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

Correctional/8/9/2015/(2) Tuberculosis Screening Guidelines * *As recommended by the National Commission for Correctional Health Care. On admission Mandatory symptom screening Mandatory symptom screening Symptoms: isolate & evaluate Symptoms: isolate & evaluate No previous positive test Tuberculin skin test Tuberculin skin test TST + TST + – HIV+ (or high risk) ≥5 mm induration at hrs – Chest radiograph – Sputum analysis for HIV+ with respiratory symptoms Annual screening recommended

Correctional/8/9/2015/(3) Tuberculosis and the HIV+ Incarcerated * HIV infection  risk of active TB HIV infection  risk of active TB HIV+/active TB may be TST negative HIV+/active TB may be TST negative Chest x-ray atypical or normal Chest x-ray atypical or normal Complicates TB treatment Complicates TB treatment – Drug interaction risk Effective ART may result in Effective ART may result in – Immune reconstitution syndrome, resulting in temporary worsening of TB HIV infection  risk of active TB HIV infection  risk of active TB HIV+/active TB may be TST negative HIV+/active TB may be TST negative Chest x-ray atypical or normal Chest x-ray atypical or normal Complicates TB treatment Complicates TB treatment – Drug interaction risk Effective ART may result in 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): Burman WJ et al. Clin Infect Dis. 1999;28:

Correctional/8/9/2015/(4) Tuberculosis Latent or Active in Prisoners on HAART Latent TB In practice, TST+/HIV+ cases >>> active TB/HIV+ cases In practice, TST+/HIV+ cases >>> active TB/HIV+ cases Preferred regimen: 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 INH may be concurrent with NRTIs, PIs, NNRTIs Latent TB In practice, TST+/HIV+ cases >>> active TB/HIV+ cases In practice, TST+/HIV+ cases >>> active TB/HIV+ cases Preferred regimen: 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 INH may be concurrent with NRTIs, PIs, NNRTIs Active TB (AIDS-defining) Preferred regimen: Preferred regimen: – 4-drug: incl rifampin or rifabutin + INH, pyrazinamide + ethambutol Rifampin and rifabutin interact with PIs & NNRTIs Rifampin and rifabutin interact with PIs & NNRTIs New Jersey Medical School National TB Center (NTBC) Pocket Guide. CDC Treatment Guidelines for the Concurrent Treatment of HIV and TB. Hepatotoxicity risk from TB treatment; also test for HBV, HCV, follow LFTs

Correctional/8/9/2015/(5) Hepatitis C and B Screening and Treatment National Commission for Correctional Health Care recommends all prisoners be tested for HBV, HCV National Commission for Correctional Health Care recommends all prisoners be tested for HBV, HCV Combination therapy for HCV usually includes * Combination therapy for HCV usually includes * – Daily treatment with ribavirin and weekly PEG-interferon injections National Commission for Correctional Health Care recommends all prisoners be tested for HBV, HCV National Commission for Correctional Health Care recommends all prisoners be tested for HBV, HCV Combination therapy for HCV usually includes * 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. *Criteria for HCV treatment may vary slightly from one correctional system to another. National Commission on Correctional Health Care Clinical Guideline. De Groot AS. HEPP News (Brown Medical School), April Paar D. HEPP News (Brown Medical School), June/July 2001.

Correctional/8/9/2015/(6) Hepatitis C and B Consequences of Co-Infection With HIV HBV infection  HIV replication (  VL) HBV infection  HIV replication (  VL) HIV – –  Hepatic fibrosis (chronic HCV+) – –  Hepatic failure (HBV+) Most HBV co-infected patients (vs HBV alone) have 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 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 x over HIV-/HCV+ Co-infection with HIV+/HCV+  risk of developing hepatocellular carcinoma by x over HIV-/HCV+ Hadler SC et al. J Infec Dis. 1991;163: McNair ANB et al. Semin Liver Dis. 1992;12: NIH Consensus Development Conference Panel. Hepatology. 1997;26(Suppl 1):2S-10S.

