CM II Week 8 (HIV)

immune system review

B cells

–Main function: humoral immunity (creating specific antibodies)

T cells

–Two main functions: regulating immune system and killing cells with specific target Ag’s

•CD4+ helper cells: activate B cells, killer cells, and macrophages

•CD8+ cells: two types

–Cytotoxic CD8+ cells which kills cells infected by viruses or bacteria

–T-suppressor cells which inhibit immune responses

HIV

what type of virus? types? where?

HIV is a retrovirus in the Retroviridae family (Lentivirus genus)

Two species: HIV-1 and HIV-2

‣ HIV-1 more virulent and more infective than HIV-2

Most patients in US are HIV-1 infected

HIV-2 mostly confined to West Africa

HIV structure & overall what does it cause?

HIV viruses are enveloped, single-stranded RNA viruses with a DNA intermediate

• DNA intermediate is an integrated viral genome (provirus) that persists within the host-cell DNA

HIV causes severe damage to the immune system and eventually destroys it

what population is at increased risk for HIV?

black males, females.

not high numbers on PrEP - we as providers need to recognize this in treatment

HIV vs AIDs definition

HIV – Human Immunodeficiency Virus: Virus which can lead to AIDS

AIDS – Acquired Immune Deficiency Syndrome

• Disease caused by the damage that HIV does to the immune system

• Defined as an absolute CD4+ count <200 cells/microL or presence of an AIDS-defining condition

• Most severe phase of HIV infection

HIV and AIDS are NOT the same thing

HIV Viral Structure

Cylindrical center surrounded by a sphere-shaped lipid bilayer envelope

Inner sphere contains 2 SS copies of RNA as well as multiple proteins and enzymes necessary for HIV replication and maturation

• p24, p17, reverse transcriptase, integrase, and protease

Two major viral glycoproteins in lipid bilayer of HIV

gp120 and gp41

help virus to attach to and invade CD4+ cells

Integrated HIV proviral DNA is _______ DNA flanked by _________

Integrated HIV proviral DNA is double-stranded DNA flanked by LTRs

Three principle genes of HIV

HIV contains 9 major genes that encode structural, enzymatic, regulatory, and accessory proteins

Three principle genes: Gag (structural), Pol (enzymatic), Env (envelope)

•Regulatory proteins: Tat, Rev

•Accessory proteins: Vpu, Vpr, Vif, Nef

HIV Viral Entry

HIV gains access to its target cells via viral proteins w/ receptors on cell membrane

gp120 binds with high affinity to the CD4+ receptor (which normally fxns as co-R in activation of helper T cells)

CD4+ binding induces a conformational change in gp120, exposing its co-receptor binding sites on the host cell surface

CD4+ binding induces a conformational change in gp120, exposing its co-receptor binding sites on the host cell surface... what are they?

Either CCR5 or CXCR4

Viral Entry - Binding of gp120 to the coreceptor exposes?

Binding of gp120 to the coreceptor exposes the fusion domain of gp41

gp41 then inserts its hydrophobic peptide into the target cell membrane

fusion - HIV viral entry

gp41 inserts its hydrophobic peptide into the target cell membrane

this then forms a pore through which the viral capsid enters

this process is known as fusion

Reverse Transcription and Integration

‣After fusion, viral disassembly occurs before reverse transcription can take place

‣RNA must undergo reverse transcription into DS-DNA and integrate into host genome

‣Reverse transcription begins when the viral RNA is released into the cytoplasm and un-coats

‣Reverse transcriptase (RT) then produces DS-DNA from the viral RNA template

‣The newly synthesized viral DNA then integrates into the hosts DNA via integrase (IN)

Viral Production

‣Once integrated into host DNA, viral genome can remain latent or undergo active expression

•Active expression is dependent on cellular and viral factors that activate viral promoters

•In active infection, viral DNA is first transcribed into mRNA which then make viral regulatory proteins

‣Gag protein mediates assembly of progeny virions by packing genomic RNA within viral particles

‣Finally, HIV protease (PR) catalyzes the cleavage of the gag-pol precursor protein (p55) yielding structural proteins that form the mature virion

‣Assembly of mature virus occurs at the cell membrane and the viral particles exit via budding

