Evolving Strategies in HIV Diagnosis and Treatment

1. Evolving Strategies in HIV Diagnosis and Treatment Rob Smith September 27,2013

5. Current Success Rate for cART • Undetectable viral load in 85% of treated patients • Reasons for treatment failure: adherence (co-morbidities), access, drug resistance (<5% of pts) • Not all treated patients achieve immune reconstitution (especially if CD4 nadir <200)

6. NEJM Mar., 2010

7. HIV Stats in the US • 50,000 new cases/yr; 18,000 deaths/yr • 20-30% do not know HIV status • These 20% account for ½ of new cases • By 2015, ½ of all HIV cases will be >50 yo

8. HIV in Maine • 1800 HIV positive; prevalence 0.1% • 300-500 do not know their HIV status • 50 new cases per year; >50% “late stage” • 60% MSM; 10% hetero w known positive partner; 16% hetero w/o known at risk partner; 12% IVDU

9. Why Do We Still See AIDS in the US? • “Late testers”: 30-40% present with AIDS or develop in one year –this is true in Maine as well as nationally (NEJM 2006;354:438). • Retention in care, adherence to meds (Psychiatric disease, substance use, other barriers to ongoing treatment—CID 2007:44:1493)

10. CID Sept. 15, 2010

11. Recent MMC Case • 50 yo man seen in MMC ER w “difficulty breathing”. • Evaluated w BMP, CXR (“interstitial infiltrates”). Rx albuterol. • 3 wks later: Admit to MMC - hypoxic. • Relevant Hx: 25 lb weight loss since Jan; cough x 3-4 months. Single male. Not currently sexually active.

13. Exam: thrush; oral hairy leucoplakia; circular dermatophytic rash in axilla. • CT: bilat ground glass opacities in upper and lower lobes • BAL: Pneumocystis; CMV • HIV VL 200,000; CD4 45

14. Another Recent MMC Case • 55 yo married man with fatigue, weight loss, intermittent fever x 6 months. Rx for “chronic Lyme” with 3 months oral doxycycline. • Refer to dermatology for Rx psoriasis with topical steroids • Refer to surgery for rectal fissure • Develops right facial droop, arm weakness; thalamic brain mass on CT scan--?tumor. Admit to MMC. • HIV positive; CD4 40

15. Newer Testing Strategies • CDC proposals (2006): Routine testing on adults (13-64) Annual testing in those at risk Pregnancy, contemplated pregnancy “Opt out provision”; implied consent • Rapid Diagnostic Tests: 6 approved “Point of care” Home testing Confirm Positives! (NEJM 2006;354:438;PLOS ONE 2012 ;7(9): e44417)

16. Maine HIV Testing Law 2007 • Changes in state law: No pre-test counseling required No written informed consent…..BUT • Does require “A patient must be informed orally or in writing that an HIV test will be performed unless (they) decline” “Information must include an explanation of what an HIV infection involves, and the meaning of positive and negative test results” “If a test is positive, post-test counseling must be provided”

17. Barriers to Routine HIV Testing • Lack of knowledge of CDC recommendations • USPHT DID not endorse –DOES as of 2013 • Assumptions re: patient risk • Low priority—lack of time • Uncertainty re: informed consent law

18. Traditional Diagnostic Tests-HIV 1 ELISA plus Western Blot Sensitivity: 99.5% post 3 months disease Specificity: 99.99% False negatives: Window period; agammaglobulinemia; SubType O,N False Positives: “autoantibodies”

19. New HIV Diagnostic Algorithm-2012 • HIV 1/2 Immunoassay screen (includes antibody screen and p24 antigen) • If positive, reflex to Multispot (HIV 1 vs 2 assay) and HIV RNA (viral load) • If initial screen is negative, no additional testing UNLESS clinical concern of acute HIV disease; in this event, do HIV RNA • Adapted from CLSI consensus guideline (June 2011)

20. HPI • 22 y.o. female with no hx illness who experienced HA and fever 1 week after returning from vacation to resort in Caribbean. Symptoms progressed to severe fatigue and fainting. • 9/19 went to ER. Febrile with UA showing 3-5 WBC. Diagnosed with UTI and given ciprofloxacin. • 9/22 back to ER for worsening dizziness, fever, HA, fatigue. WBC 4.8 with 29% bands. Monospot negative. Given IV hydration and sent home for unspecified viral illness.

