tb and hiv · study week 0 8 24 hiv+ tb primary endpoint trial design for 3 rcts: camelia, ... n...

TB/HIV Coinfection of 20

This image cannot currently be displayed.

TB and HIV

Julie Higashi MD, PhDTB Controller/Deputy Health OfficerSan Francisco Department of Public Health


Estimated HIV Coinfection in Persons Reported with TB, United States, 1993 – 2013*

*Updated as of June 11, 2014.

Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group.

% C

oin

fect

ion

0

10

20

30

40

50

60

70

All Ages Aged 25 ‐ 44






What changes with HIV?

Multiple effects of HIV infection on the course of TB infection and disease



Reactivation RiskHIV+20x

Source: Murray & Nadell’s Text of Respiratory Medicine


TB Diagnosis in HIV positive

Symptoms – may have typical symptoms, but may be asymptomatic

Sputum microscopy (smear) – low threshold to get sputum for testing

Chest X-ray – may be normal, even with disease

Xpert MTB/RIF Assay

MTB Culture


TB Diagnosis in HIV: Look for active disease aggressively

• Ambulatory HIV+ adults w/ CD4>200 enrolled in a TB vaccine trial• 10/500 w/ subclinical TB (2%)

• 274 HIV+, ART-naïve ambulatory patients in South Africa• 18 (8.5%) asymptomatic, but MTB culture+



TB Diagnosis in HIV: U.S.

• 22% HIV infected with n=31 normal CXRs vs. 5% non HIV infected with n=22 normal CXRs• HIV more likely to be symptomatic (93%) than non HIV infected (68%) with normal CXR


TB Diagnosis in HIV: U.S.

• 22% HIV infected with n=31 normal CXRs vs. 5% non HIV infected with n=22 normal CXRs• HIV more likely to be symptomatic (93%) than non HIV infected (68%) with normal CXR

Bottom line – lower threshold to collect sputa for HIV than non HIV with normal CXR


TB Diagnosis in HIV: Microscopy

Overall sensitivity of sputum microscopy ~50%

Lower in HIV+

0%

5%

10%

15%

20%

25%

30%

35%

0-50 51-100 101-150 151-200 201-250 251-300 301-350 351-400 401-450 451-500 >500

CD4 Cell Count (cells/μL)

% N

egat

ive

AF

B S

mea

r

Chamie et al, IJTLD, 2010Chamie, IJTLD 2010



TB Diagnosis in HIV: Chest x-ray

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

0-50 51-100 101-150 151-200 201-250 251-300 301-350 351-400 401-450 451-500 >500


% w

ith

Cav

itat

ion

0%

5%

10%

15%

20%

25%

30%

35%

0-50 51-100 101-150 151-200 201-250 251-300 301-350 351-400 401-450 451-500 >500


% N

orm

al C

he

st

X-r

ay

(p<0.001, for trend)

(p<0.001, for trend)

Chamie et al, IJTLD, 2010Chamie, IJTLD 2010


Xpert MTB/RIF Assay

In HIV positives – pooled sensitivity for Xpert in culture positive cases is only 79%

Boehme, NEJM, 2010; Theron AJRCM 2011

Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults., Cochrane Review, 2014

Non HIV


What is new in …

Timing of ART start in TB patients

TB IRIS

Use of ART drugs in TB patients



Case 1: TB and low CD4

23 Brazilian man, recently moved to US

Presents with fever, night sweats, severely debilitated

Wasted, diffuse lymphadenopathy

AFB smear positive

Newly diagnosed HIV+

CD4 count is 2 cells/μL

He is started on RIPE


When to start ART?

Competing Risks in the timing of ART during TB treatment

Adapted from: W. Burman, CROI - Boston, 2011

“Immediate” ART (<2 weeks) “Early” ART (<2 months)Benefits• Risk of OIs

Risks• Drug-drug Interactions• IRIS risk• pill burden, and

possible adherence• Could decrease ART

efficacy

Benefits• Risk of IRIS

Risks• OIs


TB treatment

TB treatment

ART

ART

Study week

80 24

HIV+TB

Primary endpoint

Trial Design for 3 RCTs: CAMELIA, STRIDE, and integrated arms of SAPIT

“Immediate” ART(within 2 weeks))

“Early” ART(2-3 months)

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011



Key characteristics of trials of timing of ART during TB treatment

Study Setting Key enrollment criteria

Median CD4 (IQR)

Primary endpoint

CAMELIA Cambodia Smear +, CD4 < 200

25 (10 - 56) Death

STRIDE Multi-national Clinical TB, CD4 < 250

77 (36 – 145) AIDS or death

SAPIT South Africa Smear +, CD4 < 500

150 (77 – 254) AIDS or death

Blanc, Vienna, 2010, Havlir, CROI, 2011, Karim , CROI, 2011 Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011


