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

1. HIVI HIV 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

2. 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) Horberg, Aberg, et. al., CID, 2009 *--ever screened

3. 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 † needs revision

4. 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

5. 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 care • Do not forget social services! • All doctors treating HIV should know how to do all of this! HIVMA/IDSA HIV Primary Care Guidelines—revised version out soon!

6. 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

7. Why Worry About Syphilis Here Rates if Syphilis Incidence in Kaiser Permanente Northern California, by HIV Status 25 20 HIV-infected 15 Rate (per 1,000 person-year) 10 5 HIV-uninfected 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year Horberg, et. al., Sex Transmitted Dis. 2010; 37(1): 53-58

8. Syphilis Serology - The Old Way Nontreponemal Test: RPR or VDRL - + Treponemal Test No syphilis - + Syphilis No syphilis (false + RPR)

9. Syphilis Serology - The New Way Syphilis Antibody (EIA) - + RPR or VDRL No syphilis - + Syphilis Discrepant result - Do TP-PA* + - No syphilis (false + EIA) Syphilis (false - RPR) *--or MHA-TP or FTA-ABS

10. The New Strategy • Be Aware— • Primary syphilisFalse negative RPR • Late latent syphilis False negative RPR • False-positive EIA True negative RPR • Successfully treated syphilis True negative RPR • Accidentally treated syphilis True negative RPR • AdvantagesDisadvantages • EIA can be automated New class of patients: • No more false-positive RPRs Positive EIA, negative RPR • Can pick up RPR-negative cases Discrepant treponemal tests are confusing

11. What to do if you forget the logic • Ask: Why was the test done? Is there a history of syphilis? EIA RPR TP-PA Interpretation Do No syphilis or very early - Be happy or treat + + Syphilis Treat for stage - + No syphilis? Repeat in 1 month + - + Syphilis Treat for stage; be aware of history

12. 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

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

14. 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

15. 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

16. TB Calculator • TSTIGRAInterpretation • - -TB likely not present • - +TB may be present • + -TB may be present • + +TB very likely present • Of course, clinical thinking comes first.

17. 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 Testing • HLA B*5701 • Coreceptor Tropism Assay

18. 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

19. 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.

20. 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)

21. 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-γ • All of this data is from observational studies • These markers would not change management Boulware, JID, 2011; 203: p.1637-1646.

22. 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 Ongoing Monitoring of HIV+ Patients

23. Some Comments about Medication Monitoring • In general, therapeutic drug monitoring not needed • Toxicity 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

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

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

26. 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 *Recent recommendations say all HIV+ men>50

27. 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 earlier • Anal paps issue is what to do for follow-up • GET YOUR PATIENTS TO STOP SMOKING!!!! • Also, alcohol and substance use counseling and screening • Also, sexual risk behavior counseling, diet and exercise, seat belt use

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

29. “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