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Module 6. Co-Infections and Their Effects on HIV Therapy

Module 6. Co-Infections and Their Effects on HIV Therapy. TB Screening Hepatitis C. Return to Main Menu. Tuberculosis Screening Guidelines *. On admission Mandatory symptom screening Symptoms: isolate & evaluate. No previous positive test Tuberculin skin test. TST +

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Module 6. Co-Infections and Their Effects on HIV Therapy

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  1. Module 6.Co-Infections and Their Effects on HIV Therapy TB Screening Hepatitis C Return to Main Menu

  2. Tuberculosis Screening Guidelines* On admission • Mandatory symptom screening • Symptoms: isolate & evaluate No previous positive test • Tuberculin skin test • TST + • HIV+ (or high risk) ≥5 mm induration at 48-72 hrs • Chest radiograph • Sputum analysis for HIV+ with respiratory symptoms Annual screening recommended *As recommended by the National Commission for Correctional Health Care.

  3. Tuberculosis and the HIV+ Incarcerated* • HIV infection  risk of active TB • HIV+/active TB may be TST negative • Chest x-ray atypical or normal • Complicates TB treatment • Drug interaction risk • Effective ART may result in • Immune reconstitution syndrome, resulting in temporary worsening of TB *Consult an HIV/TB expert for management of HIV-related TB disease.CDC. MMWR. 2000;49(No. RR-6):8. CDC. MMWR. 2000;49(46):1041-1044. Burman WJ et al. Clin Infect Dis. 1999;28:419-429.

  4. Latent TB In practice, TST+/HIV+ cases >>> active TB/HIV+ cases Preferred regimen: Isoniazid (INH) (300 mg) daily for 9 months - or 900 mg + B6 (50 mg) twice a week INH may be concurrent with NRTIs, PIs, NNRTIs Active TB (AIDS-defining) Preferred regimen: 4-drug: incl rifampin or rifabutin + INH, pyrazinamide + ethambutol Rifampin and rifabutin interact with PIs & NNRTIs TuberculosisLatent or Active in Prisoners on HAART Hepatotoxicity risk from TB treatment; also test for HBV, HCV, follow LFTs New Jersey Medical School National TB Center (NTBC) Pocket Guide. CDC Treatment Guidelines for the Concurrent Treatment of HIV and TB.

  5. Hepatitis C and BScreening and Treatment • National Commission for Correctional Health Care recommends all prisoners be tested for HBV, HCV • Combination therapy for HCV usually includes* • Daily treatment with ribavirin and weekly PEG-interferon injections *Criteria for HCV treatment may vary slightly from one correctional system to another.National Commission on Correctional Health Care Clinical Guideline. http://www.ncchc.org/hiv.pdf .De Groot AS. HEPP News (Brown Medical School), April 2001.Paar D. HEPP News (Brown Medical School), June/July 2001.

  6. HBV infection  HIV replication ( VL) HIV  Hepatic fibrosis (chronic HCV+)  Hepatic failure (HBV+) Most HBV co-infected patients (vs HBV alone) have  HBV DNA  Serum ALT  Liver inflammation/cirrhosis Chronic HIV+, HBV/HCV patients are more likely to have clinically significant hepatotoxicity on HAART Co-infection with HIV+/HCV+  risk of developing hepatocellular carcinoma by 12-300 x over HIV-/HCV+ Hepatitis C and BConsequences of Co-Infection With HIV Hadler SC et al. J Infec Dis. 1991;163:454-459. McNair ANB et al. Semin Liver Dis. 1992;12:188-196. NIH Consensus Development Conference Panel. Hepatology. 1997;26(Suppl 1):2S-10S.

  7. HIV and Hepatitis C Coinfection

  8. Outline of coinfection talk • HCV manifestation • epidemiology • natural history • treatment • HCV coinfection • epidemiology • natural history • treatment

  9. Worldwide prevalence of hepatitis and HIV

  10. Risk factors for Hepatitis C infection IVDU Cocaine 10% Exposure to infected sex partner or multiple partners 10% 20% Occupational, hemodialysis, household, perinatal 55% 5% No recognized source http://www.cdc.gov/ncidod/diseases/hepatitis/c_training/edu/transmission modes; 2000