•Budding occurs in lipid raft areas along the cell membrane 

HIV life cycle

1. Binding and entry

–gp120 and gp41 bind to CD4+ cell receptors

–HIV membrane fuses with the CD4+ cell membrane

2. Reverse transcription via reverse transcriptase enzyme

3. Integration

–Viral enzyme integrase inserts the viral DNA into the CD4+ cell’s DNA

4. Replication

5. Budding

6. Maturation

–HIV protease enzyme cuts the long HIV proteins of the virus into smaller functional units which then reassemble to form a mature virus

What 2 glycoproteins are found within the envelope of the HIV virus?

gp120 and gp41

What gene encodes for the enzymes reverse transcriptase, protease, and integrase?

Pol gene

Can you be infected with HIV without having AIDS?

Yes

Stages of HIV infection

Viral transmission

Acute HIV infection

•Also called primary HIV infection or acute retroviral syndrome (ARS; bit outdated term but still used)

Chronic HIV infection

• Without AIDS

• With AIDS

–Absolute CD4+ count <200 cells/microL or presence of an AIDS-defining condition

HIV infection is usually acquired through?

sexual intercourse, exposure to infected blood, or perinatal transmission

For all modes of transmission, a ______ viral load in the source individual living with HIV is associated with a ________ risk of transmission

For all modes of transmission, a higher viral load in the source individual living with HIV is associated with a greater risk of transmission

The risk of HIV transmission is higher during acute infection

Exposures that lead to mucosal disruption and bleeding are associated with higher risk than other exposures. Example of this?

Unprotected receptive anal intercourse conveys the greatest probability of sexual transmission of HIV

Concurrent_____ have been long known to increase the risk of both acquiring and transmitting HIV infection

Why?

STI's

•Why? Damage to mucus membranes allows for easier viral transmission

•STI such as herpes and syphilis can cause sores or ulcers on mucous membranes

Acute HIV Infection

time? benefit to early recognition?

6 month period from date of HIV acquisition

• Period of rapid viral replication 

Benefit to early recognition: early antiretroviral therapy (ART) initiation!

Acute HIV Infection

Characterized by?

Characterized by fever, lymphadenopathy, sore throat, oral ulcers, rash, myalgia / arthralgia, diarrhea, and headache

•40-90% of patients will be symptomatic

•Commonly missed by medical professionals

‣High index of suspicion is critical

Acute HIV Infection

‣Plasma viral RNA level is typically ______

‣Plasma viral RNA level is typically very high

‣Seroconversion refers to?

‣Plasma viremia reaches a steady-state level by?

‣Seroconversion refers to the development of detectable antibodies against HIV antigens

‣Plasma viremia reaches a steady-state level by ~6 months

Chronic HIV Infection without AIDS

‣Characterized by relative stability of viremia and progressive decline in CD4+

‣Mostly ASX, but some might have non specific sx such as fatigue, sweats, or weight loss

‣Decline in CD4+ typically slow with considerable variation in rate of decline (months to years)

Chronic HIV Infection with AIDS

defined as?

survival?

AIDS is an outcome of chronic uncontrolled HIV infection

Defined as CD4+ <200 cells/microL or the presence of any AIDS-defining condition

In the absence of effective ART, the median survival of patients with advanced HIV infection (CD4+ <50 cells/microL) is 12-18 months

when does patient no longer have AIDS

Once CD4+ >200 cells/microL with ART and no AIDS-defining conditions present, patient no longer has AIDS

HIV Controllers (rare)

• ≤0.5% can maintain very low or undetectable levels of HIV RNA in the absence of ART

• These individuals may also maintain high CD4+ cell counts

• Those without detectable virus by standard assays are referred to as "non-viremic" or "elite" controllers

• Whether or not to start ART in HIV or elite controllers remains controversial

Routine Screening for HIV

CDC recommends HIV testing for everyone 13-64 at least once as part of routine health care

For higher risk individuals, CDC recommends testing at least annually:

•MSM with sexual partners who are HIV-infected or w/ unknown HIV status

- More frequent testing (q3-6 months) may be beneficial in this population

•PWID

•Persons who exchange sex for money or drugs

•Sex partners of persons who are HIV-infected/bisexual/inject drugs

•Persons who have sex with partners whose HIV status is unknown

•Anyone on PrEP (more on this later)

Early identification of HIV infection is important

•Initiate preventive care measures

•Reduce HIV transmission through reductions in viral load

•Change HIV risk behaviors

•Cost effective as demonstrated in multiple studies

~15% of HIV-infected individuals in the US are unaware of their status. Undiagnosed infections are responsible for majority of HIV transmissions.

