HIV Coinfections, Malignancies, and Comorbidities

HIV Coinfections, Malignancies, HIV Coinfections, Malignancies, andand

ComorbiditiesComorbidities


ComorbiditiesComorbidities HIV-hepatitis C coinfectionHIV-hepatitis C coinfection

HIV-hepatitis B coinfectionHIV-hepatitis B coinfection

Hepatotoxicity, HIV-hep coinfection, and Hepatotoxicity, HIV-hep coinfection, and antiretroviral therapyantiretroviral therapy

HIV-related malignanciesHIV-related malignancies

Psychiatric concerns in persons with HIVPsychiatric concerns in persons with HIV

Overlapping HCV and HIV Overlapping HCV and HIV EpidemicsEpidemics

Up to 33% of HIV+ patients in EuroSIDA are Up to 33% of HIV+ patients in EuroSIDA are HCV Ab+ (75% among intravenous-drug HCV Ab+ (75% among intravenous-drug

users)users)

40 million40 million200 million200 million

10 million10 million

HIVHIV Hep CHep C

Variables to Consider Before Variables to Consider Before Initiating HCV Therapy in HIV+ Initiating HCV Therapy in HIV+

PatientsPatients HIV-related:HIV-related:

– CD4CD4– HIV RNAHIV RNA– Antiretroviral therapyAntiretroviral therapy

Liver-related:Liver-related:– GenotypeGenotype– HCV loadHCV load– TransaminasesTransaminases– HistologyHistology

Others:Others:– Neuropsychiatric historyNeuropsychiatric history– Drug addiction and alcohol consumptionDrug addiction and alcohol consumption

Randomized Clinical Trials:Randomized Clinical Trials: Peg-IFN + RBV in HIV+ Persons Peg-IFN + RBV in HIV+ Persons

ACTG5071ACTG5071 APRICOTAPRICOT RIBAVICRIBAVIC LagunoLaguno

No. with Peg + ribavirin (RBV)No. with Peg + ribavirin (RBV) 6666 289289 205205 5252

Type of peg IFNType of peg IFN 2a2a 2a2a 2b2b 2b2b

IDUsIDUs –– 62%62% 81%81% 75%75%

CirrhoticsCirrhotics 11%11% 15%15% 40%40%(F3-F4)(F3-F4) 19%19%

Genotypes 1-4Genotypes 1-4 77%77% 67%67% 69%69% 63%63%

Normal ALT levelsNormal ALT levels –– 00 15%15% 00

Mean CD4 countMean CD4 count –– 520520 525525 512512

On HAARTOn HAART –– 84%84% 82%82% 94%94%

Premature discontinuationPremature discontinuation –– 25%25% 41%41% 25%25%

EOT (ITT)EOT (ITT) 41%41% 49%49% 36%36% 52%52%

SVR (ITT)SVR (ITT) 27%27% 40%40% 27%27% 44%44%

Main Predictors of Sustained Main Predictors of Sustained Virologic ResponseVirologic Response

HCV genotypeHCV genotype

Baseline HCV RNABaseline HCV RNA

Adherence (80/80/80)Adherence (80/80/80)

Week 4 virologic response (best positive Week 4 virologic response (best positive predictive value [PPV] of sustained predictive value [PPV] of sustained virologic response [SVR])virologic response [SVR])

What Can We Do to Improve What Can We Do to Improve SVR SVR

in HIV/HCV Coinfection?in HIV/HCV Coinfection? Select candidates correctlySelect candidates correctly

Prevent and optimally manage side effectsPrevent and optimally manage side effects

Enhance early virologic responseEnhance early virologic response

– Induction doses: peg-IFN and/or RBVInduction doses: peg-IFN and/or RBV

Reduce relapse ratesReduce relapse rates

– Extending the length of therapyExtending the length of therapy

Week 12 Predictive Value of Week 12 Predictive Value of SVRSVR

HCV RNAHCV RNAdrop > 2 logsdrop > 2 logs

n = 453n = 453

n = 89n = 89

SVRSVR

SVRSVR

YESYES

NONO

YESYES

NONO

86%86%

58%58%

14%14%

42%42%

YESYES

NONO

65%65%

56%56%

35%35%

44%44%

3%3%

0%0%

97%97%

100%100%

HIV-neg: Fried et al. HIV-neg: Fried et al. N Engl J MedN Engl J Med. 2002. 2002

HIV-pos: Soriano et al. HIV-pos: Soriano et al. Antivir TherAntivir Ther. 2004. 2004

RBV 800 mg and genos 2-3 tx 24 monthsRBV 800 mg and genos 2-3 tx 24 months

PRESCO Trial: DesignPRESCO Trial: Design

Study WeeksStudy Weeks00 9696727248482424 6060 8484

Peg

-IF

N +

RB

V

Peg

-IF

N +

RB

V

1000

-120

0 m

g/d

ay10

00-1

200

mg

/day

1212 3636

Follow-upFollow-up

G2,3G2,3

G1,4G1,4

G1,4G1,4

G2,3G2,3

Follow-upFollow-up

Follow-upFollow-up

Follow-upFollow-up

Only patients who achieved EVR (>2 log drop in HCV RNA at week 12) continued treatment.Only patients who achieved EVR (>2 log drop in HCV RNA at week 12) continued treatment.

N =

391

N =

391

13%

40%

68%

34%

46%

69%

0

10

20

30

40

50

60

70

80

>1 log >2 log Neg (<10 IU/mL)

Week 4

HC

V R

NA

Dro

p (

% P

atie

nts

) APRICOT (n=176)

PRESCO (n=94)

APRICOT (800 mg/day) vs PRESCO APRICOT (800 mg/day) vs PRESCO (1000–1200 mg/day): G1 Week 4 (1000–1200 mg/day): G1 Week 4

ResponseResponse

Ramos et al. Ramos et al. Antivir TherAntivir Ther. 2006 (in press). 2006 (in press)

On-treatment analysisOn-treatment analysis

Week 4 Virologic ResponseWeek 4 Virologic ResponseAccording to HIV Status and RBV According to HIV Status and RBV

Dose Dose Study No. Week 4 >1 log reduction

in HCV-RNA >2 log reduction in HCV-RNA

Negative serum HCV-RNA

HCV genotype 1

PRESCO 94 69.2 46.2 33.8 Fried 298 78.8 55.3 31.2 APRICOT 176 68 40 13 HCV genotype 3

PRESCO 70 93.8 89.6 85.4 Fried 140 95 90.7 84.2 APRICOT 95 87 80 37 HCV genotype 4

PRESCO 18 57.1 50 28.6 Fried 15 93.3 66.6 60 APRICOT 16 56 19 13

PRESCO: HIV+ and RBV high Fried: HIV-neg and RBV high APRICOT: HIV+ and RBV lowPRESCO: HIV+ and RBV high Fried: HIV-neg and RBV high APRICOT: HIV+ and RBV low

Clinical InterpretationClinical Interpretation

HIV negativelyHIV negatively affectsaffects the early virologic the early virologic response to HCV therapyresponse to HCV therapy

Prescription of appropriate Prescription of appropriate (high) RBV doses(high) RBV doses increase early virologic response mainly increase early virologic response mainly in genotypes 1 and 4, but also in genotypes 2 in genotypes 1 and 4, but also in genotypes 2 and 3and 3

SHORT STATEMENT OF THE FIRST EUROPEAN CONSENSUSCONFERENCE ON THE TREATMENT OF CHRONIC

HEPATITIS C AND B IN HIV CO-INFECTED PATIENTS1–2 March, 2005, Paris, France

The ECC Jury

J Hepatol 2005;42:615-24.







