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Microbiology: Treatment of HIV and Opportunistic Infections (Pogue)
GENERAL HIV INFORMATION:
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Complete eradication of HIV is currently not possible:
Pool of infected CD4 cells established during early stages of infection
Persists with a long half-life even with prolonged suppression of plasma viremia
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Optimal treatment is dynamic: routinely check to see preferred regimen (always changing)
GENERAL HIV TREATMENT:
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Treatment Goals:
Reduce HIV-related morbidity and prolong survival
Improve quality of life
Restore and preserve immunologic function
Suppress viral load
o May be difficult to achieve maximal suppression in some cases due to pre-existing resistance mutations
Prevent HIV transmission
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Current Therapy:
Should contain at least 2 (preferably 3) active drugs from multiple drug classes (avoid resistance)
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Recommendations for When to Treat:
Patient has an AIDS defining illness
Patient has CD4 <500 (stronger support for <350)
o Note: this may change soon to treat everyone early (evidence shows it lowers transmission rates)
Pregnant women (regardless of CD4)
Patient has HIV-associated nephropathy (regardless of CD4)
Patient is co-infected with HBV and undergoing treatment (regardless of CD4)
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Importance of Educating Patient:
COMPLIANCE: need to be highly compliant in order to ensure effectiveness (otherwise, resistance can develop
quickly); if it is unclear if a patient will be compliant, need to delay treatment
CLASSES OF HIV DRUGS:
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Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
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Nonnucleoside RT inhibitors (NNRTIs)
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Protease Inhibitors (PIs)
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Fusion Inhibitors (FIs)
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CCR5 Antagonists
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Integrase Inhibitors
HIV TREATMENT REGIMENS:
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Generally 2 NRTI backbone, PLUS one or more of the following:
o One NNRTI
o One boosted PI
o Raltegravir (integrase inhibitor)
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Considerations in Decision:
o Co-morbidities
o Adverse drug reactions
o Potential DDIs
o Pregnancy/pregnancy potential
o Some drug-specific concerns
o Adherence issues
NNRTI Based Regimens:
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One NNRTI + dual NRTI therapy:
Efavirenz (preferred NNRTI): except during pregnancy or in patients with high pregnancy potential
o Alternative During Pregnancy: Nevirapine
Others:
o Delavirdine
o Ertavirine
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NNRTI Class Characteristics:
MOA: non-competitive inhibitors of reverse transcriptase
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Resistance: if it develops, is conferred to the entire class (can even occur in treatment naïve patients)
Long-Half Life: can be good (less frequent dosing) or bad (if you forget a dose, low levels remain in system for
longer periods of time, increasing risk for resistance development)
Efavirenz:
Adverse Effects:
o CNS or psychiatric symptoms: up to half of patients; usually doesn’t affect adherence
o Teratogenic: neural tube defects (avoid in early pregnancy)
o Rash or SJS
Atripla: entire regimen in one pill taken once daily
Efavirenz + tenofovir + emtricitabine
Nevirapine:
Adverse Effects:
o Hepatotoxicity: usually occurring early in treatment and seen with HIGHER CD4 counts

Recommendation: do not initiate in women with CD4 >250; men >400
o Skin Rash: in roughly half of patients; may present as SJS or with flu-like symptoms
General Advantages and Disadvantages:
Advantages:
o Save PI for future use
o Long-half lives
Disadvantages:
o Low genetic barrier to resistance (making compliance extremely important)
PI Based Regimens:
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One PI (boosted or unboosted) with dual NRTI therapy
Preferred PIs:
o Atazanavir + ritonavir
o Darunavir + ritonavir
o Fosamprenavir + ritonavir
o Lopinavir + ritonavir (co-formulation)
Alternatives:
o Atazanavir (unboosted)
o Fosamprenavir (unboosted)
o Saquinavir
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PI Class Characteristics:
MOA: binds to and inhibits HIV protease, which normally activates HIV polyproteins
Adverse Events:
o Dyslipidemia: except atazanavir (unless boosted)
o Fat maldistribution
o Insulin resistance
o GI effects
o Skin rash
DDIs:
o Inhibitors AND substrates of CYP 3A4: all to differing degrees

Ritonavir:
A protease inhibitor itself
Added because it is a POTENT INHIBITOR of CYP3A4, allowing for decrease in dosing frequency and pill burden
due to higher concentrations achieved
This is known as BOOSTING
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General Advantages and Disadvantages:
Advantages:
o High genetic barrier to resistance
Disadvantages:
o Metabolic complications
o GI side effects
o CYP 3A4 issues
NRTIs:
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Backbone of all initial HAART regimens
Preferred Regimen:
o Tenofovir/emtricitabine (co-formulation)
Alternatives:
o Abacavir/lamivudine
o Didanosine/lamivudine or emtricitabine
o Zidovudine/lamivudine
General Class Characteristics:
MOA: implant into the chain and act as terminators (inhibit reverse transcriptase)
Adverse Events: a LOT, but 2 important ones for the class are
o Lactic acidosis
o Hepatic steatosis/lipoatrophy
Individual Adverse Reactions:
Abacavir:
o Abacavir hypersensitivity reaction: more common in whites; pre-test allele for susceptibility
