ID Unit 2 Flashcards
immunity and how it relates to immunology
protection against disease (not necessarily infection)
- exemption
- more rapid and greater response to subsequent exposure
- “natural” and acquired
immunology: study of mech’s of immunity against infection and adverse effects of immune response
clinical immunodeficiency
increased incidence and severity of:
- infection (decreased effector func)
- malignancy (cancers; (decreased effector func)
- autoimmunity (dysregulated immune sys)
clinical clues to immunodeficiency:
- more frequent infections
- more severe infections
- prolonged
- recurrent
- poor response to Rx
- unusual pathogens
common causes of primary immunodeficiency (public vs private)
anatomic
(skin, mucosal barriers)
phagocytes
(neutrophils and macrophages)
cellular immunity
(CD4+ T cells; CD8+ T cells; NK cells)
Humoral immunity
(Specific antibodies- B cells; complement)
immunodeficiency on lab tests
neutropenia is <500
normal CD4 cell count ~1000
HIV <700?
AIDS <200
generic common causes of immunodeficiency
anatomic
(skin, mucosal barriers)
phagocytes
(neutrophils and macrophages; chemotherapy-associated neutropenia)
cellular immunity
(CD4+ T cells; CD8+ T cells; NK cells)
Humoral immunity
(Specific antibodies- B cells; complement)
sources of immunodeficiency:
- malnutrition
- HIV/AIDS
- Age extremes
- others- meds, transplant, etc
common causes of secondary immunodeficiency
acquired (more common)
primarily cell-mediated immune defects
different in different areas of the world developing country: -malnutrition -HIV-1/AIDS -Measles -Age developed country: -immunotherapy (esp steroids) -HIV-1/AIDS -cancer therapy -transplantation
- CLL- low Ig’s; B “arrest”
- multiple myeloma- high IgG (monoclonal), but low IgM, IgA
- Renal and GI loss
- Medications (anticonvulsants)
common causes of primary immunodeficiency (public vs private)
primary: genetic (uncommon)
- public phenotype- multiple infections w/ MULTIPLE ORGANSIMS
- private phenotype- susceptibility to ONE organism
70% are humoral rares are low most are single gene defects -IgA deficiency -CVID -IgG(2) subclass deficiency -Hyper-IgE syndrome (Job's Syndrome)
Antibody structure and function
Variable region:
F(ab): Antigen binding region
-each is unique
constant region:
Fc: defines isotope (IgG,A,M,E)
-activates complement
-binds phagocytes via Fc receptors
Antibody structure and function
Variable region:
F(ab): Antigen binding region
-each is unique
constant region:
Fc: defines isotope (IgG,A,M,E)
-activates complement
-binds phagocytes via Fc receptors
life cycle steps targeted by antiretroviral drugs
Virus maturation: protease required for virus maturation (protease is a popular drug target)
targets of anti-retroviral drugs:
- protease inhibitors
- entry inhibitors
- RT inhibitors
- Integrase inhibitors
2 types of cancers developed in HIV- positive individuals
HIV-1 s a group 1 carcinogen
HIV pts are getting:
-AIDS-defining cancers, where CD4 counts are relevant
-AIDS-defining cancers are dropping:
Kaposi sarcoma
Non-Hodgkin’s lymphoma
cervical cancer
-Non AIDS-defining cancers
-Non-AIDS-defining cancer numbers are slightly increasing:
anal cancer
Hodgkin’s lymphoma
liver cancer
skin cancer
head and neck cancer
lung cancer
kidney cancer
therapeutic challenges for HIV-positive cancer pts
there are interactions and overlapping toxicities between chemotherapeutics and antiretroviral agents
—adverse effects on liver enzyme CP450 activation/inhibition mix
adverse events from the overlap:
- myelosuppression
- N/V
- Heptatotoxicity
- Neuropathy
- Nephrotoxicity
- Diarrhea
HAART should be continued during chemotherapy
human diseases assoc w/ Human T cell Lymphotropic Virus HTLV
HTLV-1 is first retrovirus linked to human disease
- -a delta-retrovirus that infects human T lymphocytes
- -causes lymphoproliferative disorders
Suggested transmission routes:
- from mother to child during breastfeeding
- via sexual intercourse
- exposure to infected blood products
- sharing of needles/syringes
HTLV cannot be found in pts blood, so that means transmission requires direct cell-to-cell contact
Human diseases caused by HTLV-1:
- adult T cell leukemia/lymphoma (ATL)
- HTLV-1-associated myelopathy (HAM) (tropical spastic paraparesis)
- Uveitis
Other HTLV-1 assoc diseases that need further study:
- arthritis
- pneumonitis
- UT disorders
- increased susceptibility to infectious diseases
4 Clinical types of ATL:
- Acute ATL
- Lymphomatous ATL
- Chronic ATL
- Smoldering ATL
- —-overall, these are aggressive and survival is dismal
Natural course from HTLV-1 infection to onset of ATL:
- HTLV-1 infection
- “Immune evasion” / clonal proliferation by virus
- malignant expansion and alteration of host genome