Chu et al. Chu et al. GastroenterologyGastroenterology. 2003;125:444.. 2003;125:444.

A 34.7%

B 22.0%

C 30.8%

D 10.4%

E, F, G 2.1%

Midwest (25%) East (17%)

n=694 adults, in 17 centers

Hepatitis B Virus Hepatitis B Virus Genotypes in the United StatesGenotypes in the United States

10%

13%

12%

37%

15%

33%

13%2%

37%

17%

23%

18%

5%

South (19%)West (39%)

18%

34%41%

5%2%

63%

2%

Sequelae of Chronic HBV Sequelae of Chronic HBV InfectionInfection

Hepatocellular carcinoma (HCC)Hepatocellular carcinoma (HCC)

– ~500,000 deaths annually worldwide~500,000 deaths annually worldwide11

– ~50% of cases associated with HBV infection~50% of cases associated with HBV infection11

Viral factors linked to greater risk of HCC Viral factors linked to greater risk of HCC include HBeAg positivity, serum HBV DNA include HBeAg positivity, serum HBV DNA levels >10levels >1055 copies/mL, and genotype C copies/mL, and genotype C22

Risk of HCC increase based on HBV DNA Risk of HCC increase based on HBV DNA levels, even in patients with normal ALT at levels, even in patients with normal ALT at baselinebaseline33

1. Parkin DM, et al.1. Parkin DM, et al. Int J Cancer Int J Cancer. 2001;94:153-156. . 2001;94:153-156. 2. Yu MW, et al. 2. Yu MW, et al. J Natl Cancer InstJ Natl Cancer Inst. 2005;97:265-272.. 2005;97:265-272.3. Iloeje UH, et al. 3. Iloeje UH, et al. J HepatolJ Hepatol. 2005;42:16S [Abstract 495].. 2005;42:16S [Abstract 495].

% W

ith

dis

ease

pro

gre

ssio

n%

Wit

h d

isea

se p

rog

ress

ion

Time to Disease ProgressionTime to Disease ProgressionTreatment and Off-Treatment Treatment and Off-Treatment

Follow-upFollow-up

Placebo (n=215)Placebo (n=215) ITT populationITT populationLamivudine (n=436)Lamivudine (n=436) PP = .001 = .001

Time to disease progression (months)Time to disease progression (months)

LamivudineLamivudine

PP = .001 = .001

2525

2020

1515

1010

55

0000 66 1212 1818 2424 3030 3636

9%

21%

Placebo

Lamivudinen=385n=385

n=198n=198

n=417n=417

n=173n=173n=122n=122

n=198n=198

Liaw YF, et al. Liaw YF, et al. N Engl J MedN Engl J Med. 2004;351:1521-1531.. 2004;351:1521-1531.

HIV/HBV Coinfection: HIV/HBV Coinfection: Effect on Liver-Related Effect on Liver-Related

MortalityMortality

00

22

44

66

88

1010

1212

1414

1616

HIV-/HBsAg-HIV-/HBsAg- HIV+HIV+ HBsAg+HBsAg+ HIV+/HBsAg+HIV+/HBsAg+

Liv

er-r

elat

ed m

ort

alit

y ra

te

Liv

er-r

elat

ed m

ort

alit

y ra

te

(per

100

0 p

erso

n-y

ears

)(p

er 1

000

per

son

-yea

rs)

P <P < .001 .001P P = .04= .04

P P < .0001< .0001

Thio CL, et al.Thio CL, et al. Lancet Lancet. 2002;360:1921-1926. . 2002;360:1921-1926.

Impact of HBV InfectionImpact of HBV Infectionon HIV Outcomeon HIV Outcome

111 HIV/HBV-coinfected patients and 387 111 HIV/HBV-coinfected patients and 387 HIV-infected patients without HBV or HCV HIV-infected patients without HBV or HCV prospectively observed between June 1994 prospectively observed between June 1994 and February 2003and February 2003

After a median of 25 monthsAfter a median of 25 months– Coinfected patients were more likely to develop Coinfected patients were more likely to develop

hepatitis hepatitis – Coinfected patients were much more likelyCoinfected patients were much more likely

to develop hepatic decompensationto develop hepatic decompensation HBV-infected patients had an increased riskHBV-infected patients had an increased risk

for virologic failure and death after HAART for virologic failure and death after HAART was initiatedwas initiated

Sheng WH, et al. Sheng WH, et al. Clin Infect DisClin Infect Dis. 2004;38:1471-1477. . 2004;38:1471-1477.

Occult HBV Is Frequent in HIV Patients, Occult HBV Is Frequent in HIV Patients, Is More Common in Patients With Is More Common in Patients With

Chronic HCV, and Enhances Severity of Chronic HCV, and Enhances Severity of Liver Disease Liver Disease

955 HIV-infected patients from 4 ID units in Italy955 HIV-infected patients from 4 ID units in Italy

– 581 (61%) anti-HBc+581 (61%) anti-HBc+

– 64 (7%) HBsAg+64 (7%) HBsAg+

– 361 (38%) anti-HBs+361 (38%) anti-HBs+

– 190 (20%) anti-HBc+ alone190 (20%) anti-HBc+ alone

– 402 (42%) coinfected with HCV402 (42%) coinfected with HCV

Liver cirrhosis observed only in HCV+ patientsLiver cirrhosis observed only in HCV+ patients

– 16% in anti-HBc+ vs 1.5% in anti-HBc- (16% in anti-HBc+ vs 1.5% in anti-HBc- (PP < .0001) < .0001)Marino N, et al. EASL Marino N, et al. EASL 2005. Abstract 514. 2005. Abstract 514.

HBV Evaluation and MonitoringHBV Evaluation and Monitoringin HIV/HBV-Coinfected Patientsin HIV/HBV-Coinfected Patients

362 HIV patients found to be HBsAg+ between 362 HIV patients found to be HBsAg+ between 1999 and 2003 in Parkland HIV Clinic1999 and 2003 in Parkland HIV Clinic

Patients identified as HBsAg+ after 1999 Patients identified as HBsAg+ after 1999 are receiving HBV testing more rapidlyare receiving HBV testing more rapidly

Still, almost 50% initially identified as HBsAg+ Still, almost 50% initially identified as HBsAg+ did not receive initial evaluation for HBV did not receive initial evaluation for HBV status, cirrhosis, or HCCstatus, cirrhosis, or HCC

Opio CK, et al. DDW Opio CK, et al. DDW 2005. Abstract S932. 2005. Abstract S932.