21. HPI continued • 9/24 Returned to ER. Fever, fatigue, dizziness, new right inguinal LAD, dry cough and mild diarrhea. Febrile to 101.4, marked orthostatic hypotension. WBC 2.6, platelets 105, CRP 3, CMP WNL • Admitted to an outside hospital with ? PID versus Lyme. ID and Gyn consulted and started on empiric Piperacillin/Tazobactam and Doxycycline. • Exam unremarkable --- ultrasound with 2 cm inguinal node. CT abd/pelvis negative except a question of inflammation in the right inguinal node. Cardiac echo negative. CXR LLL infiltrate versus atelectasis.

22. HPI continued • Further workup revealed: • Erhlichia serology negative • Lyme ELISA equivocal • Rapid strep negative • HIV ELISA (antibody) test negative • VDRL negative • C-diff and cryptosporidium negative • Chlamydia swab positive • Blood, stool, and urine cultures showed no growth. • WBC and platelet count improved and sent home 9/27 to complete a 2 week course of doxycycline for presumptive chlamydia/LGV, ? atypical PNA, ? Lyme • Continued to feel lightheaded so saw her family physcian on 10/2. Afebrile: WBC 5.6 (21% reactive lymphs), HCT 37, plat 354, ALT 69. Doxycycline extended 3 weeks. ID consulted.

23. DDx Expanded • Hx of unprotected sexual intercourse while on vacation. No new findings on exam. Doxycycline discontinued. • HIV viral load >750,000 copies/mL • Repeat HIV testing showed + ELISA and Western blot • Pan-sensitive genotype • Pt started on anti-retroviral Rx for “Acute retroviral syndrome’ or “Primary HIV”

24. Acute Retroviral Syndrome- Symptoms Fever (96%) Lymphadenopathy (74%) Pharyngitis (70%) Rash (70%) Myalgia/arthralgia (54%) Headache Diarrhea Nausea and vomiting Hepatosplenomegaly Weight loss Thrush Neurologic symptoms

25. Baseline Tests –HIV Dx • HIV viral load, CD4 count • HIV genotype • CBC, CMP, RPR, Hep B/C serologies, RPR, Toxo IgG (if CD4,200) • PPD (>5mm) or IGRA assay • Immunizations: PCV13 (Prevnar) followed 8 wks later by PPSV23 (Pneumovax); Hep A/B if indicated

26. OI Prevention Guidelines (CDC 2009) • CD4<200 (or 14%): PCP—TM/SZ (daily), dapsone (+/-pyrimethamine for toxo), atovoquone ($$), aerosol pentamidine • CD4<100: Toxoplasmosis—if seropositive; tm/sz or dapsone plus pyrimethamine/leucovorin • CD4<50: MAI—azithromycin weekly or clarithromycin daily

27. Who to Rx: DHHS Guidelines 2012 • Rx recommended for all HIV-infected individuals. Strength of recommendation varies on the basis of preRx CD4 count. • CD4 <350 AI • CD4 350 to 500 AII • CD4 >500 BIII A=strong evidence;B=moderate

28. Why Rx Everyone with HIV • Rx reduces HIV-related events, HIV-unrelated events and malignancies (Note that CD4 nadir and “viremia copy years” predict adverse outcomes) • Public health benefit with reduced HIV transmission (HPTN 052; Nejm 2011) • Timing may depend on presence of opportunistic infections (Inconclusive evidence for “elite controllers, long-term non-progressors”)

29. Preferred Regimens (DHHS-2012) • Efavirenz/tenofovir/emtricitabine • Ritonavir-boosted atazanavir and tenofovir/emtricitabine (“truvada”) • Ritonavir-boosted darunavir and tenofovir/emtricitabine • Raltegravir and tenofovir/emtricitabine (http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf)

30. Alternative Regimens • Rilpivirine/tenofovir/emtricitabine • Eltegravir/cobicistat/tdf/ftc • Lopinavir/r (“Kaletra”)/tdf/ftc • May substitute abacavir/lamivudine (“Epzicom”) for tenofovir/emtricitabine in patients with renal disease, osteoporosis