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Fever/rash/fatigue/abdominal pain
Stavudine:
o Pancreatitis
o Peripheral neuropathy
Didanosine:
o Pancreatitis
o Peripheral neuropathy
o Hepatotoxicty
Lamivudine:
o Safest and most well tolerated
Tenofovir:
o Renal insufficiency
Zidovudine (originally AZT):
o Bone marrow suppression
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Combination Products:
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NRTI:
Truvada: emtricitabine + tenofovir
Trizivir: abacavir + lamivudine + zidovudine (not as effective as having NNRTI or PI based therapy)
Epzicom: abacavir + lamivudine
Combivir: lamivudine + zidovudine
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PI:
Kaletra: lopinavir + ritonavir
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Whole Regimen:
Atripla: efavirenz + emtricitabine + tenofovir
Fusion Inhibitors:
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Enfuvirtide:
MOA: binds gp41 (aids in viral entry into the cell)
Administration: twice daily subQ
Use: resistance scenarios
ADE:
o Injection site reactions
o Pneumonia
o Hypersensitivity
CCR5 Antagonist:
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Maraviroc:
MOA: antagonist of CCR5, which is a chemokine receptor necessary for viral entry into the cell (in some strains of
HIV- need to test)
Use: treatment experienced patients
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ADE:
o
o
o
o
o
o
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DDIs:
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Hepatotoxicity
Arhtralgia/myalgias
Rash/pruritis
Cough
Dizzines
Upper respiratory infection (most common but uncertain if it is due to the drug)
Fever
Be careful with PIs: CYP3A4 substrate
Integrase Inhbitors:
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Raltegravir:
MOA: blocks HIV viral integrase (integrates proviral RNA and human DNA)
Use: new, but now considered an option for primary therapy
Side Effects: generally well tolerated
o GI effects
o Pyrexia
o CPK elevations/rhabdomyolysis
Drug Interactions:
o Not a CYP substrate, but is a substrate of secondary metabolism enzymes that can be induced or
inhibited
o Give twice the dose if given with rifampin (also induces these enzymes)
OPPORTUNISTIC INFECTIONS
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Pneumocystitis pneumonia (PCP):
Cause: Pneumocystitis jirovecii
Prophylaxis:
o When: CD4 <200
o DOC: TMP/SMX
o Alternatives:
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Dapsone
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Dapsone + pyrimethamine + leucovorin
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Aerosolized pentamadine
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Atovaquone
o Discontinue: when CD4 >200 for >3 months
o Prophylaxis for Life: if patient develops PCP at some point
Treatment of PCP Infection:
o DOC: high dose TMP/SMX
o Moderate to severe disease: use corticosteroids as an adjunct (add within 72 hours)
o Duration: 21 days
o Alternatives:
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IV pentamidine
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Clindamycin + primaquine
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Atovaquone
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Dapsone + TMP
Pentamidine:
o MOA: interferes with protozoal RNA/DNA protein synthesis
o Use: PCP (prophylaxis and treatment) and leishmaniasis
o Administration: once monthly inhalation of prophylaxis (nice, but toxicity generally limites use)
o ADEs:
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Bone marrow suppression
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Hepatotoxicity
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Nephrotoxicity
o DDIs: CYP2C19 substrate
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Azole antifungals
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Omeprazole (PPIs)
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Mycobacterium avium complex (MAC):
Prophylaxis:
o When: CD4 <50
o DOC: MACROLIDES-high dose azithromycin or clarithromycin once weekly (long half life)
o Alternative: rifabutin (derivative of rifampin, therefore induces CYP3A4)
o Discontinue: when CD4>100 for >3 months
Treatment: 2 or more anti-mycobaterial drugs used together to delay resistance
o DOC: clarithromycin (azithromycin can be used if necessary) + ethambutol as 2nd agent
o Others: some add rifabutin (improve survival and delay resistance; remember CYP3A4 induction)
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Cryptosporidiosis:
Greatest risk when CD4 <100
Symptoms: acute or subacute onset of non-bloody, watery diarrhea and abdominal symptoms
Prophylaxis: not routinely given because HAART is the best prophylaxis (keep CD4 counts higher)
o Others potentially used: rifabutin or clarithromycin
Treatment:
o CD4 restoration: >100, leads to complete clinical resolution (INITIATE HAART!!)
o Symptomatically treat diarrhea: REHYDRATION
o Nitazoxanide: sometimes used, but ironically only FDA approved for a 3 days course in non-HIV infected
patients
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Toxoplasma gondii encephalitis (TE):
Encephalitis is most common presentation in HIV patients
Prophylaxis:
o When: CD4 <100
o DOC: TMP/SMX (but already should be on for PCP prophylaxis)
o Alternatives: same as PCP (except cannot use inhaled pentamidine)
Treatment: sulfa regimens
o Pyrimethamine (penetrates BBB well) + sulfadiazine + leucovorin
o Pyrimethamine + clindamycin + leucovorin
o TMP/SMX NOT studied for treatment*
Pyrimethamine:
o MOA: inhibits parasitic DHF reductase (kind of like TMP); acts synergistically with sulfa drugs
o Side Effects: bone marrow suppression
o Addition of leucovorin: to decrease bone marrow suppression (it is a reduced form of folic acid, which
is important in purine synthesis)
o DDIs: substrate of CYP3A4 (be careful with PIs)
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