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Use of Bedaquiline and Anti Retroviral Therapy

By Micheal Mazzi | 25 Sep, 2018

Dear Colleagues, i salute all.
I would kindly want to understand. If i have a patient who is stable on Tenofovir/Lamivudine/Efavirenz , and is not eligible for Nevirapine but i would like to start the patient on a DR-TB regimen with Bedaquiline, what do i substitute for the Efavirenz? The patient is an adult
Thank you



Erica Lessem Replied at 5:13 PM, 25 Sep 2018

Michael, I don't have your email but if you email me off-list at
I will introduce you to very
experienced HIV/MDR-TB clinicians who can help

Dr. Saswata Dutt Replied at 1:39 PM, 26 Sep 2018

Dear Micheal and Erica,

Thank you for bringing up the subject Micheal.

Please Erica - may the very experienced HIV/DR-TB clinicians reply in the
forum, so that many patients all over the world can be benefited.

I also tried to search papers on the subject - attached four of them here.
They are bit old. Though it has been said LPV-r may be used in specific
situations like this under close observation, we all know close observation
is challenging in community treatment in most developing countries, where
patient numbers are always much higher than availability of beds in
hospitals in the country.

If anyone has recent publication on the subject, will be thankful if shared.
Dutt, Nigeria.

Dr. Saswata Dutt Replied at 1:45 PM, 26 Sep 2018

Please there are five out of nine - fictitious attachment in my mail below.
I am not sure, how they come about. Please disregard them.
Sorry about that.
Dutt, Nigeria.

Erica Lessem Replied at 1:48 PM, 26 Sep 2018

Dear all,
Here was the advice given:

There are 2 options: One is to give lopinavir/ritonavir the other
raltegravir. With lopinavir/ritonavir, there were data from a cohort in
South Africa showing that the use of this drug with BDQ resulted in higher
BDQ exposures, but there was no difference in clinical outcomes and no
increased side effects. So this is what most of us do. If you have access
to raltegravir or dolutegravir, then these are great options as there are
no drug-drug interactions.

Some people were using triple nucleosides, but this is not a great option
for viral control.

It’s always a good idea to check a viral load in patients on ART when
starting MDR treatment, whether using BDQ or not, to make sure they are
stable on their ART. It also gives you information on whether the patient
will need to switch to second line ART (usually with a PI based regimen).

Dr. Saswata Dutt Replied at 1:55 PM, 26 Sep 2018

Great advises Erica - appreciate. Would be nice to have references (if any)
to put in National guidelines.

Erica Lessem Replied at 2:48 PM, 26 Sep 2018

Good suggestion. Bedaquiline is metabolized by CYP3A4, so interactions are
of concern with ARVs that are also metabolized through that pathway.

TAG is issuing shortly an updated bedaquiline guide shortly which includes
info on using BDQ with ARVs, here is the section on BDQ use in PLHIV, which
you can feel free to use/adapt:
"Thousands of people living with HIV have taken bedaquiline with similar
effectiveness and safety as in HIV-negative individuals. Bedaquiline cannot
be give with certain antiretrovirals, most notably efavirenz: efavirenz
cannot be used with bedaquiline since it can significantly decrease
bedaquiline levels. Persons on efavirenz should be changed to nevirapine or
ideally an integrase inhibitor while on bedaquiline. Taking
lopinavir/ritonavir increases bedaquiline levels, but it is not clear what
this means for patients—no increase in adverse events was seen in patients
who received bedaquiline with lopinavir/ritonavir. Because protease
inhibitors are commonly used for second-line antiretroviral therapy,
lopinavir/ritonavir may be used with bedaquiline with appropriate ECG
monitoring. It is essential that people on antiretrovirals when starting
bedaquiline have their viral load tested prior to any changes in their
antiretroviral regimen, as a high viral load can signal antiretroviral
therapy failure and the need for careful regimen selection. Ketoconazole,
an antifungal commonly taken as part of HIV treatment, increases the amount
of bedaquiline in the body and can increase QT prolongation in people
taking bedaquiline. Ketoconazole and bedaquiline should not be taken
together for more than two weeks at a time unless the potential benefit
outweighs the risk."

Here is the reference for lopinavir/ritonavir:
Pandie M, Wiesner L, McIlleron H, et al. Drug-drug interactions between
bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in
HIV-infected patients with drug-resistant TB. J Antimicrob Chemother. 2016
Apr;71(4):1037-40. doi: 10.1093/jac/dkv447.

Reference for efavirenz:
Model-Based Estimates of the Effects of Efavirenz on Bedaquiline
Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected
with HIV and Tuberculosis Elin M. Svensson, Francesca Aweeka, Jeong-Gun
Park, Florence Marzan, Kelly E. Dooley, Mats O. Karlsson
DOI: 10.1128/AAC.00191-13

reference for ketoconazole:
Food and Drug Administration (U.S.). Application Risk Assessment and Risk
Mitigation Review(s), Application Number: 204384Orig1s000. Center for Drug
Evaluation and Research (U.S.), Food and Drug Administration. 2012 Dec 19.