DDX

T or F: HIV can be transmitted through saliva?

FALSE

A CD4+ count below what number indicates AIDS?

CD4+ count <200 cells/microL

T or F: people who smoke marijuana should be screened for HIV more frequently.

FALSE

People who inject drugs should be.

Establishing a Diagnosis of HIV

Clinicians should have a LOW threshold to suspect HIV infection given the wide range of symptoms

•When in doubt, check HIV screen!

Diagnosis is established by the detection of HIV virus in the blood

Establishing a Diagnosis of HIV

Two buckets of testing to consider:

•Screening tests

–Antibody only testing

–Combination HIV antigen and antibody testing

•Confirmatory tests

–HIV-1/HIV-2 differentiation assay

–Western blot

–Viral load

Screening Tests: Antibody (Ab)-only tests

ELISA can be used as an initial screen test

Detect presence of HIV-1 and HIV-2 antibodies as early as 3 weeks after viral exposure

More sensitive than rapid Ab tests

Positive test should be confirmed with HIV-1/HIV-2 differentiation assay*

Screening Tests: Combination Ag/Ab tests

MOST COMMONLY USED

Fourth-generation tests detect both HIV Ab and HIV p24 Ag

•Sensitivity and specificity near 100% (chronic HIV infection)

–Not as sensitive as HIV RNA testing

•These tests are able to identify acute/early infection in up to 80% of patients whose HIV dx would have been missed by Ab-only testing

HIV-1/HIV-2 differentiation assay

Rapid laboratory-based test

•Used to confirm a positive fourth-generation test and to distinguish between HIV-1 and HIV-2 infection

•Turnaround time (TAT) is generally <20 minutes

•Preferred confirmatory test

Western blot (less utilized)

•Historically performed on +ELISA to exclude the possibility of a false-positive screening test

•Detects IgG antibody to HIV-1

– Can take up to 2 months after HIV acquisition for the test to turn fully positive

•Special HIV-2 Western blot must be requested if considering HIV-2 infection

•Most labs in US have ceased offering Western Blot testing

eclipse phase of HIV

HIV-1 begins to replicate in mucosa almost immediately after exposure; 7-21 days

NO HIV TEST IS POSITIVE DURING THIS PHASE

pathway for HIV screening

Example of HIV infected

HIV non-infected example

can check viral load prior to the screeners when REALLY concerned.

when in doubt you can check it (but still try to follow step wise approach)

Example of HIV infected (acute infection)

viral load confirms dx

too early for high Ab development

Consent to Test in Pennsylvania?

•Written informed consent is no longer required for an HIV test

•Tests may now be offered in an “opt-out” format–HIV test will be given unless the patient specifically declines this

Negative tests results no longer need to be given in person, positive tests results still must be given in person

resistance testing

HIV susceptibility testing to guide therapy leads to better viral suppression

Genotypic assays are by far the most common resistance testing you will order as a PA.... detect the presence of specific drug resistance mutations

Obtain genotype testing for?

•On any treatment naïve patient

•On any PrEP patient who seroconverts

•On any patient who has fallen out of care/stopped taking ART for many months

•On any patient with an increasing viral load despite ART adherence

Resistance Testing: Genotype assays

•Require a viral load of at least 500-1,000 copies/mL

•Standard tests frequently include testing for NRTI’s, NNRTI’s, and PI resistance

• Assessing for integrase inhibitor resistance must be requested separately (though this is rare)

Resistance Testing: Phenotype assays

Most useful for complicated patients with multidrug resistant virus

Resistance Testing: Always look back at old genotypes in a treatment-experienced patient... why?

Once ART is discontinued, wild-type (WT) virus will reemerge to replace the drug-resistant virus

–Why? Mutations make virus less effective at replicating. In the presence of ART, resistant virus has a survival advantage. In the absence of ART, WT virus can outcompete resistant virus.

