
  radiation treatment, chemotherapy and sclerosing
  agents have been, used to control oral lesions

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Immune Reconstitution Disease

• Case Definition
• A paradoxical deterioration in clinical status
  after initiating highly active antiretroviral
  therapy (HAART) attributable to the recovery of
  the immune response to latent or subclinical
  infectious or other inflammatory processes
• Other Nomenclature
• Immune reconstitution inflammatory syndrome
  (IRIS)
• Immune restoration/restitution/recovery disease

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IRIS with ART and Tuberculosis
At Presentation
6 Weeks of ART and Anti-TB Rx

Chien et al. Chest, 1998
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Paradoxical Reactions and IRIS in HIV-Infected
Patients with TB

• Paradoxical reactions and IRIS
• Unmasking emergence of signs and symptoms of
  TB that was subclinical or undiagnosed at the
  time ART was started
• Paradoxical reaction - worsening of TB signs and
  symptoms shortly after initiation of ART
• Reported in 8-45 of HIV/TB co-infected pts
  within 2-4 weeks after starting ART
• Risk factors
• Shorter interval between initiation of TB
  treatment and ART
• Disseminated TB
• Low CD4 (lt 100 cells/µL) and high viral load

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Incidence of IRIS after Starting ART

• 25 overall of ART responders in an Australian
  cohort within 28 weeks of starting ART
• 31 of pts with MAC average of 18-210 days after
  starting ART (15 cases per 100 pt yrs)
• 29 - 43 of HIV-infected pts with TB
• 0 to 10 in HIV-infected pts not on ART or HIV
  (-) pts

Narita M. Am J Respir Crit Care Med 1998 Navas
E. Arch Intern Med 2002 Breen RA. Thorax 2004
Breton G. Clin Infect Dis 2004 Shelburne S. AIDS
2005
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Risk of IRIS Based on Time from TB Diagnosis to
Initiation of ART
Lawn SD, et al. AIDS 2007 21335-41
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Management of IRIS

• Rule out relapse or recurrence of underlying OI
  or malignancy
• Continue antiretroviral therapy in most cases
• Pathogen-specific therapy
• Initiate or continue as appropriate
• NSAIDs as initial adjunctive therapy for
  inflammatory symptoms
• Use corticosteroids in severe cases 40-60 mg
  prednisone x 3-4 weeks then taper

Gardner EM, Connick E. Curr Infect Dis Rep 2004
6483
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Use of Antiretroviral Therapy
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Overview

• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• When to change therapy
• Second line therapies
• New drugs recently approved

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Benefits of ART

• Prevention of mother to child transmission
• Clinical management of patients with HIV
• Reduces HIV replication
• Increase or maintain CD4 numbers
• Maintain less fit mutated HIV
• Post exposure prophylaxis (PEP)
• Secondary prevention of HIV transmission
• Primary prevention (?)

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Current antiretroviral targets
Fusion Inhibitor Enfuvirtide
Entry Inhibitors CCR5, MRV
Viral protease Inhibitors
RNA
RNA
Proteins
Reversetranscriptase Inhibitors
RT
SQV RTV IDV NFV APV LPV FOS ATZ TPV DRV
RNA
RNA
ZDV, ddI, ddC, d4T, 3TC, ABC, TDF, FTC DLV,
NVP, EFV, ETV
DNA
RT
DNA
DNA
Provirus
Integrase Inhibitor RAL
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Currently available drugs in USA
NRTIs Zidovudine (ZDV) Dideoxyinosine
(ddI) Dideoxycytidine (ddC) Stavudine
(d4T) Lamivudine (3TC) Abacavir
(ABC) Emtricitabine (FTC) Tenofovir (TDF)
PIs Saquinavir (SQV) Ritonavir (RTV) Indinavir
(IDV) Nelfinavir (NFV) Amprenavir
(APV) Lopinavir/Ritonavir (LPV/r) Atazanavir
(ATV) Fos-amprenavir (f-APV) Tipranavir
(TPV) Darunavir (DRV)

• NNRTIs
• Delavirdine (DLV)
• Nevirapine (NVP)
• Efavirenz (EFV)
• Etravirine (ETV)

