STIs (HIV/AIDS) Flashcards
What type of virus is HIV?
Belongs to the lentivirus group, RNA virus
HIV attacks and destroys CD4 T cells
What are the possible mode of transmission of HIV?
- Unprotected sexual intercourse
- Sharing infected syringes and needles
- Mother to child transmission during pregnancy, at birth, and breastfeeding
- Transfusion with contaminated blood and blood products
*Note that HIV is transmitted through body fluids (blood, semen, genital fluids, breastmilk)
Who should be tested for HIV?
- IV drug user
- Unprotected sex with multiple partners
- MSM
- CSW
- Persons treated for STDs
- Recipients of multiple blood transfusion
- Sexually assaulted
- Pregnant women (mandatory)
What tests can be done to diagnose HIV infection?
- Serum antibody detection
- HIV enzyme immunoassay antibody tests (HIV EIA tests)
- Western Blot
- HIV RNA detection/quantification (viral load)
- Nucleic acid amplification (PCR)
What are the 4 different stages of HIV?
A) Acute (primary) HIV infection
B) Asymptomatic stage
C) Persistent generalized lymphadenopathy
D) AIDS & related conditions
Describe the acute (primary) stage of HIV infection
- Occurs soon after contracting HIV
- Flu-like illness with swollen lymph nodes, fever, malaise, rash
- Lasts 2-3 weeks
Describe the asymptomatic stage of HIV infection
- No S&S
- This stage can persist for many years
Describe the persistent generalized lymphadenopathy stage of HIV infection
- Persistent unexplained lymph node enlargement in neck, underarms, groin
- For more than 3 months
Describe AIDS and its related conditions
- What defines/constitutes AIDS
AIDS = CD4 <200/mm^3 OR Presence of AIDS-defining disease
AIDS defining diseases:
- Opportunistic infections: TB, recurrent bacterial pneumonia (pneumocystis - fungal), candidiasis, cytomegalovirus (CMV) [*CMV can cause blindness]
- Rare cancers: Non-Hodgkins lymphoma, Kaposi sarcoma
- AIDS dementia complex
- Wasting syndrome, unexplained weight loss
Systemic symptoms of AIDS include: fever, unexplained wieght loss, persistent diarrhea, extremem fatigue, swollen glands in the neck, armpits, groin
May have multiple organ involvement: lung, eyes, GIT, CNS, skin etc.
What are the primary goals of anti-retroviral therapy?
- Reduce HIV-associated morbidity and mortality (by maintaining CD4 cell count and reducing development of other AIDS associated diseases)
- Prolong the duration and quality of survival
- Restore and preserve immunologic function
- Maximally and durably suppress plasma HIV viral load (to undetectable amounts, hence preventing transmission)
- Prevent HIV transmission
Describe the uses of CD4 as a surrogate marker in HIV
CD4 cell count (normal: 500-1200, AIDS: <200)
- Indicator of immune function
- Strongest predictor of subsequent disease progression and survival
- Determines urgency for initiating ART
- Assess response to ART therapy
- Assess need for initiating or discontinuing prophylaxis for opportunistic infections (e.g., prophylaxis for pneumocystis pneumonia is started when CD4 <200)
Using CD4 cell count as surrogate marker,
What are the time intervals to assess response to ART therapy?
What defines an adequate CD4 response?
Assess at baseline, and every 3-6 months after treatment initiation, followed by every 12 months after adequate response
Adequate response: increase in CD4 count in the range of 50-150 cells/mm3 during the first year of therapy
Describe the uses of viral load as a surrogate marker in HIV
Using HIV RNA to determine viral load
- Most important indicator of response to ART (better than CD4)
- Useful in predicting clinical progression (CD4 better)
When is viral load measured?
Also state when viral suppression is typically achieved
How long does an effective regimen generally take to achieve viral suppression?
Before initiation of therapy at baseline and within 2-4 weeks (not later than 8 weeks) after treatment initiation of modification, followed by every 4-8 weeks until viral load suppressed
In patients on stable regimen and suppressed viral load, monitoring can be done every 3-6 months
Effective regimen generally achieve viral suppression by 8-24 weeks
Who is ART recommended for?
All HIV-infected individuals, regardless of CD4 cell count
- reduce morbidity and mortality a/w HIV, maintain CD4 cell count, reduce viral load, prevent transmission
When should ART be started?
Should start after educating pt on benefit + considerations + strategies to optimize adherence
- 95% adherence required, or else 1. risk of resistance to ART agents 2. risk of treatment failure
DO NOT start (consider deferring) if pt unable to be adherent (e.g., clinical and/or psychosocial factors)
What are the benefits of earlier ART treatment?
- Maintain higher CD4 count, prevent irreversible damage to immune system
- Decrease risk for HIV-associated complications (when CD4 >350, may develop complications such as TB, cancer, peripheral neuropathy, cognitive impairment)
- Decrease risk of non-opportunistic conditions (CVD, renal disease, liver disease, non-AIDs associated malignancies and infections)
- Decreased risk of HIV transmission through viral load suppression
What are the limitations of earlier ART treatment?
