Nurse Case Management Phoenix, Arizona February 20-22, 2008

Transcription

1 Nurse Case Management Phoenix, Arizona February 20-22, 2008 TB/HIV: Managing the Co-Infected Patient Adriana Vasquez, MD February 21, 2008 HIV Treatment Guidelines DHHS December 1,2007 TB/HIV Managing the Co-infected Patient Adriana Vasquez, MD Associate Professor of Medicine, UTHCT 1

2 AIDS is a severe acquired immune deficiency syndrome first described in 1981 Opportunistic (rare) infections or cancers represent the end stage of infection with Human Immunodeficiency Virus (HIV). Infectious Agent: Retrovirus (Viral RNA converted to DNA). Two types: HIV 1 HIV 2 HIV 2 appears less pathogenic than HIV 1. More common in West Africa. 2

3 AIDS Case Definition: Serologic evidence of HIV infection. Enzyme Linked Immunosorbent Assay (ELISA). Western Blot (Confirmatory test). Opportunistic infections: Tuberculosis, MAC, toxo, cryptococcal meningitis Neoplasms: Kaposi s Sarcoma, primary CNS lymphoma, invasive cervical CA CD4+ cell count below

4 HIV Replication Natural Course of HIV (Untreated) uhavax.hartford.edu/bugl/hiv.htm 4

5 ACUTE HIV INFECTION 5

6 Case # 1 Mr. John is a 30 y.o male, captain of the baseball team. He comes to the ER with complaints of fatigue, sore throat, painful nodes on his neck, and generalized body rash. All symptoms started 2 months after his last business trip. Case # 1 What other questions would you ask? What is your differential diagnosis? What tests would you order? 6

7 Acute Retroviral Syndrome Rash (40-80%) erythematous maculopapular with lesions on face and trunk (rarely extremities) mucocutaneous ulceration involving the mouth, esophagus. Rash would help differentiate from infectious mononucleosis Acute HIV Infection Symptoms present days to weeks after initial exposure Most common symptoms on presentation: fever, lymphadenopathy, pharyngitis and rash Nonspecific symptoms overlap with common viral illnesses High index of suspicion is CRITICAL 7

8 Acute HIV Differential DX Influenza Epstein-Barr virus mononucleosis Severe (streptococcal) pharyngitis Secondary syphilis Primary CMV infection Drug reaction Viral hepatitis Primary HSV infection Rubella Brucellosis Malaria West Nile Virus Diagnostic Testing for PHI HIV RNA 1 mil 100,000 10,000 1,000 HIV RNA P24 + Ab + _ HIV-1 Antibodies Exposure Symptoms Days 8

9 Clinical Scenario A 35 year-old male is diagnosed with HIV after he sought testing because of sexual exposure to another man 5 years ago who he learned was HIV-infected. He is asymptomatic, physical exam is normal. CD4 is 184/µL, Viral load is 13,043 copies/ml. What is most appropriate at this time? A. Delay treatment until he is symptomatic B. Delay treatment until the VL is >100,000 copies/ml C. Start HAART and begin PCP prophylaxis with TMP-SMX D. Obtain a genotype E. C and D Changes from October 10, 2006 Genotype recommended in all treatment-naïve patients initially Regardless of decision to start treatment Start HAART CD4 <350 (previously <200) AIDS-defining illness Pregnant HIV-associated nephropathy HBV co-infection when treatment for HBV is indicated Tropism assay prior to starting CCR5 antagonist HLA-B*5701 prior to starting abacavir New HAART (CCR5 antagonists, integrase inhibitors) 9

10 Goals of Therapy & Tools to Achieve Goals Improved quality of life Reduction of HIV-related morbidity and mortality Restoration and/or preservation of immunologic function Maximal and durable suppression of viral load Prevention of vertical transmission Prevention of transmission to sexual partners Selection of ARV regimen Preservation of future treatment options Maximizing adherence Use of resistance testing Labs 10

