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HIV Coinfections, Malignancies, and Comorbidities

HIV Coinfections, Malignancies, and Comorbidities. HIV Coinfections, Malignancies, and Comorbidities. HIV-hepatitis C coinfection HIV-hepatitis B coinfection Hepatotoxicity, HIV-hep coinfection, and antiretroviral therapy HIV-related malignancies Psychiatric concerns in persons with HIV.

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HIV Coinfections, Malignancies, and Comorbidities

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  1. HIV Coinfections, Malignancies, andComorbidities

  2. HIV Coinfections, Malignancies, andComorbidities • HIV-hepatitis C coinfection • HIV-hepatitis B coinfection • Hepatotoxicity, HIV-hep coinfection, and antiretroviral therapy • HIV-related malignancies • Psychiatric concerns in persons with HIV

  3. HIV Hep C 40 million 200 million 10 million Overlapping HCV and HIV Epidemics Up to 33% of HIV+ patients in EuroSIDA are HCV Ab+ (75% among intravenous-drug users)

  4. Variables to Consider Before Initiating HCV Therapy in HIV+ Patients • HIV-related: • CD4 • HIV RNA • Antiretroviral therapy • Liver-related: • Genotype • HCV load • Transaminases • Histology • Others: • Neuropsychiatric history • Drug addiction and alcohol consumption

  5. Randomized Clinical Trials: Peg-IFN + RBV in HIV+ Persons ACTG5071 APRICOT RIBAVIC Laguno No. with Peg + ribavirin (RBV) 66 289 205 52 Type of peg IFN 2a 2a 2b 2b IDUs – 62% 81% 75% Cirrhotics 11% 15% 40%(F3-F4) 19% Genotypes 1-4 77% 67% 69% 63% Normal ALT levels – 0 15% 0 Mean CD4 count – 520 525 512 On HAART – 84% 82% 94% Premature discontinuation – 25% 41% 25% EOT (ITT) 41% 49% 36% 52% SVR (ITT) 27% 40% 27% 44%

  6. Main Predictors of Sustained Virologic Response • HCV genotype • Baseline HCV RNA • Adherence (80/80/80) • Week 4 virologic response (best positive predictive value [PPV] of sustained virologic response [SVR])

  7. What Can We Do to Improve SVR in HIV/HCV Coinfection? • Select candidates correctly • Prevent and optimally manage side effects • Enhance early virologic response • Induction doses: peg-IFN and/or RBV • Reduce relapse rates • Extending the length of therapy

  8. HIV-neg: Fried et al. N Engl J Med. 2002 HIV-pos: Soriano et al. Antivir Ther. 2004 RBV 800 mg and genos 2-3 tx 24 months Week 12 Predictive Value of SVR 65% YES 86% 56% SVR 35% YES 58% n = 453 NO HCV RNA drop > 2 logs 44% 3% n = 89 NO YES 14% 0% SVR 97% 42% NO 100%

  9. PRESCO Trial: Design G1,4 Follow-up G1,4 Follow-up Peg-IFN + RBV 1000-1200 mg/day N = 391 G2,3 Follow-up G2,3 Follow-up 84 72 60 48 96 24 36 12 0 Study Weeks Only patients who achieved EVR (>2 log drop in HCV RNA at week 12) continued treatment.

  10. APRICOT (800 mg/day) vs PRESCO (1000–1200 mg/day): G1 Week 4 Response On-treatment analysis Ramos et al. Antivir Ther. 2006 (in press)

  11. Week 4 Virologic ResponseAccording to HIV Status and RBV Dose PRESCO: HIV+ and RBV high Fried: HIV-neg and RBV high APRICOT: HIV+ and RBV low

  12. Clinical Interpretation • HIV negativelyaffects the early virologic response to HCV therapy • Prescription of appropriate (high) RBV doses increase early virologic response mainly in genotypes 1 and 4, but also in genotypes 2 and 3

  13. SHORT STATEMENT OF THE FIRST EUROPEAN CONSENSUS CONFERENCE ON THE TREATMENT OF CHRONIC HEPATITIS C AND B IN HIV CO-INFECTED PATIENTS 1–2 March, 2005, Paris, France The ECC Jury J Hepatol 2005;42:615-24.

  14. HIV Coinfections, Malignancies, andComorbidities • HIV-hepatitis C coinfection • HIV-hepatitis B coinfection • Hepatotoxicity, HIV-hep coinfection, and antiretroviral therapy • HIV-related malignancies • Psychiatric concerns in persons with HIV

  15. Hepatitis B Virus Genotypes in the United States Midwest (25%) East (17%) 5% 2% 13% 18% 37% 37% 33% A 34.7% B 22.0% C 30.8% D 10.4% E, F, G 2.1% 23% 17% 15% West (39%) South (19%) 2% 2% 5% 12% 18% 13% 41% 63% 10% 34% n=694 adults, in 17 centers Chu et al. Gastroenterology. 2003;125:444.

