4-Mycobacterium Infection and HIV PDF

Mycobacterium Infection
and HIV
Weerawat Manosuthi, MD
Bamrasnaradura Infectious Diseases Institute
Ministry of Public Health
Outlines
 Update on “current HIV/TB epidemics”
 Summary/update of the evidence of “treatment and prophylaxis of TB”
– 6 months vs. 9 months for TB treatment
– Rifampicin- vs. non-rifampicin containing anti-TB regimen
– Update drug development for drug-resistant TB
– INH prophylaxis
 Summary/update of ART in co-infected HIV/TB patients
– Optimal timing to initiate ART
– Appropriate ART regimen to start with
– PK and clinical data regarding ARV and anti-TB drugs interactions
Overlapping Epidemiology of HIV and

TB Co-infection
HIV XDR TB
TB MDR TB
9.4 million
WHO Report 2010: TB-related

Mortality in HIV Patients
 33.3 million people live with
HIV/AIDS worldwide
 9.4 million new TB cases in
 1/3 (11 million) of HIV-infected 2009
patients are infected with
Mycobacterium tuberculosis – 1.1 million (11.7%) cases
were patients with HIV
– 1/10 (1.1 million) developed
TB disease annually
380,000 people with HIV died from TB

(4700 deaths a day)
Global tuberculosis control 2010.
Available at http://www.who.int/tb/publications/global_report/en
Synergy of HIV and TB
Vermund SH, et al. Tuberculosis 2007;87:S18-25.

Cumulative Survival after TB Treatment in

813 Patients in Bangkok and Nonthaburi
•Death was associated with

1. TB/HIV co-infection (P=<0.001, HR=2.801) 3. Elderly (P=0.005, HR=1.439), and
2. Low body weight (P=0.005, HR=1.637) 4. Extrapulmonary/disseminated TB (P=0.021, HR=2.184)
Manosuthi W, et al. Unpublished data.
HIV Co-infection and MDR/XDR

Tuberculosis
 272 MDR TB and 382 XDR TB
cases were diagnosed in South
Africa, from 2005 to 2007
 One-year mortality MDR TB
– 71% for “MDR TB patients”
– 83% for “XDR TB patients” XDR TB
 30-day mortality
– 40% for “MDR TB patients”
– 51% for “XDR TB patients”
Gandhi N, et al. Am J Respir Crit Care Med 2010;181:80–86.

Treatment of Tuberculosis
1.Duration of anti-TB regimen
2. Rifampicin- vs. non-rifampicin containing anti-TB
regimen in co-infected HIV/TB patients
3. New pipeline drugs and redeveloped drugs for
MDR and non-MDRTB
4. Izoniazid preventive therapy
Treatment of Active TB/HIV Patients: A

Systematic Review
1. Rates of relapse and death were significantly higher among patients who
received a rifamycin for only 2 months.
2. Intermittent treatment during initial intensive phase was associated with
significantly higher rates of failure and relapse.
3. Receipt of ART was associated with non-significantly lower rates of failure
and relapse
Khan F, et al. Clin Infect Dis 2010; 50:1288–1299.
Duration of TB treatment in HIV

Patients: 6 months vs. 9 months
 To compare the efficacy of an intermittent thrice-weekly
in HIV/TB patients
– 6-month regimen (Reg6M: 2EHRZ3/4HR3) vs. 9-month regimen
(Reg9M: 2EHRZ3/7HR3)
 Primary outcomes:
– Favorable responses at the end of treatment: (83% vs. 76%;
P>0.05)
– Bacteriological recurrences (15 vs. 7%;P<0.05)
 Secondary outcome:
– Death by 36 months: (36% vs. 35%; P >0.05)
Swaminathan S, et, el. Am J Respir Crit Care Med2010;181:743–751.

Importance of Rifampicin in Anti-TB

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

Ma Z, et al. Lancet2010;375:2100-09.
Compound in Clinical Development
Ma Z, et al. Lancet2010;375:2100-09.
Grouping of Anti-TB Drugs

To consider
Any effective group 1 drugs
An injectable to which the strain
is susceptible
A later generation
fluoroquinolone (moxifloxacin)
All group 4 agents that have not
been used extensively in the
previous regimen
2 or more agents from group 5
High dose H and adjuvant
surgery
WHO/HTM/TB/2008.402
“Quinolone” for XDR TB: “TMC 207” for MDR TB

Systematic Review
and Meta-analysis
Jacobson K, et al. Clin Infect Dis2010;51:6–14. Diacom A, et al. NEJM2009;23:2397–2405.

