update current hiv treatment guideline and case management · update current hiv treatment...

UPDATE CURRENT HIVTREATMENT GUIDELINE AND CASE MANAGEMENTWeerawat Manosuthi, MD

Bamrasnaradura Infectious Diseases Institute, MOPH

Outline

Update on the latest ARV recommendations

EACS, DHHS, and Thai

Advantages and disadvantages by class and individual medication

Case management

Management of viral hepatitis and cryptococcosis

Update on the latest recommendations for HIV/TB co-infection

Case management

Q: Which first-line ARV drug is recommended in the latest “Thai guideline”?

1. Raltegravir

2. Efavirenz

3. Dolutegravir

4. Darunavir

5. None of the above

Q: Which first-line ARV drug is notrecommended in the latest DHHS guideline?

1. Raltegravir

2. Efavirenz

3. Dolutegravir

4. Darunavir

5. None of the above

Current ARV Recommendations

DHHS 2016

What do the guidelines of resource-rich settings say?

EACS 2015

DHHS guidelines. January 2016. http://aidsinfo.nih.gov/guidelines

DHHS Guideline: January 2016Guidelines for Initial ARV Regimens

CD4 cell count Recommendation

< 350 cells/mm3 Start ART (AI)

350-500 cells/mm3 Start ART (AI)

>500 cells/mm3 Start ART (AI)

A= strong B = moderate, C = optional recommendation

I = 1+ RCT, II = 1+ non-RCT, III = expert opinion

DHHS Guideline: January 2016Guidelines for Initial ARV Regimens

CD4 cell count Recommendation

< 350 cells/mm3 Start ART (AI)

350-500 cells/mm3 Start ART (AII)

>500 cells/mm3 Start ART (BIII)

Conditions Favoring More Urgent Initiation of Therapy

Pregnancy AIDS-defining conditions, including HAD AIDS-associated malignancies Acute OIs Lower CD4 counts (e.g., <200 cells/mm3) HIVAN Acute/Early Infection HIV/HBV co-infection HIV/HCV co-infection


•A=strong, B=Moderate, C=optional

DHHS Guideline: January 2016Guidelines for “Recommended” Initial ARV Regimens

ClassAll Patients, Regardless of

Baseline VL or CD4

1. Boosted PI DRV/r + TDF/FTC (AI)

2. INSTI

RAL + TDF/FTC (AI) EVG/COBI/TDF/FTC (CrCl >70) (AI) EVG/COBI/TAF/FTC (CrCl ≥30 mL/min) DTG + ABC/3TC (HLA-B*5701negative) (AI) DTG + TDF/FTC (AI)

•A= strong B = moderate, C = optional recommendation

•I = 1+ RCT, II = 1+ non-RCT, III = expert opinion


DHHS guidelines. April 2015.

DHHS Guideline: January 2016Guidelines for “Alternative” Initial ARV Regimens

Class Regimens

1. NNRTI EFV/TDF/FTC (BI)

RPV/TDF/FTC only if pretreatment VL <100,000 and CD4 >200

(BI)

2. PI

ATV/c + TDF/FTC (BI)

ATV/r + TDF/FTC (CrCl >70) (BI)

(DRV/c or DRV/r) + ABC/3TC (HLA-B*5701 negative) (BIII for

DRV/c and BII for DRV/r)

DRV/c + TDF/FTC (AI) (CrCl >70) (BII)

•A= strong B = moderate, C = optional recommendation

•I = 1+ RCT, II = 1+ non-RCT, III = expert opinion

EACS Guideline: Oct 2015

http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf

ART should always be recommended irrespective of CD4 count with the possible exception of elite controllers with high and stable CD4 count.

EACS Guideline: Oct 2015

http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf

Six recommended regimens

1

2

3

Manosuthi W, et al. AIDS Research Therapy 2015;12:12.

Thai Guideline 2014:Guidelines for Initial ARV Regimens


Thai Guideline 2016 (Draft):Guidelines for Initial ARV Regimens

เกณฑการเร �มยาตานไวรสในประเทศไทย

ยาตานไวรสในผตดเช �อทกรายในทกระดบCD4 รายการยาเพ�มใหมใน สปสช ท�สามารถเบกจาย

ได “มนาคม 2559”1. Rilpivirine

2. Abacavir

3. Abacavir/lamivudine

4. Tenofovir/emtricitabine

5. Tenofovir/emtricitabine/efavirenz

Thai Guideline 2014:Guidelines for Initial ARV Regimens


Guidelines for Treatment of HIV-Infected Patients

ART initiation now recommended for all pts, regardless of CD4+ cell count

•1. EACS HIV Guidelines. V 8.0. October 2015. 2. DHHS Guidelines. April 2015. 3. Günthard H, et al. JAMA. 2014;312:410-425. 4. WHO When to Start Guidelines. September 2015.5.

5. Manosuthi W, et al. AIDS Research Therapy 2015;12:12.

Guideline AIDS or

HIV-Related Symptoms

CD4+ Cell Count, cells/mm3

< 350 350-500 > 500

EACS 2015[1] Yes Yes Yes Yes

DHHS 2016[2] Yes Yes Yes Yes

IAS-USA 2014[3] Yes Yes Yes Yes

WHO 2015 [4] Yes Yes Yes Yes

Thai 2014 [5] Yes Yes Yes Yes

Comparison of Current International Guidelines for Treatment-Naive Pts

RegimenDHHS[1]

2016EACS[2]

2015BHIVA[3]

2015IAS-USA[4]

2014Thai [5]

2014WHO 2016

EFV/TDF/FTC

RPV/TDF/FTC

ATV/RTV + TDF/FTC

DRV/RTV + TDF/FTC

DTG/ABC/3TC

DTG + TDF/FTC

EVG/COBI/TDF/FTC

RAL + TDF/FTC

EVG/COBI/TAF/FTC

•1. DHHS Guidelines. Jan 2016. 2. EACS HIV Guidelines. V 8.0. October 2015. 3. BHIVA Guidelines. 2015. 4. Günthard H, et al. JAMA. 2014;312:410-425. 5. Manosuthi W, et al. AIDS Research Therapy 2015;12:12.