11 Baseline Evaluation CD4 Genotype testing Plasma HIV RNA (viral For those with pretreatment VL >1000 load) CBC, Chem 10, LFTs, UA Psychosocial evaluation Substance abuse RPR, VDRL Social support PPD Psychiatric illness Toxoplasma gondii IgG HLA-B*5701 screening Hepatitis serologies If starting abacavir Pap smear (females) Coreceptor tropism assay GC/chlamydia If starting CCR5 inhibitor If risk for CV disease Lipids, blood glucose Frequency of checking CD4, VL CD4 Baseline Every 3-6 months When to start HAART Response to HAART When to start OI prophylaxis Average increase of cells/mm³ per year immunologic suppression Viral Load Baseline 2-8 weeks after starting HAART 1 log10 copies/ml drop 2-8 weeks after changing HAART Every 3-4 months Achieve VL less than 50 copies/ml by weeks of starting therapy 11

12 Why do resistance testing? Risk that transmitted virus will be resistant to >1 HIV drug is 6-16% 3-5% of transmitted viruses have resistance to drugs from more than one class Even in those not about to start HAART Resistant virus can decrease to undetectable levels over time but can still increase risk of future treatment failure when HAART initiated Can acquire more resistance over time Repeat resistance testing when starting HAART Genotype vs Phenotype General Advantages Genotype 1. Detects resistance mutations in viral genes 2. Preferred to phenotype 1. Rapid results (1-2 weeks) Phenotype 1. Measures ability of HIV to grow in different concentrations of HAART drugs 2. Similar to antibiotic susceptibility 1. Easier to interpret 2. Quantitative values Disadvantages 1. Interpretation requires expert opinion 2. Insensitive for minor viral species 1. Longer turnaround (2-3 weeks) 2. Cost more than genotype 3. Insensitive for minor viral species 12

13 Indications for resistance testing Any HIV patient entering into clinical care Regardless of whether HAART will be initiated Regardless of whether acute or chronic HIV When starting HAART When considering changing HAART regimen in cases of virologic failure While taking HAART or within 4 weeks of stopping HAART All pregnant patients prior to starting HAART Must be done when VL >1,000 Amplification of the virus not reliable when VL <1,000 Treatment 13

14 Clinical Scenario A 35 year-old male is diagnosed with HIV after he sought testing because of sexual exposure to another man 5 years ago who he learned was HIV-infected. He is asymptomatic, physical exam normal. CD4 is 184/µL, VL 13,043. ALT is 85, AST 63, HCV ab neg, HBsAg pos, HBcAb pos, HBsAb neg What is the most appropriate HAART regimen at this time? A. Delay treatment until he is symptomatic B. Delay treatment until his VL is >100,000 C. Start zidovudine, didanosine, and nelfinavir D. Start lamivudine, efavirenz, and tenofovir HIV/TB co-infection Latent to active TB progression increased X100 in setting of HIV TB associated with rapid progression of HIV If not on HAART Start TB therapy Delay HAART for 4-8 weeks Avoid paradoxical reaction Better defines causes of drug reactions Do not delay HAART if CD4 <50 14

15 Goals of HAART Reducing HIV-related morbidity Prolonging survival Restoring/preserving immune function Maximally suppress viral load To delay drug resistance mutations To preserve CD4 To maximize clinical benefit Prevent HIV transmission Initiation of HAART Regardless of CD4 Pregnant Reduce perinatal transmission of HIV HIV-associated nephropathy Viral replication causes kidney injury HAART in these patients prolongs survival and improves renal function Need to renally dose HAART (especially NRTIs) HBV co-infection (when HBV treatment indicated) tenofovir plus lamivudine or emtricitabine 15