- ATL
HTLV-1-associated myelopathy (HAM):
- resembles multiple sclerosis: weak/stiff legs
- high HTLV-1 replication and strong immune response
- possibly, autoimmune destruction of neural cells by T cells
human diseases assoc w/ Human T cell Lymphotropic Virus HTLV
HTLV-1 is first retrovirus linked to human disease
- -a delta-retrovirus that infects human T lymphocytes
- -causes lymphoproliferative disorders
Suggested transmission routes:
- from mother to child during breastfeeding
- via sexual intercourse
- exposure to infected blood products
- sharing of needles/syringes
HTLV cannot be found in pts blood, so that means transmission requires direct cell-to-cell contact
Human diseases caused by HTLV-1:
- adult T cell leukemia/lymphoma (ATL)
- HTLV-1-associated myelopathy (HAM) (tropical spastic paraparesis)
- Uveitis
Other HTLV-1 assoc diseases that need further study:
- arthritis
- pneumonitis
- UT disorders
- increased susceptibility to infectious diseases
4 Clinical types of ATL:
- Acute ATL
- Lymphomatous ATL
- Chronic ATL
- Smoldering ATL
- —-overall, these are aggressive and survival is dismal
Natural course from HTLV-1 infection to onset of ATL:
- HTLV-1 infection
- minimal Tax
- “Immune evasion” / clonal proliferation by virus
- malignant expansion and alteration of host genome
- ATL
HTLV-1-associated myelopathy (HAM):
- resembles multiple sclerosis: weak/stiff legs
- increased Tax
- high HTLV-1 replication and strong immune response
- possibly, autoimmune destruction of neural cells by T cells
- spinal cord inflammation and demyelination
origins of AIDS epidemic
1981- AIDS first described
1984- HIV-1 isolated
1987- first antiretroviral approved by US FDA
1996- beginning of HAART era
how HIV infection leads to AIDS
HIV is on the surface of the CD4 lymphocyte
- HIV uses the CD4 receptor and a co-receptor (either CCR5 or CXCR4)
- leads to CD4 depletion
- but a CCR5 delta 32 mutation have a higher survival rate (lower risk of AIDS)
CD4 cells are the main host cell for HIV and their count correlates w/ disease progression
plasma HIV RNA level/ viral load is a measure of the extent of ongoing replication in lymphoid tissue
natural history of HIV infection:
- it can take years of untreated HIV to decrease CD4 cell counts to start showing symptoms/signs
- different autoimmune diseases take varying levels of CD4 counts to occur (progression)
common clinical manifestations of acute HIV infection
initial HIV infection
- often assoc w/ acute febrile illness, a mononucleosis-like illness with or without aseptic meningitis
- usually occurs 2-3 weeks after HIV exposure
- occurs in >50% of pts, although is often unrecognized
signs/symptoms of primary HIV infection: fever fatigue non-characteristic maculopapular rash myalgia HA pharyngitis cervical nodes arthralgia oral ulcers* odynophagia weight loss diarrhea oral candidiasis photophobia
common clinical manifestations of chronic HIV infection
at risk for opportunistic infections (when CD4 counts are low)
- pneumocystitis pneumonia (PCP)
- Kaposi sarcoma
- pseudomembranal candidiasis (thrush) leading to AIDS-defining esophagitis
- CMV retinitis
- CNS toxoplasmosis
- extrapulmonary tuberculosis
how antiretroviral drugs prevent/reverse the clinical manifestations of HIV
targets for antiretroviral therapy on CD4 cell:
-entry inhibitors:
—Target fusion or CCR5
(prevent binding, alters co-receptor binding, and prevents fusion)
- reverse transcriptase inhibitors:
- –NTRIs and NNRTIs
- Integrase inhibitors
- -Protease inhibitors
effects of antiretroviral therapy:
-Virologic and immunogenic effect:
potent inhibition of viral replication
prevents immunologic deterioration in early HIV
allows immunologic recovery in advanced HIV
-clinical effect:
prevention of opportunistic infections OIs
improvement in existing OIs
reduced hospitalization, long-term care facility use, medications for OIs, and cost
factors that contribute to HIV evolution:
- genetic diversity (mutations)
- fast replication rates
- selective pressures (genetic bottle necks)
a population of viruses exists in an infected pt
- a quasispecies
- genetically distinct viral variants evolve from initial virus inoculum
- variants are generated due to error-prone nature of viral replication
- quasipecies in 1 pt are more similar to e/o than to virus in other infected pts
maximally suppressive antiretroviral therapy requires a combination of 2-3 drugs
expected response to antiretroviral therapy:
- reduction in plasma HIV-1 RNA levels (viral load), ideally to undetectable levels
- increase in CD4 lymphocyte count
- improvement of existing opportunistic complications
- prevention of new opportunistic infections