  16. Sequelae of Chronic HBV Infection • Hepatocellular carcinoma (HCC) • ~500,000 deaths annually worldwide1 • ~50% of cases associated with HBV infection1 • Viral factors linked to greater risk of HCC include HBeAg positivity, serum HBV DNA levels >105 copies/mL, and genotype C2 • Risk of HCC increase based on HBV DNA levels, even in patients with normal ALT at baseline3 1. Parkin DM, et al. Int J Cancer. 2001;94:153-156. 2. Yu MW, et al. J Natl Cancer Inst. 2005;97:265-272. 3. Iloeje UH, et al. J Hepatol. 2005;42:16S [Abstract 495].

  17. Time to Disease ProgressionTreatment and Off-Treatment Follow-up 25 21% n=198 20 Placebo 15 P = .001 % With disease progression 10 n=173 n=122 9% 5 Lamivudine Lamivudine n=385 n=198 n=417 0 0 6 12 18 24 30 36 Time to disease progression (months) Placebo (n=215) ITT population Lamivudine (n=436) P = .001 Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

  18. HIV/HBV Coinfection: Effect on Liver-Related Mortality P < .0001 16 14 12 Liver-related mortality rate (per 1000 person-years) 10 8 6 4 P < .001 P = .04 2 0 HIV-/HBsAg- HIV+ HBsAg+ HIV+/HBsAg+ Thio CL, et al. Lancet. 2002;360:1921-1926.

  19. Impact of HBV Infectionon HIV Outcome • 111 HIV/HBV-coinfected patients and 387 HIV-infected patients without HBV or HCV prospectively observed between June 1994 and February 2003 • After a median of 25 months • Coinfected patients were more likely to develop hepatitis • Coinfected patients were much more likelyto develop hepatic decompensation • HBV-infected patients had an increased riskfor virologic failure and death after HAART was initiated Sheng WH, et al. Clin Infect Dis. 2004;38:1471-1477.

  20. Occult HBV Is Frequent in HIV Patients, Is More Common in Patients With Chronic HCV, and Enhances Severity of Liver Disease • 955 HIV-infected patients from 4 ID units in Italy • 581 (61%) anti-HBc+ • 64 (7%) HBsAg+ • 361 (38%) anti-HBs+ • 190 (20%) anti-HBc+ alone • 402 (42%) coinfected with HCV • Liver cirrhosis observed only in HCV+ patients • 16% in anti-HBc+ vs 1.5% in anti-HBc- (P < .0001) Marino N, et al. EASL 2005. Abstract 514.

  21. HBV Evaluation and Monitoringin HIV/HBV-Coinfected Patients • 362 HIV patients found to be HBsAg+ between 1999 and 2003 in Parkland HIV Clinic • Patients identified as HBsAg+ after 1999 are receiving HBV testing more rapidly • Still, almost 50% initially identified as HBsAg+ did not receive initial evaluation for HBV status, cirrhosis, or HCC Opio CK, et al. DDW 2005. Abstract S932.

  22. HBV Goals of Therapy • Long-term viral suppression • No resistance development • Decrease risk of HCC • What is optimal therapy?

  23. Currently Approved Antiviral Therapies • Interferon alfa-2b • Peginterferon alfa-2a • Lamivudine (LAM) • Adefovir dipivoxil (ADV) • Entecavir (ETV)

  24. Mutations in the HBV Genome Lead to Resistance to Antiviral Therapies Terminal protein Spacer Reverse transcriptase Rnase H Lamivudine resistancemutations M204V or I L180M V173L YMDD 1 344 B F G A C D E A181V or T K318Q N236T K241E Observed in ADV treated patients

  25. HBV Antiviral TherapyCross-Resistance In Vitro N236T L180M A184G M204V M250V A181V V173L M204I S202I LAM ETV LdT FTC ADV TDF

  26. Prevalence of Resistance in HIV- Patients Treated With ADV or LAM ADV (N236T or A181V) LAM(YMDD) Locarnini S, et al. J Hepatol. 2005;42(suppl 2):17.

  27. HBV DNA and ALT Normalization With ADV in LAM-Resistant HBV/HIV-Coinfected Patients HBV DNA ≤ 1000 copies/mL ALT normalization Benhamou Y, et al. 12th CROI. Boston, MA. 2005. Abstract 935.

  28. Peg alfa 2a Response by GenotypeHBeAg Loss at 6 Months Post-Rx, HIV- Pts 47% 50 44% 40 28% 30 25% % 20 10 0 A n=90 B n=23 C n=39 D n=103 Janssen H, et al. Lancet. 2005;365:123-129.