16 Indications for Initiating ART: Chronic Infection Clinical Category and/or CD4 Count History of AIDS-defining illness CD cells/mm³ Pregnant women HIV-associated nephropathy Hepatitis B coinfection, when HBV treatment is indicated* Recommendation Initiate ART *Treat with fully suppressive drugs active against both HIV and HBV. Current Antiretroviral Medications NRTI Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine NNRTI Delavirdine Efavirenz Nevirapine PI Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Entry Inhibitor Fusion Inhibitor Enfuvirtide CCR5 Coreceptor Antagonist Maraviroc Integrase Inhibitor Raltegravir 16

17 Mechanism of action of HAART Entry Inhibitors: Fusion of HIV to host cells contingent on conformational changes of gp41. Fusion inhibitors bind to gp41 to inhibit these conformational changes. NRTIs (Nucleoside and Nucleotide reverse transcriptase inhibitors) Act as nucleoside analogues that interfere with reverse transcriptase Only active when phosphorylated by nucleoside kinases after intracellular processing. NNRTIs (Non-nucleoside reverse transcriptase inhibitors) Do not require intracellular processing or phosphorylation to be activated. Integrase Inhibitors Inhibits integrase, which cleaves viral DNA and ultimately allows it to be incorporated into host cell DNA Protease Inhibitors HIV needs the protease enzyme to cleave gag and gag-pol proteins in order to produce mature proteins. PIs block this cleavage producing defective viral particles. 17

18 Initial Treatment: Preferred Components NNRTI Option Efavirenz* OR PI Options Atazanavir + ritonavir Fosamprenavir + ritonavir (BID) Lopinavir/ritonavir (BID) + NRTI Options Tenofovir + emtricitabine** Zidovudine + lamivudine** *Avoid in pregnant women and women with significant pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa. ARV Medications: Should Not Be Offered at Any Time ARV regimens not recommended: Monotherapy (except possibly zidovudine used to prevent perinatal HIV transmission) Dual NRTI therapy 3-NRTI regimen (except abacavir/lamivudine/ zidovudine and possibly lamivudine/zidovudine + tenofovir NRTI-sparing regimens 18

19 Monitoring patients on HAART Treatment Failure: Definitions Virologic failure: inability to achieve or maintan suppressed viral load (<50 copies/ml) Incomplete virologic response 2 consecutive VL >400 after 24 weeks or >50 by 48 weeks of HAART in treatment naiive patients Virologic rebound After sustained period of VL <50, repeated VL above 50 Immunologic failure: failure to achieve and maintain adequate CD4 count despite virologic suppression Some studies use > over 4-7 years No specific definition Clinical progression: occurrence of HIV-related events after atleast 3 months of HAART, excluding IRIS 19

20 Treatment Interruptions Long-term Not typically recommended, even in patients with treatment failure and extensive resistance as partial virologic suppression has some clinical benefit SMART study: interruption at CD4>350 and restarting when CD4<250 associated with increased disease progression and mortality vs continuous HAART Conclusion Genotype recommended in all treatment-naïve patients initially Regardless of decision to start treatment Start HAART CD4 <350 (previously <200) AIDS-defining illness Pregnant HIV-associated nephropathy HBV co-infection when treatment for HBV is indicated Tropism assay prior to starting CCR5 antagonist HLA-B*5701 prior to starting abacavir New HAART (CCR5 antagonists, integrase inhibitors) Be mindful of special situations Acute HIV, Adolescents, IVDU, pregnant women, HBV/HCV/TB coinfection 20

21 HIV TB Objectives Discuss the epidemiology of HIV TB Identify the best practices for their evaluation and management of the HIV + person at risk for tuberculosis Identify strategies to successfully address the challenges to treatment of HIV TB patients; drug drug interactions, IRIS reactions, adverse drug reactions 21

22 What Are Things to Worry About When Managing HIV TB? Diagnosis is difficult Immune Reconstitution Reactions (IRIS) Drug Drug Interactions Increased incidence of disseminated disease Increased incidence of medication toxicity Increased risk of relapse, treatment failure Increased risk of acquired drug resistance Not to mention the contact investigation and infection control issues Global TB/HIV Epidemiology 2005 Estimated #new TB cases: 8.8 million Estimated # deaths 1.6 million HIV intected TB deaths Estimated # TB infections 2 billion 22

