SG7: HIV Flashcards
What classes of antiretroviral agents are available? Describe their mechanism of action and their major adverse effects.
- NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS
- NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
- PROTEASE INHIBITORS
- ENTRY INHIBITORS
- INTEGRASE INHIBITORS
NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS Features
Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine
MOA
The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase; incorporation into the growing viral DNA chain results in premature chain termination due to inhibition of binding with the incoming nucleotide. NRTIs require intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate. Most have activity against HIV-2 as well as HIV-1.
ADVERSE EFFECTS
- NRTIs can inhibit mitochondrial DNA polymerase gamma, resulting in mitochondrial toxicity (didanosine and stavudine highest aff)
- pancreatitis, peripheral neuropathy, myelosuppression, or cardiomyopathy,
- Zidovudine is associated with bone marrow suppression in individuals with advanced HIV disease. Concurrent administration with ganciclovir can result in additive neutropenia. Zidovudine also assoc w lactic acidosis.
NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Features
Delavirdine Efavirenz Etravirine Nevirapine
MOA
The NNRTIs bind directly to HIV-1 reverse transcriptase, resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase. The binding site of NNRTIs is distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. In addition, they lack in vitro activity against HIV-2.
ADVERSE EFFECTS
main adverse effects of efavirenz involve the CNS: dizziness, impaired concentration, dysphoria, insomnia, psychosis. CNS side effects generally resolve within the first 4 weeks of therapy.
NNRTIs are substrates of CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine), or mixed inducers and inhibitors (efavirenz, etravirine). Drug-drug interactions must be expected.
PROTEASE INHIBITORS Features
Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir
MOA
PIs prevent processing of viral proteins, resulting in the production of immature, noninfectious viral particles. PIs are active against both HIV-1 and HIV-2. They do not need intracellular activation.
ADVERSE EFFECTS
Disorders in carbohydrate and lipid metabolism. The syndrome includes hyperglycemia, insulin resistance and hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy.
PIs are extensively metabolized by CYP3A4.
ENTRY INHIBITORS Features
Enfuvirtide
MOA
Enfuvirtide is a polypeptide that binds to the transmembrane glycoprotein gp41 thus preventing the conformational change necessary for HIV to gain entry into the host cell.
ADVERSE EFFECTS: local injection site reactions.
INTEGRASE INHIBITORS Features
Raltegravir
MOA
Raltegravir inhibits integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. By doing so, it inhibits integration of reverse-transcribed HIV DNA into the chromosomes of host cells.
ADVERSE EFFECTS
- Diarrhea, nausea, dizziness, and headache.
- Increases in creatine kinase.
What are the preferred antiretroviral regimens?
NNRTI-based Regimen
Accidental needle-stick (HIV): Updated guidelines from the United States Public Health Service
- postexposure prophylaxis regimen containing at least 3 antiretroviral drugs.
- The guidelines no longer require assessing the severity of exposure. The preferred regimen for occupational post-exposure prophylaxis is:
- Raltegravir plus tenofovir plus emtricitabine for 28 days.
Drug regimen for PCP in HIV Pt?
TMP-SMX is always the first choice for the treatment of PCP unless the patient has a history of life-threatening intolerance.
The recommended duration of therapy for PCP is 21 days.
MOA
Sulfamethoxazole competitively inhibits dihydropteroate synthase, the enzyme responsible for the incorporation of (PABA) into dihydropteroic acid, the immediate precursor of folic acid.
TMX exerts a synergistic effect with sulfonamides. Coadministration of a sulfonamide and trimethoprim introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate.
Adverse
High- dose therapy entails significant toxicity, especially in patients with AIDS. Adverse effects include:
PCP adjunctive corticosteroid therapy?
Patients with moderate-to-severe PCP, as defined by room air pO2 <70 mm Hg or arterial-alveolar O2 gradient >35 mm Hg, should receive adjunctive corticosteroids as early as possible. Oral prednisone or IV methylprednisolone are used.
What alternative regimens can be used to treat PCP?
- Clindamycin + primaquine.
- Dapsone + TMP (mild-to-moderate PCP only).
- Atovaquone (mild-to-moderate PCP only).
- Pentamidine (high rate of side effects: acute renal failure, hypotension, pancreatitis, hypo- and hyperglycemia, and electrolyte abnormalities).
What opportunistic infections may appear in HIV-infected patients?
Asymptomatic patients with moderate immunosuppression (CD4+ counts 200–500) may become infected with herpes viruses and Candida and/or develop pneumonias, enteric infections, and meningitis with common pathogens.
Primary prophylaxis is strongly recommended against which infections?
Strongly recommend primary prophylaxis against PCP, toxoplasmosis, Mycobacterium tuberculosis, MAC, and varicella-zoster virus (VZV).
Vaccinations to prevent Streptococcus pneumoniae, hepatitis B virus, hepatitis A virus, and influenza virus infection generally are recommended for all HIV- infected patients.
Primary prophylaxis for fungal infections (Cryptococcus neoformans and Histoplasma capsulatum), CMV, and bacterial infections are not routinely recommended for most patients, except in unusual circumstances.
Secondary prophylaxis is strongly recommended against which infections?
PCP, toxoplasmosis, MAC, CMV, Salmonella species, and infections caused by endemic fungi and C. neoformans.
Secondary prophylaxis regimen
Preferred regimen: TMP-SMX Alternative regimens:
