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HIV Management 2011

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Title: MKSAP HIV/AIDS Author: John Kiran Midturi Last modified by: CSIMPSON Created Date: 1/23/2010 8:00:48 PM Document presentation format: On-screen Show (4:3) – PowerPoint PPT presentation

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Title: HIV Management 2011


1
HIV Management 2011
  • John K. Midturi
  • April 16, 2011

2
Objectives
  • Recognize HIV/AIDS prevalence rates in USA
  • Recognize populations at highest risk for HIV
    infections
  • Understand rationale for CDC recommendations on
    routine testing
  • Be able to decide when to initiate HAART
  • Be able to select initial antiretroviral regimen

3
Epidemiology
  • Reported 25 yrs ago
  • Industrialized nations
  • Chronic manageable disease
  • Developing world
  • Devastating effects on individuals, family units,
    general community
  • High mortality and morbidity rates

4
Estimated Incidence of AIDS, Deaths, and
Prevalence
by Quarter-Year of Diagnosis/Death,
United States, 1985-1999
25,000
350,000
1993 definition
AIDS
implementation
Deaths
300,000
Prevalence
20,000
250,000
15,000
200,000
Number of Cases/Deaths
Prevalence
150,000
10,000
100,000
5,000
50,000
0
0
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
Quarter-Year
Adjusted for reporting delays
5
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6
Estimated Rates for Adults and Adolescents Living
With HIV Infection (not AIDS)
34 States and 5 U.S. Dependent Areas, 2007
American Samoa
NorthernMarianaIslands
Guam
DC
Estimated HIV Rateper 100,000
Confidential name-basedHIV infection reporting
not implemented as of 2003
2.2 51.7
AK
HI
51.8 103.8
103.9 170.5
Puerto Rico
170.6 282.0
Note Rates have been adjusted for reporting
delays. Inset maps not to scale. HIV/AIDS
Surveillance Report, 2007. Vol 19, table 11.
Data classed using quartiles Total rate 154.2
per 100,000
U.S. Virgin Islands
6
7
Awareness of HIV Status in the US
HIV estimated prevalence1 1,056,400 - 1,156,400
Undiagnosed1 232,700
Estimated newannual infections (2006)2 56,300
  • From 2004 to 2007, the estimated number of newly
    diagnosed HIV/AIDS cases increased 153

1CDC. HIV prevalence estimateUnited States,
2006. MMWR. 200857(39)1073-1076. 2Hall HI, et
al. Estimation of HIV incidence in the United
States of America. JAMA. 2008300520-529. 3CDC.
HIV/AIDS surveillance reportcases of HIV
infection and AIDS in the United States and
dependent areas, 200719.http//www.cdc.gov/hiv/t
opics/surveillance/resources/reports/2007report/de
fault.htm. Accessed July 23, 2009.
7
8
US Population Demographics Total Population and
HIV/AIDS Cases by Race/Ethnicity
Total US Population (2006) (N 247.1 million)1
Estimated HIV/AIDS Prevalence by Race/Ethnicity
(2006) (N 1,106,400)2
Otherlt2
Other 4
Hispanic/Latino18
White 71
Black 12
Black46
White35
Hispanic 13
Campsmith M, Rhodes P, Hall HI. 16th CROI 2009
Montreal. Abstract 1036.
8
9
Estimated HIV/AIDS Prevalence and New Infections
by Transmission Category in the US (2006)
Estimated New HIV Diagnoses
Estimated Prevalence of HIV/AIDS
Other1
High-Risk Heterosexual Contact (Male)9
MSM IDU4
MSM IDU5
IDU (Female)7
IDU12
IDU (Male)12
High-Risk Heterosexual Contact31
MSM53
MSM48
High-Risk Heterosexual Contact (Female)18
CDC. HIV Incidence. Available at
http//www.cdc.gov/hiv/topics/surveillance/inciden
ce.htm.
9
10
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13
Pathophysiology and Natural History
  • Family of Retroviruses
  • Subfamilies
  • Oncoviruses
  • Lentiviruses- slow viruses
  • HIV- long replication periods prior to clinical
    manifestations
  • Spumaviruses- not associated with human disease

14
  • HIV genome consists of three structural genes
  • gag- codes for viral capsid proteins, p15, p17,
    p24
  • pol- codes for proteins responsible for viral
    replication, and reverse transciptase
  • env- codes for envelope proteins gp120, gp41

15
Ontogeny of HIV
  • Simian immunodeficiency virus (SIV) is
    evolutionarily adapted to its natural hosts,
    chimpanzees and sooty mangeby monkeys
  • Inoculation of SIV into other primates typically
    produces an HIV-like disease
  • SIV is the closest known relative of HIV-1 and 2
  • These findings suggest that the HIV pandemic
    began with infection of humans by SIV variants
  • Phylogenetic analysis suggests that HIV became
    established in humans early in the 20th century

16
HIV Types 1 and 2
  • Geographic distribution
  • HIV-1 Global
  • HIV-2 West Africa
  • Transmission
  • Identical for the two virus types
  • Pathogenicity
  • HIV-2 appears to be less pathogenic than HIV-1

17
HIV-1 Classification System
  • Group M (main)
  • Subtypes (clades) A to D, F, G, H to K
  • Recombinant forms
  • Group O (outlier)
  • Group N (non-M/non-O)

18
Subtype, circulating recombinant forms
19
HIV-1 Subtypes Implications for Diagnosis and
Treatment
  • Several studies suggest differential rates of HIV
    disease progression and transmission by subtype
  • There may be differential rates of emergence of
    resistance to ARVs by subtype

20
Transmission
Un.org
  • Probability of infection
  • Blood transfusion/ transplant 95-100
  • MTCT with ART 25
  • Needle Sharing 1/150, 0.6
  • Occupational needle stick, 1/300, 0.3
  • Sexual contact (single event) 0.2

Medipulse.com
Brandonyeoh.com
21
HIV Life Cycle
2. Membranefusion entry
Maturation
3. Uncoating reverse transcription
7. Nuclearexport
1. Receptorbinding
8. Translation Assembly
6. Transcription RNA processing
9. Budding
4. Nuclearuptake
5. Integration
22
Immunopathogenesis of HIV
  • CD4 cells are the principle targets of HIV in
    the host
  • Helper/inducer T-lymphocytes
  • Fetal thymocytes
  • Macrophages/monocytes
  • Dendritic cells
  • Microglia
  • Placental trophoblast cells

23
Clinical Presentation
24
Acute infection
  • 40-90 of primary infections develop
    mononucleosis like syndrome
  • 2-6 weeks after exposure
  • Acute retroviral syndrome
  • Signs/symptoms
  • Fever 96, LAD 74, Exudative pharyngitis 70,
    myalgia's/arthralgia 54, diarrhea 32, headache
    32
  • Duration of illness is lt2weeks
  • Diagnosis
  • HIV RNA viral load (high) and HIV antibody (/-)

25
  • Progressive loss of CD4 lymphocytes
  • 50-80 CD4 cells/uL per year
  • Infection to development of AIDS- 6-8years
  • Dependent on viral load, CD4 count, age,
    socioeconomic status, host genetics
  • Rapid progressor
  • Long term non-progressors
  • Elite controllers (viral load lt48copies w/o
    therapy)

Chronic Infection
26
WHO HIV clinical stages
27
Definitions for AIDS
A CD4 T-cell count below 200 cells/µL or a CD4 T-cell percentage of total lymphocytes of 14 and/or the following AIDS-defining infections
 Candidiasis of bronchi, trachea, or lungs
 Esophageal Candida
 Coccidioidomycosis, disseminated or extrapulmonary
 Cryptococcosis, extrapulmonary
 Cryptosporidiosis, chronic intestinal for gt 1 mo
 Cytomegalovirus disease (other than liver, spleen, or lymph nodes)
 Encephalopathy (HIV-related)
 Herpes simplex chronic ulcer(s) for gt 1 mo or bronchitis, pneumonitis, or esophagitis
 Histoplasmosis, disseminated or extrapulmonary
 Isosporiasis chronic intestinal (for gt 1 mo)
 Mycobacterium avium complex
 Mycobacterium, other species, disseminated or extrapulmonary
 Pneumocystis jiroveci (formerly carinii) pneumonia
 Pneumonia recurrent (gt 1 recurrent episode in a 12-mo period)
 Progressive multifocal leukoencephalopathy
 Salmonella septicaemiae (recurrent)
 Toxoplasmosis of the brain
 Tuberculosis
 Wasting syndrome due to HIV
And/or the following AIDS-defining malignancies
 Cervical cancer (invasive)
 Lymphoma Burkitt's, immunoblastic or primary brain
 Kaposi's sarcoma
1993 Centers for Disease Control and Prevention
Revised Surveillance Definitions of AIDS
28
Screening and Diagnosis
  • CDC recommendations
  • 13-64 years of age
  • Routine HIV testing in all health care settings
  • Informed to opt out, no written consent required
  • Must screen for HIV
  • TB treatment
  • STD treatment
  • High risk behavior
  • IV drug users
  • Exchange sex for money
  • Sex partners of HIV infected person
  • Men who have sex with men
  • Heterosexual persons or partners with more than
    one partner since last test