HBV Goals of TherapyHBV Goals of Therapy

Long-term viral suppressionLong-term viral suppression

No resistance developmentNo resistance development

Decrease risk of HCCDecrease risk of HCC

What is optimal therapy?What is optimal therapy?

Currently Approved Currently Approved Antiviral TherapiesAntiviral Therapies

Interferon alfa-2bInterferon alfa-2b

Peginterferon alfa-2aPeginterferon alfa-2a

Lamivudine (LAM)Lamivudine (LAM)

Adefovir dipivoxil (ADV)Adefovir dipivoxil (ADV)

Entecavir (ETV)Entecavir (ETV)

Mutations in the HBV Genome Mutations in the HBV Genome Lead Lead

to Resistance to Antiviral to Resistance to Antiviral TherapiesTherapies

Terminal proteinTerminal protein

V173L

V173L

A181V or TA181V or T

Lamivudine resistanceLamivudine resistancemutationsmutations

SpacerSpacer Reverse transcriptaseReverse transcriptase Rnase HRnase H

FF GG AA BB CC DD EE

L180ML180M

YMDDYMDD

M204V or I

M204V or I

N236T K241EN236T K241EK318QK318Q

34434411

Observed in ADV treated patientsObserved in ADV treated patients

HBV HBV Antiviral TherapyAntiviral TherapyCross-Resistance Cross-Resistance IIn n VViitrotro

M204VM204V

V173LV173L

A181VA181V

M250VM250V

L180ML180M

A184GA184G

S202IS202I

N236TN236T

M204I

M204I

LAMLAM

ADVADV

ETVETV

LdTLdT

FTCFTC

TDFTDF

0% 2%7%

15%

24%

42%

53%

70%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Year 1 Year 2 Year 3 Year 4

Pre

vale

nce

of

Res

ista

nce

Prevalence of Resistance in Prevalence of Resistance in HIV- Patients Treated With ADV HIV- Patients Treated With ADV

or LAMor LAM

Locarnini S, et al.Locarnini S, et al. J Hepatol J Hepatol. 2005;42(suppl 2):17.. 2005;42(suppl 2):17.

ADV (N236T or A181V)

LAM (YMDD)

HBV DNA and ALT Normalization With HBV DNA and ALT Normalization With ADV in LAM-Resistant HBV/HIV-ADV in LAM-Resistant HBV/HIV-

Coinfected PatientsCoinfected Patients

0%

27%

36%

3%

37%

64%

6%

19%

0%

10%

20%

30%

40%

50%

60%

70%

Baseline Week 48 Week 96 Week 144

Weeks on ADV

Pat

ien

ts (

%)

HBV DNA ≤ 1000 copies/mL

ALT normalization

Benhamou Y, et al. 12th CROI. Boston, MA. 2005. Abstract 935. Benhamou Y, et al. 12th CROI. Boston, MA. 2005. Abstract 935.

A n=90

47%44%

Bn=23

28%

C n=39

25%

D n=103

0

10

20

30

40

50

%

Peg alfa 2a Response by Peg alfa 2a Response by GenotypeGenotype

HBeAg Loss at HBeAg Loss at 6 Months Post-Rx, 6 Months Post-Rx, HIV- PtsHIV- Pts

Janssen H, et al. Janssen H, et al. LancetLancet. 2005;365:123-129.. 2005;365:123-129.

Adefovir vs Tenofovir in HIV-Adefovir vs Tenofovir in HIV-Coinfected Patients With LAM-Coinfected Patients With LAM-

Resistant HBVResistant HBV

2233

44 4444

78

94100

0

20

40

60

80

100

120

Week 12 Week 24 Week 36 Week 48% o

f P

atie

nts

w/H

BV

DN

A <

400

cop

ies/

mL

Adefovir

Tenofovir

Van Bommel F, et al. Van Bommel F, et al. HepatologyHepatology. 2004;40:1421-1425.. 2004;40:1421-1425.

LAM + TDF Shows Greater Decline in LAM + TDF Shows Greater Decline in HBV DNA Than LAM Alone or LAM Prior HBV DNA Than LAM Alone or LAM Prior to LAM + TDF in HBV/HIV-Coinfected to LAM + TDF in HBV/HIV-Coinfected

Patients Patients Group 1 (n=10) received LAM 150 mg bid only; group 2 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 (n=8), LAM + TDF 300 mg qd, and group 3 (n=12), ≥1 yr of LAM followed by LAM + TDFof LAM followed by LAM + TDF

Group 2 had greatest average log drop at year 1, 3.2 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, logs, compared with 1.5 and 1.1 logs in groups 1 and 3, respectively (respectively (PP = .05) = .05)

Sequential regimen less effective than in previous Sequential regimen less effective than in previous controlled trialscontrolled trials

Most patients in this study have HBV genotype A and Most patients in this study have HBV genotype A and appear more likely to respond to either therapy than appear more likely to respond to either therapy than those with non-A genotypesthose with non-A genotypes

Study is ongoing, as more data are needed to confirm Study is ongoing, as more data are needed to confirm these findings and explore possible synergy between these findings and explore possible synergy between LAM and TDFLAM and TDF

Mamta K, et al. 55th AASLD. Boston, MA. 2004. Abstract 1168. Mamta K, et al. 55th AASLD. Boston, MA. 2004. Abstract 1168.

ETV-038: Mean Change in HBV ETV-038: Mean Change in HBV DNADNA

From Baseline by PCR in HIV+ From Baseline by PCR in HIV+ PtsPts

Estimated difference in mean HBV DNA reduction (entecavir – placebo) Estimated difference in mean HBV DNA reduction (entecavir – placebo) was -3.76 logwas -3.76 log1010 copies/mL (95% CI [-4.49, -3.04]; P<0.0001). copies/mL (95% CI [-4.49, -3.04]; P<0.0001).

PP < .0001 for all analyses performed at week 24. < .0001 for all analyses performed at week 24.

