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Microbiology: Treatment of HIV and Opportunistic Infections (Pogue) GENERAL HIV INFORMATION: 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 Optimal treatment is dynamic: routinely check to see preferred regimen (always changing) GENERAL HIV TREATMENT: 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 Current Therapy: Should contain at least 2 (preferably 3) active drugs from multiple drug classes (avoid resistance) 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) 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: Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) Nonnucleoside RT inhibitors (NNRTIs) Protease Inhibitors (PIs) Fusion Inhibitors (FIs) CCR5 Antagonists Integrase Inhibitors HIV TREATMENT REGIMENS: Generally 2 NRTI backbone, PLUS one or more of the following: o One NNRTI o One boosted PI o Raltegravir (integrase inhibitor) 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: 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 NNRTI Class Characteristics: MOA: non-competitive inhibitors of reverse transcriptase 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: 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 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 General Advantages and Disadvantages: Advantages: o High genetic barrier to resistance Disadvantages: o Metabolic complications o GI side effects o CYP 3A4 issues NRTIs: 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 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 - Combination Products: NRTI: Truvada: emtricitabine + tenofovir Trizivir: abacavir + lamivudine + zidovudine (not as effective as having NNRTI or PI based therapy) Epzicom: abacavir + lamivudine Combivir: lamivudine + zidovudine PI: Kaletra: lopinavir + ritonavir Whole Regimen: Atripla: efavirenz + emtricitabine + tenofovir Fusion Inhibitors: 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: 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 - - ADE: o o o o o o o DDIs: o 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: 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 Pneumocystitis pneumonia (PCP): Cause: Pneumocystitis jirovecii Prophylaxis: o When: CD4 <200 o DOC: TMP/SMX o Alternatives: Dapsone Dapsone + pyrimethamine + leucovorin Aerosolized pentamadine 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: IV pentamidine Clindamycin + primaquine Atovaquone 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: Bone marrow suppression Hepatotoxicity Nephrotoxicity o DDIs: CYP2C19 substrate Azole antifungals Omeprazole (PPIs) 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) - 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 - 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) -