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

Overlapping HCV and HIV Epidemics
40 million 200 million 10 million HIV Hep C Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course. Up to 33% of HIV+ patients in EuroSIDA are HCV Ab+ (75% among intravenous-drug users)

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 Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course.

Randomized Clinical Trials: Peg-IFN + RBV in HIV+ Persons
ACTG5071 APRICOT RIBAVIC Laguno No. with Peg + ribavirin (RBV) Type of peg IFN 2a 2a 2b 2b IDUs – 62% 81% 75% Cirrhotics 11% 15% %(F3-F4) 19% Genotypes % 67% 69% 63% Normal ALT levels – 0 15% 0 Mean CD4 count – On HAART – 84% 82% 94% Premature discontinuation – 25% 41% 25% EOT (ITT) 41% 49% 36% 52% SVR (ITT) 27% 40% 27% 44% Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course.

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]) Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course.

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 Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course.

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 14% YES Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course. SVR 0% 97% 42% 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 NO 100%

PRESCO Trial: Design G1,4 Follow-up G1,4 Follow-up
Peg-IFN + RBV mg/day N = 391 G2,3 Follow-up G2,3 Follow-up Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course. 12 24 36 48 60 72 84 96 Study Weeks Only patients who achieved EVR (>2 log drop in HCV RNA at week 12) continued treatment.

APRICOT (800 mg/day) vs PRESCO (1000–1200 mg/day): G1 Week 4 Response
Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course. On-treatment analysis Ramos et al. Antivir Ther (in press)

Week 4 Virologic Response According to HIV Status and RBV Dose
Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course. PRESCO: HIV+ and RBV high Fried: HIV-neg and RBV high APRICOT: HIV+ and RBV low

Clinical Interpretation
HIV negatively affects 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 Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course.

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: Soriano, V. “Management of Hepatitis C in HIV-Infected Patients.” From HIV Management 2006: The New York Course.

Hepatitis B Virus Genotypes in the United States
Midwest (25%) East (17%) 2% 5% 13% 18% 37% 37% 33% 23% A 34.7% B 22.0% C 30.8% D 10.4% E, F, G 2.1% 17% 15% West (39%) South (19%) 2% 2% Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. 5% 12% 18% 13% 41% 63% 34% 10% n=694 adults, in 17 centers Chu et al. Gastroenterology. 2003;125:444.

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 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. 1. Parkin DM, et al. Int J Cancer. 2001;94: 2. Yu MW, et al. J Natl Cancer Inst. 2005;97: 3. Iloeje UH, et al. J Hepatol. 2005;42:16S [Abstract 495].

Time to Disease Progression Treatment 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=198 n=385 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. n=417 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:

HIV/HBV Coinfection: Effect on Liver-Related Mortality
16 P < .0001 14 12 Liver-related mortality rate (per 1000 person-years) 10 8 6 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. 4 P < .001 P = .04 2 HIV-/HBsAg- HIV+ HBsAg+ HIV+/HBsAg+ Thio CL, et al. Lancet. 2002;360:

Impact of HBV Infection on HIV Outcome
111 HIV/HBV-coinfected patients and 387 HIV-infected patients without HBV or HCV prospectively observed between June and February 2003 After a median of 25 months Coinfected patients were more likely to develop hepatitis Coinfected patients were much more likely to develop hepatic decompensation HBV-infected patients had an increased risk for virologic failure and death after HAART was initiated Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Sheng WH, et al. Clin Infect Dis. 2004;38:

955 HIV-infected patients from 4 ID units in Italy
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) Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Marino N, et al. EASL Abstract 514.

HBV Evaluation and Monitoring in HIV/HBV-Coinfected Patients
362 HIV patients found to be HBsAg+ between and 2003 in Parkland HIV Clinic Patients identified as HBsAg+ after are receiving HBV testing more rapidly Still, almost 50% initially identified as HBsAg+ did not receive initial evaluation for HBV status, cirrhosis, or HCC Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Opio CK, et al. DDW Abstract S932.

