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
DHHS guidelines. January 2016. http://aidsinfo.nih.gov/guidelines
•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. January 2016. http://aidsinfo.nih.gov/guidelines
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
Manosuthi W, et al. AIDS Research Therapy 2015;12:12.
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
Manosuthi W, et al. AIDS Research Therapy 2015;12:12.
Thai Guideline 2014:Guidelines for Initial ARV Regimens
Manosuthi W, et al. AIDS Research Therapy 2015;12:12.
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
ARV Regimen Considerations as Initial Therapy based on Specific Clinical Scenarios
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
ARV Regimen Considerations as Initial Therapy based on Specific Clinical Scenarios
Patient/Regimen
CharacteristicsClinical
Scenario Consideration(s)
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
ARV Regimen Considerations as Initial Therapy based on Specific Clinical Scenarios
Patient/Regimen
CharacteristicsClinical
Scenario Consideration(s)
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.
ARV Regimen Considerations as Initial Therapy based on Specific Clinical Scenarios
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.
SC 1185068, 45 year-old MSM
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.
SC 1185068, 45 year-old MSM
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
SC 1185068, 45 year-old MSM
SC 1185068, 45 year-old MSM
Feb 15: Developed bloody diarrhea. Internal hemorrhoid was diagnosed.
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
SC 1185068, 45 year-old MSM
Feb 15: Developed bloody diarrhea. Internal hemorrhoid was diagnosed.
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
LovastatinSimvastatin
AtorvastatinPravastatinRosuvastatin
Pitavastatin
EVG/COBI/TDF/FTC
LovastatinSimvastatin
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
Case 1172447: 49 year-old Female
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
Case 1172447: 49 year-old Female
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.
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.
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
Case 1172447: 49 year-old Female
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.
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. 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.
Case 1172447: 49 year-old Female
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.
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. 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
Case 1172447: 49 year-old Female
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.
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.
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. 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. 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?
Case 1172447: 49 year-old Female
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.
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.
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. 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. 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”.
Case 1172447: 49 year-old Female
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.
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.
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. 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. 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
Boulware D, et al. N Engl J Med 2014;26:2487.
Survival in Patients with CSF WBC ≥5 and <5 Cells/mm3 at Randomization
Boulware D, et al. N Engl J Med 2014;26:2487.
•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
Manosuthi W, et al. AIDS Research Therapy 2015;12:12.
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
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
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 ”
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 Yes
Prevention of further OIs and other morbidity
Yes
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
Prevention of further OIs and other morbidity
Yes
Non-CNS OIs CNS OIs
Potential disadvantages of early initiation of ART
High pill burden Yes
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 ”
Potential disadvantages of early initiation of ART
High pill burden Yes
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
> 50 Within 8-12 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
> 50 Within 8-12 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: 2-8 wks
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
>50 Severe TB: within 2 wksNot severe TB: 2-8 wks
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.
DC917113, 35 Year-old man
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
DC917113, 35 Year-old man
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
DC917113, 35 Year-old man
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
ANRS 12180 Reflate TB
ANRS 12180 Reflate TB
Grinsztejn B, et al. Lancet ID 2014;14:459-467.
ANRS 12180 Reflate TB
Grinsztejn B, et al. Lancet ID 2014;14:459-467.
ANRS 12180 Reflate TB
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
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
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