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I.
Introduction: over 20 years ago …
A.
B.
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D.
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II.
Kaposi’s sarcoma and Pneumocystis carinii pneumonia – June 1981 MMWR
At-risk groups in the U.S. – early 1980’s
AIDS = acquired immunodeficiency syndrome; acronym from 1982
Retrovirus isolated in 1983
HIV’s introduction in the U.S. back-dated to 1978 or earlier
Introduction: over 10 years ago …
A. Death toll in the U.S. passed 100,000 but still considered a “niche” disease
B. WHO predicts up to 40 million HIV infections by the year 2000
III.
Worldwide epidemiology of HIV/AIDS
“Statistics are people with the blood and tears dried off …”
Number of infections currently  42 million and over 60 million to date
Number of fatalities to date  24 million
By regions: sub-Saharan Africa, Asia, Latin America, North America; in the US, the
biggest lies about AIDS include The AIDS epidemic is over – Everyone knows about
safer sex – AIDS is for the older generation – You can be safe without condoms –
The government is doing everything it can – Nobody dies of AIDS – and We’re all
going to die anyway, and there’s nothing we can do.
E. Other countries: Russia (Ukraine), India, China
F. Causes of death vary widely (infections in Africa vs. liver/blood/kidney
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B.
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IV.
Pathogenesis of HIV infection
A. Zoonosis by Pan troglodytes troglodytes chimpanzee in Africa
1. Mother virus of HIV resides in chimps, makes the “jump” to humans
2. Infections remain rural but spread to urban areas
3. Epidemics: horizontal (sex or needles) and vertical (mother-to-child)
B. Risk of transmission routes
1. Behaviors at risk (sexual contact, needle sharing, mother-to-child, blood)
2. Probability of infection by type of exposure
3. Viral load of infected source and genital disease significantly alter risks
C. HIV infection of host cells: binding by HIV at 2 sites on host cell, followed by viral
enzyme activity (reverse transcriptase, integrase, and protease)
D. Immunologic processing and dissemination of HIV into lymph nodes after infection
E. Host’s immune response to HIV infection
1. CD4 T cells  IL-2  “memory” T cells become specific for HIV  Ifn
gamma  T killer cells specific for HIV-infected T helper cells
HIV infects the very cells that orchestrate an immune response against it
HIV replicates in CD4 cells (free virus) and in lymph tissue
Balance between production of HIV and destruction of infected cells
F. Viral load averages 10 billion viruses produced daily
1. Measurements by polymerase chain reaction or branched DNA
2. Viral load must be measured in log units
3. Viral load reflects the speed of CD4 cell destruction and progression to AIDS
G. AIDS is the culmination of a continuous, progressive pathogenic process
1. Primary infection, chronic/asymptomatic phase, symptomatic phase with
opportunistic infections and neoplasms
2. Average time to severe immunosuppression after infection is 10-11 years
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3.
4.
H. CDC definitions: 1987 (25 indicator conditions), 1993 (CD4 count < 200, HIV )
V.
Introduction to antiretroviral therapy
A. Suppress viral replication as low as possible using combinations of drugs
B. Nucleoside reverse transcriptase inhibitors (NRTIs) mimic nucleoside components of
viral DNA, are inserted into viral DNA chain and prevent reverse transcription
C. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) alter the structure of virus-
associated reverse transcriptase and render the expanding viral DNA non-functional
D. Protease inhibitors (PIs) block the catalytic site of HIV-associated protease and
render new viral progeny non-infectious
VI.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine, AZT; RetrovirTM
Didanosine, ddI; VidexTM
Zalcitabine, ddC; HividTM
Stavudine, d4T; ZeritTM
Lamivudine, 3TC; EpivirTM
Zidovudine + lamivudine fixed combination; CombivirTM
Abacavir, ABC; ZiagenTM
Zidovudine + lamivudine + abacavir fixed combination; TrizivirTM
Tenovofir disoproxil fumarate; VireadTM
Any NRTI is insufficiently strong when used singly; evolutionary pressure selects for
viral mutants that resist the drug (survival of the fittest)
K. NRTI pairs without overlapping toxicity: d4T/3TC, AZT/3TC, d4T/ddI, AZT/ddI
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B.
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H.
I.
J.
VII.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
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B.
C.
D.
Nevirapine; ViramuneTM
Delavirdine; RescriptorTM
Efavirenz; SustivaTM
NNRTI group considerably stronger than NRTI but resistance occurs quickly if viral
suppression is incomplete
VIII. Protease inhibitors (PIs)
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B.
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D.
E.
F.
G.
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IX.
Saquinavir hard-gel; InviraseTM
Saquinavir soft-gel; FortovaseTM
Ritonavir capsules, liquid, soft-gel; NorvirTM
Indinavir; CrixivanTM
Nelvinavir; ViraceptTM
Amprenavir; AgeneraseTM
Lopinavir + ritonavir fixed combination; KaletraTM
Combination therapy with PIs is complex, due to short drug half-lives, difficult food
requirements, timing of doses, and toxicity (GI and metabolic abnormalities)
Recommended regimens for highly active antiretroviral therapy (HAART) –
released by Department of Health and Human Services (DHHS) 2/01
A.