HBV Goals of Therapy Long-term viral suppression
No resistance development Decrease risk of HCC What is optimal therapy? Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course.

Currently Approved Antiviral Therapies
Interferon alfa-2b Peginterferon alfa-2a Lamivudine (LAM) Adefovir dipivoxil (ADV) Entecavir (ETV) Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course.

Mutations in the HBV Genome Lead to Resistance to Antiviral Therapies
Terminal protein Spacer Reverse transcriptase Rnase H Lamivudine resistance mutations M204V or I V173L L180M YMDD 1 344 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. F G A B C D E A181V or T K318Q N236T K241E Observed in ADV treated patients

HBV Antiviral Therapy Cross-Resistance In Vitro
V173L L180M A181V A184G M204V N236T S202I M204I M250V LAM ETV LdT Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. FTC ADV TDF

Prevalence of Resistance in HIV- Patients Treated With ADV or LAM
ADV (N236T or A181V) LAM (YMDD) Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Locarnini S, et al. J Hepatol. 2005;42(suppl 2):17.

HBV DNA and ALT Normalization With ADV in LAM-Resistant HBV/HIV-Coinfected Patients
HBV DNA ≤ 1000 copies/mL ALT normalization Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Benhamou Y, et al. 12th CROI. Boston, MA Abstract 935.

Peg alfa 2a Response by Genotype HBeAg Loss at 6 Months Post-Rx, HIV- Pts
47% 50 44% 40 28% 30 25% % 20 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. 10 A n=90 B n=23 C n=39 D n=103 Janssen H, et al. Lancet. 2005;365:

Adefovir vs Tenofovir in HIV-Coinfected Patients With LAM-Resistant HBV
Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Van Bommel F, et al. Hepatology. 2004;40:

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 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Mamta K, et al. 55th AASLD. Boston, MA Abstract 1168.

ETV-038: Mean Change in HBV DNA From Baseline by PCR in HIV+ Pts
1 +0.11 log10 -1 *P< for each comparison on-treatment HBV DNA by PCR (log10 copies/mL) -2 * -3 Placebo * -3.66 log10 -4 ETV * Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. -5 2 12 24 Weeks n (ETV) n (PBO) 51 17 49 16 46 16 48 16 Estimated difference in mean HBV DNA reduction (entecavir – placebo) was log10 copies/mL (95% CI [-4.49, -3.04]; P<0.0001). P < for all analyses performed at week 24.

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 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course.

Evolving Treatment Paradigms in HBV, HBV/HIV
Current Future 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 Dieterich DT. “To Worry About B or Not To: HBV and HIV 2006.” From HIV Management 2006: The New York Course. Complete Response Undetectable HBV DNA Normalization of ALT Minimal resistance HBeAg loss/seroconversion Sustained viral load reduction off treatment

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 McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course.

Role of Hepatic Steatosis in HIV/HCV-Coinfected Patients
McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course. McGovern B et al. Clin Infect Dis (2006); in press.

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) McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course. Reisler, IAS 2001, Buenos Aires, Abst. 43; Reisler, J Acquir Immune Defic Syndr. 2003;34.

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 McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course.

Risk Factors for NVP-Associated Symptomatic Events in All Trials
Rash-Associated Hepatic Events Other Symptomatic Hepatic Events 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 McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course. Stern JO et al, 14th Int AIDS Conference, 2002, Barcelona.

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 McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course. Cooper, CID 2003;36:1585; Sulkowksi, AIDS 2004;18:2277; Bruno, Clin Gastroenterol Hepatol. 2005;3:482.

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 McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course. Arribas J et al, 9th EASL.

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 McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course.

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 McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course. Puoti, J Acquir Immune Defic Syndr. 2003;32:259; Aceti, Int J STD AIDS. 2005;16:148.