Preferred/recommended

ARV Regimen Considerations as Initial Therapy based on Specific Clinical Scenarios

Patient/RegimenCharacteristics

ClinicalScenario

Consideration(s)

Pre-ARTCharacteristics

CD4 count <200 Do not use following regimens:• RPV-based regimens• DRV/r plus RAL

HIV RNA >100,000copies/mL

Do not use following regimens:• RPV-based regimens• ABC/3TC with EFV or ATV/r• DRV/r plus RAL

HLA-B*5701 positive Do not use ABC-containing regimen

Must treat beforeHIV drug resistanceresults available

Avoid NNRTI-based regimen

Patient/RegimenCharacteristics

ClinicalScenario

Consideration(s)

ART SpecificCharacteristics

One pill once daily regimen desired

ART Options Include:• DTG/ABC/3TC• EFV/TDF/FTC• EVG/c/TDF/FTC• EVG/c/TAF/FTC• RPV/TDF/FTC (if HIV RNA <100,000copies/mL and CD4 count >200)

Food effects Regimens that Should be Taken with Food:• ATV/r or ATV/c-based regimens• DRV/r or DRV/c-based regimens• EVG/c/TDF/FTC• RPV/TDF/FTCRegimens that Should be Taken on anEmpty Stomach:• EFV-based regimens


Patient/Regimen

CharacteristicsClinical

Scenario Consideration(s)

Presence of OtherConditions

Chronic kidneydisease (eGFR<60)

Consider avoiding TDF.If eGFR is <70 mL/min, Do Not Use:• EVG/c/TDF/FTC, or• ATV/c with TDF, or• DRV/c with TDFOptions for CKD PatientsUse ABC/3TC if HLA-B*5701 Negative:• If HIV RNA >100,000 copies/mL, do not

use ABC/3TC with EFV or ATV/r.• If CrCl <50 mL/min, do not use

coformulated ABC/3TC because 3TCrequires dose adjustment.

Other Options:• DRV/r plus RAL (if HIV <100,000/mL and

CD4 count >200/mm3), or• LPV/r plus 3TC, or• Modify TDF dose


Patient/Regimen



Presence of OtherConditions

High cardiac risk Consider avoiding ABC- and LPV/r -based regimens.

Hyperlipidemia The Following ARV Drug Classes or Drugs have been Associated with Deleterious Effects on Lipids:• PI/r, EFV, EVG/c

Osteoporosis Consider avoiding TDF.Use ABC/3TC if HLA-B*5701 negativeIf HIV RNA >100,000 copies/mL, do notuse ABC/3TC plus (EFV or ATV/r)

Psychiatricillnesses

Consider avoiding EFV-based regimens


Patient/Regimen



Presence of Co-Infections

HBV infection Use TDF/FTC (or TDF plus 3TC) whenever possible.If TDF is Contraindicated:• For treatment of HBV, use FTC or 3TC with entecavir or another drug active against HBV.

TB infection If Rifampin is Used:

• EFV-based regimens have the least drug-drug interactions.

• If RAL is used, increase RAL dose to 800 mg BID.

If using a PI-based regimen, rifabutin

should be used in place of rifampin in the TB regimen.


SC 1185068, 45 year-old MSM

Q 1: What ARV would you recommend to start in this anxious patient with depressive disorder and HLP?

1.NNRTI-based ART (efavirenz) 4. PI-based ART

2. NNRTI-based ART (Nevirapine) 5. Ins-based ART

3. NNRTI-based ART (Rilpivirine)

15 Nov 14: Presented with node enlargement at neck without fever. He had previously also been diagnosed with depressive disorder and had been receiving sertraline and lorazepam from OSH. His HIV serology test was positive one month ago. He has so far had no HIV-associated complications. He really wanted to receive HIV treatment but concerned about side effects of HIV treatment.

CD4 cell count was 452 (25%) cells/mm3 and HIV RNA was 20,400 c/mL.Genotypic resistance testing revealed no major relevant drug resistance mutations. HBs Ag and anti-HCV were negative. Serum creatinine was 1.0 mg/dl and AST was 32 U/L. LDL-c was 170 mg/dL. Chest X-ray was normal.


15 Nov 14: Presented with node enlargement at neck without fever. He had previously also been diagnosed with depressive disorder and had been receiving sertraline and lorazepam from OSH. His HIV serology test was positive one month ago. He has so far had no HIV-associated complications. He really wanted to receive HIV treatment but concerned about side effects of HIV treatment.

CD4 cell count was 452 (25%) cells/mm3 and HIV RNA was 20,400 c/mL. Genotypic resistance testing revealed no major relevant drug resistance mutations. HBs Ag and anti-HCV were negative. Serum creatinine was 1.0 mg/dl and AST was 32 U/L. LDL-c was 170 mg/dL. Chest X-ray was normal.

29 Nov 14: TDF/FTC/Rilpivirine was started. Drug-drug interactions and food-restriction was emphasized.

Dec 14. The patient returned after 2 weeks for follow-up and reports that he had experienced of acute diarrhea and sleep problem.

Jan 15: Presented with URI.


Feb 15: Developed bloody diarrhea. Internal hemorrhoid was diagnosed.

Mar 15: He was anxious and developed Herpes simplex infection at lips.

Mar 15: He had chronic epigastric pain for 3-4 weeks. EGD and colonoscopy were performed. Chronic gastritis and internal hemorrhoid were diagnosed. PPI was started.

Q 2: How would you manage ARV for this patient (Depression, sleep disorder, HLP, gastritis)?

1. Continue his current ART unchanged

2. Modify ART by switching RPV to Raltegravir

3. Modify ART by switching RPV to protease inhibitors

4. Others



Mar 15: He was anxious and developed Herpes simplex at lips.