02468

1012141618

CAMELIA STRIDE SAPIT

Immediate Early

Effect of ART timing on death (CAMELIA) or death/AIDS (STRIDE, SAPIT)

34% ↓p=0.004

19% ↓p=0.45

11% ↓p=0.73

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011


All studies showed significant reduction in death/AIDS among those with CD4 < 50

0

5

10

15

20

25

30

CAMELIA STRIDE SAPIT

Immediate Early

34% ↓p=0.004

42% ↓p=0.02

68% ↓p=0.06

Blanc, Vienna, 2010, Havlir, CROI, 2011, Karim , CROI, 2011



When to start ART?

Competing Risks in the timing of ART during TB treatment

Adapted from: W. Burman, CROI - Boston, 2011

“Immediate” ART (<2 weeks) “Early” ART (<2 months)Benefits• Risk of OIs/Death

Risks• Drug-drug Interactions• IRIS risk• pill burden, and

possible adherence• Could decrease ART

efficacy

Benefits• Risk of IRIS

Risks• OIs


TB IRIS Greater in Immediate vs. Early Arms

02468

1012141618

STRIDE SAPIT

IRD

Immediate Early

p=0.009

p=0.02

IRIS


HIV RNA and CD4 Responses Similar at 48 weeks

N 370 380 361 365 355 349 349 347 331 332 N 368 379 357 364 350 347 346 343

333 333

CD4 change from entry 156 cells/mm3

No difference between armsHIV RNA suppression 74% at 48 weeksNo difference between arms

Toxicity similar between Arms



No differences in TB Rx response by ART use

No TB therapy failures occurred in either study arm

TB recurrences:

ART = 3

No ART = 4 (p=.5)

25

50

75

10

00

0 2 4 6

% M

TB

Cul

ture

Pos

itive

Time to MTB Culture Negative

025

5075

100

0 2 4 6

% A

FB

Sm

ear

Pos

itive Time to AFB Smear Negative

ART & TB Rx Response Smear+/Culture-Does immediate ART enhance clearance of TB?

No difference in time to TB culture negative

No difference to AFB smear negativity

Chamie, CID, 2010


Case 1: TB and low CD4

• Start within 2 weeks of TB therapy

• Anticipate TB IRIS as a complication

23 Brazilian man, recently moved to US

Presents with fever, night sweats, severely debilitated

Wasted, diffuse lymphadenopathy

AFB smear positive

Newly diagnosed HIV+

CD4 count is 2

He is started on RIPE

Key Points


Case 2: TB and high CD4

47 yo latino male in ER with cough and weight loss

Chest radiograph consistent with TB, AFB+

Initially refuses HIV test

Seen in TB clinic, starts on 4 drug therapy, with rifampin

On the day he starts TB Rx, agrees to HIV test

HIV + and CD4 680

Is ART necessary? If so, when?



SAPiT Study

642 HIV+ adults in Durban, South Africa

AFB smear + pulmonary TB

CD4 count <500

Randomized to

• ART during TB therapy at 2 weeks

• ART during TB therapy after induction

• ART after TB therapy completion (“sequential therapy”)

Karim S, et al. New Engl J Med 2010


Mortality reduced when ART started during vs. after TB treatment: SAPIT

Karim S, et al. New Engl J Med 2010

HR: 0.44, p<0.003


DHHS HIV Rx Guidelines - 2015

• “Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.

• ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.”



Case 2: TB and high CD4

• Get HIV genotype• Start ART when

genotype returns & ideally by 8 weeks of TB treatment

• ART regimen may require replacing rifampin with rifabutin

47 yo latino male in ER with cough and weight loss

Chest radiograph consistent with TB, AFB+

Initially refuses HIV test

Seen in TB clinic, starts on 4 drug therapy, with rifampin

On the day he starts TB Rx, agrees to HIV test

HIV + and CD4 680

Is ART necessary? If so, when?