- decreased morbidity and mortality
- reduced HIV transmission
role of antiretroviral therapy in HIV prevention
strategies in HIV prevention:
in clinical practice:
- abstention and other behavioral changes
- male circumcision
- condoms
- pre-exposure prophylaxis PrEP
- post-exposure prophylaxis after exposure PEP
- ART in the HIV+ pt (treatment as prevention)–> 96% reduction in HIV transmission
under study:
- HIV vaccine
- microbicides
the risk of HIV transmission varies during the course of HIV infection
viral protein definition
retrovirus:
- unique life cycle (reverse transcriptase; integration into host chromosome)
- -breaks central dogma- can go RNA–>DNA
associated with serious human diseases:
- immune disorders (AIDS)
- cancers (leukemia and lymphoma)
virus classifications and structure
4 different retrovirus classifications:
- oncoviruses: delta Human T-cell lymphotropic virus
- Lentivirus: HIV (very slow progression)
- Spumaviruses: not assoc w/ human disease
- Endogenous retroviruses: HERV-K and HERV-W; ~8-10% of human genome is composed of retrovirus
Virus structure:
- 3 structural proteins (envelope, matrix, capsid)
- 3 viral enzymes (reverse transcriptase, integrase, protease)
- viral genome (2 RNA molecs)
3 different retroviruses based on genome:
- MuLV (simple)
- HTLV (complex)
- HIV-1 (complex)
Genome structure:
- most proteins are made from 2 precursor proteins: Gag precursor and Gag-Pol precursor
- cleaved to make mature/functional proteins
- various accessory proteins required for full virus life cycle (Tat transactivator, Rav nuclear exporter)
- LTR (long terminal repeats) required for many elements (reverse transcription, gene transcription, splicing, virus integration)
life cycle steps targeted by antiviral drugs
Retrovirus life cycle:
Reverse transcription and integration
- HIV starts w/ binding to surface molecs (CD4) and co-receptor CCR5 or CXCR4
- once it binds, HIV can fuse into host membrane and enter
- reverse transcription: happens in cytoplasm (viral reverse transcriptase: inefficient, error-prone; most is eliminated by host)
Retroviral genome integration:
- uses viral integrase (required for virus replication and transcription)
- reverse transcribed to CDNA enters nucleus and integrates into host chromosome
- important for viral gene expression and DNA replication- required for retroviruses (but not HPV)
Viral gene transcription:
-Tat transactivator (viral transcription factor activating viral transcription; can also regulate host gene expressions, important in cancer?)
Virus assembly and release:
- Vpu is required for virus release
- virus particles released from host
Virus maturation:
- protease is required for virus maturation
- cleaves precursor proteins to produce fully mature viruses
types of Severe Combined Immunodeficiency Disease SCID
SCID:
-syndrome of diverse genetic etiologies that results in profound deficiency of: the cell type being mutated and where the mutation is in lymphocyte development
Block in lymphocyte development could mean:
- defective re-arrangement of antigen specific T and B cell receptors
- defective signaling (cytokines or cytokine receptor defects)
- defective purine metabolism
start w/ immature progenitor
-receives cues to become the pro-cells then the mature cells
clinical presentation:
failure to thrive
diarrhea
opportunistic infections (PJP, Candida, CMV)
absence of lymphoid tissue- lymphoid is best to palpate (except 1 form of SCID)
CXRL
X-linked SCID AKA the common gamma chain SCID
- chain that’s part of receptor of many IL cytokine receptors
- the cytokines are important for B cell, T cell, and NK cell development
SCID newborn assay
T cell excision circles TRECs:
- pieces of DNA cut out during intrarhythmic T cell receptor gene rearrangement
- VDJ cut-out recombinations give you different circles of genes and T cell receptors (and therefore T cells)
when TRECs are low:
- do confirmatory testing
- blood draw and look for CD3 (T cells) via flow cytometry
- -CD45/RA (naive CD4 T cells) should be at least 50% of total CD4 T cells
- -CD45/RO (memory CD4 T cells)
- -CD8
- -CD16/CD56 NK cells
- CD19 or CD20 B cells
CBC lab abnormality:
- low absolute lymphocyte count (ALC)
- anemia (Reticulocyte count to look for production vs destruction problem; Coombs test to look for RBC antibodies/destruction)
Early recognition of SCID is considered a pediatric emergency:
- exposure to non-irradiated blood product transfusions, live vaccines, and common infections in pts in SCID can be life-threatening
- part of newborn screen because it saves lives and saves money
treatment choices for SCID:
-bone marrow transplant is 1st choice
microorganisms that SCID pts are most susceptible to
?