5117

4616

4816

n (ETV) n (PBO)

4916

HB

V D

NA

by

PC

R

(lo

g10

co

pie

s/m

L)

*P<0.0001 for each comparison

on-treatment

-3.66 log10

-5

-4

-3

-2

-1

0

1

0 2 12 24

Placebo

ETV

+0.11 log10

*

*

*

Weeks

Other Combinations for HBV Other Combinations for HBV at AASLD 2005at AASLD 2005

Emtricitabine (FTC) and clevudine (L-Emtricitabine (FTC) and clevudine (L-FMAU)FMAU)

LAM and ADVLAM and ADV

Tenofovir (TDF) rescue of ADV failureTenofovir (TDF) rescue of ADV failure

Combination therapy and resistance lights Combination therapy and resistance lights starting to pop on very slowlystarting to pop on very slowly

Evolving Treatment Paradigms Evolving Treatment Paradigms in HBV, HBV/HIVin HBV, HBV/HIV

SuppressionSuppression Reduce HBV DNAReduce HBV DNA Improve ALTImprove ALT Potential for resistancePotential for resistance Hope for seroconversionHope for seroconversion Indefinite course of therapyIndefinite course of therapy

Complete ResponseComplete Response Undetectable HBV DNAUndetectable HBV DNA Normalization of ALTNormalization of ALT Minimal resistanceMinimal resistance HBeAg loss/seroconversionHBeAg loss/seroconversion Sustained viral load Sustained viral load

reduction off treatmentreduction off treatment

EliminationEliminationComplete response, plusComplete response, plus Eradication of cccDNAEradication of cccDNA No hepatic flares off treatmentNo hepatic flares off treatment Reduce progression Reduce progression

of liver diseaseof liver disease

Current FutureFuture







Patterns of SteatosisPatterns of Steatosis

Macrovesicular steatosis:Macrovesicular steatosis: Hepatocytes contain a single large vacuole of Hepatocytes contain a single large vacuole of

fat (TG) that fills up the cell and displaces the fat (TG) that fills up the cell and displaces the nucleus to the peripherynucleus to the periphery

Microvesicular steatosis:Microvesicular steatosis: Hepatocytes are filled up with numerous small Hepatocytes are filled up with numerous small

lipid vesicles that leave the nucleus in the lipid vesicles that leave the nucleus in the center of the cellcenter of the cell

““Its presence implies impairment of Its presence implies impairment of mitochondrial oxidation of fatty acids mitochondrial oxidation of fatty acids and severe energy crisis” – D. Pessayreand severe energy crisis” – D. Pessayre

Role of Hepatic Steatosis in Role of Hepatic Steatosis in HIV/HCV-Coinfected PatientsHIV/HCV-Coinfected Patients

183 Biopsies

Steatosis absent (57)

Steatosis present

(126)

Minimal23%

Mild 28%

Moderate to severe

19%

McGovern B et al. McGovern B et al. Clin Infect DisClin Infect Dis (2006); in press. (2006); in press.

HAART and HepatotoxicityHAART and Hepatotoxicity

10,000 patients from 21 ACTG trials10,000 patients from 21 ACTG trials

– High rate of severe drug-induced liver injury High rate of severe drug-induced liver injury (DILI) irrespective of class(DILI) irrespective of class

3,927 pts with follow-up for 3 years on ART3,927 pts with follow-up for 3 years on ART

– The most common grade 4 adverse events The most common grade 4 adverse events were liver relatedwere liver related

– Risk was higher in patients with viral hepatitis Risk was higher in patients with viral hepatitis (OR = 5.97 for HBV; OR = 2.74 for HCV)(OR = 5.97 for HBV; OR = 2.74 for HCV)

Reisler, IAS 2001, Buenos Aires, Abst. 43; Reisler, Reisler, IAS 2001, Buenos Aires, Abst. 43; Reisler, J Acquir Immune Defic Syndr.J Acquir Immune Defic Syndr. 2003;34. 2003;34.

NRTIs and Mitochondrial NRTIs and Mitochondrial ToxicityToxicity

Impaired mitochondrial function can lead Impaired mitochondrial function can lead to a decrease in fatty acid oxidationto a decrease in fatty acid oxidation

FFAs accumulate and are metabolized FFAs accumulate and are metabolized to triglyceridesto triglycerides

Long-term administration can lead Long-term administration can lead to hepatic steatosisto hepatic steatosis

Risk Factors for NVP-Risk Factors for NVP-Associated Associated SymptomaticSymptomatic

Events in All TrialsEvents in All Trials

NVP (RR = 11.2; NVP (RR = 11.2; PP < .01) < .01)

Female gender (RR = 3.2; Female gender (RR = 3.2; PP < .01) < .01)

Female with baseline CD4 Female with baseline CD4 ≥ ≥ 250 (RR = 9.8; 250 (RR = 9.8; PP < .01) < .01)

Male with baseline CD4 Male with baseline CD4 ≥ ≥ 400 (RR = 6.4; 400 (RR = 6.4; PP < .01) < .01)

Baseline ALT or AST >2.5x Baseline ALT or AST >2.5x ULN (RR = 3.2; ULN (RR = 3.2; PP < .01) < .01)

HBV coinfection (RR = 3.9; HBV coinfection (RR = 3.9; PP < .01) < .01)

Baseline CD4 found to be Baseline CD4 found to be an inconsistent factoran inconsistent factor

Rash-Associated Hepatic Events Other Symptomatic Hepatic Events

Stern JO et al, 14th Int AIDS Conference, 2002, Barcelona.Stern JO et al, 14th Int AIDS Conference, 2002, Barcelona.

PIs and HepatotoxicityPIs and Hepatotoxicity

Ritonavir use had a higher overall incidence of Ritonavir use had a higher overall incidence of moderate and severe hepatotoxicity compared moderate and severe hepatotoxicity compared with other PIswith other PIs

Conflicting data in subsequent large cohorts Conflicting data in subsequent large cohorts using high-dose ritonavir; however, low-dose using high-dose ritonavir; however, low-dose appears to be safeappears to be safe

Nelfinavir and indinavir associated with lowest Nelfinavir and indinavir associated with lowest incidence of DILI in one large cohortincidence of DILI in one large cohort

Cooper, CID 2003;36:1585; Sulkowksi, AIDS 2004;18:2277; Cooper, CID 2003;36:1585; Sulkowksi, AIDS 2004;18:2277; Bruno, Bruno, Clin Gastroenterol Hepatol.Clin Gastroenterol Hepatol. 2005;3:482. 2005;3:482.

Pharmacokinetics of Pharmacokinetics of Lopinavir/Ritonavir in HIV/HCVLopinavir/Ritonavir in HIV/HCV

Ritonavir pK sampling on day 14 in 12 Ritonavir pK sampling on day 14 in 12 HIV/HCV patients with mild and moderate HIV/HCV patients with mild and moderate liver disease:liver disease:

AUC:AUC:

41% higher in mild liver disease41% higher in mild liver disease

185% higher in moderate liver disease185% higher in moderate liver disease

Arribas J et al, 9th EASL.Arribas J et al, 9th EASL.

Can We Avoid Drug-Induced Can We Avoid Drug-Induced Liver Injury (DILI) by Risk Liver Injury (DILI) by Risk

Stratification?Stratification? GenderGender HIV infection and low glutathione levelsHIV infection and low glutathione levels Genetic polymorphisms: CYP2D6Genetic polymorphisms: CYP2D6 ObesityObesity Acetylator statusAcetylator status AgeAge Duration of treatmentDuration of treatment Alcohol useAlcohol use and ROS, 2E1, glutathione and ROS, 2E1, glutathione New risk factorNew risk factor: Chronic viral hepatitis: Chronic viral hepatitis

Cumulative Effects of Liver Cumulative Effects of Liver InjuryInjury

Is a “trial by error” approach potentially Is a “trial by error” approach potentially harmful?harmful?