  29. Adefovir vs Tenofovir in HIV-Coinfected Patients With LAM-Resistant HBV Van Bommel F, et al. Hepatology. 2004;40:1421-1425.

  30. LAM + TDF Shows Greater Decline in HBV DNA Than LAM Alone or LAM Prior to LAM + TDF in HBV/HIV-Coinfected Patients • Group 1 (n=10) received LAM 150 mg bid only; group 2 (n=8), LAM + TDF 300 mg qd, and group 3 (n=12), ≥1 yr of LAM followed by LAM + TDF • Group 2 had greatest average log drop at year 1, 3.2 logs, compared with 1.5 and 1.1 logs in groups 1 and 3, respectively (P = .05) • Sequential regimen less effective than in previous controlled trials • Most patients in this study have HBV genotype A and appear more likely to respond to either therapy than those with non-A genotypes • Study is ongoing, as more data are needed to confirm these findings and explore possible synergy between LAM and TDF Mamta K, et al. 55th AASLD. Boston, MA. 2004. Abstract 1168.

  31. ETV-038: Mean Change in HBV DNAFrom Baseline by PCR in HIV+ Pts 1 +0.11 log10 0 -1 *P<0.0001for each comparisonon-treatment HBV DNA by PCR (log10 copies/mL) * -2 -3 * Placebo -3.66 log10 -4 ETV * -5 0 2 12 24 Weeks n (ETV) n (PBO) 5117 4916 4616 4816 Estimated difference in mean HBV DNA reduction (entecavir – placebo) was -3.76 log10 copies/mL (95% CI [-4.49, -3.04]; P<0.0001). P < .0001 for all analyses performed at week 24.

  32. Other Combinations for HBV at AASLD 2005 • Emtricitabine (FTC) and clevudine (L-FMAU) • LAM and ADV • Tenofovir (TDF) rescue of ADV failure • Combination therapy and resistance lights starting to pop on very slowly

  33. Evolving Treatment Paradigms in HBV, HBV/HIV Future Current • Suppression • Reduce HBV DNA • Improve ALT • Potential for resistance • Hope for seroconversion • Indefinite course of therapy • Elimination • Complete response, plus • Eradication of cccDNA • No hepatic flares off treatment • Reduce progression of liver disease • Complete Response • Undetectable HBV DNA • Normalization of ALT • Minimal resistance • HBeAg loss/seroconversion • Sustained viral load reduction off treatment

  34. HIV Coinfections, Malignancies, andComorbidities • HIV-hepatitis C coinfection • HIV-hepatitis B coinfection • Hepatotoxicity, HIV-hep coinfection, and antiretroviral therapy • HIV-related malignancies • Psychiatric concerns in persons with HIV

  35. Patterns of Steatosis Macrovesicular steatosis: • Hepatocytes contain a single large vacuole of fat (TG) that fills up the cell and displaces the nucleus to the periphery Microvesicular steatosis: • Hepatocytes are filled up with numerous small lipid vesicles that leave the nucleus in the center of the cell • “Its presence implies impairment of mitochondrial oxidation of fatty acids and severe energy crisis” – D. Pessayre

  36. Role of Hepatic Steatosis in HIV/HCV-Coinfected Patients McGovern B et al. Clin Infect Dis (2006); in press.

  37. HAART and Hepatotoxicity • 10,000 patients from 21 ACTG trials • High rate of severe drug-induced liver injury (DILI) irrespective of class • 3,927 pts with follow-up for 3 years on ART • The most common grade 4 adverse events were liver related • Risk was higher in patients with viral hepatitis (OR = 5.97 for HBV; OR = 2.74 for HCV) Reisler, IAS 2001, Buenos Aires, Abst. 43; Reisler, J Acquir Immune Defic Syndr. 2003;34.

  38. NRTIs and Mitochondrial Toxicity • Impaired mitochondrial function can lead to a decrease in fatty acid oxidation • FFAs accumulate and are metabolized to triglycerides • Long-term administration can lead to hepatic steatosis

  39. NVP (RR = 11.2; P < .01) Female gender (RR = 3.2; P < .01) Female with baseline CD4 ≥ 250 (RR = 9.8; P < .01) Male with baseline CD4 ≥ 400 (RR = 6.4; P < .01) Baseline ALT or AST >2.5x ULN (RR = 3.2; P < .01) HBV coinfection (RR = 3.9; P < .01) Baseline CD4 found to be an inconsistent factor Risk Factors for NVP-Associated Symptomatic Events in All Trials Rash-AssociatedHepatic Events Other SymptomaticHepatic Events Stern JO et al, 14th Int AIDS Conference, 2002, Barcelona.

