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Special Issues Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents published October 2006 AETC NRC Slide Set About this Presentation These slides were developed using the October 2006 Treatment Guidelines and the April 2007 Supplement to the Guidelines. The intended audience is clinicians involved in the care of patients with HIV. The user is cautioned that due to the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC NRC http://www.aidsetc.org 10/06 Special Issues: Contents Acute HIV infection Treatment for Adolescents Treatment for Pregnant Women Injection Drug Users Patients with Hepatitis B or C Co-Infection Mycobacterium Tuberculosis Prevention Counseling 10/06 Acute Retroviral Syndrome: Signs and Symptoms - I Fever Lymphadenopathy Pharyngitis Rash Myalgia or arthralgia Diarrhea 96% 74% 70% 70% 54% 32% 10/06 Acute Retroviral Syndrome: Signs and Symptoms - II Headache Nausea and Vomiting Hepatosplenomegaly Weight Loss Thrush Neurological Symptoms 32% 27% 14% 13% 12% 12% 10/06 Acute Retroviral Syndrome: Rash Erythematous maculopapular with lesions on the face and trunk and sometimes extremities (including palms and soles) Mucocutaneous ulceration involving mouth, esophagus, or genitals (distinguishes HIV from mononucleosis (EBV) 10/06 Acute Retroviral Syndrome: Neurological Symptoms Meningoencephalitis or aseptic meningitis (uncommon) Peripheral neuropathy or radiculopathy Facial palsy Guillain-Barré syndrome Brachial neuritis Cognitive impairment or psychosis 10/06 Acute HIV Infection: Laboratory Testing Detectable HIV RNA with negative or indeterminate HIV antibody test Low-positive HIV RNA (<10,000 copies/mL) may be false positive If diagnosis is made by HIV RNA testing, confirmatory serologic testing should be performed subsequently 10/06 Acute HIV Infection: Treatment Limited outcome data from clinical trials; therapy based largely on theoretic considerations 10/06 Acute HIV Infection: Treatment Possible benefits: Possible risks: Decrease the severity of acute disease Alter the viral “set point” Reduce the rate of mutation Preserve immune function Reduce risk of viral transmission Drug-related toxicity Earlier emergence of drug resistance Limitation of future treatment options Potential need for indefinite treatment Adverse effects on quality of life 10/06 Primary Treatment Regimen Same as for chronic infection 10/06 The HIV Infected Adolescent Timing of infection; perinatal vs. acquired during adolescence Early intervention 10/06 The HIV Infected Adolescent Drug pharmacology in puberty Dosing based on Tanner stages Use adult dosing schedules for those in late puberty For females, address gynecologic care, contraception (including interactions with ARV); avoid efavirenz Adherence concerns 10/06 The HIV Infected Adolescent Challenges to adherence: Denial and fear of HIV infection; misinformation Distrust of the medical establishment; Fear and lack of belief in the effectiveness of medications Low self-esteem Unstructured and chaotic lifestyles Lack of familial and social support 10/06 Treatment for Pregnant Women* To reduce risk of perinatal transmission: Antiretroviral (ARV) therapy recommended in all pregnant women Reduction of HIV viral load to <1000 copies/mL * See also the US Public Health Services Task Force “Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States.” 10/06 Treatment for Pregnant Women In women not already on ARVs, consider delaying treatment until 10-12 weeks gestation In women already on ARVs, consider continuing therapy, though effects of ARVs on fetus in first trimester are uncertain Perform resistance testing before starting ARV therapy or prophylaxis, and in women on ARV therapy with detectable HIV RNA 10/06 Treatment for Pregnant Women Regimen considerations: Potential pharmacokinetic changes caused by pregnancy, different dosing requirements Potential adverse effects of antiretroviral drugs on pregnant women Effect on the risk for perinatal HIV transmission Potential short- and long-term ARV effects on the fetus and newborn 10/06 Treatment for Pregnant Women Include zidovudine, if possible, in ARV regimen Recommend 3-part zidovudine prophylaxis regimen to reduce perinatal transmission for all pregnant women with HIV infection, regardless of viral load 10/06 Safety and Toxicity of ART in Pregnant Women: NRTIs Clinical trial data in human pregnancy available for AZT, lamivudine, didanosine, stavudine Mitochondrial toxicity possible with all NRTIs Increased risk of lactic acidosis/hepatic steatosis with didanosine + stavudine* * This combination should be used only if no other alternatives are available. 