HIV & AIDS Flashcards
Which group of the retrovirus family does HIV belong to?
Lentivirus
Which specific target cell in the immune system does HIV attack & destroy?
CD4 T-helper cells
Describe the mode of transmission for HIV.
Through specific body fluids - blood, semen, genital fluids & breast milk:
1) Unprotected sexual intercourse (98% of new cases in SG)
2) Sharing infected syringes & needles (between IV drug users)
3) Vertical / Mother-to-child transmission during pregnancy, child-bearing or through breastfeeding
4) Contaminated blood & blood products
Which specific populations should be screened preemptively for HIV?
- IV drug users
- Individuals who have unprotected sex w/ multiple partners
- MSM
- Prostitution / Commercial sex workers
- Pt w/ STDs
- Recipients of multiple blood transfusions
- Individuals who have been sexually assaulted
- Pregnant women (mandatory in SG)
How is HIV diagnosed in a suspected patient?
1) Serum Ab detection
- HIV EIA (enzyme immunoassay) Ab tests
- Western blot
2) HIV RNA detection / quantification (Viral load)
- PCR amplification of HIV
Describe the clinical presentation of an HIV pt.
1) Acute/Primary:
- Occurs soon after contracting HIV
- Flu-like symptoms (fever, malaise & rash) w/ swollen lymph nodes x 2-3 weeks
2) Asymptomatic/Latent: persists for many years
3) Persistent Generalised Lymphadenopathy:
- Persistent unexplained lymph node enlargement in neck, underarms & groin for > 3 months
4) AIDS:
- Defined as CD4 < 200 cells/mm3 or presence of AIDS-defining diseases
- Advanced stage of HIV infection; pt succumbs to infections by 1 of 26 unusual organisms that uninfected person can resist
- Involve lung, eyes, GIT, nervous system & skin
- Systemic smx like fevers, unexplained weight loss & diarrhea are common
- Rare cancer (e.g. Non-Hodgkin’s lymphoma & Kaposi sarcoma) may be found
- Pneumocystis pneumonia is a possible complication
What are the primary therapeutic goals of antiretroviral therapy?
Reduced HIV-associated morbidity & mortality
Prolong duration & quality of survival
Restore & preserve immunologic function
Maximally & durably suppress plasma HIV infection
Prevent HIV transmission
Which laboratory markers are used as surrogate markers in the management of HIV patients on antiretroviral therapy (ART)? How are they used to monitor HIV patients on antiretroviral therapy?
1) CD4 T-lymphocyte Count
- Healthy CD4 count = 500-1200 cells/mm^3
- Most important lab indicator of immune fx in HIV pt.
- Strongest predictor of subsequent disease progression & survival (prognosis)
- Used to assess response to ART
- Assessed at baseline & q 3-6 months after Tx initiation, q 12 months after adequate response
- Adequate CD4 response = increase in CD4 of 50-150 cells/mm^3 during 1st year of Tx
- Used to assess need to initiate or discontinue prophylaxis for opportunistic infections (upon hitting certain thresholds)
- e.g. prophylaxis for pneumocystis pneumonia starts when CD4 < 200 cells/mm3
2) Viral Load (via PCR)
- Most important indicator of response to ART & useful in predicting clinical progression
- Measured before Tx initiation & w/in 2-4 weeks (no later than 8 weeks) after Tx initiation or modification; thereafter, q 4-8 weeks until viral load is suppressed
- Effective regimen generally achieve viral suppression (i.e undetectable HIV RNA load) in 8-24 weeks
- Pt on stable regimen & suppressed viral load to be monitored q 3-6 months (can be up to q 1 yr)
Under what conditions will it be considered as an adequate therapeutic response in HIV pt on ART?
Increase in CD4 of 50-150 cells/mm3 during 1st year of Tx
AND
Undetectable HIV RNA load in 8-24 weeks
When should we recommend initiating antiretroviral therapy (ART) to HIV pt?
Recommend regardless of CD4 count to ALL HIV-infected pt to reduce HIV-associated morbidity & mortality, as well as to prevent HIV transmission.