Entry and Fusion Inhibitors Maraviroc
(MRV) Enfuvirtide (ENF)
Integrase Inhibitors Raltegravir (RAL)
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CASCADE CollaborationOverall Mortality and
Causes of Death
Overall Mortality
Causes of Death
Pre-HAART (n1424) HAART (n514)
31.7
Pre-HAART
19.3
Deaths ()
Proportion ()
10.0
9.9
HAART
4.9
4.3
3.2
2.5
2.5
1.3
0 5 10
15
OIs
CVD/ DM
Not Specified
Hepatitis Liver
Malig- nancy
Years Since Seroconversion
AIDS-Related
Non-AIDS-Related
n7680 seroconverters, of whom 1938 died (26
1424 pre-HAART and 514 during HAART). no change
in the following causes of death AIDS-related
malignancy, other infections, organ failure, and
unknown causes.
Smit C, et al. AIDS. 200620741-749.
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Breakdown of causes of death France 2005
AIDS
Cancer Hepatitis C
CVD Suicide Non-AIDS
infection Accident
Hepatitis B Liver disease OD /
drug abuse neurologic
renal pulmonary
digestive iatrogenic
metabolic psychiatric
other unknown
N 937 deaths
Lewden et al, CROI 2007
ANRS EN19 Mortalité 2005
Percent
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US Surveillance ofTransmitted Drug Resistance
787 Newly Diagnosed, Treatment-Naïve
Patients From 89 Sites in 6 States (2003-2004)
14.5
Prevalence of Resistance ()
8.4
7.1
3.1
2.8
Any Class NRTI NNRTI
PI gt2 Classes
Bennett D, et al. 12th CROI. Boston, 2005.
Abstract 674.
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Prevalence ofTransmitted Drug Resistance
2208 Newly Diagnosed, Treatment-Naïve
Patients From 19 European Countries (1996-2002)
1996-1998 1999-2000 2000-2002
P0.74
P0.48
Resistance ()
P0.02
P0.65
P0.39
Any Class NRTI NNRTI
PI gt2 Classes
Wensing AM, et al. J Infect Dis. 2005192958-966.
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Overview

• Changing Epidemiology of AIDS in United States
• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• When to change therapy
• Second line therapies
• New drugs recently approved

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When to initiate ART?
Toxicity Risk Adherence commitment Resistance
development Cost and readiness
Risk of progression
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When to Start Treatment
Severe symptomsunexplained fever or diarrhea gt2
to 4 weeks, oral candidiasis, or gt10 unexplained
weight loss, pregnant women, HIVAN, HBV
co-infected needing HBV therapy.
Available at http//aidsinfo.nih.gov/Guidelines/.
December 1, 2007. Hammer S, et al. JAMA.
2006296827-843.
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Prognosis From Starting HAART
Viral Load (log10 copies/mL)
CD4 Cell Count (cells/µL)
25 20 15 10 5 0
gt5
Probability of AIDS or Death ()
4-4.9
3-3.9
lt3
0 1 2
3
Years From Starting HAART
Egger M, et al. Lancet. 2002360119-129.
Antiviral Therapy Collaborative Group, n12,574
from 13 centers
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Overview

• Changing epidemiology of AIDS in the United
  States
• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• Second line therapy
• New drugs recently approved

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Recommended Regimens forTreatment-Naïve
Patients DHHS 2008
Preferred Regimens

TDF FTC or ZDV 3TC
Efavirenz Lopinavir/r 2X/d Atazanavir/r Fosampren
avir/r 2X/d
Alternative Regimens
Atazanavir Fosamprenavir Fosamprenavir/r
1X/d Lopinavir/r 1X/d or Nevirapine
ABV 3TC or ddI 3TC or FTC

Not recommended for use in 1st trimester, or in
women with high pregnancy potential. Ritonavir
100 mg/day recommended when tenofovir DF is used
with atazanavir. Low-dose 100 to 400 mg/day as
a pharmacologic booster. Adult females and males
with CD4 cell counts lt250 and lt400 cells/mm3,
respectively. Soft-gel or hard gel capsules, or
tablets.
Available at http//aidsinfo.nih.gov/Default.aspx
. Revision December 1, 2007.
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What Not to Use

• Guidelines IAS-USA1, WHO2, DHHS3
• Inferior but acceptable
• AZT 3TC ABV (TZV)
• Nelfinavir, d4T 3TC
• Not recommended
• Any mono- or dual-therapy combo
• DRV, TPV, ENF
• ddI TDF
• IDV unboosted or boosted
• SQV unboosted
• RIT

1Hammer S, et al. JAMA 2006296827-843
2Available at www.UNAIDS.org 3Available at
http//aidsinfo.nih.gov/Default.aspx. Revision
December 1, 2007.
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ACTG 5142 Efavirenz Versus Lopinavir/Ritonavir
Regimens
Time to Virologic Failure