Absence of a detectable resistance mutation must be interpreted with caution in a patient who has recently discontinued ART ... consider proviral DNA assay test

Phenotype assays will always include a ______

Phenotype assays will always include a genotype

Baseline laboratory evaluation for ALL patients

HIV Specific Labs and Routine

HIV antigen/antibody screening test

CD4 count and percentage

HIV viral load

HIV resistance testing (INSTI recommended if suspicion for INSTI mutation transmission)

Tropism assay* (if CCR5 antagonist)

HLA B5701* (if abacavir)

routine labs in image

Tests that may be performed under certain circumstances

Follow up lab monitoring with what 2 labs

•HIV viral load

•CD4+ cell count

HIV viral load lab

- 2-4 weeks after initiation of ART (no longer than 8 weeks)

- q4-8 weeks until viral suppression, then

- q3-4 months for first 2 years

- q6 months in patients with stable CD4 and viral suppression for at least 2 years

CD4+ cell count lab

-q 3-6 months for the first 2 years of starting ART, if viremia develops or CD4+ < 300

-q 12 months if CD4+ 300-500 and viral suppression for at least 2 years

-Optional if CD4+ > 500 and viral suppression for at least 2 years

If a patient is overwhelmed, it’s OKAY to delay?

bloodwork, pharmacy consultations, and social/case management visits until the patient has had time to process

‣Remember to remain patient, calm, empathetic, and non-judgmental when delivering a new positive result

‣Allow open communication and collaborative decision making

‣Help patients modify behaviors that lead to poor retention in HIV care

If a fourth generation test is positive and subsequent antibody testing is indeterminate/negative, what should your next test be?

HIV viral load

In PA, do I need to obtain written consent prior to HIV testing?

No

T or F: HIV phenotype testing should be performed for every treatment naïve patient.

False

GENOTYPE = YES

When to Start ART

‣As soon as possible! NEED TO START MEDS as early as possible. multiple drugs often.

‣Concern for initiating ART during early infection is suboptimal adherence leading to resistance

• no clinical evidence that resistance is more likely in pts tx during early HIV infection than with long-est dz

The benefits to the individual and to public health outweigh the possible drawbacks of earlier ART

such as?

-Reduction on symptomatic disease

-Improved clinical markers of disease

-Decreased risk of transmission

-Decreased viral reservoir and improved markers of immune cell function

Immune Reconstitution Inflammatory Syndrome (IRIS)

inflammatory disorders associated w/ paradoxical worsening of preexisting infectious processes after starting antiretroviral therapy

sx usually develop within 1 week to a few months after the initiation of ART

likelihood and severity of IRIS correlates with 2 factors:

•The extent of CD4+ immune suppression prior to the initiation of ART

•The degree of viral suppression and immune recovery following the initiation of ART

Treatment Goals of HIV

‣Maximum and durable viral suppression to prevent resistance, tx failure, and opportunistic infections

‣Restoration/preservation of immune system

‣Reduction of HIV morbidity/mortality

‣Improvement in QoL

‣Prevent transmission of HIV transmission

U = U

Undetectable = Untransmittable

goal!!

Undetectable VL in this context: <200c/mL

Classes of ART

HIV Regimen Basics

Each drug: generic, brand, and 3 letter name

•Ex. BIC/TAF/FTC (Biktarvy)

Most HIV regimens contain 3 active HIV drugs

•2NRTI + other class

•Exceptions

–A few regimens only use 2 drugs

–Protease inhibitors require boosters

Drug Abbreviations

NRTIs

In general, very well tolerated with few drug interactions

BBW: lactic acidosis

NNRTIs

•Typically end in –virines

•CYP3A4 inducers (except rilpivirine and doravirine); rash and hepatotoxicity; cross-resistance within generations, but not necessarily between

INSTIs

•Typically end in –tegravir

•In general, well tolerated; AE’s include HA, weight gain, elevation in CK

PIs

•Typically end in –navir

•Need to be boosted with Cobicistat or low dose ritonavir

•AE’s include hyperlipidemia, insulin resistance, lipodystrophy, and elevated LFTs

most common drug used for treatment of HIV?

Biktarvy! (INSTI + 2 NRTIs)

3 drug regimens are most common starting off

HIV Dual therapy

benefits, efficacy?