7 HIV and Hepatitis C Coinfection

Correctional/8/9/2015/(8) Outline of coinfection talk HCV manifestation HCV manifestation – epidemiology – natural history – treatment HCV coinfection HCV coinfection – epidemiology – natural history – treatment HCV manifestation HCV manifestation – epidemiology – natural history – treatment HCV coinfection HCV coinfection – epidemiology – natural history – treatment

Correctional/8/9/2015/(9) Worldwide prevalence of hepatitis and HIV

Correctional/8/9/2015/(10) Risk factors for Hepatitis C infection 20% 10% 5% 55% 10% IVDU Cocaine Exposure to infected sex partner or multiple partners Occupational, hemodialysis, household, perinatal No recognized source modes; 2000

Correctional/8/9/2015/(11)

Correctional/8/9/2015/(12) Cocaine use as a risk factor for HCV 5% of HCV infected people have cocaine use as their only risk factor 5% of HCV infected people have cocaine use as their only risk factor

Correctional/8/9/2015/(13) Natural history of hepatitis C 1% Hepatocellular CA 20% Cirrhosis 70% Chronic hepatitis (abnormal liver biopsy) 85% Chronic hepatitis C Acute hepatitis C

Correctional/8/9/2015/(14) Hepatitis C--the facts 1.8 % of Americans are infected 1.8 % of Americans are infected approximately 4 million Americans are infected approximately 4 million Americans are infected leading cause of liver transplantation in the United States leading cause of liver transplantation in the United States 1.8 % of Americans are infected 1.8 % of Americans are infected approximately 4 million Americans are infected approximately 4 million Americans are infected leading cause of liver transplantation in the United States leading cause of liver transplantation in the United States

Correctional/8/9/2015/(15) Years % progression to cirrhosis Stage Stage Stage Likelihood of progression to cirrhosis based on fibrosis

Correctional/8/9/2015/(16) 6 months12 months18 months Lower limit of detectable virus RELAPSE SUSTAINED RESPONSE NON-RESPONSE Hepatitis C: Patterns of Response to Treatment

Correctional/8/9/2015/(17) HCV Elisa AB + “Chronic hepatitis C” Refer for staging of liver disease Qualitative PCR +? “Cleared hepatitis C” Repeat Elisa Ab yesno

Correctional/8/9/2015/(18) False negative antibody results ~ 6% of patients have HCV viremia and negative antibody results-- most often in patients with median cd4 = 36 1 ~ 6% of patients have HCV viremia and negative antibody results-- most often in patients with median cd4 = 36 1 A recent study of 100 HIV+ patients seronegative for HCV: 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 assay 2 ~ 6% of patients have HCV viremia and negative antibody results-- most often in patients with median cd4 = 36 1 ~ 6% of patients have HCV viremia and negative antibody results-- most often in patients with median cd4 = 36 1 A recent study of 100 HIV+ patients seronegative for HCV: 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 assay 2 1 Bonacini, et al. JAIDS 2001;26: George, et al. JAIDS 2002;31:

Correctional/8/9/2015/(19) Screening for HCV in HIV patients False negative antibody results can occur, particularly in patients with low CD4 counts 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 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 False negative antibody results can occur, particularly in patients with low CD4 counts 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 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

Correctional/8/9/2015/(20) Evolution of treatment for hepatitis C McHutchinson, et al. NEJM 1998;339: Zeuzem, et al. NEJM 2000;343: Manns, MP et al. Lancet 2001;358:

Correctional/8/9/2015/(21) Pegylated interferon: Schematic

Correctional/8/9/2015/(22) Pegylated interferon study: Results Manns, MP et al. Lancet 2001;358:

Correctional/8/9/2015/(23) Standard interferon vs pegylated interferon STANDARD 3x/week 3x/week monthly cost ~$1500 monthly cost ~$1500 response rates response rates – ~33% genotype 1 – ~79% genotypes 2 & 3 STANDARD 3x/week 3x/week monthly cost ~$1500 monthly cost ~$1500 response rates response rates – ~33% genotype 1 – ~79% genotypes 2 & 3 PEGYLATED 1x/week 1x/week monthly cost ~$2500 monthly cost ~$2500 response rates response rates – ~42% genotype 1 – ~82% genotypes 2 & 3

Correctional/8/9/2015/(24) Pegasys versus Peg-Intron

Correctional/8/9/2015/(25) PEG (40 kDa) IFN alfa-2a--SVR by Genotype Patients (%) Genotype 1Genotype 2, 3 (n = 285) (n = 145) (n = 140) P =.008 P =.016 PEG (40 kDa) IFN alfa-2a + RBV IFN alfa-2b + RBV Fried et al. DDW; May 20-23, 2001; Atlanta, Ga. (n = 298)

Correctional/8/9/2015/(26) 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 4455 Headache 5252 Pyrexia 3856 Myalgia 4250 Rigors 2335 Insomnia 2339 Nausea 2533 Arthralgia 2925 Depression 2030 *Injection site reaction 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.

Correctional/8/9/2015/(27) Contraindications to Treatment IFN-related risk IFN-related risk – Significant psychiatric disease especially depression – Autoimmune disease (including psoriasis) – Decompensated liver disease – Severe comorbid conditions RBV-related risk 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 IFN-related risk IFN-related risk – Significant psychiatric disease especially depression – Autoimmune disease (including psoriasis) – Decompensated liver disease – Severe comorbid conditions RBV-related risk 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.

