HIV and HIV therapy

Question 1

What are the modes of transmission for HIV?

Answer 1

sexual contact (horizontal), mother to child (vertical), contaminated blood/blood products, contaminated needles, occupational exposure

Question 2

Describe the structure of the HIV virus itself and how it binds to host

Answer 2

a retrovirus, stores genetic info as RNA , it’s an obligate parasite so cannot make its own protein and viral parts, surface gp120 molecule has strong affinity for CD4 receptor on T helper and CNS cells. Interaction causes conformational change of gp120 uncovering the fusion protein gp41 which interacts with host chemokine receptors

Question 3

How does the virus causes disease upon entry?

Answer 3

HIV uncoats allowing RNA to enter host cells cytoplasm, uses reverse transcriptase to make viral DNA which is incorporated into host DNA, viral DNA enters cell nucleus using the enzyme integrase which splices viral DNA into host cell DNA. Once integrated, transcription of viral genome begins to produce further viral RNA. Full length viral RNA assemble at cell membrane and bud off host cell. Process causes destruction to T helper cells so CD4 count drops

Question 4

How is HIV manifested clinically?

Answer 4

asymptomatic people and those with symptoms can either be non-specific such as fever, night sweats, lethargy, weight loss or infections such as oral candida, herpes zoster and herpes simplex

Question 5

What is the CD4 count for AIDS vs normal cell count and which conditions are classified as an AIDS defining illness?

Answer 5

<200 cells/mm3 whilst normal range is 400-1600 cells/mm3, PCP, TB, CMV, Kaposi’s sarcoma and lymphoma

Question 6

What investigations or monitoring needs to be done for someone with HIV?

Answer 6

monitor CD4 counts (marker of immune system status) : ART treatment threshold is 350 cells/mm3 and give PCP prophylaxis if <200 cells/mm3 & Plasma viral RNA load (indicates treatment efficacy)

Question 7

What are the goals of therapy in HIV patients?

Answer 7

improve life expectancy and quality of life, prevent deterioration of immune function, restore immune function, prevent or treat opportunistic infections and malignancies, relieve symptoms where underlying cause is unknown

Question 8

Drug treatment for HIV can be classified into what groups?

Answer 8

antiretroviral, management of opportunistic infections and malignancies & symptom control

Question 9

When should you start ART?

Answer 9

when a patient has a diagnosis of HIV regardless of CD4 count or when CD4 is less than 200 cells/mm3 or within 2 weeks of AIDS diagnosis

Question 10

What viral load should you aim for when giving ART?

Answer 10

less than 50 copies/ml

Question 11

What are the classes of ARVs and some examples of each?

Answer 11

NRTIs (tenofovir, Abacavir, Emtricitabine, , Lamivudine, Zidovudine), nNRTIs ( Efavirenz, Nevirapine, Travertine, Rilpivirine) , Protease Inhibitors ( Lopanavir, Darunavir, Atazanivir all boosted with ritonavir, Indinavir), Integrase Inhibitors (Raltegravir, Elvitegravir, Doultegravir) & Entry/Fusion Inhibitors (Maraviroc and Enfuviritide)

Question 12

How do NRTIs work?

Answer 12

They are phosphorylated intracellularly and inhibit the viral reverse transcriptase enzyme by acting as a false substrate. This halts viral DNA synthesis

Question 13

What are some NRTI combination products?

Answer 13

Truvada, Kivexa, Combivir, Trizivir- 3 drugs (aid adherence)

Question 14

How do nNRTIs work?

Answer 14

they inhibit reverse transcriptase enzyme by binding to active site, don’t require prior phosphorylation

Question 15

How do protease inhibitors work?

Answer 15

bind to active site on HIV protease enzyme, preventing maturation of newly produced virion so they remain non infectious

Question 16

Why are all protease inhibitors boosted with ritonavir?

Answer 16

This synergy exploits enzyme inhibition of ritonavir, lowers dose of each drug used, and lessens pill burden and number of doses a day. Also increases drug exposure which increases efficacy

Question 17

What is lipodystrophy & lipoatrophy?

Answer 17

side effect of protease inhibitors, increased risk of CVD and fat is redistributed to areas around body

Question 18

How do Entry inhibitors work and when are they used?

Answer 18

inhibits HIV from fusing, binding and entering cell by inhibiting gp41. Enfuvirtide binds to the gp41 protein but Maraviroc binds to CCR5, a coreceptor on CD4 cells

Question 19

How do Integrase inhibitors work?

Answer 19

blocks integrase enzymes and prevents incorporation of viral DNA into host cell DNA

Question 20

When starting initial therapy what drugs should be given?

Answer 20

2 NRTIs + of either: nNRTI, boosted PI or Integrase inhibitor

Question 21

What is the purpose of post-exposure prophylaxis and what drugs are given?

Answer 21

recommended depending on risk following sex or occupational exposure, it inhibits viral replication and integration into host DNA this aborting HIV infection. Used within 72 hours of exposure. Drugs include Tenofovir and Emtricitabine (Truvada) and Raltegravir

Question 22

What baseline bloods do patients taking post exposure prophylaxis need?

Answer 22

FBC, U&Es, LFTs, glucose, lipids, Hep B and C, STIs

Question 23

What is the purpose of pre-exposure prophylaxis?

Answer 23

To protect uninfected individuals in high prevalence groups from HIV. Given in the form of tablets and vaginal gels

Question 24

What are some barriers to adherence?

Answer 24

failure to acknowledge treatment is needed, lack of understanding of benefits, concern about ADRs, difficulty understanding regimen, forgetting to take meds and fear that meds will disclose their HIV status

Question 25

Which groups of antiretroviral drugs cause inhibition of reverse transcriptions?

Answer 25

NRTIs and nNRTIs

Question 26

What is AZT, its class, MoA and structure?

Answer 26

NRTIS, it’s an analogue of deoxythymidine, enters host cell via passive diffusion then converted to triphosphate by host enzyme. Triphosphate is a competitive inhibitor is reverse transcriptase. The N3 chain terminating group of the 3’ sugar doesn’t allow any further replication of viral DNA. Active against HIV1 and 2

Question 27

What combination of drugs are used as first line therapy?

Answer 27

Tenofovir disoproxil fumarate & Lamivudine. Tenofovir has a pseudo phosphate, CH2 instead of an oxygen to make drug more hydrophobic to enter cells.

Question 28

Do nNRTIs act at active site?

Answer 28

no act at allosteric site remote from AS

Question 29

What drugs are used as part of triple therapy for first line treatment?

Answer 29

Tenofovir disoproxil fumarate & Lamivudine & Efavirenz

Question 30

HIV proteases are part of which protease group?

Answer 30

aspartyl

Question 31

What type of inhibitors are protease inhibitors?

Answer 31

act as transition state inhibitors

Question 32

What is saquinavir and why wasn’t it effective?

Answer 32

first protease inhibitor developed, the lead was a peptide with weak activity, certain changes made such as the addition of asparagine residue and a bulky hydrophobic quinolone group but resistance is common and has low bioavailability

Question 33

How does the HIV aspartate protease work?

Answer 33

acts as a dimer, catalyses the cleavage of peptide bonds