Mar 15: He had chronic epigastric pain for 3-4 weeks. EGD and colonoscopy

were performed. Gastric biopsy showed chronic gastritis without an evidence

of malignancy. Chronic gastritis, and internal hemorrhoid was diagnosed. PPI

was started. His ARV regimen was changed to TDF/FTC/Raltegravir.

May 15: He was admitted due to acute diarrhea. CD4 was 516 (28%) and

undetectable HIV VL.

Jun 15: His abdominal symptom was improved after one and a half month of

PPI treatment. He wanted to switch back his ART owing to less frequent

dosing and cost.

Q3: Do you agree with his decision?

1. I do

2. I don’t 3. I have no idea



Mar 15: He was anxious and developed Herpes simplex at lips.

Mar 15: He had chronic epigastric pain for 3-4 weeks. EGD and colonoscopy were performed. Gastric biopsy showed chronic gastritis without evidence of malignancy. Chronic gastritis, and internal hemorrhoid was diagnosed. PPI was started. His ARV regimen was changed to TDF/FTC/Raltegravir.

May 15: He was admitted due to acute diarrhea. CD4 was 516 (28%) and undetectable HIV VL.

Jun 15: His abdominal symptom was improved after one month of PPI treatment. He insisted to switch back after a long discussion owing to less frequent dosing and cost. He developed recurrent epigastric pain after one week of ARV switching and PPI discontinuation. PPI was resumed and rilpivirine was replaced with raltegravir again.

ART and Effects on Lipids

TDF ABCRAL

DTG

ATV/RTV or ATV/COBI

DRV/RTV or DRV/COBI

EVG/COBI

EFVRPV

ETV

Drug–Drug Interactions With First-line ART and Lipid-Lowering Therapy

Antiretroviral Contraindicated Titrate Dose No Dose Adjustment

EFV - AtorvastatinSimvastatinPravastatinRosuvastatin

Pitavastatin

RPV - - AtorvastatinPitavastatin

ATV/RTVATV/COBI

LovastatinSimvastatin

AtorvastatinRosuvastatin

Pitavastatin

DRV/RTVDRV/COBI


AtorvastatinPravastatinRosuvastatin

Pitavastatin

EVG/COBI/TDF/FTC


AtorvastatinRosuvastatin

-

DTG - - -

RAL - - -

DHHS Adult Guidelines. April 2015.

Case 1172447: 49 year-old Female

Apr 14: She got the first diagnosis with HIV infection because her husband got ill with PCP. Her CD4 was 249 (18%). HBsAg, anti-HCV and VDRL were negative. Anti-HBs was positive. Her baseline serum creatinine was 0.59 mg/dl and ALT was 13 U/L.

Q1: What third agent of first-line ARV regimen would you recommend for this patient?

A. Efavirenz

B. Nevirapine

C. Rilpivirine

D. Boosted protease inhibitor


1 Apr 14: She got the first diagnosis with HIV infection because her husband got ill with PCP. Her CD4 was 249 (18%). HBsAg, anti-HCV and VDRL were negative. AntiHBs was positive. Her baseline serum creatininewas 0.59 mg/dl and ALT was 13 U/L.

TDF/FTC/Efavirenz was started.

4 Apr 14: She developed fever and diffuse skin rashes at trunk and extremities. CBC was normal and ALT was 90 U/L. Efavirenz was discontinued.

Q2: What a new third agent would you choose?

A. Nevirapine

B. Rilpivirine

C. Boosted protease inhibitor

D. Integrase inhibitor


1 Apr 14: She got the first diagnosis with HIV infection because her husband got ill with PCP. Her CD4 was 249 (18%). HBsAg, anti-HCV and VDRL were negative. AntiHBs was positive. Her baseline serum creatinine was 0.59 mg/dl and ALT was 13 U/L.



18 Apr 14: NVP was started She experienced recurrent diffuse skin rashes after 2 days of NVP exposure. ALT was 29 U/L and normal CBC.

26 Apr 14: Her skin lesions was resolved.

Q3: What a new third agent of first-line ARV regimen would you choose?

A. Rilpivirine

B. Boosted protease inhibitor

C. Integrase inhibitor






26 Apr 14: Her skin lesions was resolved. Atazanavir/rtv was introduced. She developed skin rashes after 2 days of atazanavir and she decided to stop atazavir/r. She reported that her skin rashes got improved after few days since then.

3 May 14: She visit at the clinic and complained recurrent skin rashes.




4 Apr 14: She developed fever and diffuse skin rashes at trunk and extremities. CBC was normal and ALT was 90 U/L.. Efavirenz was discontinued.


26 Apr 14: Her skin lesions was resolved. Atazanavir/rtv was introduced. She developed skin rashes after 2 days of atazanavir and she decided to stop atazanavir/r. She reported that her skin rashes got improved after few days since then.

3 May 14: She visit at the clinic with a complaint of fever and recurrent diffuse skin rashes.

Q4: How do you manage her current event?

A. Discontinue all ARV drugs

B. Continue all ARV drugs and supportive treatment

C. Discontinue FTC

D. Something else







3 May 14: She visit at the clinic with a complaint of fever and recurrent diffuse skin rashes. A fixed dos combination of TDF/FTC was replaced with TDF alone. and rilpivirine was started.

Q5: Do you think that “abacavir” has a role in the NRTI backbone for this patient?







3 May 14: She visit at the clinic with a complaint of fever and recurrent diffuse skin rashes. A fixed dos combination of TDF/FTC was replaced with TDF alone. and rilpivirine was started. HLAB*5701 test was conducted.

17 May 14: Her HLAB5701 was negative. Abacavir was introduced. The final diagnosis was allergic reactions to EFV, NVP, FTC, ATV/r. Her current ARV regimen was “tenofovir, abacavir, and rilpivirine”.







3 May 14: She visit at the clinic with a complaint of fever and recurrent diffuse skin rashes. A fixed dos combination of TDF/FTC was replaced with TDF alone. and rilpivirine was started. HLAB*5701 test was conducted.