• Treatment-naïve patients (n753)
• CD4 182 cells/mm3
• HIV RNA gt100,000 copies/mL 51
• Randomized arms
• Lopinavir/ritonavir (soft-gel 400/100 mg
  bid) 2 NRTIs
• Efavirenz 2 NRTIs
• Efavirenz lopinavir/ritonavir
• Selected NRTIs in combination with lamivudine
  zidovudine (42), stavudine XR (24), tenofovir
  DF (34)
• 96-week results
• Lopinavir/ritonavir 2 NRTIs had significantly
  shorter time to virologic failure than efavirenz
  2 NRTIs (P0.006)
• All groups had similar time to regimen completion

76/73
P0.006
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Not Failed ()
Lopinavir/ritonavir (n253) Efavirenz
lopinavir/ritonavir (n250) Efavirenz (n250)
0 16 32 48 64
80 96
Weeks
Time to Regimen Completion
PNS
61/60
Completed ()
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Lopinavir/ritonavir (n253) Efavirenz
lopinavir/ritonavir (n250) Efavirenz (n250)
0 16 32 48 64
80 96
Weeks
Riddler SA, et al. 16th IAC. Toronto, 2006.
Abstract ThLB0204.
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ACTG 5142Summary of 96-Week Efficacy Results
ITT missing values were ignored. P0.006
P0.041 and P0.003 versus lopinavir/ritonavir.
P0.01 versus efavirenz.
Riddler SA, et al. 16th IAC. Toronto, 2006.
Abstract ThLB0204.
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Pros and Cons ofInitial NNRTI Options
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Pros and Cons ofInitial Boosted-PI Options
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Patients Dont Like Surprises Short-Term Side
Effects to Discuss Before Starting Therapy

• NNRTIs
• Efavirenz neuropsychiatric side effects, rash
• Nevirapine hepatotoxicity, rash
• PIs
• Gastrointestinal toxicity
• Atazanavir jaundice and scleral icterus
• NRTIs
• Zidovudine nausea, anemia, fatigue
• Didanosine gastrointestinal toxicity,
  neuropathy, pancreatitis
• Stavudine neuropathy

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HAARTLong-Term Complications
Dyslipidemia/CHD
Abnormalities of Body Composition
Hepatotoxicity
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Overview

• Changing epidemiology of AIDS in the United
  States
• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• When to change therapy
• Second line therapies
• New drugs recently approved

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The Move TowardSimpler 3-Drug Regimens
1996
2006

• Didanosine stavudine saquinavir
• 24 pills/dose, 5 doses
• Saquinavir 6 q8h with fatty food
• Didanosine 2 bid ½ hour ac or 2 hours pc
• Stavudine 1 pill bid

• Emtricitabine/tenofovir DF efavirenz (Atripla)
• 1 pills qd
• No food restrictions

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What Degree of Adherence is Needed? Data From
Unboosted PIs
Adherence to a PI-Containing Regimen
Correlates With HIV RNA Response at 3 Months
MEMS cap data
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HIV RNA lt400 Copies/mL ( patients)
45
33
29
18
lt70 70-79
80-89 90-94 gt95
N99
PI Adherence ()
Paterson DL, et al. Ann Intern Med.
200013321-30.
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Adherence and Risk of Viral Rebound With New Drug
Resistance
Incidence per 100 Patient-Years
100 90-99 80-89 70-79 60-69 50-59
40-49 30-39 20-29 10-19 0-9
Cumulative Adherence ( doses taken)
JHU n195, all VLlt500, 1 yr data
Sethi AK, et al. Clin Infect Dis.
2003371112-1118.
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Once-Daily TherapyThe Nonadherence Fallacy

• Myth
• Its worse to miss a dose of a once-daily regimen
  than a twice-daily regimen

Reality The risks associated with missed or
delayed doses depend on pharmacokinetics, not the
dosing schedule
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Boosted PIs Administered QD Some May Forgive
a Missed Dose
10
1
Plasma Concentration (?g/mL)
0.1
APV 1200 mg BID
IC50 WT
APV 600 mg/RTV 100 mg BID
APV 1200 mg/RTV 200 mg QD
0.01
0
4
8
12
16
20
24
28
32
36
40
44
48
FDA-approved agents under evaluation for
once-daily use. Adapted from Sadler. 7th CROI
2000 San Francisco. Abstract 77. Wood. 8th
CROI 2001 Chicago. Abstract 332. Naderer.
1st IAS 2001 Buenos Aires. Abstract 352.
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Styles of Nonadherence Have Different
Implications for Resistance

• Two patients with 70 adherence
• Patient A
• Stops medications on most weekends to party
• Drugs with long half-lives may protect from
  resistance
• Patient B
• Spends about 30 of each year in jail
• Drugs with long (or different) half-lives may
  increase the risk of resistance

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Once-Daily RegimensUsing Co-Formulated NRTIs
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The Simplest Options for
Once-Daily Therapy
EFV or ATV or ATV/r or LPV/r or FPV/r
FTC/TDF or ABC/3TC

Do not use tenofovir DF with unboosted
atazanavir.
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Overview

• Changing epidemiology of AIDS in United States
• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• When to change therapy
• Second line therapies
• New drugs recently approved

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When to Change Therapy?

