AIDS Flashcards
Human immunodeficiency virus (HIV) belongs to the lentivirus group of the retrovirus family.
Human immunodeficiency virus (HIV) belongs to the lentivirus group of the retrovirus family.
HIV attacks and destroys the infection-fighting CD4 T-cells of the immune system.
HIV attacks and destroys the infection-fighting CD4 T-cells of the immune system.
Loss of CD4 T-cells makes it difficult for the immune system to fight infections, ultimately leading to the Acquired Immunodeficiency Syndrome (AIDS).
Loss of CD4 T-cells makes it difficult for the immune system to fight infections, ultimately leading to the Acquired Immunodeficiency Syndrome (AIDS).
Mode of transmission
HIV is transmitted from one person to another through specific body fluids—blood, semen, genital fluids, and breast milk. These happens through
1) Having unprotected sexual intercourse with an infected person
2) Sharing infected syringes and needles (e.g. between intravenous drug users)
3) Mother-to-child transmission (during pregnancy, at birth or through breast feeding.
4) Transfusion with contaminated blood and blood products
who should be tested for hiv
Intravenous drug users
Person who have unprotected sex with multiple partners
Man who have sex with man
Commercial sex workers
Persons treated for STDs
Recipients of multiple blood transfusion
Persons who have been sexually assaulted Pregnant women – in Singapore, it is mandatory for all pregnant women to be tested, which explains the zero transmission rate from mother-to-child since 2008.
Diagnosis - 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)
Presentation: Different stages
A) Acute (Primary) HIV Infection
B) The Asymptomatic Stage
C) Persistent Generalised Lymphadenopathy
D) AIDS & Related Conditions
A) Acute (Primary) HIV Infection
A) Acute (Primary) HIV Infection
This occurs soon after contracting HIV, and is a flu-like illness with swollen lymph nodes, fever, malaise and rash lasting about 2 to 3 weeks
B) The Asymptomatic Stage
B) The Asymptomatic Stage
There are no signs or symptoms; this stage persists for many years
C) Persistent Generalised Lymphadenopathy
C) Persistent Generalised Lymphadenopathy
Persistent unexplained lymph node enlargement in the neck, underarms and groin for more than 3 months
D) AIDS & Related Conditions
AIDS = CD4 < 200/mm3 OR presence of AIDS defining disease
This is the advanced stage of the disease and the person succumbs to infections by unusual organisms that the uninfected person can resist
The organs involved include lung, eyes, gastrointestinal tract, nervous system and skin
Systemic symptoms like fevers, unexplained weight loss and diarrhoea are also common
Rare cancers (e.g. Lymphoma and Kaposi sarcoma) may be found
26 opportunistic infection
1) TB
2) pneumocystis
3) CMV –> HSV
4) Candidiasis
5) wasting syndrome (lost >10% of wt)
6) dementia complex
Primary Goals of Anti-retroviral Therapy
Reduce HIV-associated morbidity and mortality
Prolong the duration and quality of survival Restore and preserve immunologic function
Maximally and durably suppress plasma HIV viral load
Prevent HIV transmission
Strategies to Achieve Treatment Goals
Selection of Initial Combination Regimen
- —- ART regimens recommended by DHHS guidelines have comparable efficacy
- —- Consider dosing frequency and symmetry, pill burden, drug interactions, potential side effects and cost
- —– Tailored to each patient to enhance adherence and thus improve long-term treatment success
Pretreatment Drug-Resistance Testing
—- studies suggest that the presence of transmitted drug-resistant viruses (6-16% prevalence) may lead to suboptimal virologic responses
Improving Adherence —– Conditions that promote adherence should be maximized prior to and after initiation of ART
Surrogate Markers in HIV
CD4
Viral Load
Surrogate Markers in HIV – CD4
CD4 count of a healthy person ranges from 500 to 1,200 cells/mm3
Indicator of immune function in HIV-infected patients
strongest predictor of subsequent disease progression and survival
use to determine urgency for initiating antiretroviral therapy
assessed at baseline and EVERY 3 months after treatment initiation. In clinically stable patients with suppressed (UNDETECTABLE) viral load, CD4 count can be monitored every 3–12 months.