29
Routine HIV Testing Who to Test
  • Which patients should be offered routine HIV
    testing? What guidelines and recommendations
    exist regarding routine HIV testing?

Short answer All individuals between the ages of
13 and 64 yrs should be routinely screened for
HIV infection in healthcare settings.
30
CDC Recommendations for Routine HIV Testing
  • Routine, voluntary HIV screening in healthcare
    settings recommended for all patients 13-64 yrs
    of age
  • Except in populations with documented prevalence
    of undiagnosed HIV infection lt 0.1
  • Without prevalence data, voluntary HIV screening
    appropriate until diagnostic yield lt 1/1000
    patients screened is established
  • Separate written consent not recommended
  • Pre- or post-test prevention counseling should
    not be required with testing or screening programs

Branson BM, et al. MMWR Recomm Rep. 2006551-17.
31
USPSTF HIV Testing Recommendations
  • Screening strongly recommended for all
    adolescents and adults at increased risk for HIV
    and all pregnant women

Increased risk defined as individuals with 1 risk individual factor or individuals receiving healthcare in a high-prevalence or high-risk clinical setting Increased risk defined as individuals with 1 risk individual factor or individuals receiving healthcare in a high-prevalence or high-risk clinical setting
Individual Risk Factors High-Prevalence or High-Risk Settings
Men who have had sex with men after 1975 Men and women having unprotected sex with multiple partners Past or present IDUs Men and women who exchange sex for money or drugs or have sex partners who do Individuals whose past or present sex partners were HIV infected, bisexual, or IDUs Persons being treated for STDs Persons with a history of blood transfusion between 1978 and 1985 Persons who request an HIV test despite reporting no individual risk factors may be considered at increased risk STD clinics Correctional facilities Homeless shelters Tuberculosis clinics Clinics serving men who have sex with men Adolescent health clinics with a high prevalence of STDs Any clinical setting with a known HIV prevalence 1 among the patient population being served
USPSTF recommendations. July 2005.
32
Diagnosis
  • Enzyme linked immunosorbent assay (ELISA)
    followed by confirmatory Western blot assay if
    ELISA positive
  • ELISA 99 specific, 98.5 sensitive
  • Western blot 100 sensitive, and 100 specific
    for chronically infected
  • Detects antibodies to HIV proteins
  • Core (p17, p24, p55)
  • Polymerase (p31, p51, p66)
  • Envelope (gp41, gp120, gp160)

33
Western Blot
  • p160
  • p120
  • p41
  • p68
  • p53
  • p32
  • p55
  • p40
  • p24
  • p18
  • CDC criteria 1
  • p160, p120 AND p41
  • CDC criteria 2
  • p160, p120 OR p41 PLUS p24
  • Positive reactive to gp120 and either gp41, p24
  • Negative non reactive
  • Indeterminate presence of other band pattern not
    positive

GAG POL ENV
34
Diagnosis
  • HIV antibodies appear in circulation 2-12 weeks
    after exposure
  • Window period- serologic testing is negative
  • Repeat test in 6 weeks to 3 months
  • Rapid serologic tests results in 20 minutes
  • Sensitivity and specificity 99

35
Management
  • HP
  • Social support system
  • Reaction to HIV infection
  • Anxiety, depression, adjustment disorders
  • Lab
  • Baseline- assessment of liver, bone marrow, and
    kidney function, lipids
  • Cd4, viral load, CBC with diff, LFTs, lipid, hep
    Bs antigen and antibody, hep c antibody, Toxoplas
    IgG, cmv IgG, tst, rpr, pap smear, g6pd level,
    genotype

36
Preventative measures
  • Routine immunizations
  • Cervical cancer screening
  • Medication for primary or secondary prophylaxis

