HIVI HIV Initiative of Kaiser Permanente and Care Management Institute Laboratory Monitoring for HIV+ Patients: What You Need to Know Michael Horberg, MD MAS.
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HIVI HIV Initiative of Kaiser Permanente and Care Management Institute Laboratory Monitoring for HIV+ Patients: What You Need to Know Michael Horberg, MD MAS FACP FIDSA Executive Director Research, Mid-Atlantic Permanente Research Institute Director HIV/AIDS, Kaiser Permanente Vice-Chair, HIV Medicine Association 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 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 HIV RNA control after six months on ART † Below limits of quantification for lab used needs revision 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 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! Initial Laboratory Studies for ALL HIV+ Patients: But You Likely Know This Non-HIV Disease Specific: CBC with Differential Liver Enzymes Urinalysis HAV IgG HBcAb, HBsAg, HBsAb HCV Ab ALT, AST, Bilirubin, Alk Phos Electrolytes, BUN, Creatinine RBCs, WBCs, Protein Fasting Lipids and Glucose Syphilis Screening GC/Chlamydia NAAT if available Consider all sources (genital, anus, oropharynx) Hepatitis A, B, C Screening Blood Chemistries 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 Rate (per 1,000 person-year) Rates if Syphilis Incidence in Kaiser Permanente Northern California, by HIV Status 25 20 HIV-infected 15 10 5 HIV-uninfected 0 1995 1996 1997 1998 1999 2000 Year Horberg, et. al., Sex Transmitted Dis. 2010; 37(1): 53-58 2001 2002 2003 2004 2005 Syphilis Serology - The Old Way Nontreponemal Test: RPR or VDRL - + Treponemal Test + Syphilis No syphilis No syphilis (false + RPR) Syphilis Serology - The New Way Syphilis Antibody (EIA) - + RPR or VDRL + Syphilis Discrepant result - Do TP-PA* + Syphilis (false - RPR) *--or MHA-TP or FTA-ABS No syphilis No syphilis (false + EIA) The New Strategy Be Aware— Primary syphilis Late latent syphilis False-positive EIA Successfully treated syphilis Accidentally treated syphilis Advantages EIA can be automated No more false-positive RPRs Can pick up RPR-negative cases False negative RPR False negative RPR True negative RPR True negative RPR True negative RPR Disadvantages New class of patients: Positive EIA, negative RPR Discrepant treponemal tests are confusing 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 + + + + - 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 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. 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 IGRA Interpretation - - 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 Testing HLA B*5701 Coreceptor 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) 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. 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 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 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 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 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 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 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 Aggressively treat active warts—anal and genital Many now recommend HRA +/- pap as approach 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 “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