1. Terapia ARV u chorych z koinfekcją HIV/HBV/HCV – czy istnieją preferencyjne schematy ARV.
Marek Beniowski

2. WHO Regional Office for Europe – DRAFT- WHO Clinical Protocol on Hepatitis C and HIV Co-Infection, WHO Clinical Protocol on Hepatitis B and HIV- Co-Infection – 22 Dec 2005
Alberti A, Clumeck N, Collins S, Gerlich W, Lundgren J, Palu G, Reiss P, Thiebaut R, Weiland O, Yazdanpanah Y, Zeuzem S. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol May;42(5):

3. HBV/HIV

4. Therapeutic Management of HBV/HIV Patients
Patients not requiring hepatitis B or ARV treatment
Patients requiring only hepatitis B treatment
Patients requiring only ARV treatment
Patients requiring both hepatitis B or ARV treatment

5. Recommendations for initiating HAART in HBV/HIV co-infected patients
CD4 Cells Criteria
Recommendations
< 200 cells/mm3
Antiretroviral treatment is recommended
ART regimens should contain 2 dual-activity (HBV and HIV) drugs
cells/mm3
Antiretroviral treatment should be considered (high viral load or rapid decline in CD4 count) but should be started before it falls to less than 200 cells/mm3
ART regimens containing 2 dual-activity (HBV and HIV) drugs is indicated (if indication of HBV treatment) or highly recommended

6. First line HAART regimens for HBV/HIV co-infected patients
Combination drugs
Preferential 1st line
2 NRTI + 1 NNRTI
TDF + (3TC or FTC(1)) + EFV(2)
Alternative 1st line
Triple nuke regimen
ZDV + (3TC or FTC(1)) + TDF
Emtricitabine (FTC) is equivalent to 3TC and is available in association with TDF as a fixed dose combination.
NVP can be considered instead of EFV in patients without hepatic dysfunction and with close monitoring. It should be avoided in women with CD4 count >250 cells/mm3 or in men with CD4 count >400 cells/mm3

7. Second line HAART for HBV/HIV co-infected patients
NB:
TDF/3TC should be maintained for hepatitis treatment, in addition to the 2nd line HAART
ART regimen
Combination Drugs
2 NRTI + busted PI
LPV/r or
ABC (ddI or d4T(3)) SQV/ or
NFV
1 NNRTI + 1 NRTI + busted PI
LPV/r or
EFV (ABC or d4T(3)) + SQV/r or
2 PIs (one busted)
LPV/r + SQV or
LPV/r + EFV
d4T can be considered as an option in 2nd line ART if ZDV was not used in 1st line

8. 4.3. HIV-infected patients with clinical evidence of cirrhosis
Clinical cirrhosis is an absolute indication for treatment.
HBV DNA threshold for initiation of HBV treatment is lower than in patients without cirrhosis (over 200 UI/ml, that is, as soon as detectable).
No medications are contra-indicated for patients with compensated cirrhosis.
Patients with decompensated cirrhosis should be referred for palliative care.
Patients with cirrhosis require clinical observation, liver function monitoring and drug monitoring (if available).
It might be necessary to adjust the dose of ARV metabolised by the liver. If this is not feasible, then
ddI and d4T have to be avoided and a regimen containing PI should be closely monitored.

9. 4.4. HIV-infected patients with 3TC resistant HBV strains
3TC (LAM): 50% and 90% of co-infected patients, respectively, after 2 and 4 years of 3TC therapy.
In the presence of suspected Lamivudine-resistance, the first step is to confirm if resistance testing is available. Otherwise resistance may be suspected if HBV viral load increases more than 1 log in a compliant patient taking 3TC; 3TC will have to be switched to TDF.
TDF is essential ARV for the HAART regimen in 3TC resistant patients.

