Mode of transmission for HIV
Body fluids: blood, semen, genital fluids, and breast milk
- Unprotected sex with infected person
- Sharing infected syringes/needles
- Mother-to-child: pregnancy, at birth, breastfeeding
- Transfusion with contaminated blood (products)
Why is there little mother-to-child transmission of HIV now?
Mandatory screening of all pregnant women since 2008
Who should be tested for HIV?
- IV drug users
- Person who have unprotected sex with multiple partners
- Man who have sex with man
- Commercial sex workers
- Persons treated for STDs
- Persons who have been sexually assaulted
Rare as there is screening: - Pregnant women
- Recipients of multiple blood transfusion
Diagnostic tests for HIV infection
- Serum antibody detection
- HIV EIA (enzyme immunoassay antibody) tests
- Western blot - HIV RNA detection (viral load)
- nucleic acid amplification (PCR)
What are the goals of antiretroviral therapy?
- reduce morbidity & mortality
- prolong duration and quality of survival
- restore and preserve immunologic function
- maximally & durably suppress viral load to undetectable levels
- prevent HIV transmission
What is CD4 count used as a marker for?
Indicator of immune function and predictor of disease progression & survival
- Response to ART
- Monitor: baseline, every 3-6mo after initiation, every 12mo after adequate response
- Adequate response: increase CD4 by 50-150 cells/mm3 in 1st year of therapy - Initiate/discontinue prophylaxis for opportunistic infx
- e.g. PCP prophylaxis started when CD4 <200 cells/mm3
What does viral load indicate? How should we monitor viral load?
Response to ART
- Monitor: baseline, 2-4wk (max 8 wk) after initiation or modification, every 4-8wk until suppressed
- Effective ART: viral suppression by 8-24wk
- Monitor every 3-6mo (stable regimen + suppressed viral load)
What are the benefits of starting ART early?
- Maintain higher CD4 count + prevent irreversible damage to immune system
Decrease risk for: - complications (even if CD4 >350): TB, non-Hodgkin’s lymphoma, Kaposi’s sarcoma, peripheral neuropathy, HIV-associated cognitive impairment
- non-opportunistic conditions: CV, renal, liver disease, non-HIV associated malignancies, infections
- HIV transmission
Limitations of earlier ART initiation
- side effects + toxicities
- drug resistance due to incomplete viral suppression: non-compliance
- transmission of drug-resistant virus: need to check for resistant HIV even in ART-naive patients
- less time to learn about HIV and TX, and to prepare for adherence
- increase total time on medication -> treatment fatigue
- cost
What are the recommended combinations for ART-naive patients?
2 NRTIs + 1 INSTI:
- tenofovir + emtricitabine + bictegravir
- tenofovir + emtricitabine + dolutegravir
- abacavir + lamivudine + dolutegravir (3 in 1 Triumeq)
1 NRTI + 1 INSTI:
- emtricitabine + dolutegravir
! not for: HIV RNA >500k copies/mL, HBV coinfection, before results of genotypic test or HBV test
Why is HBV coinfection contraindicated for emtricitabine + dolutegravir?
Requires at least 2 of the 3 following NRTIs: - Lamivudine - Emtricictabine - Tenofovir But only emtricitabine is used
Factors for selection of ART regimen
- Patient’s understanding of HIV
- Cost and availability
- Adherence (less issue now): pill burden, dosing frequency, food and fluid considerations
- Virologic efficacy: esp if patient has high viral load
- Potential adverse effects: comorbidities (glucose intolerance, hyperlipidemia), DDI
- Childbearing potential: teratogenic drugs
- Genotypic drug resistance testing
What are the drug targets in ART?
- Nucleoside reverse transcriptase
- Integrase strand
- Non-nucleoside reverse transcriptase
- Protease
- CCR5
- Fusion
List the 5 NRTIs
Tenofovir Emtricitabine Abacavir Lamivudine Zidovudine
What are the disadvantages of NRTIs?
- Mitochondrial toxicity: most in zidovudine
- lactic acidosis + hepatic steatosis
- lipoatrophy - Renal dose adjustment (except abacavir)
What are the ADRs of NRTIs?
All: NVD
- emtricitabine: hyperpigmentation
- tenofovir: renal impairment, decrease bone marrow density (alafenamide TAF < disoproxil fumarate TDF)
- abacavir: MI concern (avoid in high-risk CV);
hypersensitivity in HLA-B*5701 -> must test
* Hypersensitivity rxn: discontinue, don’t re-challenge
- zidovudine: myopathy, bone marrow suppression (anemia, neutropenia)
*monitor FBC for bone marrow suppression
List the 4 INSTIs
- Bictegravir
- Dolutegravir
- Raltegravir
- Elvitegravir
What are the advantages of bictegravir and dolutegravir?
- high genetic barrier to resistance
- good virologic effectiveness
What are some ADRs of INSTIs?
- weight gain, ND, headache
- CNS: depression, suicidality esp in preexisting psychiatric condition
- raltegravir: pyrexia, increase creatine kinase (rhabdomyolysis)
DDIs with INSTIs
- decrease F with polyvalent cations
- CYP3A4 substrate: bictegravir, dolutegravir, elvitegravir
What are the advantages and disadvantages of NNRTIs?
+ long t1/2 -> OD dosing
+ lower metabolic toxicity than PI
- low genetic barrier to resistance, cross resistance
- skin rash, SJS, QTc prolongation
DDIs with NNRTIs
CYP450 DDI:
- CYP3A4 substrate
- efavirenz: induce CYP2D6, 2C19
rilpivirine: concurrent PPI contraindicated
Specific ADRs of NNRTIs
Efavirenz:
- hyperlipidemia - increase LDL-C + triglycerides
- neuropsychiatric - dizziness, depression, insomnia, abnormal dreams, hallucinations
- hepatotoxicity
Rilpivirine: depression, headache
- generally milder ADR than efavirenz
List the 5 PIs
Ritonavir Lopinavir Atazanavir Darunavir Fosamprenavir - formulated with PK enhancer: ritonavir or cobicistat