  11. Cocaine use as a risk factor for HCV • 5% of HCV infected people have cocaine use as their only risk factor

  12. Natural history of hepatitis C 70% Chronic hepatitis (abnormal liver biopsy) Acute hepatitis C 85% Chronic hepatitis C 1% Hepatocellular CA 20% Cirrhosis

  13. Hepatitis C--the facts • 1.8 % of Americans are infected • approximately 4 million Americans are infected • leading cause of liver transplantation in the United States

  14. Likelihood of progression to cirrhosis based on fibrosis 100 90 80 70 Stage 3 - 4 60 50 Stage 2 - 2.9 % progression to cirrhosis 40 Stage 0 - 1.9 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 Years

  15. RELAPSE NON-RESPONSE SUSTAINED RESPONSE Lower limit of detectable virus 6 months 12 months 18 months Hepatitis C: Patterns of Response to Treatment

  16. HCV Elisa AB + Qualitative PCR +? yes no “Chronic hepatitis C” Refer for staging of liver disease “Cleared hepatitis C” Repeat Elisa Ab

  17. False negative antibody results • ~ 6% of patients have HCV viremia and negative antibody results-- most often in patients with median cd4 = 361 • A recent study of 100 HIV+ patients seronegative for HCV: • 6% by commercial assay • 9% by modified commercial assay (RNA extracted from a larger volume of whole blood) • 19% in-house assay2 1Bonacini, et al. JAIDS 2001;26:340-4. 2George, et al. JAIDS 2002;31:154-162.

  18. Screening for HCV in HIV patients • False negative antibody results can occur, particularly in patients with low CD4 counts • Current recommendation is to screen with HCV RNA in seronegative patients with elevated LFT’s or risk factors for HCV, particularly if CD4 count is low

  19. Evolution of treatment for hepatitis C McHutchinson, et al. NEJM 1998;339:1485-92 Zeuzem, et al. NEJM 2000;343:1666-1672 Manns, MP et al. Lancet 2001;358:958-865

  20. Pegylated interferon: Schematic

  21. Pegylated interferon study: Results Manns, MP et al. Lancet 2001;358:958-865

  22. STANDARD 3x/week monthly cost ~$1500 response rates ~33% genotype 1 ~79% genotypes 2 & 3 PEGYLATED 1x/week monthly cost ~$2500 response rates ~42% genotype 1 ~82% genotypes 2 & 3 Standard interferon vs pegylated interferon

  23. Pegasys versus Peg-Intron--------

  24. PEG (40 kDa) IFN alfa-2a--SVR by Genotype IFN alfa-2b + RBV PEG (40 kDa) IFN alfa-2a + RBV P = .008 80 76 P = .016 70 61 60 (n = 140) 46 50 37 Patients (%) 40 (n = 145) (n = 298) 30 (n = 285) 20 10 0 Genotype 1 Genotype 2, 3 Fried et al. DDW; May 20-23, 2001; Atlanta, Ga.

  25. Roche product (Pegasys) Adverse Events >10% PEG IFN alfa-2a IFN alfa-2b 3 MIU (40 kDa, 180 µg)+RBV (n = 451) (n = 443) (n = 223) Fatigue 44 55 Headache 52 52 Pyrexia 38 56 Myalgia 42 50 Rigors 23 35 Insomnia 23 39 Nausea 25 33 Arthralgia 29 25 Depression 20 30 *Injection site reaction23 15-36 IFN = interferon; PEG = polyethylene glycol; RBV = ribavirin. Treatment period of 48 weeks; safety data collected through week 72. *Fried et al. DDW; May 20-23, 2001; Atlanta, Ga. *Roche. Data on file.

  26. Contraindications to Treatment • IFN-related risk • Significant psychiatric disease especially depression • Autoimmune disease (including psoriasis) • Decompensated liver disease • Severe comorbid conditions • RBV-related risk • Significant cardiovascular disease • Anemia ( <12 g/dL in women, <13 g/dL in men) • Unable to be compliant with contraception • Renal failure • Hemoglobinopathy Maddrey. Semin Liver Dis. 1999;19:67-75.

  27. Flu-like symptoms Headache Fatigue or asthenia Myalgia, arthralgia Fever, chills Nausea Diarrhea Alopecia Thyroiditis Psychiatric symptoms Depression Mood lability Injection site reaction Autoimmunity Lab alterations Neutropenia Anemia Thrombocytopenia Side Effects of IFN

  28. Side Effects of RBV • Hemolytic anemia • Teratogenicity • Cough and dyspnea • Rash and pruritus • Insomnia • Anorexia Rebetron [package insert]. Kenilworth, NJ: Schering Corp; 1999.