17 May 14: Her HLAB5701 was negative. Abacavir was introduced. The final diagnosis was allergic reactions to EFV, NVP, FTC, ATV/r. Her current ARV regimen was “tenofovir, abacavir, and rilpivirine”.

Dec 14: CD4 369 (22%) and undetectable HIV VL.

Jun 15: CD4 412 (24%) and undetectable HIV VL.

A 41 Year-old Male

Jul 14: This patient was transferred from OSH with a symptom of chronic headache for 2 weeks with alteration of consciousness. CT scan of the brain showed diffuse leptomeningeal enchancement without mass. Serum CRAG was positive. Upon admission, PE revealed oral candidiasis and hepatosplenomegaly. He had sluggish response to command and stiff neck was positive. Anti-HIV was positive.

CBC: Hct 21%, WBC 2,500/ml, N58 %, Plt 54,000/UL. BUN/Cr: 30/1.4.

Amphoterin B was started and he was transferred to BIDI.

CSF finding: WBC 3-5 cells/HPF, positive india ink 3-5 cells/HPF, AFB-ve, CSF C/S: Cryptococcus neoforman

Q1: What anti-fungal regimen would you start?

1. Amphotericin B

2. Fluconazole

3. Amphotericin B + fluconazole

4. Amphotericin B + flucytosine

5. Something else

Treatment in HIV-Infected PtsAmphotericin B plus Fluconazole 800 mg/day

Successful outcomes at day 14

41% in AmpB alone

27% in AmpB+Flu 400 mg/day

54% in AmpB+Flu 800 mg/day

A trend towards better outcomes in the combination therapy arms was seen at days 42 and 70

Pappas P, et al. Clin Infect Dis 2009; 48:1775–83.

Efficacy end point was a composite end :1. CSF conversion to negative culture results, 2. stable neurological function, and 3. survival at day 14.

Jeremy D, et al. N Engl J Med 2013;368:1291-302.

Survival Rate

Fungicidal Effect

Combination Antifungal Therapy for Cryptococcal Meningitis: Amp B vs. Amp B + Flucytosine vs. Amp B + Fluconazole

For mortality at 70 days, P=0.04 for the comparison of amphotericin B plus flucytosine with amphotericin B monotherapy, and P=0.13 for the comparison of amphotericin B plus fluconazole with amphotericin B monotherapy.

P<0.001 for all comparisons

Combination Antifungal Therapy for Cryptococcal Meningitis: AmB vs. AmB + Flucy vs. AmB + Fluco

Jeremy D, N Engl J Med 2013;368:1291-302.

Induction Phase: 2 weeks

IDSA 2010 Thai 2014 WHO 2011 CDC 2013Preferred Regimens-AmB 0.7-1.0 + FC-Lipo AmB 3-4 + FC

Preferred Regimens-AmB 1.0 -AmB 0.7-1.0 + Flu 800

Preferred Regimens-AmB 0.7-1.0 + FC-AmB 0.7-1.0 + Flu 800

Preferred Regimens-Lipo AmB 3-4 + FC

Alternative Regimens-AmB + Flu -Flu +FC-Flu-Itra

FC intolerance (4-6wk)- AmB 0.7-1.0 - Lipo AmB 3-4 - ABLC 5

Alternative Regimens-Flu 1200

Alternative Regimens-AmB 0.7-1.0 (5-7 d) + Flu 800 (2 wk)-Flu 1200 + FC-Flu 1200

Alternative Regimens-ABLC 5 + Flu-AmB 0.7-1.0 + FC -Lipo AmB 3-4 + Flu800-AmB 0.7-1.0 + Flu 800

Induction Phase: 2 weeks

IDSA 2010 Thai 2014 WHO 2011 CDC 2013Preferred Regimens-AmB 0.7-1.0 + FC-Lipo AmB 3-4 + FC

Preferred Regimens-AmB 1.0 -AmB 0.7-1.0 + Flu 800

Preferred Regimens-AmB 0.7-1.0 + FC-AmB 0.7-1.0 + Flu 800

Preferred Regimens-Lipo AmB 3-4 + FC

Alternative Regimens-AmB + Flu -Flu +FC-Flu-Itra

FC intolerance (4-6wk)- AmB 0.7-1.0 - Lipo AmB 3-4 - ABLC 5

Alternative Regimens-Flu 1200

Alternative Regimens-AmB 0.7-1.0 (5-7 d) + Flu 800 (2 wk)-Flu 1200 + FC-Flu 1200

Alternative Regimens-ABLC 5 + Flu-AmB 0.7-1.0 + FC -Lipo AmB 3-4 + Flu800-AmB 0.7-1.0 + Flu 800

Four considerationsfor AmB, lipo AmB, FC, Fluco

Efficacy Adverse events

1. AmB vs. Lipo AmB = >

2. With FC vs. without FC >(CSF sterilization &

survival benefit)

>

3. With Flu vs. without Flu >(Only CSF sterilization

)

> (minimal)

4. FC vs. Flu > >

Consolidation Phase: 8 weeks

IDSA 2010 Thai 2014 WHO 2011 CDC 2013Preferred Regimens-Flu 400

Preferred Regimens-Flu 400-800

Preferred Regimens-Fluconazole 400-800 (after 2-wk AmB)-Fluconazole 800 (after 1-wk AmB of Flu)

Preferred Regimens-Flu 400

Alternative Regimens-Itra 400

Alternative Regimens-Itra 400

A 41 Year-old Male

Jul 14: This patient was transferred from OSH with a symptom of chronic headache for 2 weeks with alteration of consciousness. CT scan of the brain showed diffuse leptomeningeal enchancement without mass. Serum CRAG was positive. Upon admission, PE revealed oral candidiasis and hepatosplenomegaly. He had sluggish response to command and stiff neck was positive. Anti-HIV was positive.

CBC: Hct 21%, WBC 2,500/ml, N58 %, Plt 54,000/UL. BUN/Cr: 30/1.4.

Amphoterin B was started and he was transferred to BIDI.