Correctional/8/9/2015/(28) Side Effects of IFN Flu-like symptoms Flu-like symptoms – Headache – Fatigue or asthenia – Myalgia, arthralgia – Fever, chills Nausea Nausea Diarrhea Diarrhea Alopecia Alopecia Thyroiditis Thyroiditis Flu-like symptoms Flu-like symptoms – Headache – Fatigue or asthenia – Myalgia, arthralgia – Fever, chills Nausea Nausea Diarrhea Diarrhea Alopecia Alopecia Thyroiditis Thyroiditis Psychiatric symptoms Psychiatric symptoms – Depression – Mood lability Injection site reaction Injection site reaction Autoimmunity Autoimmunity Lab alterations Lab alterations – Neutropenia – Anemia – Thrombocytopenia Psychiatric symptoms Psychiatric symptoms – Depression – Mood lability Injection site reaction Injection site reaction Autoimmunity Autoimmunity Lab alterations Lab alterations – Neutropenia – Anemia – Thrombocytopenia

Correctional/8/9/2015/(29) Side Effects of RBV Hemolytic anemia Hemolytic anemia Teratogenicity Teratogenicity Cough and dyspnea Cough and dyspnea Rash and pruritus Rash and pruritus Insomnia Insomnia Anorexia Anorexia Hemolytic anemia Hemolytic anemia Teratogenicity Teratogenicity Cough and dyspnea Cough and dyspnea Rash and pruritus Rash and pruritus Insomnia Insomnia Anorexia Anorexia Rebetron  [package insert]. Kenilworth, NJ: Schering Corp; 1999.

Correctional/8/9/2015/(30) Take psychiatric history Take psychiatric history – Depression, mania Develop relationship with mental-health providers Develop relationship with mental-health providers Treat preexisting depression before starting (PEG) IFN Treat preexisting depression before starting (PEG) IFN Evaluate patients for development of depression at least every 2 weeks after initiation of IFN therapy Evaluate patients for development of depression at least every 2 weeks after initiation of IFN therapy Take psychiatric history Take psychiatric history – Depression, mania Develop relationship with mental-health providers Develop relationship with mental-health providers Treat preexisting depression before starting (PEG) IFN Treat preexisting depression before starting (PEG) IFN Evaluate patients for development of depression at least every 2 weeks after initiation of IFN therapy Evaluate patients for development of depression at least every 2 weeks after initiation of IFN therapy Managing Depression

Correctional/8/9/2015/(31) HCV Treatment Side Effect Management Prepare patient for IFN/RBV side effects Prepare patient for IFN/RBV side effects Important to realize that side effects are manageable Important to realize that side effects are manageable Possible ancillary medications include 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 Emphasize positive aspects of treatment Prepare patient for IFN/RBV side effects Prepare patient for IFN/RBV side effects Important to realize that side effects are manageable Important to realize that side effects are manageable Possible ancillary medications include 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 Emphasize positive aspects of treatment

Correctional/8/9/2015/(32) Tools to evaluate severity of liver disease ALT level ALT level liver synthetic function--albumin, PT liver synthetic function--albumin, PT ultrasound examination of liver ultrasound examination of liver liver biopsy (necessary in genotypes 2 and 3?) liver biopsy (necessary in genotypes 2 and 3?) ALT level ALT level liver synthetic function--albumin, PT liver synthetic function--albumin, PT ultrasound examination of liver ultrasound examination of liver liver biopsy (necessary in genotypes 2 and 3?) liver biopsy (necessary in genotypes 2 and 3?)

Correctional/8/9/2015/(33) Factors predicting sustained response to interferon Low HCV RNA level < 2 million Low HCV RNA level < 2 million Absence of fibrosis on liver biopsy Absence of fibrosis on liver biopsy Viral genotype other than type 1 Viral genotype other than type 1 Lighter patients Lighter patients Low HCV RNA level < 2 million Low HCV RNA level < 2 million Absence of fibrosis on liver biopsy Absence of fibrosis on liver biopsy Viral genotype other than type 1 Viral genotype other than type 1 Lighter patients Lighter patients

Correctional/8/9/2015/(34) 2002 NIH Consensus Conference All HIV infected persons should be screened for HCV All HIV infected persons should be screened for HCV HIV infection may accelerate the course of HCV infection 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 Preliminary data from treatment trials suggest that pegylated interferon may be better than standard interferon to treat coinfection All HIV infected persons should be screened for HCV All HIV infected persons should be screened for HCV HIV infection may accelerate the course of HCV infection 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 Preliminary data from treatment trials suggest that pegylated interferon may be better than standard interferon to treat coinfection