lab abnormalities in pts w/ Common Variable Immunodeficiency CVID
lymphocyte enumeration shows:
-normal T, B, and NK cell numbers
Immunoglobulin levels:
-low IgM, IgA, and IgG
CVID diagnostic criteria:
- Recurrent sinopulmonary infections +/- autoimmune/inflammatory complications
- two serum immunoglobulins (IgG and IgA +/- IgM) at least 2 SD’s below age-specific mean
- poor (absent) vaccine responses
- B cell phenotype suggestive of arrest of maturation
- no profound CD4 T cell defects
- excluded secondary hypogammaglobulinemia
- at least 4 yo
Vaccine titers: check response to 3 types of vaccines:
- T cell independent vaccines (B cells can respond to polysaccharide vaccine like pneumovax); IgM secretion
- T cell dependent vaccines (need interaction of both T and B cells like Tetanus, Hib or diphtheria); IgG secretion
infections and non-infectious complications for CVID pts
CVID clinical presentation is variable:
- autoimmunity: ITP, AIHA, Evans Syndrome, SLE, RA
- GI disease: IBD-like disease, malabsorption
- Chronic lung disease: GILD
- Malignancy: lymphoid predominant
- Immunodeficiency: recurrent sinupulmonary infections (pneumonias: Strep pneumao, Hib, mycoplasma)
lab methods for HIV tests:
test HIV infection (ELISA, Western Blot, RT-PCR)
test virus load (quantitative RT-PCR)
disease status (CD4+ number, percentage, ratio)
antiretroviral drug resistance (genotyping, phenotyping)
Confirm active infection of HIV:
-HIV RNA by PCR with a LLOQ of 20 or 50 copies/mL
ELISA:
- detects anti-HIV Ab in sera using recombinant HIV proteins
- fast and sensitive
- high throughput
- high false positive
- cannot detect HIV in window period
Western Blot:
- detects anti-HIV antibodies
- more specific than ELISA
- less false positives
- less sensitive
- takes more time and effort than ELISA
- use after 2 positive ELISAs to confirm
RT-PCR:
- detects viral DNA
- very sensitive
- can detect very recent infection
- costly; requires special equipment
- can perform immediately
disease status:
-CD4 < 200 = AIDS
ELISA/Western blot tests look for antibodies to viral proteins; these tests often are falsely ⊝ in the 1st 1–2 months of HIV infection and falsely ⊕ initially in babies born to infected mothers (anti-gp120 crosses placenta).
Presumptive diagnosis made with ELISA (sensitive, high false ⊕ rate and low threshold, rule out test); ⊕ results are then con rmed with Western blot assay (speci c, low false ⊕ rate and high threshold, rule in test).
Viral load tests determine the amount of viral RNA in the plasma. High viral load associated with poor prognosis. Also use viral load to monitor effect of drug therapy.
antiretroviral drugs used in tx of HIV
classes of drugs
why cocktails of multiple drugs are used for HAART
Trimethoprim-Sulfamethoxazole (TMX-SMZ)
treatment regimens available in infant/pediatric HIV are different from adults
-AZT/3TC + LPV/r
Zidovudine ZDV (formerly AZT) or Lamivudine 3TC MOA:
- nucleoside/tide reverse transcriptase inhibitor NTRI
- need to be phosphorylated to be activated
- Competitively inhibit nucleot(s)ide binding to reverse transcriptase and terminate the DNA chain (lack a 3′ OH group)
- can be given in mother prophylactically to decrease risk of fetal transmission
Lopinavir (-navir) MOA:
- protease inhibitor (-navir tease a protease)
- prevent maturation of new viruses by preventing a protease cleave that assembles virions into functional parts
Dolutegravir (DTG) MOA
- integrase inhibitor (-tegra)
- Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase
used in combination to prevent resistance
need lifelong tx to ensure CD4 count stays high and viral load stays load
-the ART tx will never completely eliminate HIV
possible symptoms and opportunistic infections in HIV infection
retinal damage
pneumonia PCP- tx w/ TMP-SMX
thrush- tx w/ fluconazole
Pneumocystitis jiroveci pneumonia
Basic treatment principles of HIV
Improves and preserves immune func in most pts regardless of baseline CD4 count
- earlier HAART may result in better immunologic responses and clinical outcomes
- HAART strongly indicated for all pts w/ low CD4 count or symptoms
can reduce risk of HIV transmission
-recommended combinations are effective and well tolerated
most effective HAART contains:
- backbone of 2 nucleoside/tide reverse transcriptase inhibitors (NRTI)
- plus
- Base of integrate strand transfer inhibitor (INSTI)
Regimens for HIV-treatment naive pts
Preferred:
- INSTI based
- INSTI (-tegravir) + 2 NRTIs
- ex. Dolutegravir + Tenofovir AF-Emtricitabine
- ex. Dolutegravir + Abacavir-Lamivudine
Alternative: PI-based (-navir)
- PI + 2 NRTIs
- ex. Darunavir-Cobicstat or Ritonavir boosted + Tenofovir AF-Emtricitabine
Alternative: NNRTI-based
- NNRTI + 2 NRTIs
- ex. Rilpivirine + Tenofovir AF-Emtricitabine
ART Regimens for Post-exposure prophylaxis
