HIV Flashcards
Stages and Sysmptoms of HIV - 1. Acute HIV infection
-Most people infected with HIV experiencea short, flu-like illness that occurs 2-6weeks after infection (Stage 1 infection)
Common symptoms:
- Fever
- Sore throat
- Rash
- Tiredness
- Joint pain
- Muscle pain
- Swollen glands
- The symptoms usually last 1-2 weeks, but can be longer
Stages and Sysmptoms of HIV - 2. Chronic HIV infection
- After the acute stage, HIV may not cause anysymptoms for several years
- This process can vary from person to person, but may take up to 10 years, during which the patient will feel and appear well
CDC symptom guide for advanced HIV infection
- rapid weight loss
- dry cough
- recurring fever/ night sweats
- profound and unexplained fatigue
- swollen lymph glands
- chronic diarrhoea
- pneumonia
- blotches on skin, mouth, nose, eyelids
- memory loss, depression, other neurological
Stages and Sysmptoms of HIV - Acquired immunodeficiency syndrome (AIDS)
-AIDS is the term used to describe a number of potentially life-threatening infections and illnesses that happen when the immune system has been severely damaged by the HIV virus
- These include opportunistic infections and infection-related cancers
Dignosis of AIDs
-CD4 count of <200 cells/mm3
-Presence of certain opportunistic infections, e.g.
- Bacterial: Tuberculosis
- Fungal: Candidiasis
- Viral: HSV
- Parasitic: Toxoplasmosis
Molecular biology of HIV
- HIV is a retrovirus
- Its genome is carried on two copies of RNA
- These get reverse transcribed to DNA inside the infected cell
- HIV hijacks the machinery of the infected cell and incorporates its genome into the DNA of the infected cell
- HIV infects and kills CD4 cells (T helper/helper T cells/lymphocytes)
- These are important cells in our immune system
The HIV replication cycle
.
Current drugs licensed for treatment.
- Fusion inhibitors
- Entry inhibitors
- Nucleoside reverse transcriptase inhibitors (NRTIs)
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- HIV integrase strand transfer inhibitors
- Protease inhibitors
- Fusion inhibitors
Enfuviritide (Fuzeon)
- Biomimetic peptide
- Binds to a viral surface envelope glycoprotein (gp41)
- Prevents HIV from binding to the surface of CD4 lymphocytes (T helper cells)
- Given by subcutaneous injection, 90 mg bd
- High cost (approx. $25000 per annum)
- Useful only when patient does not respond to other antiretrovirals
- Entry inhibitors
Maraviroc (Selzentry/Celsentri)
- Potent, orally bioavailable and selective
- Antagonist for chemokine coreceptor 5 (CCR5)
- This blocks the binding of another viral envelope glycoprotein, gp120, to CCR5
- Thereby preventing fusion of the two membranes and stopping viral entry into the cell
- Nucleoside reverse transcriptase inhibitors (NRTIs)
Drugs acting on Reverse Transcriptase
- “Fake” building blocks of normal nucleosides used to make DNA
- Act as competitive substrates for reverse transcriptase
- Become incorporated into proviral DNA
- Malformed DNA transcript containing nucleoside analogues cannot be integrated into the host cell genome
Necloside analogues
- zidovudine - Retrovir (AZT, ZDV)
- emtricitabine – Emtriva (FTC)
- didanosine - Videx, Videx EC (ddI)
- zalcitabine - HIVID (ddC)
- stavudine - Zerit (d4T)
- lamivudine - Epivir (3TC)
- abacavir - Ziagen (ABC)
nucleotide analogue
tenofovir - Viread (TDF)
Prodrugs of tenofovir
- Tenofovir disoproxil (TDF)
- Tenofovir alfenamide (TAF)
Drugs acting on Reverse Transcriptase
3. Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine – Retrovir (AZT, ZDV)
- Thymidine analogue
- First HIV drug approved, first NRTI, 1987
- Treatment of HIV infection when CD4 cell count is <500/mm3 or symptomatic
- Also approved for use in HIV-infected pregnant women in 2nd and 3rd trimesters, along with IV ZDV during labour and delivery, and ZDV syrup to newborn for 6 weeks
- Toxicity issues – neutropenia, anaemia, leucopoenia
Drugs acting on Reverse Transcriptase
3. Nucleoside reverse transcriptase inhibitors (NRTIs)
Mainly undergo renal excretion, with the exception of:
- Zidovudine (AZT) which undergoes glucuronidation
- Abacavir metabolised by alcohol dehydrogenase
Do not have P450 drug interactions
- Limited food restrictions, except for: Didanosine – take on empty stomach (+/- 2hrs)
Drugs acting on Reverse Transcriptase
3. Nucleoside reverse transcriptase inhibitors (NRTIs) Adverse affects
- Lactic acidosis (inadequate clearance of lactic acid from blood by liver)
- Hepatic steatosis (fatty liver)
- Rare but potentially fatal complication
Drugs acting on Reverse Transcriptase
4. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Hepatic metabolism – no renal dosage adjustments necessary
- Single mutation confers cross resistance to all available NNRTIs
- Many P450 drug interactions
Class adverse effects
- Increased transaminase levels
- Rash (usually on commencing therapy resolves by 1 month)
- Especially nevirapine
- Severe hepatotoxicity also associated with nevirapine use
- Integrase inhibitors
- Raltegravir (Isentress)
- First in class, HIV Integrase Inhibitor
- Raltegravir demonstrated antiviral activity in cell culture against a broad panel of HIV isolates
- Including isolates resistant to protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Other examples
- Dolutegravir – Tivicay
- Bictegravir – given in combination with emtricitabine and tenofovir AF as Biktarvy
- Protease inhibitors