Dheda K, et al. Respirology2010;15, 433–450.

“Supporting Data” for Isoniazid Preventive

Therapy in “HIV-infected Patients”
Pre HAART Era Country Comments
Pape W, et al. Haiti 71% reduction in TB rate
LANCET 1993;343:268-72. after 12-month INH Rx.
Whalen C, et al. Uganda 67% reduction in TB rate
N Eng J Med 1997;337:801-8. after 6-month INH Rx
Mwinga A, et al. Zambia 73% reduction in TB rate
AIDS 1998;12:2447-57. after 6-month combined Rx
arms (INH, RFP+PZA)
HAART Era Country Comments

Golub E, et al. Brazil 76% reduction in TB rate
AIDS 2007; 21:1441-8. patients receiving both ART
and IPT
Elzi L, et al. Switzerland 1.6/100 vs. 0/100 person-
Clin Infect Dis 2007;44:94-102. years in without vs. with IPT
(INH, RFP+PZA, RFP)
Isoniazid Preventive Therapy in “HIV-

infected Patients
Akolo C, et al. Cochrane 2010.

Isoniazid Preventive Therapy in HIV-

infected Patients
Khawcharoenporn T, Manosuthi W, et al. Unpublished data.

Adverse Events Related to Any TB

Drugs for Preventive Therapy
Akolo C, et al. Cochrane 2010.

When is the optimal timing to

initiate ART?
Effect of ART on Survival Rate

1.1 Possible risk factors for mortality in
1.0
Received co-infected HIV and TB patients
ART, n=411
.9
Risk factors HR 95% CI P
.8
Probability of Survival
.7
value
.6 Not receiving ART 20.00 8.62-45.45 <0.001

P <0.001
.5
MDR-TB 2.00 1.04-3.78 0.038
.4
.3 Gastrointestinal TB 9.22 1.10-78.02 0.042

.2 Not received ART,
Weight 0.99 0.96-1.01 0.349
.1
n=592
0.0 Pulmonary TB 0.86 0.55-1.35 0.513
0 12 24 36 48 60 72
CNS TB 0.75 0.18-3.11 0.691

Time (months)
Manosuthi, W et al. JAIDS 2006. 43:42-46.

Early vs. Delay ART Initiation during

TB Treatment
Early ART Delayed ART
(before 8 wks of TB treatment) (after 8 wks of TB treatment)
Adherence demand Problematic with use of 4-drug for TB Less problematic because fewer
and multidrug therapy for HIV drugs necessary for TB treatment
Ability to determine the Complex because of the large number Simpler because the number of
cause of adverse events of medications started in a short time drugs for TB treatment is less and
period and overlapping side effects there has been more time to
profiles evaluate response to TB treatment
Drug-drug interaction Problematic Problematic
Severe immune Risk may be increased Risk may be decreased
reconstitution
inflammatory events
HIV disease progression Risk may be decreased Risk may be increased
(new OI or death)
Burman WJ, et al. Clin Chest Med 2005;26:283-294.

Early ART Delay ART
Advantage Disadvantage Advantage Disadvantage
High rate of immune Low rate of immune

Reduces mortality and reconstitution reconstitution Mortality and morbidity
morbidity due to TB inflammatory syndrome inflammatory syndrome due to TB
(IRIS) (IRIS)
Reduces mortality and potential drug-drug Low potential drug-drug Mortality and morbidity
morbidity due to HIV interactions interactions due to HIV
Faster sputum overlapping drug Can differentiate drug Delay sputum

conversion toxicities toxicities conversion
Timing for ART Initiation: SAPIT

55% lower mortality in integrated TB-HIV treatment
 HIV Infection with CD4 < 500 and sputum AFB smear positive & receiving standard
anti-TB therapy regimens
 ART: Didanosine + Lamivudine + Efavirenz once daily
Abdool S, et al. N Eng J Med 2010, 697-706.

Timing for ART Initiation: Cambodian Early versus Late

Introduction of Antiretroviral Drugs (CAMELIA)
 A RCT of 661 HIV patients who diagnosed newly AFB-positive TB and CD < 200
 All patients received standard TB regimen for 6 months
 Compared timing of (d4t, 3TC, EFV) ART initiation at: Wk 2 (n=332) vs. wk 8 (n-329)
 Primary outcome: death
 Significantly higher incidence of IRIS with early vs. late ART: 4.03 vs 1.44 per 100
person-months (p<0.001)
Blanc FX, et al. AIDS Conference 2010; abstract THLBB206.