Risk of HIV infection following occupational exposure:
- percutaneous exposure: 0.33%
- mucosal exposure: 0.03%
- intact skin exposure: no cases in 1 study
Recommendations:
- start w/in 72 hrs
- continue for 4 weeks
- F/U HIV Ab testing for >4-6 weeks post-exposure
Regimen:
- 3 or more active drugs should be used
- Preferred: Tenofovir DF-Emtricitabine + Dolutegravir
Nucelotide/side reverse transcriptase inhibitors NRTIs MOA Resistance TDF Pharmacokinetics ADRs
MOA:
- activation by intracellular kinases to activate triphosphate
- phosphorylated analogs competitively inhibit viral RT and cause termination when incorporated into viral DNA
- prevents genome replication and est of provirus
Resistance:
- assoc w/ various mutations on RT
- cross-resistance within class is common- basis for avoiding certain NRTI combinations
Tenofovir TDF = safer from of TAF
- minimizes renal and bone effects
- high potency for suppressing HIV
Pharmacokinetics:
- important consideration is NRTI plasma levels (too low= risk resistance; too low = risk toxicity)
- Abs: oral; must consider food/pH effects on abs
- Elimination: Hepatic glucuronidation (Abacavir and Zidovudine) or Renal excretion (all others)- know elimination to avoid DDIs
ADRs:
- activity against DNA polymerase (anemia, myopathy, granulocytopenia, neuropathy)
- lactic acidosis (hepatic steatosis, potentially fatal)
- renal impairment potential (Tenofovir DF-TAF is less)
- Lamivudine (3TC) and Emtricitabine (FTC) are best tolerated NRTIs; both agents are also active against HBV in co-infected pts
Non-Nucleoside Reverse transcriptase inhibitors MOA Resistance Pharmacokinetics ADRs
MOA:
- do NOT require activation by intracellular kinases
- bind to non-catalytic hydrophobic region
- non-competitively inhibit HIV RT
- prevents genome replication/establishment of provirus
Resistance:
- assoc w/ single AA substitutions at various RT positions
- developing resistance to one NNRTI converse cross-resistance to other class members
- newer member Etravirine appears to have higher barrier to resistance
Pharmacokinetics:
-oral; (Rilpivirine must be admin w/ meal); PPIs impair absorption
-Elim: innumerable DDIs via induction/inhibition of CYP450; may alter levels of co-admin PIs
(Rilpivirine: P450 substrate only NOT induce-inhibitor)
(Efavirenz: CYP3A4 inducer (decreases methadone levels))
(Eftravirine: CYP3A4 inducer)
ADRs:
- Rilpivirine: generally well tolerated; most commonly see depression, insomnia, HA, rash; cautious use in pts w/ long QT
- Efavirenz: most common are rash, dizziness, HA, insomnia, impaired conc, more severe CNS side effects possible; only antiretroviral agent in pregnancy category D
- Etravirine: generally well tolerated; Rash (rare but can be severe), nausea, HTN, peripheral neuropathy
- Hepatotoxicity
Protease inhibitors MOA Resistance Pharmacokinetics Boosters ADRs
end in -navir
MOA:
- noncleavable peptidomimetic agents that selectively target retroviral aspartyl proteases (not host proteases)
- HIV protease cleaves and processes HIV gag and pol proteins necessary for survival and replication, thus inhibition prevents viral maturation
Resistance:
- resistance requires multiple mutations- seldom develops in “boosted” PI-based regimens
- relatively higher barrier to resistance vs NNRTIs and Integrase inhibitors
Pharmacokinetics:
- Abs: oral; some best w/ food, some w/ no food, some don’t matter
- Elim: metabolized by CYP3A4 and innumerable DDIs occur due to inhibition of CYP3A4
- admin w/ “boosters” increases potential for DDIs
Boosters:
- Ritonavir (most potent of PIs for inhibition of CYP3A4; used in low doses for boosting of co-admin PIs; also boosts Elvitegravir; many DDIs due to inhibition AND induction of CYP)
- Cobicistat (more selective w/ no enzyme inducing properties; lower drug interaction profile)
ADRs:
- many PIs cause DI distress, hyperglycemia, insulin resistance, hyperlipidemia, and inc risk of CAD
- peripheral lipoatrophy: central fat accumulation
- hepatotoxicity more common in pts w/ HPV-HCV
- Atazanavir: less effects on lipid profiles; reversible jaundice; mild-mod rash
- Darunavir: rash can be severe (Stevens-Johnson Syndrome)
Integrase Strand Transfer inhibitors MOA Resistance Pharmacokinetics ADRs
Raltegravir, Dolutegravir, Elvitegravir
end in -tegravir
MOA:
- viral integrate involved in processing of DNA strands and catalyzing direct insertion of viral DNA into host cell DNA
- Raltegravir inhibits integrate activity preventing HIV-1 replication
- no effect on human DNA polymerases alpha, beta, or gamma
Resistance:
- Raltegravir and Elvitegravir- low genetic barrier
- Dolutegravir- unlikely to develop resistance mutations (high barrier)
Pharmacokinetics:
- good oral abs
- avoid cadmic with cations for DTG
- DTG and RAL eliminated via phase 2 glucuronidation- levels decreased by inducers (eg Rifampin)
