HIVIHIV Initiative of Kaiser Permanente and Care Management Institute

Michael Horberg, MD MAS FACP FIDSAExecutive Director Research, Mid-Atlantic Permanente Research InstituteDirector HIV/AIDS, Kaiser PermanenteVice-Chair, HIV Medicine Association

Laboratory Monitoring for HIV+ Patients:What You Need to Know

Horberg, Aberg, et. al., CID, 2009

AMA/HIVMA/HRSA/NCQA Measures (1)

No measures of HIV testing rates or linkages to care

Other Screening Measures TB Screening* STI—gonorrhea/chlamydia* STI—syphilis (that year) Hepatitis B screening* Hepatitis C screening* High risk injection drug use behavior (that year) High risk sexual behavior (that year)

*--ever screened

† needs revision

AMA/HIVMA/HRSA/NCQA Measures (2)Process Measures

Medical Visit Measures retention in care

CD4 cell count twice yearly PCP prophylaxis if CD4<200 ART prescription if CD4<350 † Influenza immunization yearly Pneumococcus immunization ever Hepatitis B vaccination

Ever one time and then all three vaccinations (2 measures)

Outcome Measures HIV RNA control for all patients on ART

Below limits of quantification for lab used HIV RNA control after six months on ART

Accountability measure as needs documentation of plan if patient’s HIV RNA above limit of quantification

Caveats about the HIV Quality Measures

Measures need to change with time Entering an era of test/treat; not CD4 cutoff for starting ART?

Metrics are parsimonious—not intended to cover the “universe” of care

DHHS guidelines: q6-12 month checking of CD4 for patients with BLQ VL and high CD4

However, this doesn’t apply to Viral Loads—still at least q6months even if patient has been stable and controlled for some time

HIVMA/IDSA HIV Primary Care Guidelines—revised version out soon!

What Should HIV Primary Care Do

Getting everyone tested (HIV and STI)Get HIV+ patients into care and consider ART

HPTN 052—treating all radically↓transmission

Routine primary care is key Vaccinations—hepatitis, pneumovax, flu Cancer screening as age/gender appropriate; don’t forget! STI screening—STIs love HIV+ hosts! Depression and substance use screening—at least annually Attention to potential toxicities, metabolic and cardiovascular issues—essential!

Work hard to retain patients in careDo not forget social services!

All doctors treating HIV should know how to do all of this!

Non-HIV Disease Specific: CBC with Differential Liver Enzymes

ALT, AST, Bilirubin, Alk Phos Blood Chemistries

Electrolytes, BUN, Creatinine Urinalysis

RBCs, WBCs, Protein Fasting Lipids and Glucose Syphilis Screening GC/Chlamydia

NAAT if available Consider all sources

(genital, anus, oropharynx)

Initial Laboratory Studies for ALL HIV+ Patients:But You Likely Know This

Hepatitis A, B, C Screening HAV IgG HBcAb, HBsAg, HBsAb HCV Ab

G-6-PD Level Especially Black, Mediterranean,

and Asian Serum Testosterone—where indicated

Note adjustment for age Especially for males with fatigue,↓weight or

libido, erectile dysfunction,↓BMD Toxoplasma Antibody

Why Worry About Syphilis Here

Rates if Syphilis Incidence in Kaiser Permanente Northern California, by HIV Status

Year

Horberg, et. al., Sex Transmitted Dis. 2010; 37(1): 53-58

HIV-infected

HIV-uninfected

20051998 1999 200420031995 1996 2002200120001997

Rate

(per

1,0

00 p

erso

n-ye

ar) 25

15

10

5

0

20

Nontreponemal Test: RPR or VDRL

+

Treponemal Test

-

No syphilis

-

No syphilis (false + RPR)

+

Syphilis

Syphilis Serology - The Old Way

Syphilis Antibody (EIA)

+

RPR or VDRL

-

No syphilis

-

Discrepant result - Do TP-PA*

+

Syphilis

+

Syphilis(false - RPR)

No syphilis(false + EIA)

-

*--or MHA-TP or FTA-ABS

Syphilis Serology - The New Way

The New Strategy

Be Aware—Primary syphilis False negative RPRLate latent syphilis False negative RPRFalse-positive EIA True negative RPRSuccessfully treated syphilis True negative RPRAccidentally treated syphilisTrue negative RPR

Advantages DisadvantagesEIA can be automated New class of patients:No more false-positive RPRs Positive EIA, negative RPRCan pick up RPR-negative cases Discrepant treponemal tests are confusing

Treat for stage; be aware of history

Syphilis+-+

Repeat in 1 monthNo syphilis?-+

Treat for stageSyphilis++

Be happy or treatNo syphilisor very early

-

DoInterpretationTP-PARPREIA

What to do if you forget the logic

Ask: Why was the test done? Is there a history of syphilis?