37
Immunizations
  • Pneumococcal vaccine
  • Every 5 years x 2 doses
  • Hepatitis A and B
  • Give when CD4 above 200cell/uL
  • TST/T-Spot
  • Annually
  • gt5mm considered positive
  • CXR and if no symptoms and CXR clear therapy for
    LTBI

38
Women HIV
  • Women
  • Increased incidence of cervical dysplasia and
    invasive cervical carcinoma
  • More frequent Pap smear screenings
  • 2 Pap smears 6 months apart and then annually if
    results are normal
  • Abnormality- colposcopy
  • HSV- suppressive therapy indicated for frequent
    anogenital outbreaks

39
Care of Pregnant HIV-Infected Women
  • The current recommendations focus on use of HAART
    by known HIV-infected pregnant women, regardless
    of maternal health needs
  • reduce the risk of mother-to-child transmission
  • Perinatal transmission ratesto less than 2in
    the United States.
  • Identifying HIV infection in pregnant women with
    previously undiagnosed or newly acquired HIV
    infections
  • Preventing HIV transmission to infants through
    the use of chemoprophylaxis antiretroviral
    therapy
  • Avoiding breastfeeding

40
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Antiretroviral Therapy During Pregnancy
  • HAART should be initiated in all HIV-infected
    pregnant women regardless of CD4 cell count or
    HIV-1 RNA level.
  • Antiretroviral resistance testing before
    initiating HAART
  • CBC CMP testing before treatment initiation.
  • OI prophylaxis-based on current CD4 cell count.
  • HAART (2 NRTIs and either a PI with ritonavir
    boosting or a NNRTI)
  • Efficacy of antiretroviral therapy in preventing
    maternal to fetal transmission is primarily
    through lowering plasma HIV-1 RNA.
  • Transmission can occur at any plasma HIV-1 RNA
    level, including undetectable plasma HIV-1 RNA
  • All HIV-infected pregnant women should be
    offered HAART.

43
Viral Load and Transmission
Women Infants Transmission Study (WITS) Garcia,
et al, NEJM 1999
44
Mode of Delivery
  • HIV-1 RNA remains gt 1000 copies/mL- caesarian
    section
  • Scheduled for 38-39 weeks gestation
  • Intravenous zidovudine infusion initiated 4 hours
    before the caesarian delivery (2 mg/kg over
    1-hour loading dose, then 1 mg/kg/hour continuous
    infusion until delivery, ie, umbilical cord
    ligated)
  • Caesarian section delivery probably confers
    little added benefit in women with plasma HIV-1
    RNA lt 1000 copies/mL (Management
    Guidelines).DHHS Perinatal
  • HIV-1 RNA is lt 1000 copies/mL, a vaginal delivery
  • Induction of labor at 38-39 weeks.
  • Invasive fetal monitoring or operative delivery
    with vacuum devices or forceps should be avoided
    in HIV-infected women
  • increase risk of transmission.Mofenson 1999
    Shapiro 1999
  • Artificial or prolonged rupture of membranes
    should be avoided
  • caesarian delivery if labor does not progress 4
    hours after membranes have ruptured
  • Intravenous infusion with zidovudine should be
    initiated at the onset of labor
  • Intravenous zidovudine (2 mg/kg over 1-hour
    loading dose, then 1 mg/kg/hour continuous
    infusion until delivery, ie, umbilical cord
    ligated)

45
Prophylaxis
  • CD4 cell count is an indicator of immune
    competence
  • CD4 lt200, CD4 lt14, recurrent candidiasis,
    persistent fever, previous PCP Pneumocystis
    jirovecii pneumonia
  • TMP/SMX
  • Dapsone
  • Atovaquone
  • Pentamidine (aerosolized)

46
Prophylaxis
  • CD4 lt100 and positive IgG Toxo titer
  • Toxoplasmosis
  • TMP/SMX
  • Dapsone
  • Pyrimethamine
  • Leucovorin
  • CD4 lt50
  • MAC
  • Azithromycin
  • Clarithromycin
  • Rifabutin

47
Discontinuation of Prophylaxis
  • Discontinue primary and secondary prophylaxis for
    certain OI if sustained rise in CD4 cell count
    above threshold for prophylaxis initiation
  • PJP (gt200)
  • Toxoplasmosis (gt100)
  • MAC (gt50)
  • Secondary prophylaxis
  • Cytomegalovirus (gt150)
  • Re-initiate prophylaxis if CD4 decreased below
    threshold