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! McGovern, B. “Hepatotoxicity and HAART.” From HIV Management 2006: The New York Course. Sabin, Clin Infect Dis. 2004;S56; McGovern, IAPAC 2004, S23.

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

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 Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

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? Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course. Dal Maso L. Lancet Oncol. 2003; 4:

Highly Active Antiretroviral Therapy and Incidence of Cancer in HIV-Infected Adults
Rate ratio (RR) for through 1999 vs through 1996 Adjusted incidence rate per 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) Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course. 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:

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 Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

A Prognostic Index for Systemic AIDS-Related Non-Hodgkin’s Lymphoma Treated in the Era of Highly Active Antiretroviral Therapy Patients: 9621 HIV-positive patients, 111 in whom AIDS-related non-Hodgkin’s lymphoma was treated after 1996 Results: OS increased in the HAART era (log-rank chi-square, 9.23; P = .002) Regression modeling for patients in whom disease was diagnosed after 1996 revealed only 2 independent predictors of death: International Prognostic Index risk group (stage III/IV disease, elevated LDH, poor PS, > 1 extranodal site, age > 60) CD4 cell count These predictors yielded 4 internally validated risk strata with predicted 1-year survival rates of 82%, 47%, 20%, and 15% (P < .001). Prognostic risk scores in the highest quartile yielded a likelihood ratio for death of 7.90 (hazard ratio, 1.0), whereas a prognostic score less than 1.0 yielded a likelihood ratio of 0.23 (hazard ratio, 0.15; 95% CI, ) Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course. Bower et al. Ann Int Med. 2005; 143(4):

Presentation of Primary CNS Lymphoma (PCNSL)
Neurological symptoms and signs History of OIs, CD4 count low (< 50/μL) Imaging Few (1-3), large (2-4 cm) FBL that enhance (50%) Periventricular cerebral hemispheres; basal ganglia, brainstem, cerebellum Histology Large-cell/immunoblastic B-cell lymphoma EBV positive CSF cytology + in 20%, ocular involvement Differential diagnosis Toxoplasmosis and other infections PML, other Establishing a diagnosis Empiric trial of antitoxoplasmosis therapy CSF EBV DNA – specific for lymphoma PET/thallium may be helpful in conjunction with EBV DNA Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

Treatment of Primary CNS Lymphoma
Optimize HAART Anecdotal reports of spontaneous regression AIDS 1998; 12: 952-8; J AIDS 1992; 5: 953-4 Standard treatments Steroids Whole-brain irradiation (WBRT) Median survival, 3 months 10% survive 1 year (usually good PS) CHOD chemotherapy x 1  WBRT (U.S. Intergroup) Similar results to irradiation alone (J AIDS 2000; 23: A30, abst 63) Alternative treatments High-dose zidovudine, gancyclovir +/- IL-2 Anecdotal reports of benefit (J AIDS 1999; 15: 713-9) High-dose methotrexate-based regimens Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

Conclusions Non-Hodgkin’s lymphoma is a common complication of HIV infection Influence of HAART Incidence of lymphoma may be decreasing Lymphoma may be a more common initial manifestation of AIDS Primary CNS lymphoma Common cause of FBL May respond to anti-EBV therapy (AZT, gancyclovir) or HD MTX Systemic non-Hodgkin’s lymphoma Up to 50% may be cured with standard chemotherapy CD4 count most important prognostic factor Attention to supportive care important Reduced-dose regimens may result in inferior outcome Dose-dense or intense regimens not more effective Phase III trial of CHOP +/- rituximab completed Ongoing studies evaluating infusional therapy +/- rituximab Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

Kaposi’s Sarcoma First described by Moriz Kaposi in 1872
Clinical presentations: Classic KS: European men Endemic: African Iatrogenic: induced immunosuppression HIV associated: also immune mediated In the United States: > 90% associated with HIV Most cases in HIV-positive homosexual men Some cases in HIV-negative homosexual mean Peak incidence 1989, now at pre-1983 levels Initially described in elderly Mediterranean men, usually involving legs In Africa: Currently epidemic, where it occurs equally in women and children Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