  29. Managing Depression • Take psychiatric history • Depression, mania • Develop relationship with mental-health providers • Treat preexisting depression before starting (PEG) IFN • Evaluate patients for development of depression at least every 2 weeks after initiation of IFN therapy

  30. HCV Treatment Side Effect Management • Prepare patient for IFN/RBV side effects • Important to realize that side effects are manageable • Possible ancillary medications include • Granulocyte colony stimulating factor for neutropenia (not considered standard of care) • Antidepressants for depression and irritability • Consider Epoetin alfa for anemia (not considered standard of care) • Acetaminophen, nonsteroidal antiinflammatory drugs, histamine 2 blockers, antidiarrheal agents, etc • Emphasize positive aspects of treatment

  31. Tools to evaluate severity of liver disease • ALT level • liver synthetic function--albumin, PT • ultrasound examination of liver • liver biopsy (necessary in genotypes 2 and 3?)

  32. Factors predicting sustained response to interferon • Low HCV RNA level < 2 million • Absence of fibrosis on liver biopsy • Viral genotype other than type 1 • Lighter patients

  33. 2002 NIH Consensus Conference • All HIV infected persons should be screened for HCV • HIV infection may accelerate the course of HCV infection • Preliminary data from treatment trials suggest that pegylated interferon may be better than standard interferon to treat coinfection

  34. Prevalence of HCV infection • 1.8 % in general population • HIV infected individuals: 9-40% • Injection drug users: 52-90% • Hemophiliacs: 60-85% • incarcerated HIV+: 50% • MSM: 4-8%

  35. ~100,000 to 400,000 coinfected individuals in the United States

  36. HIV infection accelerates the natural history of HCV infection in paired liver biopsy study Fibrosis grade Years Benhamou V, et al. Hepatology;1999;30:1054

  37. Risk of HCV complications in coinfected patients • RR = 2.07 for cirrhosis in HIV+ individuals compared to HIV-1 • RR = 6.14 for decompensated liverdisease1 • RR = 4.0 for death from liverdisease2 • ESLD is the leading cause of mortality in HIV-infected inpatients with > 200 CD4 cells/mm3 1Graham CS, Baden LR, Ye E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001:33:562:569. 2Di Martino V, Ezenfis J, Tainturier Y, et al. Impact of HIV coinfection on the long-term outcome of HCV cirrhosis [abstract 567]. Presented at the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001: Chicago Ill. 3Jain M, Cloud J, Jain C, Skiest D, Berggren RE. Inpatient deaths among HIV-infected persons in Dallas, Texas: 1995 compared to 1999/2000 [abstract 723]. Presented at : Infectious Disease Society of America Annual Meeting; October 27, 2001: San Francisco, CA.

  38. Mortality in HCV-infected HIV patients compared to those without HCV coinfection Lancet 2001;357:1361-1362

  39. HCV effect on ART No apparent effect of HCV on response to ART, although HCV-coinfected patients may be less likely to receive ART1 1Sulkowski MS, Moore R, Mehta S, Thomas D. Effect of HCV coinfection on HIV disease progression and survival in HIV-infected adults [abstract 34]. Presented at 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001:Chicago, Il.

  40. HCV in coinfected patients interferon/ribavirin treatment trials non-coinfected: Manns et al. Lancet 2001;358:958-865 Bochet, et al. 8th CROI,2001;abstract1574 Landau, et al. AIDS 2001;15:2149-2155 Sauleda, et al. Hepatology 2001;34:1035-40 Perez, et al. 9th CROI,2002;abstract 1653

  41. Why would anyone use interferon???

  42. Liver transplantation in HIV/HCV • 16 coinfected patients have undergone LT • 9 have survived after ~4 years • 7 deaths all due to recurrent HCV • early mortality associated with HCV, termination of HAART • 16 survivors have tolerated HAART post LT Ragri M et al, 9th CROI, abstract 125

  43. Which coinfected patients should be treated? • Well-controlled HIV disease (?) • No or stable depression • No alcohol use • No IDU • No serious comorbid cardiopulmonary disease, uncontrolled seizures, autoimmune disease

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