10/06 Antiretroviral Drug Use in Pregnant Women: NRTIs Recommended Zidovudine agents Lamivudine Efficacy studies and extensive experience Should be included in the regimen unless significant toxicity or other contraindication Zidovudine + lamivudine is the recommended dual NRTI backbone 10/06 Antiretroviral Drug Use in Pregnant Women: NRTIs Alternate agents Didanosine Emtricitabine Stavudine Abacavir Cases of lactic acidosis with didanosine + stavudine; use only if no other alternatives Insufficient data to recommend Tenofovir No studies in human pregnancy; bone toxicity in monkey studies and some pediatric studies Not recommended Zalcitabine Teratogenic in animals 10/06 Safety and Toxicity of ART in Pregnant Women: NNRTIs Clinical trial and pharmacokinetic (PK) data in human pregnancy available only for nevirapine 10/06 Antiretroviral Drug Use in Pregnant Women: NNRTIs Recommended agent Nevirapine No evidence of teratogenicity Increased risk of liver toxicity in women who start nevirapine with CD4>250; in these women, use nevirapine-based regimens only if benefit outweighs risk Not recommended Efavirenz FDA pregnancy category D Teratogenic in monkeys Avoid in first trimester; consider after second trimester only if no other alternatives Delavirdine Teratogenic in rodent studies 10/06 Safety and Toxicity of ART in Pregnant Women: PIs PK and clinical trial data available for nelfinavir, saquinavir (soft gel capsules)/ritonavir Limited data for indinavir, ritonavir, saquinavir hard gel capsules, and lopinavir/ritonavir (capsules) PK and clinical studies on indinavir/ritonavir and lopinavir/ritonavir are underway Other PIs not yet studied Concern for increased risk of hyperglycemia: monitor closely Conflicting data re: preterm delivery in women receiving PIs 10/06 ART in Pregnant Women: PIs Recommended Lopinavir/ agents ritonavir Nelfinavir Dosing recommendations not established; may require increased dose during pregnancy No PK data on tablet formulation Limited clinical experience; study underway PK data and extensive clinical experience in pregnancy Preferred PI for use in pregnant women 10/06 Antiretroviral Drug Use in Pregnant Women: PIs Alternate Indinavir agents Lower drug levels during pregnancy Must boost with ritonavir, but optimal dosing in pregnancy is unknown Concern for possible hyperbilirubinemia in the neonate Ritonavir Lower drug levels in pregnancy May use at low dose as booster for other PIs Saquinavir (hard gel capsule)/ ritonavir Must boost with ritonavir PK studies and moderate experience with soft gel capsules; limited data on hard gel capsule No PK data on tablet formulation 10/06 ART in Pregnant Women: PIs Insufficient data to recommend Amprenavir No studies in human pregnancy Oral solution contraindicated (contains propylene glycol) Atazanavir No studies in human pregnancy Concern for possible hyperbilirubinemia in the neonate Darunavir No studies in human pregnancy Fosamprenavir No studies in human pregnancy Tipranavir No studies in human pregnancy 10/06 Antiretroviral Drug Use in Pregnant Women: Fusion Inhibitors Insufficient data to recommend Enfuvirtide No studies in human pregnancy 10/06 Injection Drug Users Transmission via injection drug use is second most common transmission route in the U.S. Injection drug users (IDU) Often have multiple comorbidities, Increased morbidity and mortality, Decreased access to HIV care Are less likely to receive ARV 10/06 Injection Drug Users Efficacy of HIV treatment In IDU who are not actively using, efficacy similar to other populations Active drug use may interfere with adherence and ARV success In some patients, substance abuse treatment may be required for ARV success Many other support mechanisms may be effective 10/06 Injection Drug Users Drug toxicities and interactions IDU may have more ARV-related adverse effects Methadone may interact significantly with ARV NRTI: no significant effects on methadone levels; AZT levels increased NNRTI: EFV and NVP decrease methadone levels PI: APV, NFV, LPV decrease methadone levels; methadone decreases APV levels Buprenorphine: limited data on interactions with ARVs 10/06 HBV/HIV Co-Infection: ARV considerations Unclear if HBV treatment improves the course of HIV infection Unclear if HIV treatment alters the course of HBV In HBV/HIV patients, liver toxicity from ARVs and flares of HBV may complicate HIV treatment 10/06 HBV/HIV Co-Infection: ARV considerations Emtricitabine, lamivudine, and tenofovir have activity against both HIV and HBV Discontinuation may cause HBV flares Case reports suggest entecavir may have activity against HIV as well as HBV HBV resistance to lamivudine monotherapy 40% at 2 years 90% at 4 years 10/06 HBV/HIV Co-Infection: ARV considerations Immune reconstitution may result in LFT deterioration Patients with immune reconstitution may have loss of e antigen (HBeAg), associated with HBV flare All PIs and NNRTIs may increase transaminase levels; ARV toxicity may be difficult to distinguish from HBV flare (and possible precursor to HBeAg seroconversion) 10/06 HBV/HIV Co-Infection: Treatment Recommendations For all HBV/HIV co-infected patients: Counsel avoidance of alcohol Vaccinate against hepatitis A (if not immune) Advise on methods to prevent HBV transmission Evaluated extent of HBV infection 10/06 HBV/HIV Co-Infection: Treatment Scenarios Need to treat HIV, not HBV: Consider the combination of tenofovir + emtricitabine or lamivudine as NRTI backbone of ART Avoid using these as single drugs with antiHBV activity, to avoid HBV resistance 10/06 HBV/HIV Co-Infection: Treatment Scenarios Need to treat both HIV and HBV: Tenofovir + emtricitabine or tenofovir + lamivudine are first-choice NRTI backbones Consider entecavir for HBV treatment, with or without one of these NRTIs Avoid using the