HIV Part 2: Antiretrovirals and Treatment Guidelines Flashcards
Current Classes of Antiretrovirals
Nucleoside/tide Reverse Transcriptase Inhibitors
(NRTIs)
* Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
* Protease Inhibitors (PIs)
* Entry Inhibitors:
– Fusion Inhibitors
– Attachment Inhibitors
– CCR5 receptor antagonists
* Integrase Inhibitors (INSTIs)
Current Antiretrovirals
Nucleoside agents mimic building blocks of of DNA. So the nucleuside agents get integrated into that growing DNA strand and they cause chain termination
Non nucleuside agents also block reverse transcriptase step, but they do it in a a non-competitive way. So they don’t mimic those building blocks, but they still block reverse transcriptase
Protease inhibitors block protease enzyme step
Integrase inhibitor blocks integrase enzymes so integration into DNA
Ccr. 5 antagonist is one of the entry inhibitors. So there’s a receptor on the surface called Ccr 5, which the these agents block, and they prevent binding and entry into the cell.
New Approaches – Long Acting
Antiretrovirals
- Cabotegravir and rilpivirine are the first long acting antiretrovirals to be approved in Canada and the US
- 12 years of age and older and weighing at least 35 kg
- Oral lead-in (e.g., 28 days) recommended – cabotegravir 30 mg po daily plus rilpivirine taken with food
- Intragluteal injections on BOTH sides for each injection:
– Every 2 Month Schedule: cabotegravir 3mL/rilpivirine 3 mL for initial
injection, then in one month and then every 2 months
– Monthly Schedule: cabotegravir 3mL/rilpivirine 3 mL for initial
injection, followed by cabotegravir 2mL/ rilpivirine 2 mL every month
– Oral bridging if miss scheduled injection by 1 week or more
Cabotegravir is integrase inhibitor
Rilp is NNRT inhibitor
Antiretroviral Therapy
(ART)…When to Start?
- Current recommendations:
– ART is recommended for all patients to reduce risk of
disease progression
– ART recommended for prevention of transmission of HIV - Recommend starting ART as soon as possible after diagnosis
- Important to engage patients in discussion about ART and
use strategies to optimize care engagement and treatment
adherence
Initial Treatment:
Recommended Regimens for Most People
with HIV
Integrase inhibitor-based (plus 1 or 2 NRTIs)
* Bictegravir + TAF + emtricitibine
* Dolutegravir + abacavir + lamivudine (patients who are HLA-B*5701
–ve and without chronic HBV)
* Dolutegravir +TDF (or TAF)+ emtricitabine
* Dolutegravir + lamivudine (except if VL > 500,000, HBV coinfection or if
genotypic resistance testing not available)
normally. We use 3 drugs to treat people with HIV. But there are a couple of regimens that are 2 drug regimens that have been shown to be just as effective.
However, this is not a preferred option. If someone has a really high viral load. And if someone has hep b coinfection
Even tho lamiv is effective against hep B it’s easy for it tdevelop resistance to lamiv monotx
Need tenofovir on board too
How is the Initial Regimen Chosen?