use to assess response to antiretroviral therapy
—– adequate CD4 response is defined as an increase in CD4 count in the range of 50–150 cells/mm3 during the first year of therapy then 50 to 100 cells/mm3 per year until a steady state level is reached
use to assess the need for initiating or discontinuing prophylaxis for opportunistic infections
———— eg prophylaxis for pneumocystis pneumonia and toxoplasmosis are started when CD4 cells are <200 cells/mm3
Surrogate Markers in HIV – Viral Load
Viral load (plasma HIV RNA) is the amount of virus in the plasma
It is the most important indicator of response to antiretroviral therapy and can be useful in predicting clinical progression
Viral load is measured BEFORE initiation of therapy and within 2 to 4 weeks (not later than 8 weeks) after treatment initiation or modification, thereafter, EVERY 4 to 8 weeks until viral load suppressed
In patients on stable regimen and suppressed viral load, monitoring can be done EVERY 3 to 4 months (even 6 months)
Effective regimen generally achieve viral suppression (ie undetectable HIV RNA level) by 8 to 24 weeks
Optimal viral suppression is generally defined as a viral load persistently below the level of detection (ie undetectable)
Virologic failure is defined as a viral load >200 copies/mL after 24 weeks of therapy initiation
When to start ART?
Antiretroviral therapy (ART) is recommended for all HIVinfected individuals, regardless of CD4 cell count, to REDUCE the morbidity and mortality associated with HIV infection.
ART is also recommended for HIV-infected individuals to PREVENT HIV transmission.
It is important to educate patients regarding the benefits and considerations regarding ART, and to address strategies to optimize adherence.
On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but therapy should be initiated as soon as possible.
Benefits of earlier treatment
Maintenance of a higher CD4 count and prevention of potentially irreversible damage to the immune system
Decreased risk for HIV-associated complications that can sometimes occur at CD4 counts >350 cells/mm3, including tuberculosis, non-Hodgkin’s lymphoma, Kaposi’s sarcoma, peripheral neuropathy, and HIVassociated cognitive impairment
Decreased risk of non-opportunistic conditions, including cardiovascular disease, renal disease, liver disease, and non–AIDS-associated malignancies and infections
Decreased risk of HIV transmission to others, which will have positive public health implications
Limitations of earlier initiation
Development of treatment-related side effects and toxicities
Development of drug resistance because of incomplete viral suppression, resulting in loss of future treatment options
Transmission of drug-resistant virus in patients who do not maintain full virologic suppression
Less time for the patient to learn about HIV and its treatment and less time to prepare for the need for adherence
Increased total time on medication, with greater chance of treatment fatigue
Increased cost
Conditions with increased urgency to start ART
Pregnancy
AIDS-defining conditions, including HIV-associated dementia (HAD) and AIDS-associated malignancies
Acute opportunistic infections (OIs)
Lower CD4 counts (<200 cells/mm3)
HIV-associated nephropathy (HIVAN)
Acute/early infection
HIV/hepatitis B virus coinfection
HIV/hepatitis C virus coinfection
Haha H pal
Factors to Consider When Selecting an Initial Regimen
Regimen selection should be individualized and should be based on a number of factors, including:
Patient’s understanding of HIV
Adherence issues
Financial situation - cost
Convenience
----- pill burden
----- dosing
frequency
----- food and fluid
considerations
Comorbidities – ADR, Drug interactions
Genotypic drug resistance testing
Predictors of virologic success
After initiation of effective ART, viral load reduction to undetectable level usually occurs within the first 12 to 24 weeks of therapy
Predictors of virologic success include:
1) low baseline viremia (low viral load to start with),
2) high potency of the ARV regimen, (can suppress replication of virus)
3) tolerability of the regimen,
4) convenience of the regimen,
5) excellent adherence to the regimen.
ART armamentarium
1) Reverse transcription inhibitors (NRTI)
2) NNRTI
3) Integrase inhibitors
4) protease inhibitors
5) Fusion/entry inhibitors.