Key Points


Török M E et al. Clin Infect Dis. 2011;52:1374-1383

TB meningitis: No benefit to immediate ART

58% mortality at 9 months

Torok, CID, 2011

Significantly more Grade 4 adverse events in immediate ART arm


Case 3: Clinical worsening after ART

29 yo man w/ HIV p/w fevers, diarrhea, abd pain

Dx’d with TB ileitis (cx+)

CD4 310, VL=385,000

Started on TB therapy, then ART (EFV, tenofovir/emtricitabine: “Atripla”) within 2 weeks

Comes to clinic 4 weeks after ART start: diarrhea, abd pain have resolved; complains of neck swelling & pain

CD4 is now 615, VL=83 Terminal ileum granulomas



Case 3

FNA: AFB smear + necrotizing, granulomatous inflammation


TB IRIS – A constant challenge to the clinician

Paradoxical TB IRIS: New or worsening or recurrent symptoms/signs and or radiographic manifestions of TB after ART • Fever, lymphadenopathy, enlarging CNS lesion, respiratory

decompensation

• Median onset 2 weeks

• Higher risk with lower CD4 cell count , higher HIV RNA


Paradoxical TB IRIS

Diagnosis: • Improvement of TB symptoms on TB treatment prior to ART

• Deterioration with features of worsening TB soon after starting ART; and

• Demonstration of a CD4 and/or HIV viral load response to ART

AND

• Exclusion of alternative causes for deterioration such as a bacterial infection or an additional OI, a drug reaction, poor adherence, or resistance to TB treatment.

Occurs in up to 25% of TB/HIV cases starting ART

Meintjes, G. et al Curr HIV/AIDS Rep, Nov. 2012



Differential Diagnosis of TB IRIS

Drug resistant TB

Other opportunistic infection

Non adherence

Malabsorption

Drug reactions


Case 4: Clinical worsening after ART

25 female pulmonary TB, fevers, wasting, diffuse lymphadenopathy

CD4 29

Started on TB therapy, then Atripla within 2 weeks

Initial improvement

Comes to clinic 3 weeks after ART start with headache, fever, meningismus and stridor


Patient has TB IRIS with compression of trachea

Steroids recommended for life threatening situations such as airway compromise, respiratory failure and enlarging mass lesions

For not life threatening TB IRIS, a 4 week course reduced hospitalization and procedures

More extended duration of prednisone may be required

ART should be continued

There is no diagnostic test for TB IRIS, although there are biomarkers associated with higher risk

Meintjes, AIDS, 2010



Patient also has cryptococcal meningitis

Positive CrAg in CSF

Always consider other opportunistic infections in the setting of TB IRIS

HIV-TB cohort in Uganda

• 26% mortality

• Risk factor for death: no ART, anergy, undiagnosed cryptococcal disease

Worodria, JAIDS, 2011


Cases 3 & 4: Clinical worsening after ART

• Continue ART and TB treatment

• Start steroids• Look for and

treat OIs• Monitor closely

Key Points

www.niaid.nih.gov


HIV Treatment is TB prevention

CIPRA HT001: Starting ART between 200-350 vs. < 200 reduced TB by 50%

HPTN 052: Early ART in HIV+ patient with CD4 ≥ 350 led to a 47% reduction in risk of TB

Severe NEJM 2010, Grinstein B, et al. 6th IAS MOAX0105, 2011



ART & TB Drug Interactions


ART and TB Drug Interactions– General Principles

Rifampin potent inducer of CYP3A and interacts with a number of ART drugs

Rifabutin is a less potent inducer of CYP3A than rifampin and preferred TB rifamycin agent when rifampin cannot be used

ART+ TB treatment regimens may call for adjustment of ART dose, rifabutin dose or both

Data covering all possible drug interactions are incomplete


What ART to start?

NRTIs (“nukes”) generally have no drug interactions with TB treatment & should be a part of most ART regimens (e.g. Truvada, Epzicom)

Non nucleoside reverse transcriptase inhibitors (NNRTI’s): Efavirenz (EFV) and Nevirapine (NVP), both reduced with rifampin coadministration • EFV AUC 78% of normal & NVP AUC 69% of normal

EFV-based ART equivalent effect with or without TB treatment in South African cohort

Limited data on Rifabutin+EFV and concern for increased toxicity with required increased Rifabutin dosing (450 mg QD)

Boulle JAMA 2008, Brennan-Benson AIDS 2005

EFV + Rifampin is preferred HIV/TB regimen



FDA recommendation to EFV to 800

Previously recommended increasing EFV to 800 mg when coadministered with RIF if weight >50 kg (http://packageinserts.bms.com/pi/pi_sustiva.pdf)

Very limited evidence to support this

One study of HIV/TB coinfected Spanish patients• EFV troughs and AUC on average decreased 22-25% if EFV 600

• Highly variable and EFV levels went UP with RIF in some patients

• EFV 800 mg+RIF associated with same levels as EFV 600 without RIF

Lopez Cortes 2002, Boulle JAMA 2008, Friedland JAC 2006, Manosuthi AIDS 2006NIH/CDC OI Guidelines 2013