* Factors to Consider:
– Baseline HIV RNA
– Baseline antiretroviral resistance (if any)
– Food requirements
– Co-infection with hepatitis B
– Pretreatment chronic kidney disease,
osteoporosis, cardiac disease etc
– Pregnancy (or individuals of child-bearing
potential)
– Adverse effects and drug-drug interactions
Goals of Therapy
maximal and durable suppression of viral load (e.g.,
<40 copies/mL)
* restore and preserve immunologic function
* decrease HIV-related morbidity and mortality
* prevent HIV transmission
Laboratory Testing
- Genotypic Antiretroviral Drug Resistance
Testing (GART)
– Baseline and after virologic failure
– Looks for resistance mutations associated with antiretroviral resistance - HIV viral load
– Baseline, at 1-2 months, every 3-6 months - CD4+ cell count
– Baseline, and every 3- 6 months (in stable patients may be yearly or less often)
look for virus mutations, and the reason we do it at Baseline is it’s possible to transmit resistant virus to someone else
Need to use most effective tx possible
Repeat q3-6 mo make sure that we’re capturing again any resistance that has has developed over time
We do look at CD. 4, and it it’s especially important when we’re thinking about opportunistic infections
but once someone’s for a load is stable, and if they have a good c. For like 300 0r up we dont tend to monitor it because it it doesn’t it’s not going to go down as long as viral load is suppressed
Adverse Effects: NRTIs
- Lamivudine/emtricitabine well tolerated
- Tenofovir disoproxil fumarate (TDF, Viread®,
Truvada®); Food: +/-
– Renal impairment (monitor Scr and urinalysis at baseline
and Scr ~q 3-6 months; baseline ACR and PCR ratio)
– Decreased bone mineral density (BMD)
– Headache, GI intolerance - Tenofovir alafenamide (TAF, Descovy®); Food: +/-
– Lower risk of renal impairment and effects on BMD due
to lower systemic exposure to tenofovir
– Has been associated with weight gain (versus TDF)
Newer formulation lowers overall risk
- TAF doesn’t cause renal impariment
- Less BMD fx
- lower systemic exposure. It tends to so target the CD4 cells more specifically.
- Associated with weight gain
Adverse Effects: NRTIs
* Abacavir (ABC, Ziagen®, Kivexa®);
Food: +/-
– Hypersensitivity reaction (frequency 5-6%)
* Median onset 9-11 days
* Symptoms: rash, fever, myalgias, malaise, GI symptoms,
respiratory symptoms
* Associated with HLA-B5701 – screen patients before starting
abacavir; only start in patients who are HLA-B5701 negative
This happens in about 5 t0 6% of people, and again is linked to that Hla B. 5 701.
we actually screen people for this gene.
and you’re either positive or you’re negative. So if if you’re negative, it’s okay to use back of your and if you’re positive, then we would just choose a different agent,
Adverse Effects: NNRTIs
- Efavirenz (EFV, Sustiva®, Atripla®); Food: -
– Neuropsychiatric common (e.g. vivid dreams, insomnia,
dizzy, depression)
– Rash - Rilpivirine (RPV, Edurant®, Complera®, Odefsey®);
Food: ++ (need to take with ~400 kcal)
– Depression
– Rash - Doravirine (DOR, Pilfetro®, Delstrigo®) ; Food: +/-
– Generally well tolerated
Adverse Effects: PIs
All PIs- Food +
– Gastrointestinal side effects (particularly diarrhea and
nausea)
– Hyperlipidemia (less with atazanavir/darunavir)
– Insulin resistance and diabetes (less with
atazanavir/darunavir)
– Lipodystrophy (less with atazanavir/darunavir)
– Elevated LFTs
Adverse Effects: Integrase Inhibitors
(INSTIs)
- Generally INSTIs well tolerated
– Headache, nausea, diarrhea, insomnia - Several studies have shown INSTIs lead to
greater weight gain
– More pronounced with DTG and BIC - DTG and BIC modestly increase Scr
– Inhibit active tubular secretion of creatinine
through organic cation transporter 2 (OCT 2)
Mechanisms of Antiretroviral Drug
Interactions
- Pharmacokinetic interactions can occur during
absorption, metabolism or elimination of antiretrovirals
(ARVs) and/or interacting drugs - Most clinically relevant drug interactions involving ARVs
occur due to alterations in CYP450 metabolism - Drug transporters (e.g. p-glycoprotein) increasingly
recognized as important factor in influencing drug
pharmacokinetics - Age related physiologic changes can also affect the
pharmacokinetic and pharmacodynamic properties of
medications
Potential for Drug Interactions
high to low risk
Protease inhibitors and cobicistat:
substrates and inhibitors of CYP3A4 and P-gp
Non-nucleoside reverse
transcriptase inhibitors
substrates of CYP3A4; some are inducers
CCR5 Antagonists
substrate of CYP3A4
Integrase inhibitors
Most substrates of
UGT1A1 and/or CYP3A4
Nucleoside Reverse
Transcriptase
Inhibitors
Absorption Interactions
Chelation
Bictegravir
Dolutegravir
Elvitegravir
Raltegravir
Antacids or
cations
Separate by ≥ 2 hours
(or take with food)-
see recommendations
in monograph
A lot of integrase inhibitors will bind or not be properly absorbed if they’re used with at the same time with things like calcium, iron.