- PK enhancer (ritonavir , cobicistat)
Antiretroviral Regimens (ART) Recommended combinations for patients naïve to ART
2 NRTIs + 1 PI (Protease inhibitor) (boosted with ritonavir or cobicistat):
- tenofovir + emtricitabine* (2-in-1, Truvada®) + darunavir (boosted with ritonavir)
2 NRTIs + 1 INSTI (Integrase inhibitor):
- tenofovir + emtricitabine* + (raltegravir or dolutegravir or elvitegravir)
- abacavir + lamivudine* + dolutegravir (3-in-1, Triumeq®)
2 NRTIs + 1 Fusion inhibitor
- tenofovir + emtricitabine* + Maraviroc (CCR5antagonist)
Alternative
2 NRTIs + 1 NNRTI:
- tenofovir + emtricitabine* + efavirenz (3-in-1, Atripla®)
- Lamivudine can substitute for emtricitabine, vis versa
Note: Ritonavir and cobicistat – are CYP450 3A inhibitors, use to increase concentrations of various ARV.
NRTI DRUGS
NNTRI DRUGS
Fusion inhibitor drugs
protease inhibitor
integrase inhibitor
NRTI Pyrimidine analogues - Zido-VUDINE - Sta-VUDINE - Lami-VUDINE -Zal-CITABINE - Emtri-CITABINE
Purine analogues
- Aba-CAVIR
- Ten-OFOVIR
- Didanosine
NNRTI
- Ela-VIR-ENZ
- Ne-VIRA-PINE
- Dela-VIR-DINE
- Etra-VIR-INE
Fusion inhibitor
- Enfu-VIR-TIDE
- Mara-VIR-OC
Integrase inhibitor
- Ralte-GRAVIR
- Dolute-GRAVIR
Protease inhibitors
- xxxx-NAVIR
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
adv and disadv
Tenofovir, Emtricitabine, Abacavir, Lamivudine, Zidovudine
Class advantages
Established dual backbone of combination ART
Renal elimination, little concerns for drug interactions.
Class disadvantages
Adverse effect related to mitochondrial toxicity (rare but serious)
- Lactic acidosis and hepatic steatosis (fatty infiltrate)
- Lipoatrophy (lost of fat)
- Zidovudine>Tenofovir=Abacavir=Lamivudine
Requires dose adjustment in renal impaired patients (except abacavir = metabolise by alcohol dehydrogenase)
NRTI ADR
Lamivudine – minimal toxicity, nausea/vomiting/diarrhea (N/V/D)
Emtricitabine – minimal toxicities, hyperpigmentation, nausea, diarrhoea
Tenofovir: – N/V/D, can cause renal impairment, decrease in bone mineral density
- Tenofovir Alafenamide (TAF) less than Tenofovir Disoproxil Fumarate (TDF)
Abacavir – N/V/D,
Hypersensitivity reaction in patients with HLAB*5701.
Symptoms incl: rash,fever, rash, malaise or fatigue, loss of appetite, sore throat, cough, shortness of breath. Can be fatal. Discontinue if it occurs,DO NOT RECHALLENGE.
Testing for absence of HLA-B*5701 is required before initiating abacavir. (Concern for association with myocardial infarction – not to be used in high cardiovascular risk patients.)
Zidovudine –N/V/D, myopathy, bone marrow suppression causing anemia or neutropenia. (MONITOR FULL BLOOD COUNT)
Integrase Strand Transfer Inhibitor (INSTI)
Adv and disadv
Raltegravir, Dolutegravir, Elvitegravir
Advantages
Virologic response non-inferior to efavirenz
Generally well tolerated
No significant CYP 3A4 drug interactions (except for elvitegravir)
elevitegravir co-formulated with cobicistat which is a cyp inhibitor
Disadvantages
Bioavailability lowered by concurrent administration of polyvalent cations
ADR - GI (Diarrhoea/Nausea), headache, fatigue; Insomnia, depression, and suicidality have been infrequently reported with INSTI use, primarily in patients with preexisting psychiatric conditions
Integrase Strand Transfer Inhibitor (INSTI) ADR
Raltegravir- pyrexia, creatine kinase elevation (rhabdomyolysis), severe skin reactions and systemic hypersensitivity reactions (rare)
Dolutegravir- Increase in serum creatinine and bilirubin*
Elvitegravir (co-formulated with cobicistat)- cobicistat causes increase in serum creatinine and bilirubin*
- Inhibits Cr secretion and decrease billirubin CL. NO impact on glomerular filtration.
therefore Cr [] increase but does not mean pt renal (f) is impaired.
