Sasisopin Kiertiburanakul, MD, MHS

Transcription

1 What s Newin Antiretroviral Therapy? Sasisopin Kiertiburanakul, MD, MHS Division of Infectious Diseases Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University Rotating RCPT, Uttaradit (July 8, 2010)

2 Outline Patient evaluation and assessment When to start What to start How to monitor

3 Patient t Evaluation and Assessment

4 History Taking Estimate the duration of HIV infection Timing of HIV seroconversion? or When was the first HIV serodiagnosis? i Risk factor Past HIV-related illness Herpes zoster Constitutional symptoms Fever, weight loss, diarrhea OI: TB, PCP, cryptococcosis, CMV

5 History Taking Prior antiretroviral therapy Response to each regimen (CD4, viral load), toxicities, adherence, and prior resistance test results ARV during gpregnant Other diseases Hepatitis, malignancy, DM, HT, CVD,. Other medications, vaccinations Social, sexual, and family histories Tobacco, alcohol, heroin, Sex partners, sex practices

6 Physical Examination General: fever, appearance Oral cavity HEENT: retinitis, lymphadenopathy Lung: dyspnea, adventitious sound(s) Abdomen: mass, organomegaly Skin: PPE, seborrheic dermatitis, papulonecrotic lesions, mollusgum-likelike lesion, psoriasis, zoster scar Anogenital examination

7 Baseline Evaluation HIV disease characterization CD4 cell count HIV RNA (virus load) Hematology CBC Women Pregnancy test Pelvic examination Serum chemistry LFT BUN/Cr FBS Lipid profiles Serological tests Syphilis (VDRL/RPR) Hepatitis B and C Others CXR, UA

8 When to Start?

9 Thai Guideline 2008 Clinical Presentations CD4 Count Recommendation (cells/mm 3 ) AIDS-defining illness Any Treat Symptoms* Any Treat Asymptomatic <200 Treat Asymptomatic Defer treatment, follow up CD4 every 3 months Asymptomatic >350 Defer treatment, follow up CD4 every 6 months *unexplained fever or diarrhea > 2-4 wks, >10% unexplained weight loss, oral candidiasis, or PPE Sungkanuparph S et al. J Med Assoc Thai 2008;91:

10 WHO Guideline 2009: Key Messages The best time to start ART is before patients become unwell or develop their first opportunistic infection Promote earlier treatment, when CD4 count <350 cells/mm 3, regardless of symptoms ~ 1-2 years additional exposure to ART Adhering to treatment t t vs. prolonged and healthier life Rates of death, morbidity and HIV and TB transmission are all reduced

11 Thai Guideline 2010 Clinical Presentations CD4 Count (cells/mm 3 ) Recommendation AIDS-defining illness Any Treat HIV-related symptoms* Any Treat Asymptomatic <350 Treat Asymptomatic >350 Deferred treatment, follow up CD4 every er 6 months Pregnancy Any Discontinued after delivery, if CD4 >350 **oral candidiasis, PPE, unexplained fever or diarrhea >2 weeks, >10% unexplained weight loss in 3 months, or herpes zoster involved >2 dermatomes Sungkanuparph S et al. Asian Biomed (in press)

12 AIDS-defining Illness Esophageal candidiasis Lymphoma Tuberculosis Kaposi s sarcoma Cervical cancer Non-tuberculosis mycobacteria, disseminated/extrapulmonary Progressive multifocal leukoencephalopathy Pneumocystis carinii pneumonia HIV wasting syndrome Cryptococcosis, extrapulmonary HIV encephalopathy (AIDS Histoplasmosis, disseminated or dementia complex) extrapulmonary Penicilliosis illi i Toxoplasmosis Cytomegalovirus Recurrent pneumonia, recurrent Salmonella septicemia

13 DHHS Guideline 2009 Clinical Conditions CD4 Count Recommendation (cells/mm 3 ) History of AIDS-defining illness Any Treat Asymptomatic <350 Treat Pregnant women* Any Treat HIV-associated nephropathy Any Treat HBV co-infection when HBV treatment indicated Asymptomatic without specific conditions above Asymptomatic without specific conditions above Any Treat % voted for strong recommendation (A) >500 50% voted favor starting ART (B) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Department of Health and Human Services. December 1,

14 Earlier Initiation of HIV Treatment Benefit Reduction in mortality and/or AIDS-related morbidity Reduction in HIV-related morbidity Nephropathy Hepatitis co-infection Cardiovascular disease Malignancies Neurocognitive decline Age and treatment-related immune reconstitution T-cell activation and inflammation Prevention of HIV transmission Limitations Drug toxicity Quality of life Drug resistance Nonadherence to therapy Cost Infrastructures t CD4 <200 CD4 <350