NRTIs as single drugs with anti-HBV activity, to avoid HBV resistance 10/06 HBV/HIV Co-Infection: Treatment Scenarios Need to treat HBV, not HIV (1): To avoid drug resistance to HIV, consider Pegylated interferon-alpha (no anti-HIV activity) Adefovir (no anti-HIV activity at doses used for HBV treatment; theoretic risk for development of HIV resistance) Avoid emtricitabine, lamivudine, and tenofovir except as components of fully-suppressive ART, unless preexisting HIV resistance 10/06 HBV/HIV Co-Infection: Treatment Scenarios Need to treat HBV, not HIV (2): Entecavir no longer recommended in patients not on suppressive ART Case reports suggest entecavir may be active against HIV; the risk of developing HIV resistance cannot be excluded 10/06 HBV/HIV Co-Infection: Treatment Scenarios Need to discontinue emtricitabine, lamivudine, or tenofovir: Flares of HBV possible; monitor closely Consider adefovir or entecavir* to prevent flares, especially if hepatic reserve is marginal * Do not use without concomitant suppressive ART 10/06 HCV/HIV Co-Infection Higher rates of progressive liver disease in HIV/ Hepatitis C (HCV co-infection Unclear if HCV increases HIV progression Poor prognosis; unclear if HIV treatment improves morbidity and mortality for untreated HCV Higher rates of ARV-associated hepatotoxicity 10/06 HCV/HIV Co-Infection Treatment indicated: Detectable plasma HCV RNA and bridging or portal fibrosis on liver biopsy Consider other factors such as: stage and stability of HIV disease other co-morbidities probability of adherence possible contraindications to HCV medications 10/06 HCV/HIV Co-Infection: Treatment Pegylated interferon + ribavirin for 48 weeks Low rates of sustained virologic response in genotype 1 Limited data on patients with CD4 <200 cells/mm³ 10/06 HCV/HIV Co-Infection: Treatment Potential for drug-drug interactions and additional toxicity in HIV/HCV: Avoid use of DDI with ribavirin (neuropathy, pancreatitis, lactic acidosis) Avoid use of AZT with ribavirin, if possible (anemia) Monitor closely for hepatotoxicity due to ARV Monitor closely for neutropenia (due to interferon) and anemia (due to ribavirin); hematopoetic growth factors 10/06 TB/HIV Co-Infection Increased risk of progression from latent to active TB Increased risk of HIV progression 10/06 TB/HIV Co-Infection: Treatment Considerations The treatment of TB in patients with HIV infection should follow the same principles for persons without HIV infection For active TB, initiate treatment immediately Directly observed therapy is strongly recommended 10/06 TB/HIV Co-Infection: Treatment Considerations In patients on ARV therapy, evaluate ARV regimen for interactions with TB drugs In ARV-naive patients, avoid simultaneous initiation of treatment for TB and HIV consider delay of ARVs for 4-8 weeks after initiation of TB treatment to avoid overlapping of adverse reactions and paradoxical reactions 10/06 TB/HIV Co-Infection: Treatment Considerations Rifampin/rifabutin-based regimens should be given at least three times weekly in patients with CD4+ T cell count <100 cells/mm3 Once weekly rifapentine is not recommended in HIV-infected patients 10/06 TB/HIV Co-Infection: Treatment Considerations Rifamycin should be included in TB regimens Potential drug-drug interactions with PIs and NNRTIs Rifampin may be used only with efavirenz or full-dose ritonavir Rifampin may not be used with ritonavir-boosted PIs Rifabutin recommended with nevirapine, other PIs Dosage adjustment may be necessary 10/06 TB/HIV Co-Infection: Treatment Considerations Paradoxical reactions more common with immune reconstitution due to ARV Continue treatment for tuberculosis and HIV, use non-steroidal anti-inflammatory agents In severe cases consider use of highdose prednisone 10/06 Prevention Counseling in the Patient with HIV Infection Recent increases in HIV seroprevalence in some populations, especially MSM Associated increase in sexually transmitted infections (STI) and unsafe sex practices 10/06 Prevention Counseling in the Patient with HIV Infection An essential component of HIV patient care: Reinforce prevention messages at each encounter Assess patient’s understanding of HIV transmission Assess patient’s HIV transmission behaviors Discuss strategies to prevent transmission (individualize) 10/06 Prevention Counseling in the Patient with HIV Infection Sexual transmission Decreased with low plasma VL (though inconsistent relationship between plasma and genital fluid VL) Increased with: concurrent STI, genital irritation (incl. nonoxynol-9), menstruation, OCP use, non-circumcision in men 10/06 Prevention Counseling in the Patient with HIV Infection Emphasize: Importance of barrier protections, “safer” sex practices, ARV adherence For women: pregnancy prevention counseling in those who wish to avoid pregnancy preconception counseling in those who wish to become pregnant 10/06 Web Sites to Access the Guidelines http://www.aidsetc.org http://aidsinfo.nih.gov 10/06 About this Slide Set This presentation was prepared by Susa Coffey, MD for the AETC National Resource Center in October 2006 and revised in April 2007. See the AETC NRC Web Site for the most current version of this presentation. http://www.aidsetc.org 10/06