10. HCV/HIV

11. Clinical Management of HCV/HIV Patients
HCV/HIV co-infection, patients can be split into four categories:
patients not requiring hepatitis C or HIV/AIDS treatment
patients requiring only hepatitis C treatment
patients requiring only HIV/AIDS treatment
patients requiring both hepatitis C and HIV/AIDS treatment

12. Therapeutic algorithm for anti HCV treatment in HIV-infected patients

13. 2.1. When to Start HAART in HCV/HIV Co-Infected Patients
CD 4 Cells Criteria
Recommendations
CD4 < 200 cells/mm3
Antiretroviral treatment is recommended
CD cells/ mm3
Antiretroviral treatment should be considered (high viral load or rapid decline in CD4 count) but should be started before it falls to less than 200 cells/mm3

14. First Line HAART Regimens for HCV/HIV Co-Infected Patients
ZDV(2) or d4T EFV(1)
 
3TC or FTC3
Preferential
1st line
2 NRTI + 1 NNRTI 
ABC or TDF NVP(1)
Alternative
1st line
Triple nuke regimen
ZDV(2) ABC(4)
 
3TC or FTC3
 
d4T TDF

15. First Line HAART Regimens for HCV/HIV Co-Infected Patients
EFV has been considered the preferential NNRTI option, but NVP can be considered in patients without evidence of hepatic dysfunction and with close monitoring.
However, NVP should be particularly avoided in HIV+ patients if CD4 is >250 in women or >400 in men.
EFV should be used with caution in women of childbearing age (Class D – FDA) and also because of additional risk of depression.
Emtricitabine (FTC) is equivalent to 3TC. FTC is available together with TDF, and 3TC is available together with ABC as a FDC, so FDC: FTC + TDF, and 3TC + ABC.
ZDV/3TC/ABC regimen is available as FDC.

16. In case of severe toxicity and side effects caused by 1st line ARVs, it is recommended to substitute to another ARV with a different toxicity profile, but within the 1st line regimens.
Switching to 2nd line ARV regimens is recommended in the absence of immunological or virological response to ART, measured by CD4 cell count and viral load.

17. Treatment Regimens for second line therapy in HIV/HCV co-infection
Combination Drugs
LPV/r ABC/TDF or
SQV/r or
ATZ/r (6) ABC/ddI(5)
Preferential 2nd line
2 NRTI + boosted PI
Alternative 2nd line
1 NNRTI +/- 1 NRTI + boosted PI
ABC TDF
SQV/r LPV/r ATZ/r(6)
z : EFV
Lub:
LPV/r + SQV lub LPV/r + EFV
(5) ddI dose in combination with TDF should be adjusted to less than 4.1mg/kg per day as not to compromise immune recovery. It is contraindicated in patients with cirrhosis and under RBV treatment. It should be used with caution in patients with less severe liver disease.
(6) Unboosted ATZ or NFV can be used.

18. Second Line HAART for HCV/HIV Co-Infected Patients
Three different drugs containing at least one new pharmacological class.
The best options are regimens which contain a boosted PI as the key drug, associated with 2 nucleosides if a classical approach with 2 NRTI + 1 NNRTI was chosen for first line therapy.
In case of a simplified first choice with 3 NRTI, the second line should use a boosted PI + 1 NNRTI +/- 1 NRTI.
Among second line NRTIs, those with the better resistant profile, such as ddI, ABC and TDF, should be given preference.
Combination of d4T+ddI has to be avoided due to risk of mitochondrial toxicity, leading to hepatic steatosis and potentially enhancing fibrosis.
TDF/ddI is also contra-indicated due to pharmacological negative interactions.

19. Algorithm for initiation of hepatitis C treatment and HAART in HCV/HIV co-infected patients
HCV treatment
Non treated patients
No indication for ARV
Treat HCV first
Indication for ARV initiation
CD4 200 – 350 cells/m3
Treat HCV first, then initiate HAART
Initiate HAART
Wait until stable, and regimen is well tolerated
Then treat HCV
CD4 <200 cells/mm3
ARV treated patients
Continue HAART
Replace ddI and ZDV if on alternative options
Possibility to interrupt HAART until the end of Hep C treatment (if CD4 nadir was never < cells/mm3, and patient asks for it)
Treat HCV if
CD4 >200cells/mm3

20. Algorithm for Initiation of Treatment for HCV/HIV Co-Infected Patients
If chronic hepatitis C is detected early in the course of HIV infection in patients who do not need HAART, hepatitis C treatment is advised before the initiation of HAART.
If a co-infected patient has severe immune deficiency (CD4 count <200 cells/mm3), the CD4 cell count should be improved using HAART before commencing anti-HCV treatment.
If CD4 is between 200 cells/mm3 and 350 cells/mm3, HCV treatment should be offered first in order to avoid interactions between HAART and anti HCV drugs and facilitate adherence. After HCV treatment is finished (12 months), HAART should be initiated.