15 Other Factors Patients willingness and readiness Adherence potential Family planning status Co-morbidity or conditions: OI, liver disease, depression or mental illness, cardiovascular disease, chemical dependency, pregnancy Potential drug interactions with other medications

16 What to Start?

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18 Antiretroviral Agents 2010 NRTI NNRTI PI abacavir (ABC) delavirdine (DLV) atazanavir (ATV) didanosine (ddi) efavirenz (EFV) darunavir (DRV) emtricitabine (FTC) etravirine (ETV) fosamprenavir (FPV) lamivudine (3TC) nevirapine i (NVP) indinavir i (IDV) stavudine (d4t) Entry Inhibitor lopinavir/r (LPV/r) tenofovir (TDF) enfuvirtide (T20) nelfinavir (NFV) zidovudine (AZT) CCR5 Antagonists ritonavir (RTV) Integrase Inhibitors maraviroc (MVC) saquinavir (SQV) raltegravir (RAL) tipranavir (TPV)

19 Antiretroviral Regimens 2 NRTIs + NNRTIs NNRTI-based regimens 2 NRTIs PIs PI-based regimens 2 NRTIs + INST Integrase-based regimens

20 ARV Combinations: Basic Regimens 2 NRTI + NNRTI/Boosted PIs Thymidine Analog + Non-Thymidine Analog + NNRTI or Boosted PIs AZT d4t ddi ABC TDF 3TC FTC EFV or NVP ATV+r DRV/r LPV/r SQV/r

21 Thai HIV Guidelines 2010 Recommendation NRTI NNRTI PI Preferred AZT + 3TC EFV or LPV/r TDF + 3TC TDF/FTC NVP Alternative ABC + 3TC d4t + 3TC ddi + 3TC - ATV/r SQV/r DRV/r Sungkanuparph S et al. Asian Biomed (in press)

22 WHO Guideline 2009: Key Messages Greater use of more patient-friendly treatment regimens Progressively phase out use of d4t as a preferred first-line therapy option Avoid disabling and disfiguring side effects and reduce costs of managing g these toxicities Move to less toxic alternatives such as AZT and TDF NNRTI: EFV or NVP

23 DHHS Guideline 2009 Recommendation NRTI NNRTI PI Preferred TDF/FTC EFV ATV/r DRV/r (pregnant women) AZT/3TC LPV/r Alternative (ABC or AZT) + 3TC EFV ATV/r LPV/r AZT + 3TC NVP TDF/FTC Acceptable ddi + (3TC or FTC) EFV (ABC or AZT) + 3TC Use with caution ABC + 3TC or TDF/FTC NVP SQV/r LPV/r ATV Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Department of Health and Human Services. December 1,

24 Combined Pill by GPO Zilarvir AZT 300 mg, 3TC 150 mg Lastavir d4t 30 mg, 3TC 150 mg GPO-VIR S30 d4t 30 mg, 3TC 150 mg, NVP 200 mg GPO-VIR Z250 AZT 250 mg, 3TC 150 mg, NVP 200 mg

25 Factors to Consider Regimen for Thais Health insurance system Inexpensive Access to HIV care Co-morbidity Concurrent OI and its treatment ART during pregnancy Efficacy

26 What Not to Use Monotherapy with NRTI Dual-NRTI regimens Triple-NRTI regimens (with exception) d4t + ddi d4t + AZT TDF + ddi ATV + IDV EFV in first trimester of pregnancy NVP in women with CD4 >250 or men with CD4 >400 cells/mm 3

27 Common Adverse Effects: NRTIs Zidovudine: headache, GI intolerance, bone marrow suppression Tenofovir: headache, h GI intolerance, renal impairment, Fanconi syndrome Stavudine: peripheral neuropathy (PN), pancreatitis Didanosine: PN, GI intolerance, pancreatitis Abacavir: hypersensitivity reaction

28 Common Adverse Effects: NNRTIs Nevirapine: hepatotoxicity, rash including Stevens-Johnson syndrome Efavirenz: neuropsychiatric, i teratogenic, t false positive cannabinoid test

29 40 Years Old Businessman Fever, weight loss, and Rt. axilla mass 4 weeks Normal CXR CD4 23 cells/mm3 Pus AFB positive Start HRZE

30 Q3: 4 weeks Later, What Next? A. Wait for another 4 weeks, then start ART B. Wait until complete TB treatment t t C. Start ART with NVP-based regimen D. Start ART with EFV-based regimen E. Start ART with PI-based regimen

31 Treatment of TB/HIV Co-infection CD4 cell count Recommendation Comments (cells/mm 3 ) <200 Start TB treatment. Start ART Recommended ART as soon as TB treatment is tolerated (after 2 weeks) Start TB treatment. Start one of the ART regimen after intensive phase of TB treatment (if severely compromised start earlier) Recommended ART >350 Start TB treatment Defer ART