Reports of worsening histology after HAARTReports of worsening histology after HAART

17 patients with severe hepatotoxicity:17 patients with severe hepatotoxicity:

– Four-month “washout” period Four-month “washout” period

– 59% successfully tolerated their medications59% successfully tolerated their medications

– However, 41% had another episode of DILI!However, 41% had another episode of DILI!

Hepatotoxicity is a sign that should be Hepatotoxicity is a sign that should be evaluatedevaluated

Puoti, Puoti, J Acquir Immune Defic Syndr.J Acquir Immune Defic Syndr. 2003;32:259; Aceti, 2003;32:259; Aceti, Int J STD AIDS.Int J STD AIDS. 2005;16:148. 2005;16:148.

Prevention of DILIPrevention of DILI

Pitfalls and limitations of current dataPitfalls and limitations of current data

Assessment of riskAssessment of risk

– Does the patient have chronic viral hepatitis?Does the patient have chronic viral hepatitis?

– What are the baseline aminotransferases?What are the baseline aminotransferases?

– Evaluate synthetic functionEvaluate synthetic function

– Staging of liver diseaseStaging of liver disease

Monitoring of laboratoriesMonitoring of laboratories

Education of the patient!Education of the patient!

Sabin, Sabin, Clin Infect Dis.Clin Infect Dis. 2004;S56; McGovern, IAPAC 2004, S23. 2004;S56; McGovern, IAPAC 2004, S23.







Concomitant Diseases and Concomitant Diseases and Comorbidities: Comorbidities: MalignanciesMalignancies

LymphomaLymphoma

Kaposi’s sarcoma Kaposi’s sarcoma

Human papillomavirus: anal and cervical Human papillomavirus: anal and cervical cancercancer

Other cancersOther cancers

Cancers Associated With Cancers Associated With HIV InfectionHIV Infection

AIDS definingAIDS defining

– Systemic and CNS lymphoma (EBV)Systemic and CNS lymphoma (EBV)

– Kaposi’s sarcoma (HHV-8)Kaposi’s sarcoma (HHV-8)

– Cervical carcinoma (HPV)Cervical carcinoma (HPV)

Non-AIDS definingNon-AIDS defining

– Aerodigestive cancers (head/neck, lung)Aerodigestive cancers (head/neck, lung)

– Hematalogic (Hodgkin’s disease, myeloma)Hematalogic (Hodgkin’s disease, myeloma)

– Skin (anal, melanoma)Skin (anal, melanoma)

– Testis (seminoma)Testis (seminoma)

– OthersOthers

HIV Infection and Risk of HIV Infection and Risk of Hematologic NeoplasmsHematologic Neoplasms

Linkage between cancer and AIDS registriesLinkage between cancer and AIDS registries

USA, Italy, AustraliaUSA, Italy, Australia

Relative risk increased forRelative risk increased for

– Intermediate- or high-grade lymphoma – 400-foldIntermediate- or high-grade lymphoma – 400-fold

– Low-grade and T-cell lymphoma – 15-foldLow-grade and T-cell lymphoma – 15-fold

– Hodgkin’s disease – 10-foldHodgkin’s disease – 10-fold

– Myeloma and leukemias – 2- to 5-foldMyeloma and leukemias – 2- to 5-fold

In Africa – risk 10x less than in developed countries In Africa – risk 10x less than in developed countries

– Underascertainment?Underascertainment?

– Earlier death from infection?Earlier death from infection?

Dal Maso L. Dal Maso L. Lancet Oncol.Lancet Oncol. 2003; 4: 110-9. 2003; 4: 110-9.

Highly Active Antiretroviral Therapy Highly Active Antiretroviral Therapy and Incidence of Cancer in HIV-and Incidence of Cancer in HIV-

Infected AdultsInfected Adults

International Collaboration on HIV and Cancer. International Collaboration on HIV and Cancer. J Natl Cancer Inst.J Natl Cancer Inst. 2000; 92: 1822-30. 2000; 92: 1822-30.

Cancer typeCancer type

Adjusted incidence rateAdjusted incidence rateper 1000 per year (No.)per 1000 per year (No.)

Rate ratio (RR) for Rate ratio (RR) for 1997 through 19991997 through 1999

vs vs 1992 through 19961992 through 1996

1992–19961992–1996 1997–19991997–1999 RR (SE)RR (SE) RR (99% Cl)RR (99% Cl)

Kaposi’s sarcomaKaposi’s sarcoma 15.2 (1489)15.2 (1489) 4.9 (190)4.9 (190) 0.32 (0.03)0.32 (0.03)

Hodgkin’s diseaseHodgkin’s disease 0.5 (38)0.5 (38) 0.4 (12)0.4 (12) 0.77 (0.26)0.77 (0.26)

Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma 6.2 (623)6.2 (623) 3.6 (134)3.6 (134) 0.58 (0.06)0.58 (0.06)

Cancer of the uterine cervixCancer of the uterine cervix 1.1 (19)1.1 (19) 2.1 (17)2.1 (17) 1.87 (0.65)1.87 (0.65)

Other cancersOther cancers 1.7 (126)1.7 (126) 1.7 (54)1.7 (54) 0.96 (0.16)0.96 (0.16)

0.10.1 11 1010

Characteristics of HIV-Characteristics of HIV-Associated Lymphoma in Associated Lymphoma in

Adults and ChildrenAdults and Children PresentationPresentation

– Primary CNS disease (10%)Primary CNS disease (10%)

– Systemic lymphoma (90%)Systemic lymphoma (90%)

HistologyHistology– Large cell or immunoblasticLarge cell or immunoblastic

– Small, noncleaved cellSmall, noncleaved cell

– Uncommon typesUncommon types Primary effusion lymphoma (KSHV)Primary effusion lymphoma (KSHV) Plasmablastic lymphoma of oral cavityPlasmablastic lymphoma of oral cavity

Extranodal involvement common (up to 80-90%)Extranodal involvement common (up to 80-90%)– Common sites: marrow, GI tractCommon sites: marrow, GI tract

– Uncommon sites: kidneys, skin, other unusual sitesUncommon sites: kidneys, skin, other unusual sites

A Prognostic Index for Systemic AIDS-A Prognostic Index for Systemic AIDS-Related Non-Hodgkin’s Lymphoma Related Non-Hodgkin’s Lymphoma

Treated in the Era Treated in the Era of Highly Active Antiretroviral Therapyof Highly Active Antiretroviral Therapy

Patients:Patients:– 9621 HIV-positive patients, 111 in whom AIDS-related non-Hodgkin’s 9621 HIV-positive patients, 111 in whom AIDS-related non-Hodgkin’s

lymphoma was treated after 1996lymphoma was treated after 1996 Results:Results:

– OS increased in the HAART era (log-rank chi-square, 9.23; OS increased in the HAART era (log-rank chi-square, 9.23; PP = .002) = .002)

– Regression modeling for patients in whom disease was diagnosedRegression modeling for patients in whom disease was diagnosedafter 1996 revealed only 2 independent predictors of death: after 1996 revealed only 2 independent predictors of death:

International Prognostic Index risk group (stage III/IV disease, International Prognostic Index risk group (stage III/IV disease, elevated LDH, poor PS, > 1 extranodal site, age > 60)elevated LDH, poor PS, > 1 extranodal site, age > 60)

CD4 cell countCD4 cell count

– These predictors yielded 4 internally validated risk strata with These predictors yielded 4 internally validated risk strata with predicted 1-year survival rates of 82%, 47%, 20%, and 15% (predicted 1-year survival rates of 82%, 47%, 20%, and 15% (PP < .001). < .001).