Timing for ART Initiation: TB Meningitis in

Vietnam
 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. ICCAC Conference 2009; abstract H1224.
Optimal Timing to Initiate ART:

Summary Guideline
WHO Guideline 2009 BHIVA Guideline 2009
CD4 Recommendation CD4 Recommendation
<100 As soon as practical
Any CD4 level As soon as
possible 100-200 As soon as practical, can
wait until completing 2 m
>200 to After 6 months
DHHS Guideline 2009 <350
CD4 Recommendation Thai Guideline 2010
<100 After 2 weeks CD4 Recommendation
100 to 200 After 8 weeks <200 2-8 weeks
200 to 350 After 8 weeks 200 to <350 After 2 months
>350 After 8 - 24 weeks or > 350 Defer ART, monitor
after the end of TB CD4 q 6 months
treatment
Ongoing Trials Studying Timing of

ART in HIV/TB Patients
Trial Study site Treatment arms Primary outcome
ISRCTN77861053 South Africa, Uganda, Arm 1: at 2 wks Composite endpoint
Zambia, Tanzania Arm 2: placebo for 6 m 1. TB Rx failure
followed by ART 2. Death
NCT00108862 USA, Brazil, Haiti, South Arm 1: ART initiation at 2 wks Survival without
(ACTG A5221) Africa, Kenya, Malawi, Arm 2: ART initiation at 8-12 progression to AIDS
India, Thailand wks
NCT00078247 Uganda Arm 1: immediate ART CD4 decline and
for 6 m progression to AIDS
Arm 2: ART delayed until CD4
<250
NCT01014481 Thailand Arm 1: at 4 wks Composite endpoint
(TIME study) Arm 2: at 12 wks 1. Death
2. Hospitalization
3. Adverse reactions
NCT00737724 Mexico Arm 1: immediate ART 1. S/S of active TB
Arm 2: ART initiation after 2 m 2. Mycobacterial load in
affected tissues
What is the Appropriate Regimens

to Initiate?
Rifampicin-ARV Drugs Interactions
Wilkinson GR, et al. NEJM 2005;352:2211-2221.

Greiner B, et al. J Clin Invest 1999;104:147-153.
EFV Levels and Treatment Outcomes

between EFV 600 and 800 mg
Virological Outcome:
Time to virological success
25.0
Kaplan-Meier failure estimates, by efv
22.5
1.00
20.0
Plasma EFV level (mg/L)
0.75
17.5
p=0.632
15.0
0.50
12.5
0.25
10.0
7.5
0.00
5.0 0 16 24 36 48
analysis time
3.39 (median)
2.5 3.02
efv = 600 efv = 800
0.0
EFV 600 mg EFV 800 mg
Dose per day
1. Manosuthi W, et al. AIDS 2005;19:1481-1486.

2. Manosuthi W, et al. AIDS 2006;20:131-132.
Interaction between Nevirapine and

Rifampicin
 10 HIV/TB patients
 Co-administraion of NVP
and RIF result in Cmax
↓36% (p=0.04), Cmin 21%
La Ribera et al. Avihingsanon A, Manosuthi W, et al.

JAIDS 2001,28:450-453. Antiviral Therapy 2008;13:529-536.
NVP Levels and 4-year Treatment Outcome

p = 0.047
25.0
p = 0.048
22.5
20.0
17.5
Plasma NVP level (mg/L)
15.0
12.5
10.0
7.5 6.6+3.1 6.4+3.4

5.4+3.5
5.0
2.5 •3.4
0.0
NVP + RFP NVP NVP + RFP
we e k 8+12 we e k 8+12 we e k 60 (no RFP)
Treatment Group
Manosuthi W, et al. CID 2007; 44:141–4.

Manosuthi W, et al. Int J Infect Dis 2010;14:e1013-7.
What to Start in HIV/TB Co-infected Patients?