Histology and Pathogenesis
Associated with KSHV infection Human herpes virus (HHV-8) – DNA sequences found in KS lesion; IHC for LNA-1 (encoded by ORF-73) HHV-8 also associated with PEL, Castleman’s disease HHV-8 detectable in semen, saliva Incidence parallels HHV-8 seroprevalence Histologic hallmarks: Spindle cell proliferation Red cell extravasation Cellular infiltration Malignant cell appears to be of clonal lymphoepithelial origin HIV viral antigens (eg, Tat) and cytokines (eg, IL-6) may promote proliferation Decreased incidence and virulence with HAART therapy Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

Principles of Management
Indications for cytotoxic therapy Life-threatening visceral involvement Cosmesis and/or lymphedema Other therapeutic options HAART Biological agents: alpha-IFN, imatinib, thalidomide Irradiation Cryotherapy Topical retinoids Intralesional therapy Cytotoxic agents Liposomal anthracyclines (Doxil, DaunoXome) Antitubulin agents (paclitaxel, vinorelbine) Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

Cancer and HIV Infection
HIV-associated cancers have diminished but are not uncommon Lymphoma is potentially life-threatening but curable KS has a more indolent course in the HAART era Non-AIDS-defining cancers are more common HIV infection is not a contraindication to cytotoxic therapy Patients benefit from a multidisciplinary approach Clinical trials are available for patients with HIV-associated cancers – AIDS Malignancy Consortium ( Sparano, JA. “Lymphoma and Other Cancers.” From HIV Management 2006: The New York Course.

Natural History of Cervical Neoplasia
0–1 Year 0–5 Years 1–20 Years Initial HPV infection Continuing infection CIN 2/3 Invasive cervical cancer Potential Cofactors for Progression: HPV-related: type, variants, viral load Parity, oral contraceptive use Smoking Chlamydia, HSV-2 coinfection Diet (vitamins A, C, E, carotenoids, folic acid, etc.) Immunogenetics (HLA type) Host factors: immune response CIN 1 Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course. Median duration, 1-2 years Cleared HPV infection Adapted from Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43:

Percent With Cervical HPV Infection
70 80% 10 20 30 40 50 60 CD4>500 <200 HIV- HIV+ Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course. P < .001

Percent With Abnormal Cervical Cytology
60% 50 40 30 20 Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course. 10 HIV- HIV+ HIV+ HIV+ P < .001 CD4>500 <200

Guidelines for Assessment of CIN in HIV+ Women
Pap smear at initial evaluation Repeat Pap smear 6 months later If both negative, can do annual Pap Low threshold for colposcopy Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Clinical Challenges in HIV+ Women
Poor response to standard therapy Need for multiple treatments with different therapeutic modalities Faster progression of invasive cancer with poorer therapeutic response Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Anal and Cervical Cancer Incidence
Cervical cancer prior to cervical cytology screening: 40-50/100,000 Cervical cancer currently: 8/100,000 Anal cancer among HIV- MSM: 13-35/100,000 Anal cancer twice as high among HIV+ MSM as in HIV- MSM Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Percent With Anal HPV Infection
100% 90 80 70 60 50 40 30 Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course. 20 10 HIV- HIV+ HIV+ HIV+ CD4>500 <200

Percent With Abnormal Anal Cytology
70 80% 10 20 30 40 50 60 CD4>500 <200 HIV- HIV+ Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Anal and Cervical HPV Infection in HIV-Positive Women
Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course. >500 <200

Risk Factors for Abnormal Anal Cytology in Women
HIV positivity Lower CD4+ level History of anal intercourse Anal HPV infection Abnormal cervical cytology Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Percent of Men Developing AIN 2/3 at Intervals During Follow-up
Months of follow-up 6 % (CI) 12 % (CI) 18 % (CI) 24 % (CI) P HAART use in HIV+ men No 5 (0-11) 23 (12-34) 52 (36-67) 65 (50-82) .44 Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course. Yes 5 (1-9) 35 (27-43) 53 (44-62) 68 (58-77)