CSF finding: WBC 3-5 cells/HPF, positive india ink 3-5 cells/HPF, AFB-ve, CSF C/S: Cryptococcus neoforman

Amphotericin B + Fluconazole were given.

Bone marrow Biopsy: Normocellular marrow, No granuloma, No organism

HBsAg-positive but anti-HCV-negative

Q2: When would you start ART after starting fungal treatment in this patient?

1 week

2 weeks

4 weeks

8 weeks

Others

ART Improved Survival Rate in Patients with CM

Time (months)

12010896847260483624120

Pro

babili

ty o

f Surv

ival

1.1

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Received ART, n=281

Not received ART, n=268

P <0.01

55.3%

92.8%

42.2%

87.4%

Chottanapund S, Manosuthi W, et al. J Med Assoc Thai 2007;90:2104.

-Patients who did not receive ART has 5 times more likely to death when compare to those who received ART

-This effect was shown in the first few months after ART

Potential Advantages and Disadvantages of “Starting ART early in CNS OIs”

Potential advantages of early initiation of ART

Prevent progressive immunodeficiency Yes

More rapid immune recovery Yes

More rapid resolution of OI Yes

Rapid reduction in mortality risk No No

Prevention of further OIs and other morbidity Yes

Potential disadvantages of early initiation of ART

High pill burden Yes

Co-toxicity Yes Yes

Pharmacokinetic drug interactions Yes

Immune reconstitution disease Yes Yes (and serious)

More difficult to identify drug causing toxicity Yes

Optimal timing for ART initiation in patients with HIV infection and concurrent CM

Figure 4. Forest plot of comparison: 1 Early ART initiation versus delayed ART initiation, outcome: 1.1

Death.

•Njei B, et al. Cochrane Database Syst Rev. 2013.

Insufficient evidence in support of either early or late initiation of ART.

Because of the high risk IRIS in patients with cryptococcal meningitis, we recommend that ART initiation should be delayed

Boulware D, et al. N Engl J Med 2014;26:2487.

Overall Survival

• Patients entered trial after 7 - 11 days of antifungal treatment

=<48 hours after randomization

= 4 weeks after randomization


Survival in Patients with CSF WBC ≥5 and <5 Cells/mm3 at Randomization


•Deferring ART for 5 weeks after diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in CSF

This patient

Q3: Would you perform HIV resistance testing before ART initiation in this case?

I would

I wouldn’t

Probably

Q4: What ARV regimen would you prefer in this case?

TDF/FTC + EFV

TDF/FTC + NVP

TDF/FTC + RPV

TDF/FC + PI/r

Q5: Would you change your mind to perform HIV resistance testing before ART?

I would

I wouldn’t

Probably

He had a positive HBsAg.

His additional history is that he had been on HBV treatment for more than one year and he had not taken it for 2 weeks during this illness.

HIV Drug Resistance Report

HIV and HBV co-infection

“FTC, 3TC, and TDF” have activity against both HIV and HBV If HBV or HIV treatment is needed

ART should be initiated with combination of TDF/FTC or TDF/3TC as NRTI backbone

If HBV treatment is needed and TDF cannot safely be used Alternative recommended HBV therapy is entecavir in

addition to a fully suppressive ARV regimen Other HBV Rx regimens include

Peginterferon alfa monotherapy or adefovir in combination with 3TC or FTC

Telbivudine in addition to a fully suppressive ARV regimen

DHHS Guideline 2016

HIV and HBV co-infection

“Entecavir”, “3TC or FTC”, and “Tenofovir” have activity against HIV Their uses for HBV treatment without ART in patients with dual

infection may result in selection of… M184V: Entecavir, 3TC, FTC K65R: TDF

Entecavir must be used in addition to a fully suppressive ARV regimen

Entecavir should not be considered to be a part of ARV regimen

If ART needs to be modified due to HIV virologic failure and patient has adequate HBV suppression ARV drugs active against HBV should be continued for HBV

treatment in combination with other suitable ARV agents to achieve HIV suppression

DHHS Guideline 2016

Thai HBV Treatment Guideline 2555

Q6: What ARV regimen would you prefer in this case?

A. TDF/FTC + NNRTI

B. TDF/FTC + NNRTI + PI/r

C. 3TC + NNRTI + PI/r

D. NNRTI + PI/r

E. Something else

HBV resistance to 3TC in HIV Patients

Hepatology 1999;30:1302-6.

Outline




Case management



Case management

Study TBcharacteristic

CD4 Study arms Mortality difference Country ARVregimen

1A. SAPIT 1Abdool S, et al. NEJM 2010

Smear +ve PulTB

150 Integrated vs. sequential

- 5 vs. 12 deaths/100 PYs- 56% lower in integrated arm

SouthAfrica

ddI, 3TC,EFV

1B. SAPIT 2Abdool S, et al. NEJM 2011

Smear +ve PulTB

150 4 vs. 8-12 wks - No differences of AIDS/death - Lower in only CD4<50

- 8 vs. 26 deaths/100 PYs

SouthAfrica

ddI, 3TC,EFV

2. CAMELIABlanc FX, et al. NEJM 2011

Smear +ve PulTB

25 2 vs. 8 wks - 15% vs. 26% - 38% lower in 2-wk arm

Cambodia

d4T, 3TC, EFV

3. STRIDEHavlir D, et al. NEJM 2011

Confirmed or probable Pul TB

77 <2 vs. 8-12 wks

- No differences of mortality- Lower in only CD4<50

- 15% vs. 27%

Multi-national

TDF/FTC,EFV

4. TOROKTorok E, et al. CID2011

TB meningitis 41 <2 vs. 8 wks - No differences of time todeath

Vietnam AZT, 3TC, EFV

5. TIME Manosuthi W, et al. JAIDS 2012

Confirmed or probable any TB

43 4 vs. 12 wks - Have a tendency in CD4<50 -10 vs. 14 deaths/100 PYs

Thailand TDF, 3TC, EFV

6. TB-HAART Mfinanga S, etal. Lancet ID 2014

culture-confirmed TB

367 < 2 wks vs. 6 m

- No difference between early and late ART on composite endpoint of death, tuberculosis treatment failure, and recurrence