– Prognostic risk scores in the highest quartile yielded a likelihood ratio 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 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, than 1.0 yielded a likelihood ratio of 0.23 (hazard ratio, 0.15; 95% CI, 0.06-0.33)0.06-0.33)

Bower et al. Bower et al. Ann Int Med.Ann Int Med. 2005; 143(4): 265-73. 2005; 143(4): 265-73.

Presentation of Primary CNS Presentation of Primary CNS Lymphoma (PCNSL)Lymphoma (PCNSL)

PresentationPresentation– Neurological symptoms and signsNeurological symptoms and signs– History of OIs, CD4 count low (< 50/μL)History of OIs, CD4 count low (< 50/μL)

ImagingImaging– Few (1-3), large (2-4 cm) FBL that enhance (50%)Few (1-3), large (2-4 cm) FBL that enhance (50%)– Periventricular cerebral hemispheres; basal ganglia, brainstem, Periventricular cerebral hemispheres; basal ganglia, brainstem,

cerebellumcerebellum HistologyHistology

– Large-cell/immunoblastic B-cell lymphomaLarge-cell/immunoblastic B-cell lymphoma– EBV positive EBV positive – CSF cytology + in 20%, ocular involvementCSF cytology + in 20%, ocular involvement

Differential diagnosisDifferential diagnosis– Toxoplasmosis and other infectionsToxoplasmosis and other infections– PML, other PML, other

Establishing a diagnosisEstablishing a diagnosis– Empiric trial of antitoxoplasmosis therapyEmpiric trial of antitoxoplasmosis therapy– CSF EBV DNA – specific for lymphomaCSF EBV DNA – specific for lymphoma– PET/thallium may be helpful in conjunction with EBV DNAPET/thallium may be helpful in conjunction with EBV DNA

Treatment of Primary CNS Treatment of Primary CNS LymphomaLymphoma

Optimize HAARTOptimize HAART

– Anecdotal reports of spontaneous regressionAnecdotal reports of spontaneous regression

– AIDS 1998; 12: 952-8; J AIDS 1992; 5: 953-4AIDS 1998; 12: 952-8; J AIDS 1992; 5: 953-4

Standard treatmentsStandard treatments

– SteroidsSteroids

– Whole-brain irradiation (WBRT)Whole-brain irradiation (WBRT) Median survival, 3 monthsMedian survival, 3 months 10% survive 1 year (usually good PS)10% survive 1 year (usually good PS)

– CHOD chemotherapy x 1 CHOD chemotherapy x 1 WBRT (U.S. Intergroup) WBRT (U.S. Intergroup) Similar results to irradiation alone (J AIDS 2000; 23: A30, abst 63)Similar results to irradiation alone (J AIDS 2000; 23: A30, abst 63)

Alternative treatmentsAlternative treatments

– High-dose zidovudine, gancyclovir +/- IL-2High-dose zidovudine, gancyclovir +/- IL-2 Anecdotal reports of benefit (J AIDS 1999; 15: 713-9)Anecdotal reports of benefit (J AIDS 1999; 15: 713-9)

– High-dose methotrexate-based regimensHigh-dose methotrexate-based regimens

ConclusionsConclusions

Non-Hodgkin’s lymphoma is a common complication of HIV infectionNon-Hodgkin’s lymphoma is a common complication of HIV infection Influence of HAARTInfluence of HAART

– Incidence of lymphoma may be decreasing Incidence of lymphoma may be decreasing – Lymphoma may be a more common initial manifestation of AIDSLymphoma may be a more common initial manifestation of AIDS

Primary CNS lymphoma Primary CNS lymphoma – Common cause of FBLCommon cause of FBL– May respond to anti-EBV therapy (AZT, gancyclovir) or HD MTXMay respond to anti-EBV therapy (AZT, gancyclovir) or HD MTX

Systemic non-Hodgkin’s lymphomaSystemic non-Hodgkin’s lymphoma– Up to 50% may be cured with standard chemotherapyUp to 50% may be cured with standard chemotherapy– CD4 count most important prognostic factorCD4 count most important prognostic factor– Attention to supportive care importantAttention to supportive care important– Reduced-dose regimens may result in inferior outcomeReduced-dose regimens may result in inferior outcome– Dose-dense or intense regimens not more effectiveDose-dense or intense regimens not more effective– Phase III trial of CHOP +/- rituximab completedPhase III trial of CHOP +/- rituximab completed– Ongoing studies evaluating infusional therapy +/- rituximabOngoing studies evaluating infusional therapy +/- rituximab

Kaposi’s SarcomaKaposi’s Sarcoma

First described by Moriz Kaposi in 1872First described by Moriz Kaposi in 1872

Clinical presentations:Clinical presentations:

– Classic KS: European menClassic KS: European men

– Endemic: AfricanEndemic: African

– Iatrogenic: induced immunosuppressionIatrogenic: induced immunosuppression

– HIV associated: also immune mediated HIV associated: also immune mediated

In the United States: > 90% associated with HIVIn the United States: > 90% associated with HIV

– Most cases in HIV-positive homosexual menMost cases in HIV-positive homosexual men

– Some cases in HIV-negative homosexual meanSome cases in HIV-negative homosexual mean

– Peak incidence 1989, now at pre-1983 levels Initially described Peak incidence 1989, now at pre-1983 levels Initially described in elderly Mediterranean men, usually involving legsin elderly Mediterranean men, usually involving legs

In Africa:In Africa:

– Currently epidemic, where it occurs equally in women and childrenCurrently epidemic, where it occurs equally in women and children

Histology and PathogenesisHistology and Pathogenesis

Associated with KSHV infectionAssociated with KSHV infection

– Human herpes virus (HHV-8) – DNA sequences found in KS lesion; Human herpes virus (HHV-8) – DNA sequences found in KS lesion; IHC for LNA-1 (encoded by ORF-73)IHC for LNA-1 (encoded by ORF-73)

– HHV-8 also associated with PEL, Castleman’s diseaseHHV-8 also associated with PEL, Castleman’s disease

– HHV-8 detectable in semen, salivaHHV-8 detectable in semen, saliva

– Incidence parallels HHV-8 seroprevalenceIncidence parallels HHV-8 seroprevalence

