Management of the HIV-infected patient with co-morbid diseases

Christopher Behrens, MD

Northwest AIDS Education & Training Center

HIV Infection, Antiretroviral Therapy, dyslipidemia and heart

disease

HIV/HAART Toxicities: Lipid Abnormalities

• hypertriglyceridemia; risk of pancreatitis

• low HDL, high LDL

• Mechanism unclear

• Protease Inhibitors appear to be one of several risk factors

• growing evidence of increased risk of heart disease in patients on HAART

Percentage of patients with CHD among HIV-infected and noninfected patients in California, by age group.

Hodder S, Burtcel B, Kawabata H, Dezii C, Lillienfeld D, Stevens M. Coronary heart disease in patients with human immunodeficiency virus infection. Program and abstracts of the 39th Annual Meeting of the Infectious Diseases Society of America; October 25-28, 2001; San Francisco, California. Abstract 18.

HIV/HAART - associated Dyslipidemia: Treatment Options

• generally treated w/ fibrates and/or statins

• inconsistent results from switch studies

• beware of drug interactions, risk of myositis

Lipid Lowering Agents and ARV Therapy

DHS/ARV Rx/PP

Agent

Pravastatin

Atorvastatin

Lovastatin

Simvastatin

Gemfibrozil

Fenofibrate

Niacin

No dose adjustment

Dose titration

Avoid

Avoid

No dose adjustment

No dose adjustment

Avoid

Recommendation

From: Dube MP et al. Clin Infect Dis 2000;31:1216-24.

Management of the HIV-infected Patient with Diabetes Mellitus

1. Potential for worsening glucose intolerance

2. Peripheral Neuropathy

HIV and HAART: Association with Insulin Resistance

• progression to frank diabetes mellitus possible

• Protease inhibitors (PI’s) and efavirenz implicated but mechanism unclear

• monitor with fasting glucose values• improvement often seen when PI’s, efavirenz

are replaced by other agents• some success w/ Metformin

Currier et al, 9th CROI, February 2002, abstract 677-T

Effect of HAART on Developing Diabetes by Agent and HCV Status

Mehta et al, 9th CROI, February 2002

DHS/ARV Rx /PP

Metformin Therapy for Insulin Resistance

Insulin Levels

-414

-2930

-4000

-2000

0

2000

4000

Ins

uli

n A

UC

(1

20

min

), u

lU/m

L

Placebo x 12 weeks

Metformin 500 mg bid x 12weeks

From: Hadigan C et al. JAMA 2000;284:472-7.

Visceral Abdominal Fat

+1191

-1115

-2000

-1000

0

1000

2000

Mea

n C

hang

e in

Vis

cera

l Abd

omin

al F

at, m

m2 Placebo x 12 weeks

Metformin 500 mg bid x 12 weeks

P = 0.005

P = 0.08

N = 26

Management of the HIV-infected patient with Diabetes: Peripheral Neuropathy

• Distal Symmetric Peripheral Neuropathy (DSPN, or PN) a common complication of diabetes, HIV infection, and HIV medications

• d4T, ddI, ddC most closely associated with this complication

• early switching out of these agents may result in improvement

Management of the patient with co-morbid HIV Infection and Diabetes Mellitus: Summary

• Protease Inhibitors, efavirenz can exacerbate Insulin resistance

• monitor glucose values, Hgb A1c closely following initiation of HAART

• intensify diabetic regimen if necessary no significant interactions between diabetes agents and antiretrovirals

• beware of additive potential for peripheral neuropathy from NRTIs (esp. d4T, ddI) and from HIV itself

Management of the Patient with HIV infection and Chronic

Renal Disease• NRTIs renally cleared; renal dosing based on

creatinine clearance available for these agents• If etiology of renal impairment unclear, consider

diagnosis of HIV-associated Nephropathy (HIVAN)– predilection for young african-american men– rapid progression to renal failure possible– treatment: steroids, ACE-I, HAART

Management of the Patient co-infected with HIV and hepatitis B

• Two NRTIs - lamivudine (3TC; Epivir) and tenofovir (Viread) have activity against hepatitis B

• Hepatitis B commonly develops resistance (though slowly) to HBV when lamivudine is the only active drug deployed against it

• Usefulness of combining lamivudine and tenofovir in these patients under investigation

• may want to avoid ritonavir, nevirapine due to their potential for hepatotoxicity

Management of the Patient co-infected with HIV and Hepatitis C

Treatment of Hepatitis C

Options & Considerations

Treatment of Hepatitis C:Goals of treatment

• Ideal: Sustained Virologic Response (SVR): persistent absence of circulating virus