23 TB Resurgence, 1990 s vss L: Percent of TB patients who are HIV positive U.S. 2006: 12.4% U.S. 2005: 13.0% S. Africa 2005: 38% 23

24 TB Risk in HIV Infected Persons without antiretroviral therapy Approaches 40% after recent exposure to active case of M Tb Daley NEJM 1992; 326:231-5 Approximately 10% annual risk if latent TB infection Selwyn NEJM 1989; Early HIV Dx HIV care Recording & reporting 24

25 TB Risk in HIV-Infected Persons in HAART Era TB rate per 100,000 No ART HAART U.S ( 80%) S. Africa ( 81%) Jones. Int J Tuberc Lung Dis 2000; 4:1026 Badri. Lancet 2002; 359: 2059 CLINICAL MANIFESTATIONS OF TB IN HIV PATIENTS Difficulty of sorting out symptoms Fevers, weight loss, fatigue, dry cough None Altered TB presentations Presentation depends on immune system Increased incidence of extrapulmonary TB Skin test unreliable Often negative with lower CD4 counts 5mm or > considered positive in all HIV+ 25

26 Radiographic Appearance in HIV Positive TB by CD4 Count CD4 < 200 CD4 > 200 Normal 10/48 (21%) Normal 1/20 (5%) Lower lobe infiltrates Adenopathy Pleural effusion Postprimary 11/48 (23%) Postprimary 11/20 (55%) Upper lobe infiltrates Cavities Greenberg. Radiol diology y 1994;1 94;193:11593:115 Smear negative TB in HIV+ Risk is increased in HIV+ persons Proportion of TB in HIV + persons that is smearnegative pulmonary: 24-61% Risk of death increased Compared to HIV- smear- Compared to HIV+ smear+ TB delay in diagnosis Getahun H. Lancet 2007;369:

27 Treatment of HIV TB PRESENCE OF ACTIVE TUBERCULOSIS REQUIRES IMMEDIATE INITIATION OF TREATMENT Treatment should follow same principles for persons without HIV DOT is strongly recommended Rifamycins are essential drugs for the treatment of TB despite drug-drug interactions rifamycins should be included in the tuberculosis treatment regimen.» Guidelines for use of Antiretroviral Agents in HIV Infected Adults and Adolescents Oct 16, 2006 Acquired Rifamycin Resistance USPHS 23 INH + rifabutin twice weekly in continuation phase 169 patients enrolled 3 treatment failures + 6 relapses; 9/169 (5.3%) 8/9 (89%) acquired rifamycin resistance Risk factors for ARR: Twice weekly RX during first 2 months Low CD4 CD4 < 100: 9/73 (12%) CD4 > 100: 0/65 (0%)» Burman. Am J Respir Crit Care Med

28 Treatment of TB in HIV Infected Standard 6 month regimens should be used 6 months minimum duration even in culture negative tuberculosis MMWR Treatment of Tuberculosis, 2003» CDC, ATS, IDSA endorsed guidelines Highly intermittent (<3 x /wk) therapy should not be used when CD4 < 100 Daily therapy preferred during initiation Three times/week Rx an alternative MMWR March 15, 2002 & June 2003 Recommendations for Treatment of TB in HIV-Infected Patients TB/HIV patients with CD4 <100 should not receive once or twice weekly therapy Daily therapy during induction Daily or thrice-weekly therapy during continuation MMWR 2002,51:

29 Treatment of Culture-Positive Drug Susceptible Pulmonary TB General conclusions from the literature: Intermittent regimens (2-3x/wk): GIVEN by DOT ONLY Drug susceptible isolate Regimen contains INH and rifampin Highly intermittent (< 3 times/week) should not be used in HIV infected persons with CD4 < 100 Treatment of TB HIV HAART decreases mortality Prospective observation in Thailand patients registered for TB treatment 329 (14%) were HIV positive Death during TB treatment in HIV+ patients 4 of 71 on HAART died (7%) 94 of 219 without HAART died (43) HAART reduces death during TB treatment of HIV infected patients Emerging Infectious Diseases Vol. 13, No.7, July 2007 Emerging Infectious Diseases 2007; 13:

30 Immune Reconstitution Syndrome: Initial clinical improvement of TB patients on TX, then deterioration after HAART Hectic fevers. Lymphadenopathy (sometimes severe). Worsening of chest radiographic Worsening of other initial TB lesions. Exclude treatment failure or new OI. Paradoxical Worsening of TB Immune Reconstitution First described in treatment of TB in HIV CNS, lymphatic disease Risk appears to be greater in HIV + who initiate antiretroviral therapy Especially when HAART initiated within 2 months of TB therapy Risk 10-40% reported Usually self limited Deaths have occurred 30

31 Risk Factors for Immune Reconstitution Syndrome Risk greatest in those with low CD4 counts in those with HAART started early (< 2 mo) In those with disseminated disease, especially abdominal disease Increase in CD4% on HAART HIV-1 RNA decline on HAART Antiretroviral therapy-naive Timing of HAART Therapy in TB-HIV Considerations include: High mortality rate in HIV TB without HAART Beneficial effect of HAART on TB-HIV HAART increases CD4 and decreases risk of relapse Large pill burden for TB and HIV regimens Drug-drug interactions and toxicity Paradoxical worsening 31

32 Timing of HAART in Patients with Newly Diagnosed TB and HIV Risk of death or an AIDS event in first 2 mo of TB treatment was exceptionally high in patients with CD4 < /35 (31%) 25% of patients with CD4 < 100 had a paradoxical reaction severe enough to warrant steroid therapy Dheda. JID.2004;190:1670 Timing of HAART in Newly Diagnosed TB Patient Delay in initiation of antiretroviral therapy of 4 8 weeks Permits better definition of causes of adverse drug reactions Permits better definition of paradoxical reactions, Decrease in incidence and severity? Optimum timing to delay not known Consider earlier therapy if CD4 < 50 IRIS reactions should be treated with continuation of treatment for TB and HIV, along with non-steroidal antiinflammatory agents In severe cases of paradoxical reaction, some suggest use of high dose prednisone» Guidelines for use of Antiretroviral Agents in HIV Infected Adults and Adolescents Oct 16,

33 HAART and unmasking TB TB most common opportunistic infection seen in HIV patients during initiation of HAART Multiple potential etiologies 1. Progression of early subclinical active TB 2. New symptoms secondary to Immune Reconstitution Syndrome (IRIS) 3. Development of active TB prior to immune recovery from HAART Lawn Am J Respir Crit Care 2008 HAART and unmasking TB HAART Effects on TB 1. Shortening time of subclinical TB to become symptomatic unmasking 2. Increased rapidity of initial TB symptoms leading to diagnosis 3. Increased intensity of initial TB symptoms leading to diagnosis Lawn Am J Respir Crit Care

34 Rifamycins and TB Treatment Rifampin is the KEY DRUG for all short course (Ù 6 month) regimens. Rifampin is THE most potent inducer of hepatic microsomal enzymes known. Rifamycin Drug Interactions HAART (Protease inhibitors and efavirenz) Medications for other co morbidities Itraconazole, Fluconazole Clarithromycin Methadone Coumadin Immunosuppressive therapy for transplants Oral contraceptives Prednisone 34

35 Rifamycins: Drug-Drug Interactions Rifamycins are cytochrome P450 enzyme inducers/upregulators End result is decreased concentrations of other drugs that are metabolized by CYP450 Rifamycin CYP450 induction potency Rifampin>>Rifapentine>Rifabutin Rifampin drug interactions Rifampin markedly DECREASES serum concentration of Protease inhibitors leading to HIV treatment failures. 35