•Benefits: fewer long-term toxicities and DDIs, better tolerability, financial cost

•Fewer number of drugs must achieve same efficacy as triple therapy

•Must block same number of intracellular sites (2) in HIV replication cycle

•High level of efficacy without resistance

When NOT to switch to dual therapy:

•Pregnancy

•HBV co-infection

•Evidence of drug resistance

Idvynso (doravirine/islatravir)

First non-INSTI, tenofovir-free, 2-drug regimen

‣For virologically suppressed PLWH with:

1.No history of virologic treatment failure and

2.No known resistance substitutions to doravirine

‣Non-inferior efficacy compared to Biktarvy in a head-to-head phase 3 trial

‣Available as of 5/11/26

**brand new

What NOT To Start

Single drug monotherapy

2 NNRTIs, 2 PIs, or 2 INSTIs together

Triple NRTI therapy

Emtricitabine (FTC) + lamivudine (3TC)

Un-boosted darunavir

Confirming Complete Regimen: Triple Therapy

•Nucleoside/tide backbone (2 nucleoside analogs)

–PLUS

•Anchor drug

–Integrase inhibitor or

–Protease inhibitor (boosted) or

–Non nucleoside reverse transcriptase inhibitor

BIKTARVY

BIC (INSTI)

FTC (NRTI)

TAF (NRTI)

Use a __________ ART regimen for patients who have chronic hepatitis B virus (HBV) infection

Use a tenofovir-containing ART regimen for patients who have chronic hepatitis B virus (HBV) infection

Avoid _______ and _________ containing regimens for patients with impaired kidney function

Avoid TDF and atazanavir (PI) containing regimens for patients with impaired kidney function

Limited data regarding preferred ART regimen for patients on hemodialysis; _________ can be used (administer after dialysis on dialysis days)

Biktarvy can be used

What class of ART are considered the "backbone" of a regimen?

Reverse transcriptase inhibitors

Name two classes of ART commonly used in first line regimens.

NRTI, INSTI

A ____ containing regimen should be used with co-HBV infection?

Tenofovir

Long Term Prognosis -Most patients who remain virologically suppressed can live a ?

• Live a near-normal lifespan

•This is IMPORTANT and key to remind patients who feel like HIV is a “death sentence”

also important to note:

‣Significant disparities in mortality and life expectancy exist based on sex/gender, race/ethnicity, transmission category, and other demographic variables

‣In the absence of effective ART, medial survival of patients with advanced HIV infection is 12-18 months

Non-Infectious HIV Complications

‣Weight loss

‣Increased susceptibility to cardiovascular/metabolic disease

‣HIV-associated dementia and neurocognitive disorders

‣HIV-related peripheral nervous system disease

‣HIV-related osteopenia/osteoporosis

‣Non-infectious oral disease

•Oral hairy leukoplakia

•Aphthous ulcers

HIV Wasting Syndrome

•Progressive and unintentional weight loss of more than 10% of body weight

•Often accompanied by chronic diarrhea or weakness

•Can occur despite adequate food intake

•Often due to metabolic disturbances, malabsorption, or chronic inflammation

Lipodystrophy

Abnormal fat redistribution

-Lipoatrophy in the face, arms, and legs or

-Lipohypertrophy in abdomen, neck (buffalo hump), or breasts

Increased Susceptibility to Cardiovascular/Metabolic Disease

such as

‣Atherosclerosis and CVD

‣Metabolic Syndrome

‣Increased risk of stroke

HIV-Associated Neurocognitive Disorder (HAND)

•Spectrum ranging from asx neurocognitive impairment (ANI) to mild neurocognitive disorder (MND) and HIV-associated dementia (HAD)

-Cognitive Impairment

-Motor Symptoms

-Behavioral Changes

HIV-Associated Dementia (HAD)

In most severe form, HAD characterized by marked cognitive, motor, and behavioral dysfunction, including confusion, memory loss, and severe motor deficits

Distal symmetric polyneuropathy (DSP)

Most common form of HIV-associated neuropathy

–Burning or tingling sensation in the feet and hands, progressing proximally

–Numbness and weakness sensory loss may affect balance and coordination; muscle weakness in advanced cases

Inflammatory demyelinating polyneuropathy

Resembles Guillain-Barré syndrome, rapid onset of muscle weakness and sensory loss