• SVR associated with regression of fibrosis

• often some benefit in reduction of rate of progression of fibrosis/cirrhosis even in absence of SVR

Meta-analysis: interferon alone vs interferon + ribavirin

• HIV-negative patients• Effect of interferon alfa

plus ribavirin combination therapy versus interferon alfa alone on the risk of not having a sustained virological response 6 months after treatment

BMJ 2001;323:1151-1155

Variables that strongly affect response to treatment

• genotype– type 1: lower response rate than types 2 or 3

• co-infection with HIV– lower response rate in setting of coinfection

with HIV

• N=51 coinfected patients

• median Knodell score 11.5

• 55% with active cirrhosis

• Treated with interferon-alpha 2b + ribavirin for 12 months

• 29% discontinued treatment

• no adverse effects on HIV disease progression

• End of Treatment Response (ETR) = absence of HCV RNA at end of treatment

• Sustained Virologic Response (SVR) = absence of HCV RNA at 6 mos post-therapy

2921

0

10

20

30

40

50

60

70

80

90

100

ETR SVR

HIV/HCV coinfected

Effect of HIV co-infection on Response to Treatment of HCV

% w

ith u

ndet

ecta

ble

HC

V R

NA

Landau et al. AIDS 2001;15:2149-55

• N=51 coinfected patients

• median Knodell score 11.5

• 55% with active cirrhosis

• Treated with interferon-alpha 2b + ribavirin for 12 months

• 29% discontinued treatment

• no adverse effects on HIV disease progression

• End of Treatment Response (ETR) = absence of HCV RNA at end of treatment

• Sustained Virologic Response (SVR) = absence of HCV RNA at 6 mos post-therapy

29

60

21

45

0

10

20

30

40

50

60

70

80

90

100

ETR SVR

HIV/HCV coinfected

HCV only (data from otherstudies)

% w

ith u

ndet

ecta

ble

HC

V R

NA

Landau et al. AIDS 2001;15:2149-55

Effect of HIV co-infection on Response to Treatment of HCV

Response Rates to Therapy in the coinfected patient are

disappointing and come with significant toxicities

High rates of discontinuation in early trials due to adverse events

Discouraging Prognosis for Coinfected Patients on IFN + RBV

• Diminished SVR• High level of toxicity leading to high rates of

discontinuation

• Is PEGylated INF + RBV the answer?– Improved pharmacokinetics– improved response to treatment in HIV(-) patients

Source: pubs.acs.org/cen/coverstory/ 7838/7838scit1.html

Higher Sustained Virologic Response (SVR) with PEG-Interferon -2b

• 1530 HIV(-) pts w/ Chronic HCV randomized to 48 wks of therapy with:– INF + RBV

– low-dose PEG-INF + RBV

– high-dose PEG-INF + RBV

• similar side effect profiles in all three groups

0

10

20

30

40

50

60

70

80

90

100

All patients Genotype 1

INF/RBV

low-dose PEG-INF/RBV

high-dose PEG-INF/RBV

p = 0.01Manns MP et al. Lancet 2001; 358:958-65

SVR at 24 wks post-therapy

How well does PEG-IFN + RBV Work for Coinfected Patients?

The $64,000 Question

Therapy Options for the patient co-infected with HIV & HCV:

Summary

• PEG-IFN + RBV appears to have superior efficacy over IFN + RBV

• PEGylated regimens probably just as toxic, but discontinuation rates decreasing as we improve our abilities to manage adverse effects

• response rates for genotype 1 still sub-optimal

Controversies in the Management of HIV/HCV

co-infected Patients

Which patients are candidates for therapy?

• numerous contraindications

• serum markers do not reliably correlate with progression of disease

• liver biopsy generally required to assess rate of disease progression

• uncontrolled HIV disease accelerates course of HCV disease

• low CD4 count correlates with poor response to HCV therapy

• HIV is usually the more clinically aggressive disease

Which Infection should be treated first?

• HCV-infected patients have worse response to HAART than HCV-negative patients

• many HAART medications hepatoxic

• HCV treatment is for just 6-12 months whereas HIV treatment is for life

• reinforcing toxicities of HAART and HCV regimens

Treat HIV First Treat HCV First

Sabin, CA et al., 9th CROI, February 2002, Abstract 639-M.

Moreno S et al., 9th CROI, February 2002, Abstract 638-M

The HIV-infected Patient with Active Substance Abuse

• Active substance abuse associated with reduced adherence to antiretroviral therapy in most, though not all, studies

• dangerous interactions between protease inhibitors and some recreational drugs (esp. methamphetamines)

• Try to treat substance abuse before initiation of HAART if possible

• however, active SA not a contraindication to initiation of HAART