South Africa,

Uganda, Zambia, Tanzania

AZT, 3TC, EFV

Summary of RCTs between Early vs. Delay ART

127 patients in immediate arms and 126 in deferred arms (2 mths)

1ry end point: Death at 9 mths

ART: AZT, 3TC and EFV

Immediate ART was not associated with reduced 9-month mortality vs. deferred Rx

HR: 1.12 (95% CI: 0.81-1.55; P = .52)

Incidence of grade 3/4 AEs significantly higher in immediate vs. deferred antiretroviral therapy arm during first 2 months of treatment

Grade 4 AEs significantly more frequent in immediate vs. deferred antiretroviral therapy arm both overall and during first 2 months of treatment

Torok E, et al, et al. Clin Infect Dis. 2011 Jun;52(11):1374-83.

Timing for ART Initiation: TB Meningitis

Potential Advantages of “Starting ART early in Non-CNS OIs vs. CNS OIs ”


Prevent progressive immunodeficiency

Yes



Rapid reduction in mortality risk Yes

Prevention of further OIs and other morbidity

Yes


Prevent progressive immunodeficiency

Yes



Rapid reduction in mortality risk No

Prevention of further OIs and other morbidity

Yes

Non-CNS OIs CNS OIs



Co-toxicity Yes

Pharmacokinetic drug interactions

Yes

Immune reconstitution disease Yes, serious

More difficult to identify drug causing toxicity

Yes

Potential disadvantages of “Starting ART early in Non-CNS OIs vs. CNS OIs ”



Co-toxicity Yes

Pharmacokinetic drug interactions

Yes

Immune reconstitution disease Yes

More difficult to identify drug causing toxicity

Yes

Non-CNS OIs CNS OIs

EACS Guideline 2013

CD4 Recommendation

<100 As soon as practical (Within 2 weeks)

> 100 Within 8-12 weeks

WHO Guideline 2013

CD4 Recommendation

Any CD4 level As soon as possible

DHHS Guideline 2013

CD4 Recommendation

<50 Within 2 weeks

>50, severe TB Within 2-4 weeks

>50, less severe TB Within 8-12 weeks

US CDC Guideline 2013

CD4 Recommendation

<50 Within 2 weeks


Optimal Timing to Initiate ART During TB: Guideline Summary

Thai Guideline 2014

CD4 Recommendation

<50 Within 2 weeks

>50 Severe TB: within 2 wksNot severe TB: 4-8 wks

What if “TB meningitis”? BHIVA 2011:

Although there was a greater incidence of severe adverse events in the early arm. How this translates to UK clinical practice remains unclear

US CDC 2013:

Caution in early ART initiation is warranted in patients with TB meningitis

DHHS 2016:

Many experts feel that ART should be initiated as for other HIV/TB-coinfected patients (CIII)

THAI 2014:

กรณวนจฉยวณโรคเย�อหมสมอง พจารณารอเร �มยาตานไวรสหลงรกษาวณโรคแลวนาน 2 สปดาห

BHIVA Guideline 2011

CD4 Recommendation

<100 As soon as practical

100-350 As soon as practical, can wait until completing 2 m

> 350 Physician’s discretion

WHO Guideline 2013

CD4 Recommendation

Any CD4 level As soon as possible

DHHS Guideline 2015

CD4 Recommendation

<50 Within 2 weeks

>50, severe TB Within 2-4 weeks

>50, less severe TB Within 8-12 weeks

US CDC Guideline 2013

CD4 Recommendation

<50 Within 2 weeks


Optimal Timing to Initiate ART During TB: Guideline Summary

Thai Guideline 2014

CD4 Recommendation

<50 Within 2 weeks


Thai Guideline 2014: ART and anti-TB Initiation (Not include TB Meningitis)

การเร�มยาตานไวรสขณะท�ผปวยกาลงไดยาวณโรค

เร�มยาตานไวรสในผปวยเอชไอวทกรายท�กาลงรบการรกษาวณโรค

ระยะเวลาเร�มยาตานไวรสท�เหมาะสมพจารณาจากปรมาณเมดเลอดขาวซดส�และความรนแรงของโรคดงตาราง

Thai Guideline 2014

CD4 Recommendation

<50 Within 2 weeks


Thai Guideline 2016 (draft): ART and anti-TB Initiation (Not include TB Meningitis)

Thai Guideline 2014: ART and anti-TB Initiation

กรณวนจฉยวณโรคเย�อหมสมองพจารณารอเร�มยาตานไวรสหลงรกษาวณโรคแลวนาน 2 สปดาห

กรณท�ไมม rifampicin ในสตรยารกษาวณโรคใหพจารณาเร�มสตรยาตานไวรสตามปกต

กรณท�ม rifampicin ในสตรยารกษาวณโรคใหพจารณาดงน� 1. Efavirenz ในขนาด 600 มก.ตอวน

2. Nevirapine 200 มก.วนละ 2 คร� งโดยไมตอง lead-in 3. Raltegravir ขนาด 400 มก.วนละ 2 คร� ง4. Maraviroc ขนาด 200 มก.วนละ 2 คร� ง

Thai Guideline 2014: ART and anti-TB Initiation

การเร�มยาวณโรคขณะท�ผปวยกาลงไดยาตานไวรส

กรณผปวยกาลงไดยาตานไวรสสตร NNRTIs ท�ง efavirenz และ nevirapine ใหสตรยาวณโรคตามปกต

กรณผปวยกาลงไดยาตานไวรสสตรท�ม protease inhibitor ใหพจารณาดงน�

1. ปรบยา protease inhibitor เปนสตรท�ม NNRTIs (พจารณายา efavirenz กอน nevirapine) หรอ integrase inhibitor (ไดแก raltegravir) เปนสวนประกอบแทน และใหสตรยาวณโรคตามปกต ท�งน�ตรวจสอบและควรระวงวาผปวยไมเคยมประวตด�อยาหรอแพยาท�กาลงจะเปล�ยน

2. ถาไมสามารถใช NNRTIs และ integrase inhibitor ได ใหพจารณาปรบสตรยาวณโรคเปน 2IEZ+quinolone/10-16IE+quinolone อาจพจารณาเพ�ม streptomycin ในชวง 2 เดอนแรก

DC917113, 35 Year-old man

2003: Diagnosed HIV infection with CD4 of 7 (1%) cells/mm3. GPOvir-S was started.