48
Treatment
  • Goal
  • prolong life
  • avoid destruction of immune system
  • allow reconstitution of immune system
  • prevent OI
  • provide improved quality of life by reduction
    HIV-related symptoms
  • Effective therapy lt50copies/ml
  • Improve prognosis, minimize the development of
    resistance, and prolong duration of
    antiretroviral response

49
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51
Antiretroviral Agents - 1
  • Nucleoside / nucleotide analogues (NRTIs)
  • Abacavir C No studies. Concern for
    hypersensitivity
  • Didanosine B Concern for lactic acidosis (do
    not use w/ d4T)
  • Emtricitabine B No studies.
  • Lamivudine C Well tolerated. Widely used.
  • Stavudine C Concern for lactic acidosis (do not
    use w/ ddI)
  • Tenofovir B No studies. Animal reports of bone
    abnls
  • Zalcitabine C No studies. Teratogenic in
    animals.
  • Zidovudine C Well tolerated. The most
    experience.

52
Antiretroviral Agents - 2
  • Non-nucleoside RT inhibitors (NNRTIs)
  • Delavirdine C No studies.
  • Efavirenz D Teratogenic. 4/142 birth
    defects. Avoid in 1st trimester
  • Nevirapine C Well tolerated. Avoid initiating
    if CD4 gt250 cells/mm3.

53
Antiretroviral Agents - 3
  • Protease inhibitors (PIs)
  • Amprenavir C No studies. Oral solution
    contraindicated.
  • Atazanvir B No studies. Concern
    hyperbilirubinemia
  • Fosamprenavir C No studies
  • Indinavir C Unboosted poor blood levels in
    preg
  • Lopinavir/ritonavirC No studies
  • Nelfinavir B Registry data shows no incr in
    birth def
  • Ritonavir B Not used alone due to GI side
    effects
  • Saquinavir B Well tolerated, used boosted
  • Tripanavir C No studies

54
Antiretroviral Agents- 4
  • Integrase Inhibitors (INSTI)
  • Raltegravir C-No studies

55
Antiretroviral Agents- 5
  • Entry Inhibitors
  • Maraviroc B- No studies, requires Tropism
    test
  • Enfuvirtide B- No studies, subcut injection

56
Significant Numbers of People with HIVin the US
Are Not on Antiretroviral Therapy
1,056 1,156
835 915
675
560
Sources February, 2009 CDC estimates as of
the end of 2006 Synovate Healthcare U.S. HIV
Monitor Q3 2008
57
When to Treat History of DHHS Recommendations
1998 2001 2002 2004
2008
FACTOR RECOMMENDATION FOR TREATMENT RECOMMENDATION FOR TREATMENT RECOMMENDATION FOR TREATMENT RECOMMENDATION FOR TREATMENT RECOMMENDATION FOR TREATMENT
AIDS Treat Treat Treat Treat Treat
CD4 lt500 Treat lt200 Offer lt350 Indiv. gt350 Treat lt350 Risks/ Benefits if gt350
Viral Load gt20,000 gt55,000 gt 100,000 No specific viral load
Other Factors Pregnant women HBV co-infected HIVAN
DHHS Guidelines for the Use of Antiretroviral
Agents in HIV-1-Infected Adults and Adolescents,
1998 2008.
58
Recommendations for Initiation of Therapy in
Antiretroviral Naïve HIV-infected Patients
DHHS 2009 Guidelines
Condition Recommendation
In presence of AIDS-defining illness Pregnancy HIV-associated nephropathy HBV co-infection when HBV therapy is indicated and/or CD4 count lt350 cells/mm3 Start ART
CD4 count 350-500 cells/mm3 ART is recommended 55 of Panel members strongly recommended starting ART 45 moderately recommended starting ART
CD4 count gt500 cells/mm3 ART is recommended or optional 50 recommended starting ART 50 viewed starting ART as optional
DHHS Guidelines for the Use of Antiretroviral
Agents in HIV-1-Infected Adults and Adolescents.
December 1, 2009. Available at
http//www.aidsinfo.nih.gov.
59
Recommendations for Initiation of Therapy in
Antiretroviral Naïve HIV-infected Patients
DHHS 2009 Guidelines
  • Patients initiating antiretroviral therapy should
    be willing and able to commit to lifelong
    treatment and should understand the benefits and
    risks of therapy and the importance of adherence
  • Patients may choose to postpone therapy, and
    providers may elect to defer therapy, based on
    clinical and/or psychosocial factors on a
    case-by-case basis

