HIV and opportunistic Infections Med Chem Flashcards
HIV
-retrovirus (lentivirus)
-double stranded RNA
-infects CD4+T cells (T-tropic ) and macrophages (m-tropic)
-uses enzyme reverse transcriptase
viral rna is converted to DNA
CXCR4
major coreceptor for T-cell tropic strains
involved in the progression to AIDS
CCR5
major coreceptor for macrophage-tropic strains
involved in the transmission of infection
- strategy to block infection
History of HIV treatment
prior to 1996: one or two NRTIs
In 1996: HIV protease inhibitors were introduced
three active antiretroviral agent were shown to inhibit
-HIV replication
-reverse immune deficiency
-decrease morbidity and mortality
how doe HIV-1 enter target cells
primary receptor : CD4
failed strategy of HIV
soluble CD4
acute primary HIV infections
treat with combination antiviral therapy to suppress virus replication to levels below the detection of plasma HIV RNA assays
Patient under effective HIV treatment with viral loads below detectable
should consider infectious and should be counseled to avoid sexual and drug use behaviors
Long term non progress ors of HIV
ppl infected by HIV for over 10 years and never convert into AID
CD4+ cell levels
indicator for initiation of anti-retroviral treatment
treatment recommended for
-a CD4 lymphocyte count below 350 cells/mm^3
-asymptomatic with CD4 count between 350-400 cells/mm^3
->500 CD4 cells/mm^3 (early treatment)
Pharmacological therapy of HIV
-inhibition of viral replication
-inhibition of HIV entry and viral fusion integration
under investigation
-microbicides to prevent HIV associated infections
-vaccination to simulate a more immune response ( not FDA approved yet)
-restoration of the immune system with immunomodulatora
nucleoside analogs
act as a chin terminators or inhibitors at the sub strayer binding site of RT
- must be phosphorylated (3 steps) to their 5’ triphosphate form to become active inhibitors
Nucleotide analogs
already contain a phosphate group and only goes through 3 steps to become active
what does the 5’triphosphate of the NRTI’s compete with for binding to reverse transcriptase leading to viral DNA chain termination
2’deoxynucleoside’s 5’triphosphate
6 agents of NRTI
cytosine analog
-emtricitabine
-lamivudine
adenosine or guanosine analog
-abacavir sulfate
-didanosine
thymidine analog
-stavudine
-zidovudine
NtRTI drug
adenosine derived nucleotide reverse transcriptase inhibitor
-tenofavir disoproxil fumarate (functions as prodrug)
non nucleoside analoge reverse transcriptase inhibitor MOA
inhibit DNA replication by binding at the allosteric non bonding site of RT, causing a conformational change of the active site
do not require bioactivation by kinase
non nucleoside analoge reverse transcriptase inhibitor agents
nevirapine
delavirdine
efavirenz
rilpivirine
protease inhibitor
During there reproduction cycle of HIV protease is needed to process GAG and POL polyproteins into mature HIV components
Protease inhibitors ate specific to HIV protease bc it differs from human
HIV protease inhibitors
target the peptide linkage in GAG and GAG-POL poly protein which must be cleaved by protease
Protease inhibitor agents
-navir
atazanavir
darunavir
fosamprenavir
indinavir
lopinavir
nelfinavir
ritonavir
saquinavir
tipranavir
integrase inhibitors MOA
-tegravir
prevent or inhibit the binding of the pre-integration complex to host cell DNA, thus terminating the integration step of HIV replication
-raltegravir
-elcitegravir
-dolutegravir
virus fusion/ entry inhibitors
inerfere with virus binding to cell surface
- enfuvirtide; biomimetic peptide binds to gp41 and prevents fusion with the host cell
viral coreceptor antagonist
compete for binding of HIV to secondary CCR5 coreceptor required for HIV entry and infection
-maraviroc
advantage for combination therapy for HIV
less resistance
multiple targets
reduce individual drug toxicity (lower doses of each)
Methods of reducing drug toxicity for HIV
the use of combination therapy
-favorable synergistic properties (decreased in dose or dosing frequency)
typical anti retroviral regimen
high active anti-retroviral therapy (HARRT)
at least tree agents
-2NRTI’s +1 PI
-2NRTI’s +1 NNRTI
-2NRTI’s +2 PI’s
may not work in all pts
limitations: side effects, resistance, DI
DDI of NRTI’s
the same nuclease should not ne co-administered
the two adenosine analogs are less effective together
coadministration od didanosine and tenofovir is not recommended for initial therapy
why is it difficult to treat HIV
quick resistance due to high mutation rate
solution: drug cocktails ( more than one drug)
immunotherapies for HIV
active immunotherapy (vaccines)
passive immunotherapy (antibodies)
immune modulation (small molecules)
cell based treatment: antigen stimulated Tcell
types HIV vaccines
preventative vaccine:
-taget younger population who better tolerate to vaccine induced T cell response
-adjuvant allowed
therapeutic vaccine
- taget pst currently with AD, who have tolerance to vaccine related adverse effects
-quick antibody response
-adjuvant in not included
HIV Vaccine
Mosaic vaccine
-computer algorithm
- it takes a piece of the different viruses and sticking them together to generate immune response that can cover a broad range of HIV subtypes
no cure or viable vaccine is available
Common AIDS opportunistic infections
bacterial infections
-tuberculosis
malignancies (cancers)
viral infections
-CMV
-Hep C
-Herpes simple virus
-human papilloma virus
fungal infections
-pneumocystis pneumonia
protozoal infections
-toxoplasmosis
Major opportunistic infections and coinfection
pneunocystis carinii pneumonia
toxoplasmosis
CMV infections
cyptoccical infections
tuberculosis
HIV-HCV coinfection
mycobacterium avium complex
how to avoid opportunistic infections
-prevent exposure to opportunistic pathogens
-vaccination to prevent first episode
-primary chemoprophylaxis on certain CD4 threshold
-treat remergent OI
- secondary chemoprophylaxis to prevent recurrence
-discontinuation of certain prophylaxes with sustained ART associated immune recovery
Problems in HIV treatment ant OI
DDI
overlapping drug toxicities
an immune reconstitution inflammation syndrome
Pneumocystis and its treatment
one of the most common life threatening OI in patients with AIDS
occurs in those with CD4 counts less than 200
treatment with trimethoprim sulfamethoxazole
alternative for Pneumocystis
moderate- severe: corticosteroid
alternative
-pentamdine
-dapsone with trimethoprim
mild- moderate
- primaquine with clindamycin
-atovaquone
HIV-HCV
coinfection is common
HIV worsen the prognosis of HCV
-reduces chances HCV clearance
-accelerating HCV progression
potential liver toxicity of ART
mycobacterium avium complex (MAC)
includes 2 species
-mycobacterium avium
-mycobacterium intacellulare
infects those with low CD4 counts and causes disseminated disease with counts below 100/ microliter
MAC prophylaxis
patients with HIV infection and less than 50 CD4 cell/ microliter should get lifelong prophylaxis
MAC treatment with Riffabutin
derivative of rifamycin and blocks DNA dependent RNA polymerase of bacteria
MAC therapy
clarithromycin or azithromycin
-plus at least a second drug (cipro, rifampin, etc)