- EVG substrate for CYP3A4- administered w/ “booster”
- DTG or EVG once daily (vs BID for RAL)
ADRs:
- Generally well tolerated
- Diarrhea, Nausea, HA
Entry Inhibitors MOA Resistance Pharmacokinetics ADRs
Maraviroc
MOA:
- HIV-1 visions using CCR5 called “R5 tropic”, present during initial and chronic phases
- HIV-1 visions using CXCR4 called “X4 tropic”, associated with later stages and disease progression
- Maraviroc is a small molec antagonist of CCR5 receptor that inhibits its interaction with viral gp120
- Indicated for tx experienced adults with R5-tropic virus (assay to determine R5, X4, or dual tropism)
Resistance:
- has been observed, esp when X4 strains are present
- also assoc w/ mutations in viral gp120
Pharmacokinetics:
- good oral abs
- dose BID
- substrate of CYP3A4–> DDIs possible w/ strong CYP3A4 inducers or inhibitors (eg NNRTIs or DDIs)
ADRs:
- generally well tolerated
- mild effects incl: cough, fever, URI, dizziness, abdominal pain
- hepatotoxicity possible w/ higher dose
Fusion inhibitors MOA Resistance Pharmacokinetics ADRs
Enfuvirtide
MOA:
- synthetic peptidomimetic of the viral gp41 HR2 sequences
- binds to HR1 sequences- unavailable for hemiperfusion stalk –> prevention of viral entry into cell and infection
Resistance:
-from mutations in gp41 binding regions
Pharmacokinetics:
- MUST be administered subcutaneously
- eliminated by proteolytic hydrolysis- no CYP involvement, so NO potential for DDIs
ADRs:
- injection site reactions in almost all pts
- Eosinophilia
- Hypersensitivity rxns
- increase in bacterial pneumonia
Initial therapy advantages and disadvantages
Dual-NRTIs:
Advantages:
-established backbone of combination therapy
-minimal drug interactions
Disadvantages:
-Lactic acidosis and hepatic steatosis (lower with TDF and FDC)
-Lipodystrophy
NNRTIs: Advantages: -long half lives -less metabolic toxicity than PIs -PIs and INSTIs preserved for future use Disadvantages: -low genetic barrier to resistance- single mutation -cross resistance among most NNRTIs -rash, hepatotoxicity (esp Nevirapine) -Potential CYP450 drug interactions -transmitted resistance to NNRTIs more common than resistance to PIs
PIs: Advantages: -higher genetic barrier to resistance -PI resistance uncommon even w/ sub-optimal adherence (boosted PI) Disadvantages: -Metabolic implications (fat maldistribution, insulin resistance, dyslipidemia) -GI intolerance -Potential for CYP450 drug interactions
INSTIs:
Advantages:
-neutral effects on triglycerides and cholesterol
-high barrier for resistance w/ Dolutegravir
-fewer adverse events than efavirenz
-fewer drug interactions than w/ NNRTIs or PIs
-NNRTIs and PIs preserved for future use
Disadvantages:
-BID dosing (QD for Dolutegravir)
-lower genetic barrier to resistance than PIs (RAL-EVG)
-Myopathy, rhabdomyolysis, skin reactions reported, but rare
CCR5 Antagonist:
Advantages:
-virologic response non inferior to efavirenz
-fewer adverse events than efavirenz
-NNRTIs, PIs, and IIs preserved for future use
Disadvantages:
-requires tropism testing before use (CCR5 vs CXCR4)
-BID dosing
-less experience than w/ PI or NNRTI based ART- limited data w/ NRTIs other than ZDV-3Tc
-CYP3A4 substrate- dosage adjustment required w/ concomitant inducers or inhibitors
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why pneumonia is “great neglected disease of mankind”
pneumonia is infection of lung parenchyma from alveoli
often misdiagnosed, mistreated, and underestimated
- highest death from an infectious disease worldwide
- majority of deaths are in children; kills more children than any other illness
pneumonia from other causes of cough and resp symptoms
Respiratory syndrome could incl:
- cough, SOB, Sputum
- Head: sinusitis, pharyngitis
- Upper resp: bronchitis, exacerbation of COPD
- Lower resp: PNEUMONIA
Pneumonia has:
- cough
- fever
- +/- sputum (young children don’t make it, seniors can’t cough it up)
- Chest pain (from pleuritis with inspiration)
- tachypnic
- abnormal lung exam (pretty definitive)
- positive CXR (pretty definitive)
Dx Community Acquired Pneumonia CAP:
- cough, SOB, fever, chest pain, sputum, DOE
- tachypnea, fever, abnl lung exam
- elevated WBCs, gram stain, blood culture
- CXR is GOLD STANDARD for pneumonitis
- -distinguish pneumonia from proximal resp tract process (compare w/ previous CXR)
Pneumonia is 3rd most common pneumococcal disease in US
- otitis media
- bronchitis
- pneumonia
- bacteremia
- meningitis
How sick is a pt w/ CAP? CURB-65
- Confusion
- Uremia (BUN >7)
- RR >30
- BP (<90/60)
- > 65 yo
- number of risks correlates w/ sickness
common risks and mech’s of risk for pneumonia
Risks for CAP:
- COPD
- age
- Hospitalized within last yr
- asthma
- prednisone
- CHF
- cancer (lung, other)
- male
- diabetes
Pneumococcus produces a lot of H2O2 and epithelial injury
- chemotaxis –> diapedesis
- alveoli and neutrophils are full of bugs and releasing factors causing inflammation/injury
Prevention of pneumonia:
- managing risk, incl:
- breast milk
- avoid smoking, smoke in home
- underlying disease
- vaccines
Prevention of Pneumonia:
- aspiration (thick food; sleep upright)
- Smoking/environemantal smoke (esp cooking)
- passive immunoglobulin (RSV)
- Antimicrobials (Oseltamavir (Flu))
- Vaccine (S pneumoniae, influenza)
common causes of community-acquired pneumonia and their related risks, syndromes, and tx
CAP is a big problem in children and seniors
Lung infections:
- acute, 19yo: mycoplasma
- acute, 65yo diabetic: S pneumoniae
- Subacute, Asian immigrant: TB
- Subacute, HIV-1: Pneumocystis jirovecii (PCP)
CAP:
- Typical w/ purulent sputum (Pneumococcus)
- Typical w/ gram neg org (H influenzae)
- Typical w/ lobar infiltrate on CXR (M catarrhalis or S aureus / MRSA)
- Atypical w/ prominent cough (M pneumoniae)
- Atypical w/ Gram neg PMNs, few organisms (C pneumoniae)
- Patchy or diffuse infiltrate on CXR (L pneumonophila, Influenza, RSV, adenovirus)
CAP complications:
- effusion/empyema
- respiratory failure
- cavitation
- pneumothorax
- pulmonary embolism
- cardiovascular complications (CHF, a fib, MI, CVA/stroke)
Mortality from CAP:
- S pneumoniae
- H influenzae (not common in adults)
- Mycoplasma pn.
- Legionella sp.
- Influenza A
- Unknown
4 Risk groups of CAP:
- Previously healthy outpatients (Tx w/ macrolide; doxycycline)
- Outpatients w/ co-morbidities or aspiration (prior antibiotics; Tx Resp fluoroquinolone; macrolide + amox/Clav)
- Inpatients not in ICU (Tx: resp fluoroquinolone; macrolide + beta-lactam (ceftriaxone)
- ICU pts (tx ceftriaxone + resp fluoroquinolone or macrolide)
efficacy and caveats associated with protection provided by pneumococcal and influenza vaccines
Goal of vaccine:
- need antibodies to get bug into neutrophils
- need antibodies and phagocytes
Therapy of CAP:
-not one answer- find out what the bugs are in this pt
Problem in Adults:
- 23-valend pneumococcal vaccine: effective for bacteremia (systemic), but not effective for pneumonia (mucosal)
- 7-valent pneumococcal conjugate vaccine in children: reduced colonization, reduced bacteremia, reduced bacteria pneumonia, some reduction in otitis media and meningitis, AND reduces invasive pneumococcal disease adults (indirect effect- HERD PROTECTION)
- it’s also protecting you from a disease that will eventually not exist
Influenza A info
- seasonal (usually Dec-April)
- cough and fever
- ranges asymptomatic –> ICU
- Dx w/ rapid test, PCR, culture (too long)
- Tx w/ Oseltamavir
- Vaccine: efficacy highest 6mo-7yr; falls off
- complicated by S pneumoniae!!, S aureus, Group A strep
- RSV- Respiratory Syncytial Virus (impact on adults?)
significant diseases caused by encapsulated and unencapsulated bacterial pathogens
Meningitis: (High mortality)
- Strep pneumoniae
- Neisseria meningitis
- (H influenzae) (unencapsulated)
Bacterial Pneumonia:
- strep pneumoniae (most common)
- H influenzae (non-dyeable strains)
Otitis media: (High morbidity and healthcare costs)
- strep pneumoniae (most common)
- Moraxella sp
- H influenzae (unencapsulated)
disease of meningitis
most commonly strep pneumo, Neisseria meningitidis, and H influenzae type B
bacteria have crossed BBB
incidence of H influenzae meningitis with vaccine
decreased a little with polysaccharide vaccines in the 1980’s
then introduced conjugate vaccine and the incidence dropped drastically
H influenzae media requirements
H influenzae is encapsulated
H influenzae requires special media for growth:
- chocolate agar contains Factors V (NAD+) and X (hematin)
- requires BOTH X and V factors
H flu likes to grow near staphylococci on blood agar
- Staph secretes NAD, and H flu uses it
- called satellite colonies)
Strep pneumo info
virulent Strep pneumo have capsules
-looks different in blood vs
Strep pneumo and normal flora strep (viridans) are frequently located in the same place (resp tract) and are both alpha hemolytic
- -although S pneumo is optochin sensitive
- -S viridans is optochin resistant
Neisseria meningitidis info
-N meningitidis is a close relative of N gonorrhoeae
- it grows well on blood agar
- Gram neg diplococci
Antibodies to encapsulated organisms
H influenzae, Strep Pneumo, Neisseria meningitidis are encapsulated
Antibodies to capsules is is important for:
- ID of organism once it’s isolated
- tell the virulence of its strain
- protect against disease
- agglutination test
can do a countercurrent immunoelectrophoresis test to detect the presence of capsule in bodily fluids: spinal fluid, blood, urine
–This could be very useful if the patient has already been treated with antibiotics because these organism shed the capsular polysaccharide where it can be detected (e.g. into their urine).