31. Factors to Consider • Underlying drug resistance • Potential adverse effects of drugs, drug-drug interactions • Pregnancy or significant child bearing potential • Co-morbid conditions (Hepatitis B/C, psychiatric, substance abuse) • Post-menopausal women or other risk osteoporosis • Convenience

32. Always check for drug resistance first • HIV genotype for everyone, as a baseline and if there is viral breakthrough (>500 copies HIV) • If treatment is failing, obtain genotype while on their regimen to detect resistance mutations • HIV phenotype for known or suspected complex drug resistance mutation patterns ($$)

33. Management of HIV (DHHS 2011) • Goal is “undetectable” (<48 copies/mL) HIV viral load (Assays vary on limit of detection from <75 to <20 copies/mL) • Monitor the HIV viral load q 3 months once goal is achieved • CD4 counts can be repeated q 6-12 months if viral load controlled

34. Continue to Monitor For… • New STDs (annual RPR/syphilis screen) • New onset Hep C (annual) • TB (Risk dependent on community context) • Metabolic disorders—ie fasting glucose, lipids; creatinine and urinalysis; testosterone in symptomatic males; ?bone density

35. Be Aware of…. • Increased CAD risk • Increased risk for liver disease (fatty liver) • Increased risk for renal disease • Neuro-cognitive disorders-10x reduction in HIV dementia with ARVs, but ?increased risk over time • AIDS (lymphoma, cervical) and Non-AIDS malignancies (anal, lung, liver)—related to CD4

36. NEJM 352:1 January 6, 2005

37. Post-Exposure Prophylaxis • Occupational—CDC algorithm; UCSF PEPline (888-448-4911 or www.nccc.ucsf.edu/Hotlines/PEPline.html); risk if needlestick exposure to an HIV infected pt=0.33%; if mucosal, 0.09% risk • Needlestick risk factors: index patient status; hollow vs solid needle; visible blood; deep puncture; needle into vessel • Treat ASAP (within 2 hours if possible) • Risk reduction of 80%

38. Post-Exposure Prophylaxis: Non-Occupational • CDC recommends nPEP if: • “Substantial risk of exposure w/in 72 hrs” Mucosal or non-intact skin exposed to “body fluids” (not saliva, urine etc unless visibly contaminated w blood) from known HIV source • Case by case if HIV status unknown • Should not be used as a frequent intervention for any one patient

39. PEP:Choice of Meds • New recommendations (2013): truvada plus raltegravir (well tolerated—J AIDS 2012) • If source pts viral resistance pattern is known, choose effective alternatives • Do not use abacavir/3TC • 28d course of treatment

40. Pre-Exposure Prophylaxis (“PrePEP”)? • Effectiveness demonstrated in MSM trial: 44% overall, 73% if adherent; 66% in heterosexual females • Cost effective (<$100K per QALY)—but could result in annual expenditures of $4 billion (Ann Intern Med 2012; 156: 541) • Concerns: How to stratify risk; who pays; drug resistance; long term risks of Rx • CDC interim guidelines for MSM (2011), heterosexuals at high risk (2012); IVDU

41. Real or Functional Cures? • Berlin patient: stem cell transplant; donor was CCR5 mutation homozygous—off ARV x 5yrs • Activate resting memory cells with latent infection and Rx? Use of vorinostat (Nature 2012; 487: 482)

42. Resources • Primary Care Guidelines (IDSA-2009) CID 2009; 49: 651-681. • Pregnancy: http://aidsinfo.nih.gov/guidelines • Opportunistic Infections: http://aidsinfo.nih.gov/guidelines • Occupational Exposure http://www.cdc.gov/mmwr PEPline: 1-888-448-4911

45. How to Treat HIV • Preferred Regimens—Treatment Naïve (DHHS 01/10/2011) Efavirenz plus tenofovir/emtricitabine Atazanavir/r plus same Darunavir/r plus same Raltegravir plus same

46. HIV in Refugee Populations • Less likely to start ARV therapy • Similar CD4 at time of presentation • Higher likelihood co-infection with latent TB, Hepatitis B • Higher prevalence of a mental health disorder (especially PTSD) • Acquisition by heterosexual exposure rather than IVDU or MSM Beckwith et al; 2009;13:186. Internat J Inf Dis.

49. Science Vol. 332 May 13, 2011

50. Science Vol. 333 July 1, 2011