- Treatment-related side effects and toxicities
- Development of drug resistance, loss of future treatment option due to incomplete viral suppression (if non-adherent)
- Transmission of drug-resistant virus
- Less time to educate patient, risk of non-adherence
- Treatment fatigue due to greater total time on medication
- Increased cost
What are the factors to consider when selecting initial regimen?
- Patient’s understanding of HIV (education)
- Cost, availability
- Adherence issues (pill burden, dosing frequency, food and fluid considerations)
- Virologic efficacy (higher viral load need more efficacious agent)
- Potential adverse effects
- Childbearing potential (avoid teratogenic agents)
- Genotypic drug resistance testing (test for genes a/w resistance to certain drugs - drug resistant virus)
Briefly describe the life cycle of HIV
- Free virus
- Binding and fusion
- bind to CD4 receptor + CCR5 or CXCR4 co-receptors
- fusion of virus and host cells’ cell membrane
- VIrus penetrates cell and releases 2 viral HIV RNA strand + 3 replication enzymes (reverse transcriptase, integrase, protease)
- Reverse transcription (single strand RNA => double stranded DNA)
- Integration (viral DNA combined with host cell’s DNA)
- Transcription (RNA => protein)
- Assembly
- Budding
- Immature virus breaks free from infected cell
- Maturation (protease cleaves protein chain, makes a working virus)
ART armamentarium:
CCR5 antagonist
Fusion/entry inhibitor
Reverse transcriptase inhibitor
Integrase strand transfer inhibitor
Protease inhibitor
What are the recommended combinations for patients naive to ART?
2 NRTIs + 1 INSTI
- Tenofovir + Emtricitabine + Bictegravir (TEB)
- Tenofovir + Emtricitabine + Dolutegravir (TED)
- Abacavir + Lamivudine + Dolutegravir (LAD)
1 NRTI + 1 INSTI
- Emtricitabine + Dolutegravir (ED)
Other combi: NNRTI + NRTI
1 NRTI + 1 INSTI is not recommended for which group of patient and why?
Emtricitabine (NRTI) + Dolutegravir (INSTI)
- Not recommended for patients with HIV RNA >500,000 (very high viral load, use 2 NRTIs + 1 INSTI instead)
- Not recommended for patients with Hep B coinfection (Hep B tx require at least 2 NRTI: either Tenofovir, Emtricitabine, or Lamivudine) => incr risk of mutation and resistance of HBV
- Not recommended for patients in whom ART is to be started before the results of 1. HIV genotypic resistance testing or 2. HBV testing are available
List the Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- Tenofovir
- Emtricitabine
- Abacavir
- Lamivudine
- Zidovudine
What are the class advantages of NRTIs?
- Established dual backbone of combi ART
- Renal elimination, little concerns of CYP DDIs
What are the class disadvantages of NRTIs?
- Adverse effects related to mitochondrial toxicity
- Lactic acidosis and hepatic steatosis (fatty infiltrate)
- Lipoatrophy (lost of fat)
- More a/w Zidovudine (older drug)
- Require renal dose adjustment
Which NRTI does not require renal dose adjustment?
Abacavir
What are the specific adverse effects a/w Lamivudine?
- Minimal toxicity
- Nausea, vomiting, diarrhea
What are the specific adverse effects a/w Emtricitabine?
- Minimal toxicity
- Nausea, diarrhea
- Hyperpigmentation
HE
What are the specific adverse effects a/w Tenofovir?
- Nausea, vomiting, diarrhea
- Renal impairment
- Decrease in bone mineral density (incr risk of osteoporosis, osteopenia)
Explain the differences in the incidence of adverse effect between the two Tenofovir formulations
Tenofovir Alafenamide (TAF) vs Tenofovir Disoproxil Fumarate (TDF)
- TDF is more a/w with higher incidence or renal impairment + dcr in BMD
- FYI: TAF targets liver cells (more specific in Hep B)
What are the specific adverse effects a/w Abacavir?
- Nausea, vomiting, diarrhea
- Hypersensitivity rxn in pt with HLA-B*5701
=> Symptoms: rash, fever, malaise, LOA, sore throat, cough, SOB
=> Fatal, if occur, discontinue and do not rechallenge
=> Test for HLA-B*5701 allele
- Concern for myocardial infarction
=> do not use in high CVD risk patients
HMA
What are the specific adverse effects a/w Zidovudine?
- Nausea, vomiting, diarrhea
- Myopathy
- Bone marrow suppression - may cause anemia, neutropenia (monitor FBC)
BMZ
List the Integrase Strand Transfer Inhibitors (INSTI)
-gravir
Raltegravir
Elvitegravir
Dolutegravir
Bictegravir
(oldest to newest)
What are the class advantages of INSTIs?