Lab diagnosis of encapsulated pathogens: H influenzae, S pneumo, and N meningitidis
H influenzae:
- GN cocci
- Dx using X and V factor; capsule type
S pneumo:
- GP lancet shaped diplococci
- Dx using alpha hemolytic, optochin sensitive, presence of capsule
N meningitidis:
- GN coffee-bean shaped diplococci
- Dx using oxidase test, sugar utilization, presence of capsule
variants, disease association, chemistry, cross reactivity, and vaccines for polysaccharide capsules
H influenzae:
- 6 serotypes a-f
- > 90% caused by type B in unvaccinated pop
- chemistry: Type b,, ribose-ribitol-P
- cross reactivity: Telchoic acids of many Gram pos normal flora organisms
- Vaccines to type B only
S pneumoniae:
- > 90 serotypes
- 12 serotypes make up >80% of invasive diseases
- Chemistry: Type 14, N-acetyl D-glucosamine
- Cross creativity: Human ABO antigens (!!!!)
- 2 vaccines in use: PPSV23 and PCV13
N meningitidis:
- 9 serogroups
- Type A serogroup assoc w/ most epidemics
- chemsitry: serogroup B, N-acetyl neuraminic acid
- cross reactivity: K1 capsule of E coli and brain gangliosides
- Vaccines: for all pathogenic types
epidemiology of bacterial meningitis
frequently occurs in environments where there is constant close contact of susceptible populations
- daycare homes/schools
- military camps
- college dorms
preceding an epidemic (mini or major) a significant proportion of the population become colonized in the upper respiratory tract w/ an encapsulated strain
sporadic cases, not from these environments, may be related to trauma to the head, w/ direct invasion of bacteria to meninges
The majority of deaths during the influenza pandemic of 1918-1919 were NOT caused by the influenza virus acting alone. Rather, most deaths were caused by secondary bacterial pneumonia from S pneumo, H influenzae, S pyogenes, S aureus, and others
Despite the extraordinary number of global deaths, the vast majority of influenza cases in 1918 (>97% in industrialized nations) were self-limited and essentially indistinguishable from influenza cases today. Additionally, influenza severity and death in 1918 to 1919 correlated with the frequency of well-understood secondary bacterial pneumonias caused by common pneumopathogens
course and pathogenesis of meningitis
aerosol:
- causes colonization of nasopharynx/otitis media
- inhalation causes colonization of the lung
- the capsule escapes phagocytosis
- the teichoic acid and peptidoglycan cause inflammation
- the pneumolysin causes direct damage to the endothelial cells
—> pneumonia
—> bacteremia pneumococci in bloodstream
—> meningitis
Pathogenesis:
- presence of anti capsular IgG or IgM in bloodstream protects against serious (invasive) disease (meningitis)
- persons w/ NO anti capsular antibody to colonizing strain are at high risk for meningitis
- persons w/ IgA blocking antibody response have a higher risk for meningitis, even if they have anti capsular antibody
Pathogenesis of unencapsulated (AKA nontypable) strains
unencapsulated strains of strep pneumo and N meningitidis rarely cause major disease
S pneumo >50% otitis media in children (encapsulated vs encapsulated?)
unencapsulated strains of H influenzae are frequently responsible for:
- otitis media in children
- sinusitis
- pneumonia in adults
if Ab against capsular polysaccharide correlates w/ immunity to disease, then why not immunize everyone (particularly children) w/ capsular polysaccharides?
where does the anti capsular antibody come from in >6yo pts?
children <6yo who are most susceptible to disease respond very poorly to T cell independent antigens such as capsular polysaccharides
the protective Ab may come from an immune response normal flora antigens which cross-react (have similar antigenic structure) with he capsules of virulent specimens
genes for resistance do NOT need to be on mobile genetic elements to be transmitted world wide
currently available vaccines for Haemophilus influenzae serotype B (Hib)
Hib (alone)
Hib in combination w/ DTaP (Diptheria-Tetanus-acellular pertussis) vaccine
Hib in combination w/ recombinant hepatitis (HBV) vaccine
Who should receive vaccine:
- children <5yo starting at 2 mo
- 3-4 boosters needed
Who should NOT:
- children < 6 weeks
- previous life-threatening allergic rxn to Hib