Important to educate on the benefits & considerations of ART, and address strategies to optimise adherence.
[Case-by-case] ART may be deferred due to clinical / psychological factors, BUT Tx should be initiated ASAP.
What are some benefits of earlier initiation of ART for HIV pt?
- Maintenance of higher CD4 count & prevention of potentially irreversible damage to immune system,
- Decrease risk of HIV-associated complications when CD4 > 350 cells/mm3, including TB, Non-Hodgkin’s lymphoma, Kaposi sarcoma, peripheral neuropathy & HIV-associated cognitive impairment
- Decrease risk of opportunistic conditions, including CVD, CKD, liver disease & non-AIDS-associated malignancies & infections
- Decrease risk of HIV transmission to others
What are some limitations of earlier initiation of ART for HIV pt?
- Development of Tx-related SE & toxicities (less observed w/ newer agents)
- Development of drug resistance due to incomplete viral suppression, resulting in loss of future Tx options
- Transmission of drug-resistant HIV in pt w/o full virologic suppression maintenance (including HIV-naive pt.)
- Less time to learn about HIV & its treatment & less time to prepare for the need of adherence to Tx
- Increased total time on medication & greater chance of Tx fatigue subsequently
- Increased cost
What are some factors to consider when selecting an initial ART regimen for HIV pt?
Regimen selection should be individualised based on:
- Pt. understanding of HIV
- Cost & availability
- Adherence issues & convenience (less concerning for newer agents) such as pill burden, dosing frequency & food & fluid considerations
- Virological efficacy
- Potential adverse effects (comorbidities, DDI)
- Childbearing potential
- Genotypic drug resistance testing
List all the drug classes available in the ART armamentarium against HIV.
Backbone Regimen (2 NRTIs + 1 INSTI):
1) Nucleoside Reverse Transcriptase Inhibitor (NRTI) (-ovir, -avir, -udine, -abine)
2) Integrase Strand Transfer Inhibitor (INSTI) (-gravir)
Alternatives:
3) Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) (-virine, -virenz)
4) Protease Inhibitor (PI) (-navir)
5) Fusion Inhibitor
6) Entry Inhibitor (CXCR4/CCR5 Antagonists)
What is the mechanism of action of NRTIs & NNRTIs?
Inhibit viral reverse transcriptase that converts viral ssRNA to ssDNA to dsDNA
What is the mechanism of action of INSTIs?
Block viral integrase from integrating viral dsDNA into host dsDNA
What is the mechanism of action of entry inhibitors?
Blocks HIV from access to the CXCR4/CCR5 co-receptor and prevents the fusion process of HIV to CD4 T-lymphocytes
What is the mechanism of action of fusion inhibitors?
Inhibits fusion of the viral envelope with the host cell membrane of CD4 T-lymphocytes
What is the mechanism of action of protease inhibitors?
Inhibits viral maturation process, resulting in lack of functional virion formation
What is the recommended first-line ART for HIV-naive pt w/o Hepatitis B co-infection (i.e. first-time Tx)?
2 NRTIs + 1 INSTI: (either/or)
1) Tenofovir + Emtricitabine + Bictegravir
2) Tenofovir + Emtricitabine + Dolutegravir
3) Abacavir + Lamivudine + Dolutegravir
Alternatively, 1 NRTI + 1 INSTI:
1) Emtricitabine + Dolutegravir
What is the recommended first-line ART for HIV-naive pt w/ Hepatitis B co-infection (i.e. first-time Tx)?
2 NRTIs + 1 INSTI: (either/or)
1) Tenofovir + Emtricitabine + Bictegravir
2) Tenofovir + Emtricitabine + Dolutegravir
Emtricitabine + Dolutegravir can be recommended as a first-line ART for an HIV-naive pt who has a Hepatitis B co-infection. True or false?
False!!