“Efavirenz” vs. “Nevirapine” While Receiving RFP
Observational/retrospective Randomized controlled trials

studies Manosuthi 2009
Shipton 2009 (N2R study, Thailand, n=142)
(Botswana, n=155)
Varma 2009
(Thailand, n=126 of 667)
Boulle 2008
(South Africa, n=1,283)
Manosuthi 2008
(Thailand, n=188)
Sathia 2008
(UK, n=25 of 103)
What to Start in HIV/TB Co-infected Patients:

Observational/retrospective studies
Observational/retrospective Outcomes/comments
studies
Shipton 2009 No significant difference
(Botswana, n=155)
Varma 2009 No significant difference
(Thailand, n=126 of 667)
Boulle 2008 At 24 weeks, 83.7% in NVP+RFP vs.
(South Africa, n=1,283) 91.7% in NVP
No difference between NVP+RFP vs.
EFV+RFP
Manosuthi 2008 At 48 weeks, 77.9% in EFV+RFP vs.
(Thailand, n=188) 67.7% in EFV+RFP
Sathia 2008 Small sample size
(UK, n=29 of 103)
C12 EFV vs. C12 NVP and 48-week Outcome

of ART: N2R Study
 ART regimens containing efavirenz (600 mg per day) were less compromised by
concomitant use of rifampicin than were those that contained nevirapine (400 mg per
day) in patients with concurrent HIV-1 infection and TB.
 “Low drug exposure” and “low body weight” are important predictive factors for
treatment failure.
Manosuthi W, et al. Clin Infect Dis 2009, 48:1752-1759.
Relationship between Body Weight and C12 EFV at week 6 and

12 (A); and at Week 6, 12, and After Rifampicin (B)
26 26
24 (A) 24 (B)
22 22
20 20
18 18
Pearson’s correlation = -0.255 Pearson’s correlation = -0.239
C12 Efavirenz (mg/L)

C12 Efavirenz (mg/L)
16 16
P = 0.003
14 14 P = 0.001
12 12
10 10
8 8
6 6
4 4
2 2
0 0
-2 -2
-4 -4
30 35 40 45 50 55 60 65 70 75 80 85 90 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Body Weight (kilograms) Body Weight (kilograms)
•There appears to be a relationship between high body weight and low combined C12 efavirenz at week 6 and 12 (P=0.003,
r=-0.255).
•Conversely, plotting the regression line by defining C12 efavirenz as independent variable, C12 efavirenz at 1 mg/L
intercepted body weight at a mean of 57.5 (95% CI: 54.9-60.1) kilograms. The same trends were found at week 6 (P=0.033,
r=-0.257) and week 12 (P=0.058, r=-0.234); and also found in C12 efavirenz at week 6, week 12, and after rifampicin
discontinuation as shown in Figure 2B (P=0.001, r=-0.239).
Manosuthi W, et al. Antimicrob Agents Chemo 2009; 53:4545-8.
CYP2B6 Polymorphisms and

“EFV alone vs. EFV with RFP”
Caucasians and Blacks
Thais
Wyen C, et al. Uttayamakul S, Manosuthi W, et al.

JAC 2008;61:914–918. AIDS Research and Therapy 2010;7:8.
Rifampicin has a moderate effect on blood

levels of nevirapine and efavirenz
Effect of PI Effect of
NNRTI Rifampicin Rifampicin
Nevirapine ↓ 37-58% Saquinavir ↓ 80%
Efavirenz ↓ 13-26% Ritonavir ↓ 35%
Indinavir ↓ 90%
Nelfinavir ↓ 82%
Amprenavir ↓ 81%
Lopinavir/rtv ↓ 75%
Summary Dose Adjustment

Drug-drug Recommendation
Rifampicin + Efavirenz Use EFV 800mg/day in patients ≥60kg and
standard dose 600mg/day in patients <60kg
Rifampicin + Nevirapine Not recommended but if given then use
standard doses and perform NVP TDM
Rifampicin + Etravirine No data, not recommended
Rifampicin + Rilpivirine Not recommended
Rifabutin + Efavirenz Increase rifabutin to 450mg daily
Rifabutin + Nevirapine Not recommended but if given then use
standard doses
Rifabutin + Etravirine Use with caution; if given then use standard
doses
Rifabutin + Rilpivirine No data
Drug-drug Recommendation
Rifampicin + unboosted PI Do not use
Rifampicin + boosted PI Not recommended because of poor
pharmacokinetics and
high rates of hepatotoxicity in healthy
volunteers
Rifabutin + unboosted PI Reduce rifabutin to 150mg daily,
increase unboosted PI
Rifabutin + boosted PI Reduce rifabutin to 150mg three times
per week
Rifampicin + Raltegravir Use raltegravir 400 mg bid
Rifampicin + Maraviroc Not recommended, but if given

double dose of maraviroc
Rifabutin + Raltegravir No data, not recommended
Rifabutin + Maraviroc Use standard doses
Summary
 HIV and TB are still the major public health threat and the leading
cause of death. In addition, MDR TB and XDR TB epidemics are
rapidly expanding.
– Further strategic management and collaborative treatment is needed.
 Six- to nine-month rifamycin-based anti-TB regimen is still a standard