2004: CD4 84 cells/mm3 and VL 16,300 co/mL. RAMs were 103N and 184V. ARV regimen was switched to AZT, ddI, IDV/r.

2005: CD4 133 (6%) and VL <50

Apr 07: CD4 326 (15%) and VL 51. IDV/r was changed to ATV/r due to SE.

Oct 07: CD4 276 (14%) and VL 6,680. Reassured his adherence.

08: VL 187 (2.2log)

09: CD4 334 (19%), VL 281 (2.4log)

10: VL 22,500. RT RAMs were 41, 67, 70, 219 without PRAM.

11: CD4 208 (13%), VL 147 (2.17log). He lost to follow-up.


May 13: Presented with prolong fever with cough. Chest X-ray showed RUL infiltration. Sputum AFB was positive. CD4 27 (1%). IRZE were started.

Jun 13: Decreased infiltration at RUL and sputum smear for AFB was negative.

What is the optimal strategic treatment in this patient?

A. Switch rifampicin to another drug, then start PI-containing regimen

B. Switch rifampicin to another drug then start Ins-containing regimen

C. Continue current anti-TB regimen and start PI-containing regimen

D. Continue current anti-TB regimen and start Ins-containing regimen

E. Others


May 13: Presented with prolong fever with cough. Chest X-ray showed RUL infiltration. Sputum AFB was positive. CD4 27 (1%). IRZE were started.

Jun 13: Decreased infiltration at RUL and sputum smear for AFB was negative. Rifampicin was discontinued and ABC, 3TC, TDF, DRV/r were initiated.

Jan 14: Stopped anti-TB regimen

Mar 14: Came back with fever. Chest film showed increased RUL and effusion. Sputum AFB was positive.

How to manage this event?

Importance of Rifampicin in Anti-TB Regimen

Jindani A, et al. Lancet 2004;364:1244-1251.

8-mth regimen

without RFP in

continuation phase

8-month regimens which did not have RFP during continuation phase were significantly inferior to the standard 6-mth regimen in newly diagnosed smear-positive pulmonary TB.

What is the optimal treatment in this second event?

A. Switch rifampicin to another drug, then start PI-containing regimen

B. Switch rifampicin to another drug then start Ins-containing regimen

C. Continue current anti-TB regimen and start PI-containing regimen

D. Continue current anti-TB regimen and start Ins-containing regimen

E. Others


Mar 14: IRZELA was started. His ARV regimen was modified to ABC, 3TC, TDF, RAL 800 mg bid.

Mar 14: Rapid molecular technique showed INH resistance. INH was discontinued.

May 14: CD4 11 (4%) and VL <40 co/mL. Chest film showed improved infiltration and effusion.

Nov 14: CD4 44 (5%) and VL <40 co/mL.

Mar 14 Jun 14 Aug 14 Oct 14

Rifampicin markedly decreases blood levels of all PIs

PI Effect of rifampicin

Saquinavir 80%

Ritonavir 35%

Indinavir 90%

Nelfinavir 82%

Amprenavir 81%

Lopinavir/ritonavir 75%

• Boosted PI cannot be given with rifampicin, since PI levels are reduced by ~90%

• Combination of saquinavir (400 mg twice daily) and ritonavir (400 mg twice daily) or doubling of the usual dose of lopinavir/ritonavir can be considered; however, increase risk of hepatotoxicity 1-3

1 Veldkamp AI, et al. CID 1999:29;1586.

2 Gray A , et al. AIDS 2006:20;302. 3 La Porte CJ, et al. AAC2004:48;1553.

Effect of Rifampicin on Pharmacokinetics of Raltegravir

Wenning L, et al. Antimicrob Agents Chemother 2009; 53: 2852–2856.

RAL co-administered with RFP resulted in lower RAL concentration (61% Ctrough reduction)

Doubling RAL to 800 mg when co-administered with RFP

Compensates for effect of RFP on RAL AUC, not overcome effect on C12

No serious AE reported

600-mg RFP qd on PK of a single dose of 400-mg RAL in 10 healthy

volunteers

600-mg RFP qd on PK of 800-mg RAL bid compared to 400-mg RAL bid without RFP in

18 healthy volunteers

Grinsztejn B, et al. Lancet ID 2014;14:459-467.

ANRS 12180 Reflate TB

Efavirenz (EFV)-based regimen is ART of choice for HIV/TB co-infected patients

Potential limitations to EFV use

Adverse Events : cutaneous rash, central nervous system toxicity

Patients with NNRTI resistance

Teratogenicity

Potential interest of RAL in HIV/TB co-infection

Favorable safety profile

Not metabolized by CYP450

Induction by rifampin (Induction of UGT (UDP-glucuronosyltransferase) 1A1)

↓ Ctrough 61%, ↓AUC 40% in healthy volunteers

partially compensated by ↑ RAL 800 mg bid

Objective: estimate the antiviral efficacy of two doses of RAL +TDF+ 3TC, in HIV-1 naive

patients co-infected with TB

Phase II open label randomized multicenter trial

W0 W 24 W48

•1:1:1

•+ RAL 800 mg bid

(TDF + 3TC 300mg) qd + EFV 600 mg qd

(TDF + 3TC 300mg) qd + RAL 400 mg bid

+ RAL 400 mg bid

• Primary endpoint mITT

• HIV RNA<50copies/mL

TB drugs RHZE 2mo followed by RH 4mo

• HIV RNA>1000 cp/mL

• ART naïve

• Confirmed or probable TB

• RIF containing regimen

Sample size : 50 patients/arm, 80% power to show ≥70% success at W24



Grinsztejn B, et al. Lancet ID 2014;14:459-467.