Current Recommendation: Dose EFV at 600 mg daily (standard dosing)


Nevirapine: Alternative NNRTI

NVP decreased by RIF more than EFV

Concern for subtherapeutic NVP if already on rifampin during lead-in NVP dosing • NVP standardly dosed at 200 mg daily for 2

weeks followed by 200 mg BID to allow enzyme induction and reduce hypersensitivity

Therefore NO lead-in dosing with NVP recommended if already on Rifampin• May increase risk of NVP hypersensitivity

Boulle JAMA 2008, Brennan-Benson AIDS 2005


When NNRTIs may not be an option

NNRTI resistance • Transmitted drug resistance (up to 8% NNRTI drug

resistance in HIV treatment naïve patients in US)

• Drug resistance relatively easily acquired due to low genetic barrier

NNRTI intolerance

Pregnancy

Age < 3 (EFV not available)

HIV-2 – NNRTI’s not effective



Alternatives to NNRTIs

Ritonavir boosted protease inhibitors

Integrase inhibitors ( Raltegravir)

CCR5 Antatogists ( Maraviroc)


PROTEASE INHIBITORS


Rifamycin effect on protease inhibitors

0

20

40

60

80

100

120

LPV/RTV

ATZ/R

TV

LPV/RTV

ATZ/R

TV

% o

f n

orm

al c

on

ce

ntr

ati

on

s

AUCtrough

Rifampin

Rifabutin

Cannot coadminster Protease inhibitors with RIFAMPIN



Rifabutin and Protease inhibitors

All PIs increase Rifabutin concentrations

Current recommendation: Decrease Rifabutin from 300 mg daily to 150 mg daily for boosted PIs

CAUTION: Rifabutin dose would then be inadequate if patient stopped Protease inhibitor!


Another Caution: Rifampin resistance with PI/rifabutin

3 cases of relapse with acquired rifampin resistant TB, while on boosted PI + rifabutin 150 mg QOD TB regimen

7 of 10 patients on Kaletra/ Rifabutin 150 QOD subtherapeutic rifabutin AUC• One acquired Rifamycin resistance

Jenny Avital CID, 2009, Boulanger CID 2010

Higher dose of rifabutin now recommended with protease

inhibitors - 150 mg QD (vs. QOD)

Jenny Avital CID, 2009, Boulanger CID 2010, NIH/CDC OI Guidelines 2013


INTEGRASE INHIBITORS



Raltegravir (RAL) or Dolutegravir (DTG) + Rifampin

Current recommendations to increase RAL to 800 mg BID and DTG to 50 mg BID• Compensates for AUC decrease but trough

remains low

No dose adjustment of RAL or DTG needed if co-administered with Rifabutin

Watch for fixed dose combinations including RAL or DTG

Brainard ICAAC 2008Braininard, J Clin Pharm, 2011; Dooley, JAIDS, 2013


RALTEGRAVIR DRUG RESISTANCE: 4 in 400 bid vs 1 in 800 BID

TAKE HOME : DOUBLE THE DOSE OF RALTEGRAVIR GIVEN WITH RIFAMPIN

Grinsztejn IAS 2012 ANRS 12-180 REFLATE


Dose Adjustments with ART and TB Medications

Rifampin Rifabutin

Efavirenz Increase rifabutin

Nevirapine No NVP lead in

Etravirine

Rilpivirine Increase RPV

DRV/r or ATZ/r Decrease rifabutin

Lopinavir/r Increase LPV/r Decrease rifabutin

Raltegravir Increase RAL

Elvitegravir No data* (prob ↓RFB)

Dolutegravir Increase DTG No data

Maraviroc Increase MVC

NNRTI

PI

HIV+ pts with RIF-sensitive TB should only be treated with a regimen not containing a rifamycin if they have had a serious event that is highly likely to be due to the drug.

IntI



Conclusions

CO-TREATMENT OF HIV AND TB SAVES LIVES

ART should be started immediately (within 2 weeks of TB therapy) in TB/HIV patients with <50 CD4 cells

ART should be started between 2 weeks and 2 months in all other patients with HIV and TB, even those with high CD4

TB IRIS has broad differential and remains a challenging management problem

Rifamycins have multiple interactions with ART, and special modifications of dosing of ART and/or TB regimen may be required


Thank you!

Acknowledgements:

• Dr. Gabe Chamie, MD, Division of HIV/AIDS, UCSF

• Dr. Annie Leutkemeyer, Division of HIV/AIDS, UCSF

Disclosures: None

Thank you for your time and attention!

tb and hiv · study week 0 8 24 hiv+ tb primary endpoint trial design for 3 rcts: camelia, ... n...

Documents