32 ART Regimen in Patients with TB EFV containing regimens EFV is contra-indicated in pregnant women or women of child bearing potential without effective contraception Dosage of fefvi is 600 mg/day for weight <60 kg and 800 mg/day for weight >60 kg 1 NVP is an alternative to EFV for patient who has taken rifampicin Lead-in NVP for the first 14 days is not necessary 1. Sungkanuparph S et al. J Med Assoc Thai 2008;91:

33 Patients with active TB has newly diagnosed HIV infection Rifampicin-containing containing drug regimen ART is not indicated now ART is indicated Start t ART at least 2 weeks-2 months after TB treatment ART with EFV-based regimen (alternative NVP-based regimen) Alternatively use non refampcin-based drug regimen Re-evaluated after complete TB treatment Any standard ART regimens

34 HIV/TB Co-infection HIV-infected Patients New active TB established Continuation of ART NNRTI-based regimen (EFV or NVP) PI-based regimen Rifampicin-containing drug regimen Alternatively use non rifampicin-containing drug regimen

35 IRIS: Definition Immune recovery inflammatory syndrome Collection of inflammatory disorders associated with paradoxical worsening of pre-existing existing infectious processes following the initiation of HAART in HIV-infected individuals Systemic or local inflammatory reactions may occur at the site or sites of preexisting infection Preexisting infections Previously diagnosed d and treated Subclinical and later unmasked by the host's regained capacity to mount an inflammatory response

36 Timing of ART in the Setting of OI Early ART in hopes of Deferring ART in order to reducing the risk of AIDS- decrease the risk of IRIS related morbidity and Poor absorption of mortality therapeutic drugs during Earlier immunologic acute or advanced HIVrelated infection recovery Faster resolution of OI Additive toxicities of multiple therapeutic agents Drug interactions Problem of differentiating IRIS from other simultaneously present illnesses or infections

37 When to Start HAART after OI? No consensus When??? Absent any contraindications, early HAART initiation should be strongly considered in the AIDS patient with OI Cryptosporidiosis, microsporidiosis, PML, and Kaposi sarcoma HAART should be started t as soon as possible TB, MAC, PCP, and cryptococcal meningitis Waiting a response to OI therapy Improve signs and symptoms of the diseases

38 When to Start HAART after OI? TB 4-8 weeks after starting anti-tb PCP After completion of anti-pcp (21 days) Cryptococcal meningitis 8-10 wks after treatment Toxoplasmosis After completion treatment (6 weeks) MAC 4-8 weeks after treatment and negative blood culture

39 Treatment Goal of HAART Reduce HIV-related morbidity and prolong survival Improve quality of life Restore and preserve immunologic function Maximally and durably suppress viral load Prevention vertical HIV transmission

40 Goal of Therapy Viral load Relativ ve Leve els <50copies/mL at 6 month CD4 Limit of Detection Months Years After HIV Infection Acute HIV infection

41 Monitoring Clinical monitoring Adherence assurance/counseling Immunological monitoring Virological i l monitoring i Drug resistant testing Therapeutic drug monitoring

42 Monitoring: Thai Guideline 2010 Laboratory During the first year After the first year Note investigations CBC, CD4 6, 12 month Every 6 month Viral load First regimen: Every 12 month Before changing the regimen 6, 12 month (every 6 month, if possible) ART changing after failure: 6, 12 month Every 12 month FBS 6, 12 month Every 6 month ALT 6, 12 month Every 6 month At 3 month if starting NNRTIs Cr* 6, 12 month Every 6 month Every 6 month, if use TDF or IDV Lipid profile (TC, TG, LDL, HDL) 6, 12 month Every 6 month Urinalysis - - Every 6 month, if use TDF or IDV CXR - - Repeat, if indicated Pap smear 12 month Every 12 month Repeat, if indicated Sungkanuparph S et al. Asian Biomed (in press)

43 Laboratory Monitoring Schedule: DHHS CD4 cell count HIV RNA Resistance testing Hepatitis B serology Basic chemistry Liver function test CBC Lipid profile Fasting glucose Urinary analysis Pregnancy test Entry to care Follow up before ART every 3-6 months every 3-6 months every 6-12 months every 6-12 months every 3-6 months if normal, annually if normal, annually ART initiation or switch optional if not immune and HBsAg neg if starting ti EFV Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Department of Health and Human Services. December 1,

44 Conclusions Appropriate patient assessment Early treatment initiation is associated with more benefits than risk Asymptomatic with CD4 <350 cells/mm 3 Use less toxic drugs Appropriate timing i of ART initiation iti in patients with OI Appropriate monitoring Patients should be identified early