In this phase II study, high rates of success were achieved at week 48 with RAL 400 mg bid or 800 mg bid and EFV 600 mg qd in combination with TDF and 3TC, in patients receiving a rifampin-containing TB treatment

In the context of HIV and TB co-infection RAL 400 mg bid or 800 mg bid had a good safety profile

RAL, at the dose of 400 mg bid, seems to be a suitable alternative to EFV for HIV-TB co-infected patients????

The results may not be applicable for patients who experience HIV drug resistance.

Role of Raltegravir for HIV/TB Patients

New Thai HIV/TB Guideline is coming soon!

Outline




Case management



Case management

THANK YOU

STARTMRK: 5-Year Double-Blind Results

Adverse Event

RAL Group

(n = 281)

EFV Group

(n = 282)

n (%) n (%)

Gastrointestinal Disorders 57 (20.3) 81 (28.7)

Diarrhea 14 (5.0) 27 (9.6)

Flatulence 10 (3.6) 14 (5.0)

Nausea 25 (8.9) 29 (10.3)

General Disorders 28 (10.0) 47 (16.7)

Fatigue 12 (4.3) 25 (8.9)

Nervous System Disorders 51 (18.1) 140 (49.6)

Dizziness 22 (7.8) 99 (35.1)

Headache 26 (9.3) 40 (14.2)

Somnolence 3 (1.1) 21 (7.4)

Psychiatric Disorders 52 (18.5) 87 (30.9)

Abnormal dreams 19 (6.8) 37 (13.1)

Insomnia 21 (7.5) 23 (8.2)

Nightmare 8 (2.8) 15 (5.3)

Skin and Subcutaneous Tissue Disorders 16 (5.7) 63 (22.3)

Rash 3 (1.1) 23 (8.2)

•Rockstroh JK, et al.J Acquir Immune Defic Syndr. 2013 May 1;63:77-85.

Pooled ECHO and THRIVE: Adverse event summary†

RPVN=686

EFVN=682

p-value RPV vs EFV

Median treatment duration, weeks 56 56

Any serious AE, % 7 8 NSAny AE,% 90 92 NSGrade 2–4 AE at least possibly related to treatment, % 16 31 <0.0001‡

Discontinuations due to AEs, % 3 8 0.0005

Most common AEs of interest,§ %

Any neurologic AE 17 38 <0.0001‡

Dizziness 8 26 <0.0001‡

Any psychiatric AE 15 23 0.0002‡

Abnormal dreams/nightmares 8 13 0.0061‡

Rash (any type) 3 14 <0.0001‡

•NS = non significant; †Safety analyses performed using all available data, including beyond Week 48; ‡Fisher’s Exact test, predefined analysis for these AEs; §Well-described AEs associated with current NNRTIs at least possibly related to treatment and observed in ≥10% of patients in either group (all grades)

Cohen C, et al. JAIDS 2012;60:33–42.

Pooled ECHO and THRIVE: Most frequent treatment-related* grade 2–4 AEs†

Incidence, %RPV

N=686 EFV

N=682 p value

Any AE 16 31 <0.0001‡

Rash 1 8 <0.0001‡

Dizziness 1 6 <0.0001¶

Abnormal dreams/nightmares 1 4 0.005¶

Headache 2 2 #Insomnia 2 2 #Nausea 1 2 #

•*Occurring in at least 2% of patients in either treatment group and excluding laboratory abnormalities reported as an AE; †Safety analyses performed using all available data, including beyond Week 48; ‡Fisher’s Exact test, predefined analysis for these AEs;¶Fisher’s Exact test, post-hoc analysis; #Not determined because not pre-planned in this analysis

• Significantly lower rates of overall AEs, rash and abnormal dreams/nightmares for RPV

• Significantly fewer grade 3 or 4 laboratory abnormalities for RPV (11%) vs EFV (18%)1

Cohen C, et al. JAIDS 2012;60:33–42.

Lipid Changes From BL to Wk 48 in RCTs of First-line ART: NNRTI

•This slide is an illustration only and not meant to be a cross-study comparison.

•1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Daar E, et al. Ann Intern Med. 2011;154:445-456..

EFV + TDF/FTCATV/RTV + TDF/FTC

P < .001

ACTG 5202[2]

TC LDL HDL TG

Med

ian C

hange

(mg/d

L)

0

10

20

30

40

50

6070

22

10

40

1512

2113

24

10 82 5

148

13

29

EFV + ABC/3TCATV/RTV + ABC/3TC

P < .001P < .001

P < .001

P < .001

P = .002

21

70

34

13

22

9-14

184

P < .0001

STARTMRK[1]

TC LDL HDL TG

Mea

n C

hange

(mg/d

L)

0

10

20

30

40

50

60

70RAL + TDF/FTC

EFV + TDF/FTC

P < .0001

P < .0001

P = .0002

1516

-8

Lipid Changes From BL to Wk 48 in RCTs of First-line ART: Boosted PIs vs INSTIs

RAL + TDF/FTCATV/RTV + TDF/FTC

DRV/RTV + TDF/FTC

1. Ofotokun I, et al. Clin. Infect. Dis. 2015;60:1842-1851. 2. Quercia R, et al. Clin. Drug Invest. 2015;35:211-219.

•This slide is an illustration only and not meant to be a cross-study comparison.

DTG + 2 NRTIs DRV/RTV + TDF/FTC

ACTG 5257[1]

TC HDL TG

Mea

n C

ha

ng

e (m

g/d

L)

0

10

20

13

1

15

64

-3

66 5

FLAMINGO[2]

TC LDL HDL

Mea

n C

ha

ng

e (m

g/d

L)

0

10

20

4

23

33

-6

14

3 22

30

40

-5

30

TG

LDL

update current hiv treatment guideline and case management · update current hiv treatment...

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