I would also recommend referring to the language in the South African
guidelines. I do not have their most recent 2018 update (which now includes
BDQ as part of core regimen for all people with MDR-TB), but the language
from their 2015 on ARV interactions is still relevant (tho dolutegravir was
not available at that time):

Management of HIV-infected patients HIV infected patients who are ART naïve
or currently on ART may be started on BDQ. As per national ART guidelines,
HIV-infected patients not yet on ART should be initiated on ART.
For patients requiring ART the following are options
 NVP and two appropriate NRTIs if the CD4 is <250 in women and <350 in men
 LPV/r-containing regimen with two appropriate NRTI for patients that
require second line therapy or have CD4 is greater than 250 in women and
350 in men
 Rilpivirine and raltegravir can be considered if available.

As per the package insert under US approval of Sirturo: Efavirenz (EFV)
co-administration with BDQ may result in reduced bedaquiline exposure and
loss of efficacy. Efavirenz is a moderate inducer of CYP3A activity and
co-administration with BDQ may result in reduced BDQ exposure. This may
cause a loss of efficacy of BDQ and is not recommended. Nevirapine (200 mg
twice daily for 4 weeks ) was co-administrated with bedaquiline in
HIV-infected patients with no clinically relevant effect on BDQ exposure
(AUC increased by 3%, Cmax decreased by 20%) Lopinavir/ritonavir (400/100
mg twice daily) was co-administered BDQ to 16 HIV/TBnegative subjects
causing an increase in BDQ AUC by 22% and had no effect on Cmax. Should a
patient who is already on ART need to start BDQ, a viral load test must be
done. If the patient has a suppressed VL and a nadir CD4 less than 250 in
women and 350 in men, the patient can be changed to NVP. If the patient
does not have full viral suppression or a higher nadir, the option of LPV/r
should be considered.

Dr. Saswata Dutt Replied at 3:26 PM, 26 Sep 2018

Thanks Erica for all the details. Delamanid can also be used with ARVs, if
needed. We will wait for more results on delamanid itself.
Cost of raltegravir is still prohibitive for public health options in
developing countries.
Dolutegravir is available in many developing countries - I am not sure
about its use with bedaquiline..

Ben Cheng Replied at 3:44 PM, 26 Sep 2018

A good resource is the HIV drug interaction website that has been developed by the University of Liverpool.


Erica Lessem Replied at 3:54 PM, 26 Sep 2018

That is absolutely correct! Delamanid has very minimal drug interactions

"In a study of healthy participants, delamanid did not significantly affect
the levels of tenofovir, lopinavir/ritonavir, or efavirenz in the body,
though lopinavir/ritonavir did increase the amount of delamanid in the body
by 20 percent.15,16 When the body breaks down delamanid, one particular
molecule, DM-6705, appears to cause QT prolongation. Lopinavir/ritonavir
seems to increase the amount of DM-6705 in the body by about 30 percent,
and the EMA recommends frequent ECG monitoring if delamanid and
lopinavir/ritonavir are taken together.17"

15. Paccaly A, Petersen C, Patil S, et al. Absence of clinically relevant
drug interaction between delamanid, a new drug for multidrug-resistant
tuberculosis (MDR-TB) and tenofovir or lopinavir/ritonavir in health
subjects. Poster session presented at: 19th International AIDS Conference;
2012 July 22–27; Washington, D.C. 16.
16. Peterson C., Paccaly A., Kim J., et al. Delamanid, a new drug for
multi-drug resistant tuberculosis (MDR-TB), and efavirenz do not show
clinically relevant drug interactions in healthy subjects. Paper presented
at: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy;
2012 September 9–12; San Francisco, CA.
17. Otsuka Novel Products GmbH. Labelling and package leaflet: Deltyba

Dr. Saswata Dutt Replied at 3:56 PM, 26 Sep 2018

Thanks Ben. Interesting and looks useful.

Micheal Mazzi Replied at 11:23 AM, 27 Sep 2018

Thank you all for this fruitful discussions. Is there any information on whether combining Bdq and NVP may increase predisposition to elevation of Liver enzymes?Sent from Yahoo Mail on Android

Joven Jebio Ongole Replied at 1:22 PM, 27 Sep 2018

Bedaquiline is relatively safe with nevirapine and very rare to find an
elevated liver enzyme in the period the two drugs are used together.
It is the recommended combination in SA treatment program for DRTB cases
with HIV co-infection. Bedaquiline alone has a safe liver profile compared
to nevirapine


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Micheal Mazzi Replied at 4:47 PM, 27 Sep 2018

Thanks Joven

Sent from Yahoo Mail on Android

Kwan Ching CHAN Replied at 7:19 PM, 27 Sep 2018

Thanks so much, Ben

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