- Proteases are enzymes which catalyse the hydrolysis of peptide bonds in proteins/peptides
- HIV genome codes for all viral proteins, but as a series of polyproteins
- These polyproteins must be cleaved by HIV proteases in order to become functional
- Gag polyprotein – cleaved to become matrix, capsid and nucleocapsid proteins
- GagPol polyprotein – additional protein domains cleaved to become reverse transcriptase, integrase and protease enzymes
- The HIV-1 Protease is a novel protease with a unique cleavage specificity
- No mammalian protease exhibits the same specificity- Therefore HIV-1 Protease is a unique target
- HIV-protease inhibitors prevent cleavage of Gag and GagPol polyproteins in both acutely and chronically infected cells
- Protease inhibitors
Hepatic metabolism – no renal dosage adjustments
Resistance usually requires multiple mutations
Therapeutically useful drug interaction
Ritonavir is the most potent pharmacokinetic booster of other PIs
Ritonavir induces CYP1A2 and inhibits the major P450 isoforms
Treatment regimens
Highly-Active Antiretroviral Therapy (HAART)/Antiretroviral Therapy (ART)
BHIVA guidelines
- NRTI backbone to regimens
- First line:
- 2 NRTIs + Protease inhibitor
- 2 NRTIs + Integrase inhibitor
- 2 NRTIs + NNRTI
- Tenofovir + emtricitabine
- Zidovudine + lamivudine
- Emtricitabine and lamivudine can be used in place of each other
NON recommend treatments
3 NRTIs
The following NRTI combinations:
Stavudine + zidovudine
- Both thymidine analogues; antagonistic
Stavudine + didanosine
- Increased risk of toxicity
Emtricitabine + lamivudine
- Similar resistance profiles
- treatment aims
Achieve viral suppression (to less than 50 copies/mL)
Thus reducing HIV-associated mortality and morbidity
With a low level of drug toxicity
- treatment rationale
Preservation of specific anti-HIV immune responses that would otherwise be lost, and which are associated with long-term non-progression in untreated individuals
Reduction in morbidity associated with high viraemia and CD4 depletion during acute infection
Reduction in the risk of onward transmission of HIV
- when to start
Primary (acute) infection: Same day treatment can be offered
Established infection: Begin within 2-4 weeks of diagnosis
Patients presenting with AIDS or major bacterial infection: Within 2 weeks of initiation of specific antimicrobial therapy
- Highly Active Antiretroviral Therapy (HAART)/Antiretroviral Therapy (ART)
- A combination of at least 3 drugs is used:
- To enhance efficacy of a single agent
- To minimise toxicity by reducing individual doses
To prevent or delay drug resistance
- What to start
Prior to baseline testing:
Tenofovir + Lamivudine + One of:
or Dolutegravir
Emtricitabine Bictegravir
Darunavir
- In the context of transmitted drug resistance (TDR)
Genotypic resistance testing of reverse transcriptase, protease, and sometimes integrase, is recommended in ART-naïve individuals
What is PrEP?
PrEP is a medication patients at risk of HIV take to reduce the risk of getting HIV from sex or injection drug use
Truvada®
Generic: Tenofovir disoproxil + emtricitabine
Licensed for: all people at risk from sex or injection drug use
Descovy®
Generic: Tenofovir alafenamide + emtricitabine
Licensed for: people at risk from sex, except for females at risk of contracting HIV from vaginal sex
Dosing regimens
Taken regularly (one tablet per day)
Only taken when needed (two tablets two to 24 hours before sex, one tablet 24 hours later and a further tablet 48 hours after that)
Often called ‘on-demand’, ‘event-based’ or 2-1-1 dosing
Pre-exposure prophylaxis (PrEP)
PrEP could be a cost-effective public health intervention to help tackle HIV transmission
Concerns have been raised that it may discourage condom use
A long-acting injectable PrEP has been approved by the Food and Drug Administration (FDA) but it is not yet available in the UK
PrEP vaginal rings are used in some parts of the world but are not available in the UK
Post-exposure prophylaxis (PEP)
What is it?
A combination of HIV drugs that can stop the virus taking hold
It can be used after the event if you’ve been at risk of HIV transmission
To work, PEP must be taken within 72 hours and should be taken as soon as possible, ideally within 24 hours
28 day course:
Truvada® - tenofovir disoproxil/emtricitabine
Raltegravir
Post-exposure prophylaxis (PEP)
Who is it indicated for?
They are an uninfected sexual partner of a person known to have HIV, to prevent infection after sex without a condom or where the condom has split
PEP is generally no longer recommended if the HIV-positive partner is adherent to ART and has been confirmed as having a sustained (more than 6 months) undetectable plasma HIV viral load (less than 200 copies/ml)
They have had unprotected sex with a person in a high-risk group for HIV whose infection status is not known
PEPSE may be offered to victims of sexual assault depending on risk assessment
Co- morbidities and HIV
CNS
HIV is neurovirulent:
Frailty syndrome
Cognitive impairment, memory loss
Depression
** Renal impairment**
Damage to renal epithelial cells
Some antiretrovirals are associated with renal toxicity, e.g. tenofovir
Hypertension and diabetes, which are more common in PLWH, can contribute to kidney disease
Regular monitoring of renal function is crucial
other
Skeletal – osteoporosis
Endocrine – thyroid disease, diabetes
Reproductive - hypogonadism
