Management of the HIV-infected patient with co-morbid diseases Christopher Behrens, MD Northwest...
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Transcript of Management of the HIV-infected patient with co-morbid diseases Christopher Behrens, MD Northwest...
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