5/29- HIV Treatment Flashcards
What are the different cellular targets of HIV?
- CCR5
- CXCR
HIV drug targets?
Entry inhibitors
- CCR5 antagonists
- Fusion inhibitors RT inhibitors
Nucleoside analogs (NRTI)
Non-nucleoside analogs (NNRTI)
Integrase inhibitors (preventing incorporation of genetic material)
Protease inhibitors (prevent assembly/budding release of virus)
Name the CCR5 antagonist(s)
Maraviroc
Name the fusion inhibitor(s)
Enfuvirtide
Name the NRTI(s)
- Abacavir
- Lamivudine
- Emtricitabine
- Tenofovir
Name the NNFRTI(s)? Recongize, don’t memorize
- Efavirenz
- Etravirine
- Rilpivirine
Name the integrase inhibitor(s)? Recognize, don’t memorize
- Dolutegravir
- Elvitegravir
- Raltegravir
Name the protease inhibitor(s)? (PIs) Recognize, don’t memorize
- Atazanavir
- Darunavir
- Lopinavir/rit
- Fosamprenavir
- Indinavir
- Nelfinavir
- Saquinavir
- Tipranavir
Name the pharmokinetic booster(s)?
- Ritonavir (a PI)
- Cobistat
No antiviral activity
Overview chart of HIV drugs
How often most antiretrovirals be taken?
- Initially every 8 hours on the dot (?)
How to decrease crests/troughs antiretroviral?
Give with pharmokinetic booster
e.g. Indinavir with ritonavir (trough levels 10x higher)
Drugs with the same mechanism of action share what features?
- Elimination/metabolic pathways
- Toxicities/side effects
- Mechanisms of resistance (cross-resistance)
Goals of HIV treatment?
- Maximally/durably suppress HIV viral load (undetectable < 20 RNA copies/mL)
How many weeks of therapy does it take to get viral load below detectable levels (< 20 RNA copies/mL)
~ 9 weeks
(although huge drop by just 2 weeks)
Also, takes longer if you start with a higher viral load (up to 6 mo)
Which class of drugs has relatively less cross-resistance?
Protease inhibitors
(also, takes many mutations to render these inactive)
What factor contributes to the greatest CD4 cell count increase? (immune reconstitution)
Therapy started at low CD4 counts
(greater rise and prolonged, but less likely to normalize)
What factor contributes to the greatest likelihood of CD4 cell count normalization? (immune reconstitution)
Therapy started earlier, with higher CD4 counts
For whom is antiretroviral treatment especially recommended?
- All HIV infected pregnant women (prevent perinatal transmission)
- All at risk of transmitting HIV to sex partners
- HIV infected drug users
Risks of treatment complications and treatment failure due to?
Emergence of resistance
Strength of recommendation for treatment?
(A-strong, B- moderate, C- optional)
(I- trials, II- good trials/cohort studies, III- expert opinion)
Based on CD4 count
AI: < 350
AII: 350-500
BIII: > 500 (can wait to start until certain other issues are resolved)
Based on condition:
AI: pregnant, AIDS defining condition, infected heterosexual partner
AII: HIV-associated nephropathy, Hep B co-infection
AIII: other transmission risk groups, rapidly declining CD4 count (>100 cells/year)
BII: higher viral loads
Recommended antiretroviral regimes?
2 NRTIs (backbone)
- Emtricitabine-Tenofovir (Truvada) or
- Abacavir-Lamivudine (Epzicom)
AND either:
- Boosted PI based: Darunavir + Ritonavir or
- Integrase inhibitor: Raltegravir, Dolutegravir, or Elitegravir/coicistat
Abacavir given only to whom?
Pts that tested negative for HLA B*5701
Recommended alternative antiretroviral regimes?
Boosted PI based:
- Emtricitabine/Tenofovir
AND one of:
- Atazanavir + Ritonavir
- Atazanavir/cobicistat
- Darunavir/cobicistat
NNRTI-based:
- Efavirenz/emtricitabine/tenofovir
- Rilpivirine/emtricitabine/tenofovir
What factors determine combination of therapy?
- Virus susceptibility (test at BASELINE)
- Patient’s profile (underlying comborbidities, or ASEs to avoid)
- Patient’s preference
- Potential for drug interactions
- Cost
Treatment related complications?
Metabolic:
- Insulin resistance
- Dyslipidemia
Cardiovascular: increased MI
Bone: osteoporosis
Renal: renal insufficiency
What is lipodystrophy?