1 NRTI + 1 INSTI should NOT be recommended for pt:
1) w/ HIV RNA > 500,000 copies/mL,
2) w/ HBV co-infection, or
3) w/o results of HIV genotypic resistance testing or HBV results
Abacavir + Lamivudine + Dolutegravir cannot be recommended as a first-line ART for an HIV-naive pt who has a Hepatitis B co-infection. True or false?
True.
Two anti-HBV drugs MUST be used for HBV co-infection with HIV as first-line ART. However, ONLY tenofovir, emtricitabine & lamivudine has activity against HBV. Thus, w/ only lamivudine having anti-HBV activity, such a combination should NOT be recommended to HIV-naive pt w/ hepatitis B.
In the event of Tx failure of ART, which drug class(es) should be swapped out?
INSTIs should be swapped out for either NNSTIs or boosted PIs.
In severe resistance, entry & fusion inhibitors are used over INSTIs.
Which particular drugs in the ART armamentarium are used as pharmacokinetics enhancers for PIs?
Ritonavir (/r) & cobicistat (/c)
- CYP3A4 inhibitors included in the formulation of ART to increase concentrations of various antiretroviral drugs (esp. PIs & elvitegravir [INSTI])
Name some examples of NRTIs.
Tenofovir, Emtricitabine, Abacavir, Lamivudine, Zidovudine
Name some examples of NNRTIs.
Efavirenz, Rilpivirine
Name some examples of INSTIs.
Bictegravir, Dolutegravir, Raltegravir, Elvitegravir
Name an example of an entry inhibitor.
Maraviroc
Name an example of a fusion inhibitor.
Enfuvirtide
Name some examples of PIs.
Ritonavir, Lopinavir, Darunavir, Atazanavir, Fosamprenavir (co-formulated w/ ritonavir or cobicistat)
How are NRTIs eliminated?
Renal clearance
Which NRTI is used for the treatment of pregnant HIV pt?
Zidovudine
Which NRTI does not require renal dose adjustment in HIV pt with renal impairment?
Abacavir
What are some of the common side effects of NRTIs?
Minimal DDI
Common: Nausea, vomiting (except emtricitabine) & diarrhea
Rare but serious SE related to mitochondrial toxicity:
- Lactic acidosis & hepatic steatosis (fatty infiltrate)
- Lipotrophy (Zidovudine > Tenofovir = Abacavir = Lamivudine)
Which NRTI has the highest risk of causing lipoatrophy as a side effect?
Zidovudine
Which antiretroviral drugs amongst the NRTIs are reported to have minimal toxicities?
Emtricitabine & Lamivudine
Which particular NRTI requires prior testing to the presence of HLA-B*5701 gene in HIV pt before its initiation?
Abacavir
Which NRTI can cause hyperpigmentation as a potential side effect?
Emtricitabine
Which NRTI can cause renal impairment as a potential side effect?
Tenofovir
Abacavir + Lamivudine + Dolutegravir can be recommended as a first-line ART for an HIV-naive pt who expresses the HLA-B*5701 gene. True or false?
False!
Abacavir should NOT be given to patients who expresses the HLA-B*5701 gene due to hypersensitivity reactions that can be fatal (i.e. anaphalyxis). Do NOT rechallenge!
Which NRTI is associated with myocardial infarction & should not be used in HIV pt w/ cardiovascular risk?
Abacavir
Which NRTI has been associated with myopathy as a potential side effect?
Zidovudine
Which NRTI is associated with bone marrow suppression as a potential side effect?
Zidovudine
Rank the INSTIs from the highest to the lowest genetic barrier to resistance.
Bictegravir = Dolutegravir > Raltegravir = Elvitegravir
What are some of the common side effects of INSTIs?
Generally well tolerated Common SE: - Nausea & diarrhea - Weight gain - Headache Rare: (esp. w/ preexisting psychiatric conditions) - Depression & suicidality
What are some DDIs faced when using INSTIs as part of ART?
Bioavailability lowered by concurrent administration of polyvalent cations (e.g. antacids, Fe supplements)
CYP3A4 substrates: Bictegravir, Dolutegravir & Elvitegravir
Which INSTI is NOT metabolised by CYP3A4?