Histologic hallmarks:Histologic hallmarks:

– Spindle cell proliferationSpindle cell proliferation

– Red cell extravasationRed cell extravasation

– Cellular infiltrationCellular infiltration

Malignant cell appears to be of clonal lymphoepithelial originMalignant cell appears to be of clonal lymphoepithelial origin HIV viral antigens (eg, Tat) and cytokines (eg, IL-6) may promote HIV viral antigens (eg, Tat) and cytokines (eg, IL-6) may promote

proliferationproliferation Decreased incidence and virulence with HAART therapy Decreased incidence and virulence with HAART therapy

Principles of ManagementPrinciples of Management

Indications for cytotoxic therapyIndications for cytotoxic therapy– Life-threatening visceral involvementLife-threatening visceral involvement

– Cosmesis and/or lymphedemaCosmesis and/or lymphedema

Other therapeutic optionsOther therapeutic options– HAARTHAART

– Biological agents: alpha-IFN, imatinib, thalidomideBiological agents: alpha-IFN, imatinib, thalidomide

– IrradiationIrradiation

– CryotherapyCryotherapy

– Topical retinoidsTopical retinoids

– Intralesional therapyIntralesional therapy

Cytotoxic agentsCytotoxic agents– Liposomal anthracyclines (Doxil, DaunoXome)Liposomal anthracyclines (Doxil, DaunoXome)

– Antitubulin agents (paclitaxel, vinorelbine)Antitubulin agents (paclitaxel, vinorelbine)

Cancer and HIV InfectionCancer and HIV Infection

HIV-associated cancers have diminished but are HIV-associated cancers have diminished but are not uncommonnot uncommon

Lymphoma is potentially life-threatening but curableLymphoma is potentially life-threatening but curable

KS has a more indolent course in the HAART eraKS has a more indolent course in the HAART era

Non-AIDS-defining cancers are more commonNon-AIDS-defining cancers are more common

HIV infection is not a contraindication to cytotoxic HIV infection is not a contraindication to cytotoxic therapytherapy

Patients benefit from a multidisciplinary approachPatients benefit from a multidisciplinary approach

Clinical trials are available for patients with HIV-Clinical trials are available for patients with HIV-associated cancers – AIDS Malignancy Consortium associated cancers – AIDS Malignancy Consortium (http://www.amc.uab.edu)(http://www.amc.uab.edu)

Natural History of Cervical Natural History of Cervical NeoplasiaNeoplasia

00––1 Year1 Year 00––5 Years5 Years 11––20 Years20 Years

Invasive Invasive cervical cervical cancercancer

Cleared HPV infection

CIN 1CIN 1

InitialInitialHPV HPV

infectioninfection

ContinuingContinuinginfectioninfection

CIN CIN 2/32/3

Median duration, 1-2 yearsMedian duration, 1-2 years

Potential Cofactors for Progression:Potential Cofactors for Progression:

- HPV-related: type, variants, viral loadHPV-related: type, variants, viral load

- Parity, oral contraceptive useParity, oral contraceptive use

- SmokingSmoking

- Chlamydia, HSV-2 coinfectionChlamydia, HSV-2 coinfection

- Diet (vitamins A, C, E, carotenoids, Diet (vitamins A, C, E, carotenoids, folic acid, etc.)folic acid, etc.)

- Immunogenetics (HLA type)Immunogenetics (HLA type)

- Host factors: immune responseHost factors: immune response

Adapted from Pinto AP, Crum CP. Adapted from Pinto AP, Crum CP. Clin Obstet GynecolClin Obstet Gynecol. 2000;43:352-362.. 2000;43:352-362.

Percent With Cervical HPV Percent With Cervical HPV InfectionInfection

PP < .001 < .001

7070

80%80%

00

1010

2020

3030

4040

5050

6060

CD4>500CD4>500 <200<200

HIV-HIV- HIV+HIV+ HIV+HIV+ HIV+HIV+

201-500201-500

60%60%

00

1010

2020

3030

4040

5050

CD4>500CD4>500 <200<200


201-500201-500

Percent With AbnormalPercent With AbnormalCervical CytologyCervical Cytology

PP < .001 < .001

Guidelines for Assessment Guidelines for Assessment of CIN in HIV+ Womenof CIN in HIV+ Women

Pap smear at initial evaluationPap smear at initial evaluation

Repeat Pap smear 6 months laterRepeat Pap smear 6 months later

If both negative, can do annual PapIf both negative, can do annual Pap

Low threshold for colposcopyLow threshold for colposcopy

Clinical ChallengesClinical Challengesin HIV+ Womenin HIV+ Women

Poor response to standard therapyPoor response to standard therapy

Need for multiple treatments with different Need for multiple treatments with different therapeutic modalitiestherapeutic modalities

Faster progression of invasive cancer Faster progression of invasive cancer with poorer therapeutic responsewith poorer therapeutic response

Anal and Cervical Cancer Anal and Cervical Cancer IncidenceIncidence

Cervical cancer prior to cervical cytology Cervical cancer prior to cervical cytology screening: 40-50/100,000screening: 40-50/100,000

Cervical cancer currently: 8/100,000Cervical cancer currently: 8/100,000

Anal cancer among HIV- MSM: 13-35/100,000Anal cancer among HIV- MSM: 13-35/100,000

Anal cancer twice as high among HIV+ MSM Anal cancer twice as high among HIV+ MSM as in HIV- MSMas in HIV- MSM

CD4>500CD4>500 <200<200


201-500201-500

100%100%

00

1010

2020

4040

6060

8080

3030

5050

7070

9090

Percent With Anal HPV Infection

Percent With Abnormal Anal Percent With Abnormal Anal CytologyCytology

7070

80%80%

00

1010

2020

3030

4040

5050

6060

CD4>500CD4>500 <200<200


201-500201-500

Anal and Cervical HPV InfectionAnal and Cervical HPV Infectionin HIV-Positive Womenin HIV-Positive Women

0

10

20

30

40

50

60

70

80

90

HIV- HIV+ CD4 HIV+ CD4 HIV+ CD4

Anal

Cervical

>500 <200201-500

Risk Factors for Abnormal Anal Risk Factors for Abnormal Anal Cytology in WomenCytology in Women

HIV positivityHIV positivity

Lower CD4+ levelLower CD4+ level

History of anal intercourseHistory of anal intercourse

Anal HPV infectionAnal HPV infection

Abnormal cervical cytologyAbnormal cervical cytology

Percent of Men Developing AIN Percent of Men Developing AIN

2/3 at Intervals During Follow-2/3 at Intervals During Follow-up up

Months of follow-upMonths of follow-up

66% (CI)% (CI) PP

HAART use HAART use in HIV+ men in HIV+ men

NoNo

YesYes

5 (0-11)5 (0-11)

5 (1-9)5 (1-9)

23 (12-34)23 (12-34)

35 (27-43)35 (27-43)

52 (36-67)52 (36-67)

53 (44-62)53 (44-62)