Anal Cancer Since Introduction of HAART
Chiao et al. JAIDS. 2005;40: Pre-HIV: /100,000 HIV: /100,000 HAART: /100,000 Female-to-male ratio 1.6: :1 Bower et al. JAIDS. 2004;37: 8640 HIV+ MSM in London Pre-HAART incidence – 35/100,000 patient-years (95% CI, 15-72) Post-HAART incidence – 92/100,00 patient-years (95% CI, ) Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Who Should Be Screened? All HIV+ MSM with good prognosis
All HIV- MSM over the age of 40 ? Women with high-grade vulvar lesions or cancer ? All HIV+ women ? All HIV+ men regardless of sexual orientation ? All men and women with perianal condyloma Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Anal Cytology Screening for AIN in HIV-Positive Men
Normal ASCUS LSIL HSIL Repeat in 12 months (HIV+) Repeat in 2-3 years (HIV-) Anoscopy with biopsy Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course. No lesion seen LSIL HSIL Treat or follow Treat Chin-Hong PV et al. J Infect Dis. 2004;90:

Treatment of ASIL No HPV-specific therapy Removal of lesional tissue
Treatment approach is based on size of lesion: Limited (> 1 cm2) – local therapy, 85% TCA/LN2 Moderate – infrared coagulation Large – surgery with cold scalpel excision, electrocautery, laser Diffuse (circumferential) – “watch and wait” Palefsky, J. “HPV Infection and Genital Neoplasia.” From HIV Management 2006: The New York Course.

Leading Causes of Death (per 100,000) for Men 25-44 Years of Age
70 HIV infection Unintentional injury 60 50 40 Rate Heart disease 30 Suicide Cancer 20 Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course. Homicide Liver disease 10 Stroke Diabetes 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97* Year Source: CDC

Prior Research Has Shown That Psychiatric Patients:
Have increased risk for HIV Are less likely to receive HAART Are less likely to stay on HAART Are less likely to achieve an undetectable viral load Are more likely to die Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course.

Association Between Mental D/O and Time to HAART
1.00 Mental disorder 0.75 No mental disorder Probability of HAART Therapy 0.50 Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course. 0.25 P=0.05 0.00 2 4 6 Time in Years

Association Between Mental Disorder and Survival
1 Mental disorder Probability of Survival No mental disorder Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course. P=0.10 2 4 6 Time in Years

HIV Is a Psychiatric Epidemic
HIV increases risk for psychiatric illness Psychiatric illness increases risk for HIV Effective treatment for psychiatric illness Can improve patient outcome Can decrease HIV transmission Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course.

Depression as AIDS Develops
20 % Depressed 10 Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course. Time of AIDS -48 -36 -24 -12 6 18 Months Before and After AIDS

Neuroleptic augmentation (risk/benefit)
Pharmacotherapy Poor sleep Weight loss Anxiety GI disturbance Hypersomnia Weight gain Suicide potential Chronicity Trazodone Nefazodone Bupropion Mirtazepine MAOIs Atomoxetine Failure from side effects Nortriptyline Desipramine Fluoxetine Sertraline Paroxetine Fluvoxamine Citalopram Escitalopram Venlafaxine Duloxetine Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course. Failure after good trial Lithium augmentation Neuroleptic augmentation (risk/benefit) NEXT DRUG

Treatment of Depression Outcome by Diagnosis
100 Full Partial Percentage None Treisman, GJ. “Overcoming Psychiatric Barriers to HIV Treatment.” From HIV Management 2006: The New York Course. Dementia Substance use Personality disorder Compliant Overall

HIV Coinfections, Malignancies, and Comorbidities

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HIV Coinfections, Malignancies, and Comorbidities

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Presentation on theme: "HIV Coinfections, Malignancies, and Comorbidities"— Presentation transcript:

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