Metabolism Interactions
CYP3A4
Protease inhibitors,
cobicistat
- Fentanyl, oxycodone
- Anticonvulsants (e.g.
carbamazepine, phenytoin) - Antiplatelet agents
- Anticoagulants
- Calcium channel blockers (e.g.
amlodipine, diltiazem, nifedipine) - Corticosteroids (e.g. inhaled
fluticasone-budesonide,
triamcinolone by injection) - Phosphodiesterase inhibitors
- Psychotropics (e.g. aripiprazole,
quetiapine, ziprasidone) - Statins (e.g. lovastatin, simvastatin)
Metabolism Interactions
other cyp enzymes
Other CYP450
isoenzymes (e.g.
CYP2D6, CYP2B6,
CYP2C9/19)
Protease inhibitors,
cobicistat
- Antidepressants
- Oral hypoglycemic agents
(e.g. repaglinide,
nateglinide, rosiglitazone) - Warfarin
Ritonavir Boosted PI Regimens
- Using low dose ritonavir* in combination with
another PI
– atazanavir 300 mg/ritonavir 100 mg daily
– darunavir 800 mg/ritonavir 100 mg daily
– darunavir 600mg/ritonavir 100 mg twice daily
Riton was old protease inhibitor very toxic on its own
such a potent inhibitor of 3 4 they learned over. We’ve learned over time that it can be used to boost the other protease inhibitor
so it can be dosed once daily, and get much better from a AUC curve
Ritonavir is used essentially with all of the produce inhibitors as a booster
Case
Joe is a 38 year-old male (pronouns: he/his/they/them)
who was recently diagnosed with HIV following routine
screening by his family physician. Baseline HIV RNA
(VL) was 980 000 copies/mL and CD4 was 20 cells/uL.
Baseline GART – no drug resistance mutations. He is
not taking any other medications. Joe is initiated on
treatment with TAF/emtricitabine/bictegravir
(Biktarvy®) 1 tablet daily. VL is repeated 4 weeks after
starting therapy and is 1200 copies/mL; 12 weeks later
it is 350 000 copies/mL. What is the most likely cause?
ok
Treatment Failure
* Definition of virologic failure:
– Inability to achieve and maintain viral replication (to <
200 copies/mL)
– Low amount of viremia appears to occur more
frequently with newer, more sensitive real-time PCR
assays
Causes of Virologic Failure
Patient/Adherence Related:
* Substance use, mental health disorders, unstable housing,
missed clinic appointments, interruption of access to ART,
cost, adverse effects, pill burden or dosing frequency
HIV-Related:
* Drug-resistant virus, prior treatment failure
Antiretroviral-regimen Related:
* Suboptimal PK, virologic potency, low genetic barrier to
resistance, food requirements, drug-drug interactions,
prescription errors
the bottom line is people that are at the highest risk of developing drug resistance are the ones that are taking some drug. but not enough drug to to suppress replication fully. And that’s just again, because there’s pressure on the virus to mutate.
Assessing Adherence
What level of adherence is needed to achieve virologic
suppression?
How would you “measure” or “estimate” antiretroviral
adherence in a patient?
Nowadays some of the drugs are are
a little more forgiving. And it really is regimen dependent, because again. Some regiments are easier to get resistance to versus others, but so I would still say, we, we try to AIM for 90%. But but we’ll we’ll see people that are taking even 80% and and still doing well
The higher the better
Example –Patient Self Report of
Adherence
Can you think if you have missed a dose of
antiretroviral drugs in the last week? What
about in the last month?
Refill hx is helpful
Ask pt to self-report
Goals in HIV care
- HIV care is moving beyond helping individuals living with HIV to
maintain an undetectable viral load - Focus on reducing the epidemic and long-term management