  40. PIs and Hepatotoxicity • Ritonavir use had a higher overall incidence of moderate and severe hepatotoxicity compared with other PIs • Conflicting data in subsequent large cohorts using high-dose ritonavir; however, low-dose appears to be safe • Nelfinavir and indinavir associated with lowest incidence of DILI in one large cohort Cooper, CID 2003;36:1585; Sulkowksi, AIDS 2004;18:2277; Bruno, Clin Gastroenterol Hepatol. 2005;3:482.

  41. Pharmacokinetics of Lopinavir/Ritonavir in HIV/HCV Ritonavir pK sampling on day 14 in 12 HIV/HCV patients with mild and moderate liver disease: AUC: • 41% higher in mild liver disease • 185% higher in moderate liver disease Arribas J et al, 9th EASL.

  42. Can We Avoid Drug-Induced Liver Injury (DILI) by Risk Stratification? • Gender • HIV infection and low glutathione levels • Genetic polymorphisms: CYP2D6 • Obesity • Acetylator status • Age • Duration of treatment • Alcohol use and ROS, 2E1, glutathione • New risk factor: Chronic viral hepatitis

  43. Cumulative Effects of Liver Injury • Is a “trial by error” approach potentially harmful? • Reports of worsening histology after HAART • 17 patients with severe hepatotoxicity: • Four-month “washout” period • 59% successfully tolerated their medications • However, 41% had another episode of DILI! • Hepatotoxicity is a sign that should be evaluated Puoti, J Acquir Immune Defic Syndr. 2003;32:259; Aceti, Int J STD AIDS. 2005;16:148.

  44. Prevention of DILI • Pitfalls and limitations of current data • Assessment of risk • Does the patient have chronic viral hepatitis? • What are the baseline aminotransferases? • Evaluate synthetic function • Staging of liver disease • Monitoring of laboratories • Education of the patient! Sabin, Clin Infect Dis. 2004;S56; McGovern, IAPAC 2004, S23.

  45. HIV Coinfections, Malignancies, andComorbidities • HIV-hepatitis C coinfection • HIV-hepatitis B coinfection • Hepatotoxicity, HIV-hep coinfection, and antiretroviral therapy • HIV-related malignancies • Psychiatric concerns in persons with HIV

  46. Concomitant Diseases and Comorbidities: Malignancies • Lymphoma • Kaposi’s sarcoma • Human papillomavirus: anal and cervical cancer • Other cancers

  47. Cancers Associated With HIV Infection • AIDS defining • Systemic and CNS lymphoma (EBV) • Kaposi’s sarcoma (HHV-8) • Cervical carcinoma (HPV) • Non-AIDS defining • Aerodigestive cancers (head/neck, lung) • Hematalogic (Hodgkin’s disease, myeloma) • Skin (anal, melanoma) • Testis (seminoma) • Others

  48. HIV Infection and Risk of Hematologic Neoplasms • Linkage between cancer and AIDS registries • USA, Italy, Australia • Relative risk increased for • Intermediate- or high-grade lymphoma – 400-fold • Low-grade and T-cell lymphoma – 15-fold • Hodgkin’s disease – 10-fold • Myeloma and leukemias – 2- to 5-fold • In Africa – risk 10x less than in developed countries • Underascertainment? • Earlier death from infection? Dal Maso L. Lancet Oncol. 2003; 4: 110-9.

  49. Highly Active Antiretroviral Therapy and Incidence of Cancer in HIV-Infected Adults Rate ratio (RR) for 1997 through 1999vs 1992 through 1996 Adjusted incidence rateper 1000 per year (No.) Cancer type 1992–1996 1997–1999 RR (SE) RR (99% Cl) Kaposi’s sarcoma 15.2 (1489) 4.9 (190) 0.32 (0.03) Non-Hodgkin’s lymphoma 6.2 (623) 3.6 (134) 0.58 (0.06) Hodgkin’s disease 0.5 (38) 0.4 (12) 0.77 (0.26) Cancer of the uterine cervix 1.1 (19) 2.1 (17) 1.87 (0.65) Other cancers 1.7 (126) 1.7 (54) 0.96 (0.16) 0.1 1 10 International Collaboration on HIV and Cancer. J Natl Cancer Inst. 2000; 92: 1822-30.

  50. Characteristics of HIV-Associated Lymphoma in Adults and Children • Presentation • Primary CNS disease (10%) • Systemic lymphoma (90%) • Histology • Large cell or immunoblastic • Small, noncleaved cell • Uncommon types • Primary effusion lymphoma (KSHV) • Plasmablastic lymphoma of oral cavity • Extranodal involvement common (up to 80-90%) • Common sites: marrow, GI tract • Uncommon sites: kidneys, skin, other unusual sites

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