Protease Inhibitors (PIs) ADV AND DIS
Ritonavir, Lopinavir, Atazanavir, Darunavir, Saquinavir, Fosamprenavir (co-formulated with ritonavir or cobicistat)
PI Class Advantage:
Higher genetic barrier to resistance
PI resistance less common
PI Class Disadvantages:
Metabolic complications (dyslipidemia, insulin resistance)
Gastrointestinal side effects (nausea, vomiting, diarrhoea)
Liver toxicity (especially with chronic hepatitis B or C) CYP3A4 inhibitors and substrates: potential for drug interactions
Morphologic Complications: Fat maldistribution (Lipohypertrophy)
Increased risk of osteopenia/osteoporosis
PI ADR
Ritonavir- is a potent CYP3A4, 2D6 inhibitor; frequently combined with other PI to “boost” their levels (eg Lopinavir/ritonavir). Additional SE: paresthesia (numbness of extremities), taste perversion
Darunavir- good GI tolerability, less lipids effects. Skin rash (10%), SJS (it is a sulphonamide)
Atazanavir- good GI tolerability, less lipids effects. Absorption depends on low pH (contraindicated concurrent use with PPIs). Additional SE: hyperbilirubinemia, prolong QT interval, skin rash
Lopinavir- GI intolerance (N/V). PR and QT interval prolongation have been reported. Use with caution in patients at risk of cardiac conduction abnormalities or in patients receiving other drugs with similar effect. Possible nephrotoxicity.
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ADV AND DIS
Efavirenz, Etravirine, Rilpivirine, Nevirapine
Class Advantages
Long half-lives
Less metabolic toxicity (hyperlipidemia, insulin resistance) than with some PIs
Class Disadvantages
Low genetic barrier to resistance
Cross resistance among approved NNRTIs
Skin rash (nevirapine > efavirenz, etravirine)
Potential for CYP450 drug interactions (some are inducers and some are inhibitors)
Lactic acidosis, hepatic steatosis
NNRTI ADR
NNRTIs
Efavirenz – rash, hyperlipidemia, neuropsychiatric SE (dizziness, insomnia, abnormal dreams, hallucination), increase in LDL-C and triglycerides
Etravirine – rash, hypersensitivity reaction, nausea
Nevirapine – more rash (SJS,TEN) and hepatotoxicity (necrosis).
Mixed CYP inducer/inhibitor
NNRTI
Mixed CYP inducer/inhibitor
Efavirenz, nevirapine – CYP 3A4 substrate and inducers
Etravirine - CYP3A4, 2C9, 2C19 substrate; 3A4 inducer; 2C9 and 2C19 inhibitor
Efavirenz cause up LDL so need give statin –> check statin interaction with CYP
Fusion inhibitor ADR AND FACTs
Enfuvirtide (LAST LINE)
No appreciable drug interactions
Subcutaneous injection, 2x/day
ADR- Injection site reaction (erythema/induration, nodules/cyst, pruritis, ecchymosis in 98%), rare hypersensitivity reaction reported (fever, rash, chills, decr BP). Increased bacterial pneumonia
Maraviroc (Selzentry)
- Maraviroc should be used only in people whose strain of HIV uses the CCR5 receptor to enter the CD4 cells.
( need co-receptor tropism assay before initiation;
Must be CCR5 tropic to use maraviroc; cannot be used if is CXCR4 or Dual/mixed tropism)
- CYP 3A4 substrate. Dose varies when administered with inhibitors or inducers. Eg highest dose used when used concurrently with inducers like rifampicin.
- ADR- Abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratory tract infections, hepatotoxicity, orthostatic hypotension.
Strategies to Improve Adherence to ART
Provide accessible, trusting health care team
Utilize educational aids including pictures, pillboxes, and calendars
Review potential side effects
Simplify regimens, dosing, and food requirements (taking ARV with or without food)
Utilize team approach with nurses, pharmacists, and peer counselors
Engage family, friends
Anticipate and treat side effects
Provide education on medication dosing
Establish readiness to start therapy