Correctional/8/9/2015/(35) Prevalence of HCV infection 1.8 % in general population 1.8 % in general population HIV infected individuals: 9-40% HIV infected individuals: 9-40% Injection drug users: 52-90% Injection drug users: 52-90% Hemophiliacs: 60-85% Hemophiliacs: 60-85% incarcerated HIV+: 50% incarcerated HIV+: 50% MSM: 4-8% MSM: 4-8% 1.8 % in general population 1.8 % in general population HIV infected individuals: 9-40% HIV infected individuals: 9-40% Injection drug users: 52-90% Injection drug users: 52-90% Hemophiliacs: 60-85% Hemophiliacs: 60-85% incarcerated HIV+: 50% incarcerated HIV+: 50% MSM: 4-8% MSM: 4-8%

36 ~100,000 to 400,000 coinfected individuals in the United States

Correctional/8/9/2015/(37) Years Fibrosis grade HIV infection accelerates the natural history of HCV infection in paired liver biopsy study Benhamou V, et al. Hepatology;1999;30:1054

Correctional/8/9/2015/(38) Risk of HCV complications in coinfected patients RR = 2.07 for cirrhosis in HIV+ individuals compared to HIV- 1 RR = 2.07 for cirrhosis in HIV+ individuals compared to HIV- 1 RR = 6.14 for decompensated liver disease 1 RR = 6.14 for decompensated liver disease 1 RR = 4.0 for death from liver disease 2 RR = 4.0 for death from liver disease 2 ESLD is the leading cause of mortality in HIV-infected inpatients with > 200 CD4 cells/mm 3 ESLD is the leading cause of mortality in HIV-infected inpatients with > 200 CD4 cells/mm 3 RR = 2.07 for cirrhosis in HIV+ individuals compared to HIV- 1 RR = 2.07 for cirrhosis in HIV+ individuals compared to HIV- 1 RR = 6.14 for decompensated liver disease 1 RR = 6.14 for decompensated liver disease 1 RR = 4.0 for death from liver disease 2 RR = 4.0 for death from liver disease 2 ESLD is the leading cause of mortality in HIV-infected inpatients with > 200 CD4 cells/mm 3 ESLD is the leading cause of mortality in HIV-infected inpatients with > 200 CD4 cells/mm 3 1 Graham 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: Di 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. 3 Jain 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.

Correctional/8/9/2015/(39) Mortality in HCV-infected HIV patients compared to those without HCV coinfection Lancet 2001;357:

Correctional/8/9/2015/(40) HCV effect on ART No apparent effect of HCV on response to ART, although HCV-coinfected patients may be less likely to receive ART 1 1 Sulkowski 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.

Correctional/8/9/2015/(41) HCV in coinfected patients interferon/ribavirin treatment trials non-coinfected: Manns et al. Lancet 2001;358: Bochet, et al. 8th CROI,2001;abstract1574 Landau, et al. AIDS 2001;15: Sauleda, et al. Hepatology 2001;34: Perez, et al. 9th CROI,2002;abstract 1653

Correctional/8/9/2015/(42) Why would anyone use interferon???

Correctional/8/9/2015/(43) Liver transplantation in HIV/HCV 16 coinfected patients have undergone LT 16 coinfected patients have undergone LT 9 have survived after ~4 years 9 have survived after ~4 years 7 deaths all due to recurrent HCV 7 deaths all due to recurrent HCV early mortality associated with HCV, termination of HAART early mortality associated with HCV, termination of HAART 16 survivors have tolerated HAART post LT 16 survivors have tolerated HAART post LT 16 coinfected patients have undergone LT 16 coinfected patients have undergone LT 9 have survived after ~4 years 9 have survived after ~4 years 7 deaths all due to recurrent HCV 7 deaths all due to recurrent HCV early mortality associated with HCV, termination of HAART early mortality associated with HCV, termination of HAART 16 survivors have tolerated HAART post LT 16 survivors have tolerated HAART post LT Ragri M et al, 9th CROI, abstract 125

Correctional/8/9/2015/(44) Which coinfected patients should be treated? Well-controlled HIV disease (?) Well-controlled HIV disease (?) No or stable depression No or stable depression No alcohol use No alcohol use No IDU No IDU No serious comorbid cardiopulmonary disease, uncontrolled seizures, autoimmune disease No serious comorbid cardiopulmonary disease, uncontrolled seizures, autoimmune disease Well-controlled HIV disease (?) Well-controlled HIV disease (?) No or stable depression No or stable depression No alcohol use No alcohol use No IDU No IDU No serious comorbid cardiopulmonary disease, uncontrolled seizures, autoimmune disease No serious comorbid cardiopulmonary disease, uncontrolled seizures, autoimmune disease