1. Special Issues Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents published October 2006 AETC NRC Slide Set

2. 10/06 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 The user is cautioned that due to the rapidly changing field of HIV care, this information could become out of date quickly.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

3. 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

4. 10/06 Acute Retroviral Syndrome: Signs and Symptoms - I  Fever 96%  Lymphadenopathy 74%  Pharyngitis 70%  Rash 70%  Myalgia or arthralgia 54%  Diarrhea 32%

5. 10/06 Acute Retroviral Syndrome: Signs and Symptoms - II  Headache 32%  Nausea and Vomiting 27%  Hepatosplenomegaly 14%  Weight Loss13%  Thrush 12%  Neurological Symptoms 12%

6. 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)

7. 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

8. 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

9. 10/06 Acute HIV Infection: Treatment  Limited outcome data from clinical trials; therapy based largely on theoretic considerations

10. 10/06 Acute HIV Infection: Treatment Possible benefits:  Decrease the severity of acute disease  Alter the viral “set point”  Reduce the rate of mutation  Preserve immune function  Reduce risk of viral transmission Possible risks:  Drug-related toxicity  Earlier emergence of drug resistance  Limitation of future treatment options  Potential need for indefinite treatment  Adverse effects on quality of life

11. 10/06 Primary Treatment Regimen  Same as for chronic infection

12. 10/06 The HIV Infected Adolescent  Timing of infection; perinatal vs. acquired during adolescence  Early intervention

13. 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

14. 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

15. 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-1- Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States.”

16. 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

17. 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

18. 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

19. 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.

20. 10/06 Antiretroviral Drug Use in Pregnant Women: NRTIs Recommended agents Zidovudine 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

21. 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

22. 10/06 Safety and Toxicity of ART in Pregnant Women: NNRTIs  Clinical trial and pharmacokinetic (PK) data in human pregnancy available only for nevirapine

23. 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 Delavirdine  FDA pregnancy category D  Teratogenic in monkeys  Avoid in first trimester; consider after second trimester only if no other alternatives  Teratogenic in rodent studies

24. 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

25. 10/06 ART in Pregnant Women: PIs Recommended agents Lopinavir/ 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

26. 10/06 Antiretroviral Drug Use in Pregnant Women: PIs Alternate agents Indinavir Ritonavir Saquinavir (hard gel capsule)/ ritonavir  Lower drug levels during pregnancy  Must boost with ritonavir, but optimal dosing in pregnancy is unknown  Concern for possible hyperbilirubinemia in the neonate  Lower drug levels in pregnancy  May use at low dose as booster for other PIs  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

27. 10/06 ART in Pregnant Women: PIs Insufficient data to recommend Amprenavir Atazanavir Darunavir Fosamprenavir Tipranavir  No studies in human pregnancy  Oral solution contraindicated (contains propylene glycol)  No studies in human pregnancy  Concern for possible hyperbilirubinemia in the neonate  No studies in human pregnancy

28. 10/06 Antiretroviral Drug Use in Pregnant Women: Fusion Inhibitors Insufficient data to recommend Enfuvirtide  No studies in human pregnancy

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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)

35. 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

36. 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 anti- HBV activity, to avoid HBV resistance

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 10/06 TB/HIV Co-Infection  Increased risk of progression from latent to active TB  Increased risk of HIV progression

46. 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

47. 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

48. 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

49. 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

50. 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 high- dose prednisone

51. 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

52. 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)

53. 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

54. 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

55. 10/06 Web Sites to Access the Guidelines  http://www.aidsetc.org  http://aidsinfo.nih.gov

56. 10/06  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 About this Slide Set