36 Rifabutin and protease inhibitors Rifabutin Similar efficacy to Rifampin in TB therapy Less effect on CYP450 system Preferred to Rifampin in treating HIV/TB co-infected patients Rifabutin and Protease Inhibitors (PIs) Rifabutin does not affect serum concentration of PIs PIs (especially ritonavir-boosted regimens) increase rifabutin levels Æ rifabutin toxicity (uveitis, eye pain, elevated LFTs, neutropenia) Rifabutin and Protease Inhibitors Rifabutin and PIs DECREASE dose of rifabutin when used with PIs DECREASE rifabutin dose will be subtherapeutic if patient stops PIs Low rifabutin level leads to treatment failure/drug resistant Must assess compliance with PIs during treatment Give PI with TB meds during DOT 36

37 HIV TB with HAART: Rifamycin 3 doses used for rifabutin: 150 mg daily if used with non-boosted PI 150 mg every other day if used with a boosted PI mg daily (or 2-3 x/week) if used with EFV Rifampin mg daily with efavirenz (consider 800mg efavirenz) 600 mg daily with nevirapine (last option, hepatotoxicity) Global Plan TB/HIV Goals and Realities, Goal Reality TB patients tested for HIV TB/HIV patients on ART in Africa 600K 200K 125K 15K HIV AIDS cause of 195,000 of the 1.6 million TB deaths in

38 A Perfect Storm? HIV TB AFRICA TB: A HEALTH EMERGENCY IN AFRICA TB ANYWHERE IS TB EVERYWHERE 38

39 Extensively Drug Resistant (XDR) TB Recent Outbreak in Kwazulu Natal, SA 1500 patients evaluated 544 (35%) with TB 995 (65%) without TB 221(41%) MDRTB 323 (59%) Susceptible * Moll A et al, (10%) XDR TB All HIV+ died Time to death=16 d Extensively Drug Resistant (XDR) TB A Tale of Two Definitions XDR 1 = MDR TB + resistance to > 3/6 of major classes of 2 nd -line drugs Need > four 2 nd -line drugs for Rx XDR 2 = MDR TB + resistance to Fq & any injectable 2 nd -line (amikacin, kanamycin, capreomycin) Need Fq + injectable for better outcomes Latvia - 58% vs. 35% cure 39

40 Possible Ways HIV Impacts MDR TB / XDR TB Increasing HIV-associated TB burden overwhelmed public health systems Poor IC and nosocomial transmission Malabsorption of anti-tb drugs Acquired rifamycin resistance Advanced immunosuppression Drug/drug interactions 2 nd -line drug use for concomitant illnesses Response to MDR-TB and HIV in South Africa Improve Diagnosis Increased surveillance for drug resistant TB Increased Drug susceptibility testing Enhance screening for TB among HIV+ pts Infection Control Stop naturally ventilated hospitals (negative pressure rooms) Build negative pressure rooms Single infectious patient can infect 1/3 hospital pts. 24h Providing N95 particulate respirators to HCW HIV testing for healthcare workers to reduce risk or TB transmission Andrews JID 2007; 196:S482-S490 40

41 Response to MDR-TB and HIV in South Africa Improve Treatment Universal access to HAART Improve access to second line medications Improve co-treatment of HIV and TB Increasing expertise for MDR-TB and XDR-TB treatment Andrews JID 2007; 196:S482-S490 Conclusions HIV responsible for global TB resurgence Drug-resistant TB risk increases in AIDS Must improve diagnosis of TB in HIV+ pts HAART improves survival in HIV/TB pts Every TB patient needs HIV test Every HIV/TB co-infected patient needs a CD4 count HIV + patients with CD4 count <100 should not receive TB meds twice a week 41

42 References Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS Panel on Antiretroviral guidelines for adults and adolescents. December 1, 2007 MKSAP 14 Medical Knowledge Selfassessment program, Infectious Disease, pp