- B & D have good virologic effectiveness
- High genetic barrier to resistance (B/D > R/E)
- Generally well-tolerated
What are the class disadvantages of INSTIs?
ADR:
- Nausea, diarrhea, headache, weight gain
- Depression and suicidality (rare, primarily in pt with preexisting psychiatric conditions)
DDI:
- Lower bioavailability when administered with polyvalent cations
- B, D, E are CYP3A4 substrates
INSTIGATE DEPRESSION and SUICIDE, DO NOT MIX
What is a specific adverse effect of Bictegravir and Dolutegravir?
They incr serum creatinine by inhibiting the tubular secretion of creatinine (but do not impact glomerular function, do not cause kidney impairment)
What is a specific adverse effect of Raltegravir?
- Pyrexia (fever)
- Creatine kinase elevation (rhabdomyolysis - dark urine)
PCR
Which INSTI may require PK enhancer to increase its concentration?
Elvitegravir
(PK enhancers: Ritonavir, Cobicistat)
List the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz
Rilpivirine
ER
What are the class advantages of NNRTIs?
- Long half-life (once daily dosing)
- Less metabolic toxicity (less hyperlipidemia, insulin resistance compared to PI)
What are the class disadvantages of NNRTIs?
- Low genetic barrier to resistance
- Cross resistance among approved NNRTIs
- Skin rash, SJS (Efavirenz > Rilpivirine)
- CYP450 DDI
- QTc prolongation
LCSCQ
What are the specific adverse effects of Efavirenz?
- Rash (more than rilpivirine)
- Hyperlipidemia (incr LDL-C, TG)
- Neuropsychiatric SE (dizziness, depression, insomnia, abnormal dreams, hallucination)
- Hepatotoxicity
HHRN
What are the specific adverse effects of Rilpivirine?
- Depression, headache
*NNRTI of choice due to less SEs
Efavirenz and Rilpivirine are ______ substrates
Efavirenz is also an inducer of ___________
Efavirenz and Rilpivirine are CYP3A4 substrates
Efavirenz is a CYP2B6 and CYP2C19 inducer
Comment on Rilpivirine administration
Oral absorption is reduced with increased gastric pH
Use with PPI is contraindicated
List the Protease Inhibitors (PIs)
- navir
Atazanavir
Darunavir
Ritonavir
Fosamprenavir
Lopinavir
ADRFL (ADR From PIL)
Protease inhibitors are co-formulated with?
PK enhancers (Ritonavir or Cobicistat)
=> they are CYP450 3A4 inhibitors, included in the formation to increase the concentration of the antiviral
*Also co-formulated with INSTI - Elvitegravir - CYP3A4 substrate)
What are the class advantages of PI?
- High genetic barrier to resistance
- PI resistance less common
What are the class disadvantages of PI?
- Metabolic complications (dyslipidemia, insulin resistance)
- GI SEs (nausea, vomiting, diarrhea)
- Hepatotoxicity (esp with chronic Hep B or C)
- CYP3A4 inhibitors and substrates - DDI potential
- Morphologic complications: fat maldistribution (lipohypertrophy)
- Increased risk of osteopenia, osteoporosis (loss of BMD)
PI
HCLGMO
What are the specific adverse effects of Ritonavir?
- Potent CYP3A4, 2D6 inhibitor (PK enhancer)
- Paresthesia (numbness of extremities)
- Taste perversion
RP TP
What are the specific adverse effects of Darunavir?
- Good GI tolerability
- Less lipids effects
- Skin rash, concern for SJS
*It is a sulphonamide
What are the specific adverse effects of Atazanavir?
- Good GI tolerability
- Less lipid effects
- Hyperbilirubinemia
- Prolong QT interval
- Skin rash
Happy Birthday to SQ Agent
Administration:
- Absorption depends on low pH (CI with concurrent PPI use)
Name a fusion inhibitor
Enfuvirtide
How is Enfuvirtide administered?
Subcutaneous injection 2x/day
What are the advantages of Enfuvirtide?
- no appreciable drug interactions
What are the disadvantages of Enfuvirtide?
- injection site reaction (erythema, induration, nodules/cyst, pruritis, ecchymosis)
- rare hypersensitivity (fever, rash, chills, decrease BP)
- increased bacterial pneumonia
IRB
Name a CCR5 antagonist
Maraviroc
Explain which group of patient can use Maraviroc
Only in people whose strain of HIV uses CCR5 receptor to enter the CD4 cells
- Assess using co-receptor tropism assay before initiation
- Must be CCR5 predominant (do not use if CXCR4 or dual/mixed tropism)
What are the adverse drug reactions a/w Maraviroc?
- Abdominal pain
- Cough
- Dizziness
- Musculoskeletal symptoms
- Pyrexia
- Rash
- URTIs
- Hepatotoxicity (rare)
- Orthostatic hypotension (rare)
DDI: CYP3A4 substrate
MARVEL OH has Abs, Muscles, but URTIs and Rash