• Virologic failure
• lt0.5-0.75 log reduction in HIV RNA by 4 weeks or
  lt1.0 log reduction by 8 weeks
• Failure to suppress HIV RNA BLD by 3-4 months
• Repeated detection of HIV RNA after suppression
  BLD
• Immunologic failure
• Persistently declining CD 4 cell counts
• Clinical failure
• Clinical deterioration or disease progression

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Why Do Treatment Fail Patients?

• Poor adherence
• Baseline resistance or cross-resistance
• Use of less potent antiretroviral regimens
• Sequential mono- or dual-therapy
• Drug levels and drug interactions
• Tissue reservoir penetration
• Other, unknown reasons

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Long-Term Risk ofDeveloping Drug Resistance
Time to Multiclass Resistance

• Risk of developing antiretroviral drug resistance
  from UK CHIC Study (n4306)
• Longitudinal cohort from 6 clinics in London
• Started antiretroviral therapy with 2 NRTIs plus
  a third agent
• Overall risk of treatment failure
• 38 over 6 years
• Risk of accumulating resistance mutations to any
  drug
• 27 overall

2 classes 3 classes
Resistance ( patients)
2 Years
4 Years
6 Years
Philips A, et al. 7th DTHIVI. Glasgow, 2004.
Abstract PL6.1.
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Overview

• Changing Epidemiology of AIDS in the United
  States
• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• When to change therapy
• Second line therapies
• New drugs recently approved

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Selecting a New Regimen

• Effective in antiretroviral-experienced patients
• Potent antiretroviral drugs
• Drug(s) to which the virus is susceptible
• Adequate plasma drug levels
• Example ritonavir-enhanced PIs
• High genetic barrier to resistance
• Well tolerated
• Convenient
• Simple dosing schedule
• Low pill burden

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Genotypic Assaysfor Drug Resistance

• Determine presence or absence of specific changes
  in HIV-1 genes
• Protease
• Reverse transcriptase
• Envelop
• Pre-suppose knowledge of critical mutations
• Drug resistance is inferred by presence of known
  mutations
• Various methods and platforms
• FDA-approved kit-based methods
• Home-brew methods

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Phenotypic Assaysof Drug Resistance

• Measure the IC50 or IC90 for a drug by
  recombinant virus assay
• Antivirogram (Virco)
• PhenoSense (ViroLogic)
• Changes gt2.5- to 4-fold reliably detected
• Clinically relevant break points have been
  determined for most drugs
• Assays measure drug susceptibility
• Definition of resistance requires clinical
  correlation

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Drug Resistance Testing Caveats

• Resistance tests are most accurate in assessing
  resistance to the current regimen
• Absence of resistance to a previously used drug
  does not rule out reservoirs of resistant virus
  that might emerge after re-initiation of that
  drug
• Reduced potency should be expected from recycled
  drugs

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Overview

• Changing epidemiology of AIDS in United States
• Benefits and limitations of HAART
• When to start
• What to start with
• Simplified drug regimens and treatment adherence
• When to change therapy
• Second line therapies
• New drugs recently approved

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New Paradigm in Therapy

• Complete suppression of plasma HIV-1 RNA should
  be the goal in all patients with HIV given the
  new classes of drugs available
• Maximize virus suppression while minimizing drug
  toxicity
• For those who do not tolerate new agents, goal
  should be to maintain CD4 count as high as
  possible
• Background therapy should be chosen on the basis
  of resistance testing, treatment history,
  tolerability

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Antiretrovirals Active in Treatment-Experienced
Patients
81
New Drugs Available

• Tipranavir/ritonavir
• Approved, 2006
• Darunavir/ritonavir
• Approved, 2006
• Maraviroc (CCR5 Inhibitor)
• Approved, 2007
• Raltegravir
• Approved, 2007
• Etravirine or TMC 114 (new NNRTI)
• Approved, 2008

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Think Strategically

• Long-term strategic anti-HIV therapy is similar
  to a chess game against a vastly superior
  opponent, in which the objective is to avoid
  checkmate and remain on the board after 20 years

DD Richman, Science 1993
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Clinical Manifestation and Treatment of HIV

• QUESTIONS?
• Ronald Mitsuyasu, MD
• Professor of Medicine
• Director, UCLA Center for Clinical AIDS Research
  and Education (CARE Center)