DHHS Guidelines for the Use of Antiretroviral
Agents in HIV-1-Infected Adults and Adolescents.
December 1, 2009. Available at
http//www.aidsinfo.nih.gov.
60
Recommendations for Earlier ART Initiation
Summary of Benefits and Limitations
DHHS 2009 Guidelines
Benefits Potential Limitations
Reduction in mortality and/or AIDS-associated morbidity Improved outcomes in patients with certain co-morbidities, including HIVAN and HIV/HBV co-infection Potential to reduce risk of endothelial dysfunction and cardiovascular disease Reduced risk of AIDS-defining and non-AIDS-defining malignancies More robust immunologic response when treatment is initiated at a younger age Prevention of HIV transmission Fewer long-term safety data on newer ARVs Concerns for some unknown adverse consequences / complications of lifelong ART Potential for reduced quality of life associated with side effects in some patients, particularly those who are asymptomatic at the time of ART initiation Earlier emergent drug resistance, particularly in nonadherent patients, resulting in loss of drugs and drug classes and transmission of drug-resistant HIV Annual cost of medication
DHHS Guidelines for the Use of Antiretroviral
Agents in HIV-1-Infected Adults and Adolescents.
December 1, 2009. Available at
http//www.aidsinfo.nih.gov.
60
61
Treatment Responses in 1st Year of
HAARTImproving Over Time
  • 4143 subjects from 5 clinic cohorts in Europe and
    Canada
  • Treatment-naive started HAART from 1996-2002
  • ? risk of virologic failure, ? med. CD4 count
    increase in later years
  • Most failure now due to loss to follow-up or
    treatment discontinuation

with VL gt 500 c/mL
100
90
80
70
60
With VL gt500 on ART
50
40
30
24.8
23.0
17.3
20
12.4
10
8.4
8
10
0
1996
1997
1998
1999
2000
2001
2002
Lampe F, et al. CROI 2005. Abstract 593
62
Likelihood of Achieving a Normal CD4 Cell Count
Dependent on CD4 at Initiation of Therapy
Magnitude of increase in CD4 cell count greatest
if therapy started at low CD4 cell counts, but
greater likelihood of CD4 cell count
normalization with earlier therapy
Keruly J, et al. Clin Infect Dis.
200744(3)441-446. Gras L, et al. J Acquir
Immune Defic Syndr. 200745(2)183-192.
63
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64
Initial Treatment Preferred
NNRTI based EFV/TDF/FTC1,2
PI based ATV/r TDF/FTC² DRV/r (QD) TDF/FTC²
II based RAL TDF/FTC²
Pregnant Women LPV/r (BID)³ ZDV/3TC
1. EFV should not be used during the first
trimester of pregnancy or in women trying to
conceive or not using effective and consistent
contraception. 2. 3TC can be used in place of
FTC and vice versa.
65
Initial Treatment Alternatives
NNRTI based EFV¹ (ABC/3TC) or (ZDV/3TC)² NVP4 ZDV/3TC
PI based ATV/r (ABC/3TC) or (ZDV/3TC)2,3 FPV/r (QD or BID) (ABC/3TC) or (ZDV/3TC) or (TDF/FTC)2,3 LPV/r (QD or BID) (ABC/3TC) or (ZDV/3TC) or (TDF/FTC)2,3 SQV/r TDF/FTC2
1. EFV should not be used during the first
trimester of pregnancy or in women trying to
conceive or not using effective and consistent
contraception. 2. 3TC can be used in place of
FTC and vice versa. 3. ABC should not be used in
patients who test positive for HLA B5701
caution if HIV RNA gt100,000 copies/mL, or if high
risk of cardiovascular disease. 4. NVP should not
be started if pre-ARV CD4 gt250 in women or gt400
in men.
66
ARVs Not Recommended inInitial Treatment
High rate of early virologic failure ddI TDF
Inferior virologic efficacy ABC 3TC ZDV as 3-NRTI regimen ABC 3TC ZDV TDF as 4-NRTI regimen DLV NFV SQV as sole PI (unboosted) TPV/r
High incidence of toxicities d4T 3TC IDV/r RTV as sole PI