B.
C.
D.
E.
Indinavir, nelfinavir, or KaletraTM plus one pair of compatible NRTIs
Efavirenz plus AZT/3TC (or other compatible NRTI pair)
Saquinavir (HGC or SGC) plus low-dose ritonavir plus compatible NRTI pair
Indinavir or amprenavir plus low-dose ritonavir plus compatible NRTI pair
Abacavir plus AZT plus 3TC (TrizivirTM) if viral load < 100,000
F. Amprenavir, saquinavir-SGC, or ritonavir plus compatible NRTI pair
G. Nevirapine or delavirdine plus compatible NRTI pair
H. Choices A. thru D. preferred over E. thru G. due to potency and/or convenience
X.
Initiating treatment in HIV seropositive patients, DHHS 2001
Symptomatic patient (AIDS or severe symptoms of fever, weight loss) – TREAT
Asymptomatic patient with AIDS (CD4 < 200) – TREAT
Asymptomatic patient, 200  CD4  350 – OFFER TREATMENT
Asymptomatic patient, CD4 > 350 and elevated viral load (branched DNA > 30,000
or polymerase chain reaction > 55,000) – OFFER TREATMENT due to viral load
E. Asymptomatic patient, CD4 > 350 and lower viral load (branched DNA < 30,000 or
polymerase chain reaction < 55, 000) – FOLLOW PATIENT
F. Based on risk of progression, benefits/risks of therapy, and patient willingness
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B.
C.
D.
XI.
Initiating treatment in HIV seropositive patients, International AIDS Society
USA, 2002 version
A. CD4 < 350, regardless of viral load – RECOMMEND TREATMENT
B. CD4 350-500, regardless of viral load – CONSIDER TREATMENT
C. CD4 < 500 – DEFER TREATMENT unless viral load very high
XII.
Starting HAART in the asymptomatic patient
A. Benefits: regimens are more durable, short-term side effects are more tolerable,
fewer viral mutations have occurred, regimens most successful at higher CD4 counts
B. Risks: unknown long-term side effects, reduced quality of life, high cost, limited
options if treatment fails (only 3 unique combos available without cross-resistance)
XIII. Mutations and HIV resistance
A. Mutations occur in HIV genes coding for reverse transcriptase or protease enzymes
B. Resistance results from frequent mutations, error-prone reverse transcriptase, prolific
levels of viral replication, and evolutionary pressure selecting for resistant viruses
C. About 50% of HAART regimens are unsuccessful in “real life” due to inability to
achieve suppression of viral replication caused by previous sequential monotherapy,
low CD4 count at baseline, high viral load at baseline, poor adherence to treatment
D. Resistance testing: genotypic or phenotypic methods
XIV. Impact of HAART on AIDS healthcare
A. Immune reconstitution causing increases in CD4 numbers (both memory and naïve
cells) and improvements in cell-mediated immunity
B. Opportunistic infections have dropped over 50%, with  75% reductions in
Pneumocystis, Mycobacterium avium complex, and cytomegalovirus retinitis
C. Drug-related toxicities due to protease inhibitors include fat redistribution, lipid
abnormalities, insulin resistance, diabetes, and possible increase in MI risk
D. Drug-related toxicities due to NRTIs include focal fat loss from extremities and face
XV.
New drug strategies in the future
A. Once-daily regimens (depend on ritonavir-boosting of PIs or once-daily efavirenz)
B. Protease inhibitors: atazanavir (ZrivadaTM), tipranavir, fosamprenavir
C. NNRTI: TMC 125, DPC-083, both very potent and effective against NNRTI-
resistant HIV
D. Fusion inhibitors (T-20/FuzeonTM, T-1249) inhibit fusion of HIV with host cell
membrane; must be delivered subcutaneously
E. CCR5 binding inhibitors (SCH-C, SCH-D) prevent HIV binding at chemokine site
F. Integrase inhibitors (L-7088906 and L-731988) inhibit HIV integrase enzyme
XVI. Immunologic strategies
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B.
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F.
Interleukin-2 to improve CD4 counts
Switching from PI-based regimens to NNRTI-based or triple NRTI regimens
Structured treatment interruptions to improve host’s anti-HIV immunity
Structured intermittent therapy (on/off cycles) to  cost and improve quality of life
Pulsed therapy = stopping therapy until reaching a predetermined CD4 or viral load
Immunologic vaccines to stimulate either anti-HIV CD4 cells or killer (CD8) cells
XVII. Worldwide strategies
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Education, STD prevention, condom distribution
Vaccines
Reducing HIV transmission at birth
Increasing availability of HAART in developing countries
Reducing mortality from TB and common bacterial infections
Global AIDS fund
XVIII. Cytomegalovirus retinitis update
A. Valganciclovir (ValcyteTM) = IV ganciclovir, same toxicities, oral doses bid/qd
B. Discontinuing anti-CMV retinitis therapy with HAART-induced immune recovery
C. Immune recovery uveitis (iritis, vitritis, CME, ERM, etc.)
XIX. In-office precautions: handwashing, gloves, instrument disinfection
XX.
Conclusions