Body Habitus Changes
- Fat deposition (intrabdominal, dorsocervical, breasts)
- Fat atrophy (extremity wasting, facial lipoatrophy, mostly D4T, ddI and AZT)
Management of HIV-infected pt on treatment at each visit?
- Clinical psycho/social evaluation
- Adherence to treatment; side effects
- Counseling on prevention of transmission
- Primary care interventions
Lab evaluation for management of HIV infected pt on treatment?
General labs (to assess toxicities)
Response to treatment:
- CD4 cell count (immunologic response)
- HIV1 viral load (virologic response) **most important
HIV-1 viral load should be measured at what frequencies at different stages?
- every 2-4 wks after start of treatment
- every 3-4 months until viral load suppressed
- every 4-6 months after 2 yrs of continous suppression
CD4 cell count should be measured at what frequencies at different stages?
- every 3-4 months
- every 6-12 months for those with continuous suppression and high CD4 cell count
Virologic failure caused by what?
Caused by:
- Virologic suppression
- Incomplete virologic response
- Virologic rebound
Virologic suppression characterized how?
Viral load below level of detection (< 20 RNA copies/mL) at week 24 of treatment
Incomplete virologic response is characterized how?
Due to what?
Consecutive VL > 200 after 24 wks of treatment
Due to:
- inadequate potency
- Inadequate drug levels
- Inadequate adherence (mot common)
- Pre-existing resistance
Virologic rebound is characterized how?
VL > 200 after suppression to non-detectable levels
(More than 2 subsequent increases in viral load following previous undetectable VL)
What causes in-vivo viral drug resistance?
Poor adherence
- Social/personal issues
- Regimen issues
- Toxicities
Insufficient drug level
- Poor adherence
- Poor potency
- Wrong dose
- Host genetics
- Drug interactions
- Poor activation
Leads to:
- Viral replication in the presence of the drug
- Resistant virus
Management of virologic failure?
- Assess adherence to treatment
- Assess tolerability
- Assess for drug/food interactions
- Obtain resistance testing
(requires VL > 1000 RNA copies/mL; while pt is on failing therapy or within 4 wks)
Resistance testing for phenotype entails what?
Culturing the virus in the presence of different concentrations of the drug and determining the IC50
(drug conc required to inhibit viral replication by 50%)
Resistance testing for genotype detects what?
Mutations associated with viral resistance
Management of HIV-infected pt with resistant virus?
- Reassess barriers to adherence
- Select new antiretroviral combination
(must include at least 2 drugs and preferable 3 to which the virus is expected to be susceptible)
- Goal is to maximally suppress viral replication to below level of detection
Case 1:
- HIV infected patient, new to your clinic, never treated, asymptomatic. He is starting a new relationship with a non-HIV infected partner
- Has a CD4 cell count (CD4) of 500 and viral load of 10,000
- What parameter would be the most important in the decision to start treatment in this patient?
A. Symptoms
B. CD4 cell count
C. HIV-1 viral load
D. Risk for transmission
Case 1:
- HIV infected patient, new to your clinic, never treated, asymptomatic. He is starting a new relationship with a non-HIV infected partner
- Has a CD4 cell count (CD4) of 500 and viral load of 10,000
- What parameter would be the most important in the decision to start treatment in this patient?
A. Symptoms
B. CD4 cell count
C. HIV-1 viral load
D. Risk for transmission
Case 1 cont’d:
Patient is started on a regimen that includes one integrase inhibitor and 2 nucleoside analogues.
- At 3 months his VL is < 50
- At 6 months his VL is 190 and CD4 count is the same at 500.
What would you do next?
A. Order genotype
B. Repeat CD4 count
C. Repeat viral load
D. Change treatment
Case 1 cont’d:
Patient is started on a regimen that includes one integrase inhibitor and 2 nucleoside analogues.
- At 3 months his VL is < 50
- At 6 months his VL is 190 and CD4 count is the same at 500.
What would you do next?
A. Order genotype
B. Repeat CD4 count
C. Repeat viral load
D. Change treatment
Summary:
Key prevention of HIV:
Goal of treatment:
Means of achieving goal of treatment:
Summary:
Key prevention of HIV: test for HIV and treat
Goal of treatment: complete viral suppression
Means of achieving goal of treatment: potent ARV combination and adherence to treatment