65 (50-82)65 (50-82)

68 (58-77)68 (58-77)

.44.44

1212% (CI)% (CI)

1818% (CI)% (CI)

2424% (CI)% (CI)

Anal Cancer SinceAnal Cancer SinceIntroduction of HAARTIntroduction of HAART

Chiao et al. JAIDS. 2005;40:451-455Chiao et al. JAIDS. 2005;40:451-455

– Pre-HIV: 1973-1981 0.6/100,000Pre-HIV: 1973-1981 0.6/100,000

– HIV: 1982-1995 0.8/100,000HIV: 1982-1995 0.8/100,000

– HAART: 1996-2001 1.0/100,000HAART: 1996-2001 1.0/100,000

– Female-to-male ratio 1.6:1 1.2:1Female-to-male ratio 1.6:1 1.2:1

Bower et al. JAIDS. 2004;37:1563-1565 Bower et al. JAIDS. 2004;37:1563-1565

– 8640 HIV+ MSM in London8640 HIV+ MSM in London

Pre-HAART incidence – 35/100,000 patient-yearsPre-HAART incidence – 35/100,000 patient-years(95% CI, 15-72)(95% CI, 15-72)

Post-HAART incidence – 92/100,00 patient-yearsPost-HAART incidence – 92/100,00 patient-years(95% CI, 52-149)(95% CI, 52-149)

Who Should Be Screened?Who Should Be Screened?

All HIV+ MSM with good prognosisAll HIV+ MSM with good prognosis

All HIV- MSM over the age of 40All HIV- MSM over the age of 40

? Women with high-grade vulvar lesions? Women with high-grade vulvar lesionsor canceror cancer

? All HIV+ women? All HIV+ women

? All HIV+ men regardless of sexual orientation? All HIV+ men regardless of sexual orientation

? All men and women with perianal condyloma? All men and women with perianal condyloma

Anal Cytology Screening for Anal Cytology Screening for AIN AIN

in HIV-Positive Menin HIV-Positive Men

Chin-Hong PV et al. Chin-Hong PV et al. J Infect DisJ Infect Dis. 2004;90:2070-2076.. 2004;90:2070-2076.

ScreenScreen

NormalNormal ASCUSASCUS LSILLSIL HSILHSIL

Repeat in 12 months (HIV+)Repeat in 2-3 years (HIV-)

Anoscopy with biopsyAnoscopy with biopsy

Treat or followTreat or follow TreatTreat

No lesion seenNo lesion seen LSILLSIL HSILHSIL

Treatment of ASILTreatment of ASIL

No HPV-specific therapyNo HPV-specific therapy

Removal of lesional tissueRemoval of lesional tissue

Treatment approach is based on size of lesion:Treatment approach is based on size of lesion:

– Limited (> 1 cmLimited (> 1 cm22) – local therapy, 85% TCA/LN) – local therapy, 85% TCA/LN22

– Moderate – infrared coagulationModerate – infrared coagulation

– Large – surgery with cold scalpel excision, Large – surgery with cold scalpel excision, electrocautery, laserelectrocautery, laser

– Diffuse (circumferential) – “watch and wait” Diffuse (circumferential) – “watch and wait”







Leading Causes of Death (per Leading Causes of Death (per 100,000) for Men 25-44 Years of 100,000) for Men 25-44 Years of

AgeAge

Source: CDCSource: CDC

YearYear

Rat

eR

ate

008282

1010

2020

3030

4040

5050

6060

7070

8383 8484 8585 8686 8787 8888 8989 9090 9191 9292 9393 9494 9595 9696 97*97*

Unintentional injuryUnintentional injury

HIV infectionHIV infection

SuicideSuicide

CancerCancer

StrokeStroke

DiabetesDiabetes

Heart diseaseHeart disease

HomicideHomicide

Liver diseaseLiver disease

Prior Research Has Shown That Prior Research Has Shown That Psychiatric Patients:Psychiatric Patients:

Have increased risk for HIVHave increased risk for HIV

Are less likely to receive HAARTAre less likely to receive HAART

Are less likely to stay on HAARTAre less likely to stay on HAART

Are less likely to achieve an undetectable Are less likely to achieve an undetectable viral loadviral load

Are more likely to dieAre more likely to die

Association Between Mental Association Between Mental D/O and Time to HAARTD/O and Time to HAART

Time in YearsTime in Years

Pro

bab

ilit

y o

f H

AA

RT

Th

erap

yP

rob

abil

ity

of

HA

AR

T T

her

apy

P=0.05P=0.05

No mental disorderNo mental disorder

Mental disorderMental disorder

00 22 44 66

0.000.00

0.250.25

0.500.50

0.750.75

1.001.00

Association Between Mental Association Between Mental Disorder and Survival Disorder and Survival

No mental disorderNo mental disorder

Mental disorderMental disorder

P=0.10P=0.1000

Time in YearsTime in Years00 22 44 66

11P

rob

abil

ity

of

Su

rviv

alP

rob

abil

ity

of

Su

rviv

al

HIV Is a Psychiatric EpidemicHIV Is a Psychiatric Epidemic

HIV increases risk for psychiatric illnessHIV increases risk for psychiatric illness

Psychiatric illness increases risk for HIVPsychiatric illness increases risk for HIV

Effective treatment for psychiatric illness Effective treatment for psychiatric illness

– Can improve patient outcomeCan improve patient outcome

– Can decrease HIV transmissionCan decrease HIV transmission

Depression as AIDS Develops

Time of AIDS

Months Before and After AIDSMonths Before and After AIDS

00

1010

2020

-48-48 -36-36 -24-24 -12-12 66 1818

% D

epre

ssed

% D

epre

ssed

PharmacotherapyPharmacotherapy

Poor sleepPoor sleep Weight lossWeight loss AnxietyAnxiety GI disturbanceGI disturbance

NortriptylineNortriptylineDesipramineDesipramine

HypersomniaHypersomnia Weight gainWeight gain Suicide potentialSuicide potential ChronicityChronicity

FluoxetineFluoxetineSertralineSertralineParoxetineParoxetineFluvoxamineFluvoxamineCitalopramCitalopramEscitalopramEscitalopramVenlafaxineVenlafaxineDuloxetineDuloxetine

Failure from side effects Failure from side effects

Lithium augmentationLithium augmentationNeuroleptic augmentation (risk/benefit)Neuroleptic augmentation (risk/benefit)

Failure after good trialFailure after good trial

NEXT DRUGNEXT DRUG

TrazodoneTrazodoneNefazodoneNefazodoneBupropionBupropionMirtazepineMirtazepineMAOIsMAOIsAtomoxetineAtomoxetine

Treatment of DepressionOutcome by Diagnosis

00

100100

DementiaDementia SubstanceSubstanceuseuse

PersonalityPersonalitydisorderdisorder

CompliantCompliant OverallOverall

Full

Partial

NonePer

cen

tag

eP

erce

nta

ge

Documents

HIV Coinfections, Malignancies, and Comorbidities