- HIV virons attach to CD4 receptors and co-receptors, fuse with T cell.

- Viral RNA duplicated into DNA via reverse transcriptase enzyme

- Viral DNA integrated into host using enzyme integrase

- mRNA produced and translated into viral proteins

- Protease enzymes process HIV proteins into functional form

- HIV virus invades and replicates within human T cells (CD4 cells)

- Virus causes T-cell (CD4) destruction causing impaired immune function

- Impaired immune function enables infectious disease progression

- AIDS development

- Progression --> severe illness --> death

Describe CD4 count and Viral Load

- CD4 Count (T cells) - cells/mm3 --> indicator of immune function

- Viral Load: copies/mL --> Measures amount of virus in blood by PCR

- High CD4 count, GOOD

- Low Viral Load, GOOD

- 10^9 new virions produced daily

- Cell free virus in plasma has half life of 6 hours

- Productively infected CD4 cells have have half life of 1.6 days

- Time from release of new virion, infection of new cell, and release of another new viron is 2.6 days, 140 generations a year

- Viral transmission is 2-3 weeks

- Acute viral syndrome is 2-3 weeks

- Recovery and seroconversion is 2-4 weeks

- Asymptomatic chronic HIV infection is 8 years

- Symptomatic HIV infection/AIDS is 1.3 years.....followed by death

- Two step process

- EIA --> detection of antibodies against HIV specific antigen (oral, blood, urine, rapid tests)

- Western Blot --> More specific for HIV antibodies

- Combo has close to 100% sensitivity and specificity

- 40-90% of acutely infected patients will experience effects, will not seek treatment

- Most common sx in order of prevalence:  Fever, Lymphadenopathy, Pharyngitis, Rash, perhaps muscle aches and pains, thrush, or weight loss

- HIV with CD4 count <200 and/or presence of AIDS defining illnesses

- Viral infusion with host  cells

- CCR5 Receptors on CD4 cells

- Reverse Transcriptase process

- Integrase

- Protease viral cleavage

- Chain termination, adds  analog to chain so RT get's confused, can't produce viral DNA

- Must be phosphorylated into their active tri-phosphate form

- Nucleotides like Tenofovir already have 1st phosphorylation step complete

- Mimic different DNA analogs

Thymidine - Zidovudine, Stavudine

Adenosine - Didanosine, Tenofovir

Cytosine - Lamivudine, Emtricitabine

Guanine - Abacavir, Amdoxovir

- YES! Different dosing, side effects, resistance, etc.

Combo Products.....

Truvada - Tenofovir + emtricitabine

Epzicom - Abacavir + lamivudine

Combivir - Zidovudine + lamivudine

Trizivir - Zidovudine + lamivudine + abacavir

Atripla - Efavirenz + emtricitabine + tenofovir (not just NRTI's, this is the first combo product to span different drug classes)

Mitochondrial toxicity - Most common A/E

- Due to impaired oxidative phosphorylation b/c of inhibition of DNA polymerase y.

- Manifests as lactic acidosis, microvesicular steatosis (mostly in liver), anemia, myopathy, neuropathy, and pancreatitis

- Major offenders are d4T and ddI

Tenofovir - renal toxicity

Abacavir - Hypersensitivity rxn

Zidovudine - anemia; lipoatrophy

Lamivudine/emtricitabine - mild side effects

Didanosine - Pancreatitis; peripheral neuropathy

Stavudine - Lipoatrophy, peripheral neuropathy, increased triglycerides

- Occurs in 5-8% of patients on average

- Presents at median of 9 days

- 93% of cases happen within first 6 weeks

- Once therapy is stopped, sx resolve

- real danger with rechallenge, life threatening hypotension and even DEATH!!

- HLA-5701 B is genetic test to determine who is at risk

All NRTI's - lactic acidosis and hepatic steatosis

Lamivudine/Emtricitabine/Tenofovir - Hepatic flare with acute removal of agents in patients co-infected with Hepatitis B

Abacavir - Hypersensitivity rxn

Didanosine - reports of fatal pancreatitis

Zidovudine - Hematologic toxicity including granulocytopenia and severe anemia

- Hepatoxicity --> from raised LFT's to hepatitis and hepatic necrosis, shown in all NNRTI's but mostly in nevirapine

- Rash --> reports with all agents has been described, SJS seen as well

Effavirenz - CNS effects (grogginess)

Etravirine --> Rash (20%)

Nevirapine --> Hepatotoxicity; rash

- Bind within active pocket of protease, inhibiting binding of virus

- Without protease cleavage, virus can not cause infection!

- N/V and diarrhea

- liver enzyme elevations

- Metabolic complications:  hyperlipidemia, hyperglycemia, lipodystrophy, Atazanavir does not cause these complications

- changes in lipid metabolism seen prior to into of PI's

- Increased risk with concurrent use of PI's, NNRTI's, and stavudine (PI's largest offender!)

- Presence of hyperlipidemia with PI use is 28-80%

- HyperTG - 40-80%

- Cholesteremia - 10-50%

- PI's also block Glut-4, leading to insulin resistance

Ritonavir - coadministration with certain sedatives, antihistamines, hypnotics, antiarrhythmics, or ergot alkaloid preparations, it will SUCK

Tipranavir - Reports of fatal and non-fatal intracranial hemorrhage.  Reports of clinical hepatitis and hepatic decomposition including some fatalities

- Considered favorable for therapy

- Potent inhibitor of CYP3A4

- All PI's are substrates of 3A4

- Low level Ritonavir boosts levels of other PI's (increased efficacy, less pill burden, less resistance)

- Binding of CD4 and gp120 can be inhibited by a series of small molecules that bind to gp120

- Inhibition of coreceptors, such as CCR5

- Binding of the HR1 region of gp41

- Injectable, reconsistuted with sterile water

- Dose is 90mg q12 hours

- A/E are local injection site irritation, increased rate of bacterial pneumonia, sensitivity rxn

- Brand name Fuzeon

- Most complex synthetic peptide ever manufactured on a large scale

- Expensive

- HIV often uses CCR5 as co-receptor necessary to enter T-cells

- Maraviroc (Selzentry) was first one approved

- A/E are hepatotoxicity, cough, fever, abd. pain, pneumonia

- Inhibits viral enzyme integrase, which is necessary for insertion of viral DNA into human genomic DNA

-  First approved medication in class was Raltegravir (Insentress), dosed 400mg BID

- Nausea, h/a, pyrexia is common, myopathy and rhabdomyolosis has been reported as well

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