Other non-HIV Specific Tests to Consider

CXR Patients with evidence of Latent TB Consider if underlying lung disease present for baseline

Pap Test Anal and/or cervical For cervical: q6months until negative then annual For anal: Have a plan

CMV and other Herpesvirus CMV for patients with low risk of infection Varicella-zoster for patients who deny h/o chickenpox or shingles I don’t recommend HSV-2 testing but others do

TB screening/testing

MMWR, 2009, vol. 58, RR-4; MMWR, 2010, vol. 59, RR-12.

HSV-2 Screening—Not Needed--IMHO

70% HIV+ are HSV-2 positive; 95% HSV+ (1 or 2)CDC still recommends HSV-2 screening for HIV+

And for MSM generally Would be if partner was HSV-2+ and protect HSV-2 negative patient

HOWEVER, this info will likely NOT change your management or later diagnostics

Patients with new lesions (and no h/o anogenital herpes) should have the lesion typed (not the serum)

NOTE: Routine screening for Varicella-Zoster is also not recommended

Except for patients who don’t if they’ve ever had chicken pox or shingles Potentially eligible for vaccine

TB Screening (1)

For most patients, TST testing is sufficient TST preferred in children <5 years old

Interferon-γ Release assay (IGRA) is an option “TST in a tube” Assay measures production of interferon-g by WBC stimulated with M.

tuberculosis antigens. Can be used in lieu of TST (CDC)

Especially for patients who may not return

Advantages to IGRA: Only one visit no problems with placement or interpretation no false positives from BCG (doesn’t happen often anyway) no confusion due to boosting effect

TB Screening (2)

Disadvantages: Requires fresh blood; Cost higher than PPD. Results may fluctuate over time Optimal role not fully defined yet

For active TB: Both TST and IGRA have poor predictive value Get a tissue/sputum diagnosis!

For latent TB, studies are very limited Neither test should be used as a “test of cure”

Reversion has not been shown to reflect cure

TB Calculator

TST IGRAInterpretation

- - TB likely not present - + TB may be present + - TB may be present + + TB very likely present

Of course, clinical thinking comes first.

HIV-Specific Tests

Serologic Test for HIV If not diagnosis confirmed already Will need for ADAP certification and other purposes

CD4 Cell Count and Percentage There is variation between assays and time of day

Plasma HIV RNA level (“Viral Load”) Be aware of changes in assays and cutoffs Ideally use same assay always in same patient

HIV Resistance TestingHLA B*5701Coreceptor Tropism Assay

HIV Resistance Testing

Order at time of diagnosis before ART prescribed Even if treatment is not initially planned (although I believe in test/treat) Can “back mutate” to wild type over time (although resistance mutations are still

“archived”)

Genotype (with adequate interpretation) is sufficient For ARV naïve certainly and usually with 1st or 2nd failure Also for all pregnant women prior to starting ART Some labs cannot reliably perform if HIV RNA<1000/mL If suspect integrase inhibitor resistance, need genotype specific for that.

Phenotype should be considered when multiple mutations suspected and repeated treatment failure

Especially if multiple exposures to protease inhibitors Results can take longer to return

HLA B*5701

Should be ordered prior to abacavir therapy If HLA B*5701 positive: higher risk for abacavir hypersensitivity

Abacavir should not be prescribed if HLA(+) Note that a negative test does not rule out risk of hypersensitive

reaction 100%

Even if HLA(-), need to counsel patients about hypersensitivity reaction

But advise patients that they shouldn’t worry. No need to order if not going to prescribe abacavir Usually pretty quick turnaround for results.

Co-receptor Tropism Assay

Informs you if patient has CCR5 tropic virus, CXCR4 tropic virus, or mixed.Test should be performed prior to starting a CCR5 antagonist (at present, that’s maraviroc)

Some argue to test at time of diagnosis, due to VL needed for results However, newer assay can measure at far lower levels (including BLQ level)

Is still an expensive test. Consider also if virologic failure with CCR5 antagonist

Phenotypes and Genotypes for this In US, phenotypes have been used more frequently

IF X4 virus present—maraviroc far less likely to be effective (and can lead to incomplete suppression of HIV)

Boulware, JID, 2011; 203: p.1637-1646.

Inflammatory Markers

Markers of inflammation not recommended at this time.