Raltegravir
Which INSTI(s) may result in an increase in serum creatinine due to inhibition of renal tubular secretion?
Bictegravir & Dolutegravir
Which INSTI is associated with drug fever (pyrexia)?
Raltegravir
Which INSTI has been associated with rhabdomyolysis?
Raltegravir
Which INSTIs are associated with good virologic effectiveness?
Bictegravir & Dolutegravir
What are some common side effects of NNRTIs?
Hypersensitivity (skin rash & Stevens-Johnson Syndrome)
QTc prolongation
Hyperlipdemia: increase in LDL-C & TG
Neuropsychiatric SE: HA, depression, dizziness, insomnia, hallucination
What are the advantages & disadvantages of using NNRTIs as part of ART for HIV pt.?
(+) Long half-lives & less metabolic toxicity (hyperlipidemia, insulin resistance) than some PIs
(-) Low genetic barrier to resistance than NRTIs, presence of cross-resistance among approved NNRTIs & potential for mixed CYP450 interactions (i.e. inhibition & induction)
Which NNRTI is contraindicated in pt receiving ART while on concomitant PPI for peptic ulcer disease?
Rilpivirine
What are the advantages & disadvantages of using PIs as part of ART for HIV pt.?
(+) High genetic barrier to resistance & PI resistance is less common
(-):
- Metabolic complications (dyslipidemia, insulin resistance)
- GI SE (N/V/D)
- Heptatotoxic (esp w/ chronic heptatitis B & C)
- CYP3A4 inhibitors & inducers; DDI potential
- Fat maldistribution (Lipohypertrophy & buffalo humps)
- Increased risk to osteopenia/osteroporosis
Which NNRTI is associated with hepatotoxicity as a potential side effect?
Efavirenz
Which formulation of tenofovir has a better toxicological profile (i.e. safer)?
Tenofovir alafenamide (TAF) is safer than Tenofovir disoproxil fumarate (TDF)
Which PI is contraindicated in pt receiving ART while on concomitant PPI for peptic ulcer disease?
Atazanavir
Which PIs have generally good GI tolerability w/ less lipid SE?
Darunavir & Atanazavir
Which PI has been associated with paresthesia (numbness of extremities)?
Ritonavir
Which PI has been associated with potential Stevens-Johnson Syndrome as a rare side effect?
Darunavir (sulfonamide formulation)
Which PI has been associated with QTc prolongation?
Atazanavir
How is enfuvirtide administered?
SC injection BD
What are some side effects associated with the use of enfuvirtide?
Injection site reaction, hypersensitivity (rare), increased bacterial pneumonia
Under what conditions should maraviroc be used for the Tx of HIV pt?
ONLY pt whose HIV strain uses the CCR5 receptor to enter CD4 cells can use maraviroc
- Need co-receptor tropism assay before initiation; MUST be CCR5 predominant to use maraviroc
- NOT to use if CXCR4 predominant or dual/mixed tropism
What are some side effects associated with the use of maraviroc?
[DU CAMPHOR] Dizziness URTI Cough Abdominal pain Musculoskeletal symptoms Pyrexia Hepatotoxicity Orthostatic hypotension Rash
Maraviroc is a CYP2D6 substrate. True or false?
False. Maraviroc is a CYP3A4 substrate.
What are some reasons for Tx failure of ART?
Patient: - Adherence < 95% - Dosing schedule & requirements - Provider experience Drug: - Drug toxicities - DDI Virus: - Viral resistance
What are some strategies that can be counselled to HIV pt. to improve adherence to ART?
- Establish readiness to start therapy
- Provide education on medication dosing
- Review, anticipate & treat side effects
- Utilise educational aids including pictures, pillboxes & calendars
- Engage family & friends for support
- Simplify regimens, dosing & food requirements (taking antiretrovirals w/ or w/o food
- Utilise team approach w/ nurses, pharmacists & peer counsellors
- Provide accessible, trusting healthcare team