67
Questions
68
HIV Entry Is Triggered by Receptor Engagement
Attachment to CD4 cell
Triggered by coreceptor
Membrane fusion
1
2
3
Maraviroc
Enfuvirtide
Licensed entry inhibitors
69
Co-receptor antagonists
  • Block major entry step by binding to chemokine
    receptors (CCR5 or CXC4)

70
What Are Viral Coreceptors?
  • There are 2 viral coreceptors that matter
  • CCR5 and CXCR4
  • Both are chemokine receptors
  • Most viruses can use only CCR5 R5 viruses
  • Many can use both coreceptors R5/X4 (D/M)
  • A few can use only CXCR4 X4 viruses

71
Summary Appropriate Use of CCR5 Antagonists
  • CCR5 inhibitors beneficial when used in
    treatment-experienced patients with no detectable
    D/M or X4 virus at BL
  • In antiretroviral-naive patients with R5-only
    virus, CCR5 antagonist plus 2 NRTIs showed
    substantial activity, though not noninferior vs
    efavirenz plus 2 NRTIs
  • Phenotyping tests likely to be used to identify
    tropism of patients viral population having
    detectable X4 or D/M virus
  • Clinician can then determine if patient is
    appropriate candidate for CCR5 inhibitor therapy

72
Adverse Effects CCR5 Antagonist
  • MVC
  • Drug-drug interactions
  • Abdominal pain
  • Upper respiratory tract infections
  • Cough
  • Hepatotoxicity
  • Musculoskeletal symptoms
  • Rash
  • Orthostatic hypotension

73
Fusion Inhibitors
  • Impair membrane fusion of HIV to T cells
  • Subcutaneous injection twice daily

74
Adverse Effects Fusion Inhibitor
  • ENF
  • Injection-site reactions
  • Hypersensitivity reaction
  • Increased risk of bacterial pneumonia

75
Co-receptors-Conclusion
  • HIV entry process offers several opportunities
    for therapeutic intervention
  • Understanding Env protein is key to development
    and use of entry inhibitors
  • Coreceptor binding offers important target to
    disrupt HIV infection
  • Coreceptors are evolving target for inhibitors
  • Development of resistance likely and will pose
    challenges in how to use therapies
  • Effective use of entry inhibitors will require
    careful use of phenotypic coreceptor tropism
    assays

76
Summary Viral Envelope and Coreceptor Use
  • HIV binds to CD4 and a coreceptor
  • R5 viruses use CCR5 and are common
  • X4 viruses use only CXCR4 and are rare
  • D/M viruses can use both coreceptors and are
    common in later-stage patients
  • Coreceptor use largely defines HIV tropism
  • New infections almost always due to R5 viruses
  • In some patients, D/M and/or X4 viruses emerge
    years after infection
  • Coreceptor switch associated with faster
    progression

77
Nucleoside/Nucleotide reverse transcriptase
inhibitors (NTRI)
  • Nucleoside and nucleotide analogues
  • Impair transcription of viral RNA into DNA

78
Adverse Effects NRTIs
  • All NRTIs
  • Lactic acidosis and hepatic steatosis (highest
    incidence with d4T, then ddI and ZDV, lower with
    TDF, ABC, 3TC, and FTC)
  • Lipodystrophy(higher incidence with d4T)

79
Adverse Effects NRTIs (2)
  • ABC
  • HSR
  • Rash
  • Possible ? risk of MI
  • ddI
  • GI intolerance
  • Peripheral neuropathy
  • Pancreatitis
  • Possible noncirrhotic portal hypertension

Screen for HLA-B5709 before treatment with
ABC ABC should not be given to patients who test
positive for HLA-B5709.
80
Adverse Effects NRTIs (3)
  • d4T
  • Peripheral neuropathy
  • Pancreatitis
  • TDF
  • Renal impairment
  • Possible decrease in bone mineral density
  • Headache
  • GI intolerance
  • ZDV
  • Headache
  • GI intolerance
  • Bone marrow suppression

81
Non-nucleoside reverse transciptase inhibitors
(NNRTI)
  • Inhibit reverse transciptase by binding to the
    enzyme

82
ARV Components in Initial Therapy NNRTIs
  • DISADVANTAGES
  • Low genetic barrier to resistance single
    mutation
  • Cross-resistance among most NNRTIs
  • Rash hepatotoxicity
  • Potential drug interactions (CYP450)
  • Transmitted resistance to NNRTIs more common than
    resistance to PIs
  • ADVANTAGES
  • Long half-lives
  • Less metabolic toxicity (dyslipidemia, insulin
    resistance) than with some PIs
  • PIs and II preserved for future use