However, CRP, D-dimer, IL-6 and hyaluronic acid levels associated with increased risk of death

IRIS associated with: Elevated pre-ART TNF-α Significant 1 month increase in CRP, D-dimer, IL-6, IL-8, CXCL10,

Interferon-γAll of this data is from observational studies

These markers would not change management

Ongoing Monitoring of HIV+ Patients

HIV Specific: Viral Load/CD4 Count

q3-4 months vs. q6months Same caveats as before

Resistance testing if virologic failure Cautions about “blips” Failure if VL>200/mL (DHHS, 2011) If integrase inhibitor resistance

suspected, need to specify also genotype for this

Non-HIV Specific but related to Treatment:

Toxicity monitoring specific to medication

Routine health maintenance Check blood pressure Digital prostate exam for men

PSA? If >50 consider Dilated optho exam at least

annually if CD4<50 Fasting lipid and glucose at

least annually STI screening Bone disease screening Cancer screening

Some Comments about Medication Monitoring

In general, therapeutic drug monitoring not neededToxicity monitoring is specific to medications

As ZDV and “d” drugs less used, fewer indications for CBC, lactic acid level

Most PI medications affect lipids and glucose. Even though atazanavir does not affect lipids, aging and HIV itself

can lead to cardiovascular disease.

Many toxicities are not diagnosed through blood or urine tests

Example, facial lipoatrophy

DHHS Adult/Adolescent ART Guidelines, 2011; Rho and Perazella, Current Drug Safety, 2007

Monitoring Patients on Tenofovir

Major toxicity concern for tenofovir is renal effects Proximal renal tubular dysfunction or Fanconi Syndrome:

proteinuria, glucosuria, phosphaturia leading to hypophosphatemia, elevated creatinine

Most would recommend for tenofovir: Urinalysis (proteinuria may come first) Creatinine clearance (can be calculated from SCr) Many recommend serum phosphorous

Serum phosphate should be sufficient However, some nephrologists consider this insensitive

Can consider fractional excretion of phosphorous

Need to also consider issues of bone loss

McComsey, et. al., CID, 2010 51: p. 937-946; Calmy, et. al., JID, 2009, 200: p. 1746-1754

Bone Disease Monitoring in HIV+ Patients (1)

Low BMD is very common among HIV+ Increased fracture rates among HIV+ Likely multi-factorial causation

Poorer nutrition, weight loss, smoking and alcohol Lower Vitamin-D levels (60-75% among HIV+) Hypogonadism

Studies have described small but significant BMD loss after initation of ART

2-6%; Not usually progressive Same seen immediately among women at menopause

Possibly PIs (?more with ATV than EFV) Tenofovir has been associated with more loss than other regimens

*Recent recommendations say all HIV+ men>50

Bone Disease Monitoring in HIV+ Patients (2)What to do?All HIV+ with fragility fracture should get bone densitometry

Also for women >65, younger women if ≥1 risk factor for osteoporosis, men >50 (if risk—otherwise 70+*)

All patients with abnormal exams should be evaluated for secondary causes of low BMD

Including diet, vitamin D levels, substance use (SMOKING too!), hypogonadism (male and female), steroids use

Vitamin D levels (25-OH level) Optimal level: 30-60ng/mL More sensitive levels (1,25-OH) likely not needed

In most cases, PTH level not needed if good faith effort at repleting low vitamin D level hasn’t happened Consider also for: men>50, post-menopause women, African-American, prior h/o fragility

fracture, lower BMD Don’t usually need calcium level; recheck 6-12 months after repletion

Screening for Cancer

Colon cancer—recent data suggests no increased risk in HIV+ However, colonoscopy at age 50 and then q10 years if negative

American College Gastroenterology—start AA at age 45 (not ACS or USPSTF) Consider fecal immunohemoglobin testing annually (could be when given flu shots)

Breast Cancer—doesn’t appear to have increased risk among HIV+ women

Annually at age 50 (younger if consider higher risk?)

Cervical pap smear—discussed earlierAnal paps issue is what to do for follow-upGET YOUR PATIENTS TO STOP SMOKING!!!!

Also, alcohol and substance use counseling and screening Also, sexual risk behavior counseling, diet and exercise, seat belt use

Silverberg, Leyden, Horberg et al. AIDS 2009, 23:2337-45; MMWR, 2009, vol. 58: RR-4; HIVMA HIV Primary Care Guidelines

Anal Paps—Where We are Today

Higher risk of anal cancer among HIV+ with prior h/o anogenital warts 102-fold greater rate of anal cancer among HIV+ compared to HIV-

Vast majority of HIV+ MSM have prior HPV exposure Lower frequency if heterosexual male

Issue with anal paps is follow-up If abnormal anal pap—high resolution anoscopy by experienced anoscopist

Many now recommend HRA +/- pap as approach Aggressively treat active warts—anal and genital

Cryotherapy, topical 5-FU, laser, Anal cancer is aggressive—refer for treatment to experienced surgeon and oncologist Importance of good viral control to help treatment

However, it’s unclear what follow-up surveillance should be

“Working together, I am confident that we can stop the spread of HIV and ensure that those affected get the care and support they need.”

--President Barack Obama

Strive only for the best. Be proud.The great work continues.

Thank you