treatment regimen. Studies of new drugs in TB treatment pipeline are
on-going.
 INH preventive treatment are beneficial for a short period, especially
for patients with advanced immuno-suppression while awaiting TB
protective effect from ART.
– The optimal duration of IPT is lesser clear compared to non-HIV patients.
– Limitation of TST, rate of isoniazid resistance, duration-limited benefit of
IPT, and adverse events are the concerns in co-infected HIV/TB patients.
Summary
 Effective combined ART substantially reduce the risk of death.
– Early initiation of ART in severe immunosuppressive co-infected HIV/TB
patients is associated with improved survival but not for the TB meningitis.
– However, more clinical trials is still needed from the different medical
infrastructures.
 Standard dose of efavirenz is less compromised by concomitant

treatment with rifampicin than nevirapine in patients with concurrent
HIV infection and TB who weigh <60 kilograms.
– CYP2B6-TT genotype had impact on plasma efavirenz while co-
administration with/without rifampicin.
– Nevirapine-based ART remains an acceptable option for persons who
can not use efavirenz.
Thank you

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Mycobacterium Infection

Overlapping Epidemiology of HIV and

WHO Report 2010: TB-related

380,000 people with HIV died from TB

Synergy of HIV and TB

Vermund SH, et al. Tuberculosis 2007;87:S18-25.

Cumulative Survival after TB Treatment in

•Death was associated with

HIV Co-infection and MDR/XDR

Gandhi N, et al. Am J Respir Crit Care Med 2010;181:80–86.

Treatment of Active TB/HIV Patients: A

Duration of TB treatment in HIV

Swaminathan S, et, el. Am J Respir Crit Care Med2010;181:743–751.

Importance of Rifampicin in Anti-TB

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

Compound in Clinical Development

Grouping of Anti-TB Drugs

“Quinolone” for XDR TB: “TMC 207” for MDR TB

Jacobson K, et al. Clin Infect Dis2010;51:6–14. Diacom A, et al. NEJM2009;23:2397–2405.

Dheda K, et al. Respirology2010;15, 433–450.

“Supporting Data” for Isoniazid Preventive

HAART Era Country Comments

Isoniazid Preventive Therapy in “HIV-

Akolo C, et al. Cochrane 2010.

Isoniazid Preventive Therapy in HIV-

Khawcharoenporn T, Manosuthi W, et al. Unpublished data.

Adverse Events Related to Any TB

Akolo C, et al. Cochrane 2010.

When is the optimal timing to

Effect of ART on Survival Rate

.6 Not receiving ART 20.00 8.62-45.45 <0.001

.3 Gastrointestinal TB 9.22 1.10-78.02 0.042

CNS TB 0.75 0.18-3.11 0.691

Manosuthi, W et al. JAIDS 2006. 43:42-46.

Early vs. Delay ART Initiation during

Burman WJ, et al. Clin Chest Med 2005;26:283-294.

Early ART Delay ART

Advantage Disadvantage Advantage Disadvantage

High rate of immune Low rate of immune

Faster sputum overlapping drug Can differentiate drug Delay sputum

Timing for ART Initiation: SAPIT

Abdool S, et al. N Eng J Med 2010, 697-706.

Timing for ART Initiation: Cambodian Early versus Late

Blanc FX, et al. AIDS Conference 2010; abstract THLBB206.

Timing for ART Initiation: TB Meningitis in

 127 patients in immediate arms

 Incidence of grade 3/4 AEs significantly higher in immediate vs. deferred

Optimal Timing to Initiate ART:

Ongoing Trials Studying Timing of

What is the Appropriate Regimens

Rifampicin-ARV Drugs Interactions

Wilkinson GR, et al. NEJM 2005;352:2211-2221.

EFV Levels and Treatment Outcomes

1. Manosuthi W, et al. AIDS 2005;19:1481-1486.

Interaction between Nevirapine and

La Ribera et al. Avihingsanon A, Manosuthi W, et al.

NVP Levels and 4-year Treatment Outcome

7.5 6.6+3.1 6.4+3.4

Manosuthi W, et al. CID 2007; 44:141–4.

What to Start in HIV/TB Co-infected Patients?

Observational/retrospective Randomized controlled trials

What to Start in HIV/TB Co-infected Patients:

C12 EFV vs. C12 NVP and 48-week Outcome