83
Adverse Effects NNRTIs
  • All NNRTIs
  • Rash, including Stevens-Johnson syndrome
  • Drug-drug interactions
  • EFV
  • Neuropsychiatric
  • Teratogenic in nonhuman primates cases of
    neural tube defects in human infants after first
    trimester exposure
  • NVP
  • Higher rate of rash
  • Hepatotoxicity (may be severe and
    life-threateningrisk higher in patients with
    higher CD4 counts at the time they start NVP)

84
Protease Inhibitors (PI)
  • Impair the packaging of viral particles into
    mature virus capable of budding from the cell

85
ARV Components in Initial Therapy PIs
  • ADVANTAGES
  • Higher genetic barrier to resistance
  • PI resistance uncommon with failure (boosted PI)
  • NNRTIs and II preserved for future use
  • DISADVANTAGES
  • Metabolic complications (fat maldistribution,
    dyslipidemia, insulin resistance)
  • GI intolerance
  • Potential for drug interactions (CYP450),
    especially with RTV

86
Adverse Effects PIs
  • All PIs
  • Hyperlipidemia
  • Insulin resistance and diabetes
  • Lipodystrophy
  • Elevated LFTs
  • Possibility of increased bleeding riskfor
    hemophiliacs
  • Drug-drug interactions

87
Adverse Effects PIs (2)
  • ATV
  • Hyperbilirubinemia
  • PR prolongation
  • Nephrolithiasis
  • DRV
  • Rash
  • Liver toxicity
  • FPV
  • GI intolerance
  • Rash
  • Possible increased risk of MI

88
Adverse Effects PIs (3)
  • IDV
  • Nephrolithiasis
  • GI intolerance
  • LPV/r
  • GI intolerance
  • Possible increased risk of MI
  • PR and QT prolongation
  • NFV
  • Diarrhea

89
Adverse Effects PIs (4)
  • RTV
  • GI intolerance
  • Hepatitis
  • SQV
  • GI intolerance
  • TPV
  • GI intolerance
  • Rash
  • Hyperlipidemia
  • Liver toxicity
  • Cases of intracranial hemorrhage

90
Integrase Inhibitors
  • Prevent incorporation of viral DNA into host cell
    genome

91
ARV Components in Initial Therapy II
(Raltegravir)
  • ADVANTAGES
  • Virologic response noninferior to EFV
  • Fewer adverse events than with EFV
  • Fewer drug-drug interactions than with PIs or
    NNRTIs
  • NNRTIs and PIs preserved for future use
  • DISADVANTAGES
  • Less experience with IIs, limited data
  • Twice-daily dosing
  • Lower genetic barrier to resistance than PIs
  • No data with NRTIs other than TDF/FTC in initial
    therapy

92
Adverse Effects II
  • RAL
  • Nausea
  • Headache
  • Diarrhea
  • CPK elevation

93
Integrase Enzyme
  • Viral enzyme essential to replication of both
    HIV-1 and HIV-2
  • Integration
  • Follows reverse transcription, which synthesizes
    double-stranded DNA copy of HIV-1 RNA after
    infection
  • Essential step before viral DNA can be
    transcribed back into viral RNA
  • Incorporates or integrates viral DNA into host
    cells DNA

94
Integrase Strand Transfer Inhibitors
  • Raltegravir (pyrimidinone analogue, formerly
    known as MK-0518)1
  • First approved integrase inhibitor
  • Originally approved for use in treatment-experienc
    ed patients recently approved for
    treatment-naive patients
  • Elvitegravir (diketoacid derivative of
    dihydroquinoline-3-carboxylic acid, formerly
    known as GS-9137)2
  • Currently in phase III clinical trials
  • S/GSK13495723
  • New integrase inhibitor active against
    raltegravir- and elvitegravir-resistant isolates
    in vitro
  • Currently in phase IIb clinical trials

1. Markowitz M, et al. J Acquir Immune Defic
Syndr. 200643509-515. 2. DeJesus E, et al. J
Acquir Immune Defic Syndr. 2006431-5. 3.
Lalezari J, et al. IAS 2009. Abstract TUAB105.
95
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