Jennifer Hughes

msfb-khayelitsha-

tbdoc@msf.org.za

Background

Treatment outcomes for multi-drug resistant TB (MDR-TB) in South Africa are poor, with a treatment success rate of <50%. Existing treatment options are

severely limited for patients with extensively drug resistant TB (XDR-

TB), resulting in even worse outcomes and significant early mortality, particularly among HIV-infected individuals.

Linezolid has been shown to be effective in the treatment of DR-TB in combination with second line drugs. Access to the drug for many patients is

severely limited due to the exorbitantly high cost.

Khayelitsha township is situated 30 km from Cape Town and has a population

of more than 500,000. Antenatal HIV prevalence was 33% in 2010; ~6,000 TB

cases are diagnosed annually, with 73% of TB patients co-infected with HIV. An estimated 400 patients are infected with DR-TB each year, with 54% actually

diagnosed. A majority (>70%) of DR-TB patients are managed at primary care

level as part of the decentralised DR-TB programme in Khayelitsha.

Between July 2011 and Feb 2013, fourteen patients (4 HIV positive) started a linezolid containing regimen for the following indications:

• 9 patients had pre-XDR or XDR TB;

• 5 patients had standard M/XDR treatment failure.Median treatment duration with linezolid: 8 months (range: 1 – 20 months)

Of the four HIV-infected patients:

INTERIM

TREATMENT

OUTCOMES:

Aim

In order to ultimately improve treatment outcomes, we aim to describe the use of linezolid (LZD) within individually tailored treatment regimens for selected

M/XDR-TB patients, including HIV infected patients requiring antiretroviral

therapy (ART).

13 patients (4 HIV positive)on linezolid >3 months

10 (77%) culture converted and still

culture negative;

treatment ongoing(3 HIV positive)

2 (15%) treatment failure after:

- 8 months (HIV

negative)-9 months (HIV

positive)

1 (8%) potential treatment failure: (HIV

negative), no culture

conversion after 5 months on LZD;

treatment ongoing

CD4 count at LZD initiation:

• CD4 >350 in 3 patients

• CD4 113 in the fourth patient

On ART at linezolid initiation:• 3 on first-line ART (d4T or AZT, 3TC,

EFV)

• 1 on second line ART (TDF, 3TC, Aluvia)

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20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Perc

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live

Months from diagnostic sputum sample

Rif mono MDR, no SL res MDR plus SL res

Results

Figure 1: DR-TB mortality rates, Khayelitsha 2009 cohort

Use of linezolid for complicated drug-resistant TB: experience in HIV infected and uninfected patients in Khayelitsha, Cape Town

Jennifer Hughes1, Helen Cox1,2, Johnny Daniels1, Vivian Cox1

1Médecins Sans Frontières, Khayelitsha, South Africa; 2University of Cape Town, South Africa

Methods

Candidates are then presented to a local Clinical Advisory Committee who consider:

� clinical status and comorbid conditions (with concurrent medications)

� history of exposure to TB drugs� ART regimen

� social circumstances and treatment adherence record

� laboratory results of drug sensitivity testing and genotyping� availability of existing second-line drugs (including capreomycin and PAS) and

other group 5 drugs such as clofazimine and linezolid

The initial dose of linezolid is 600 mg once daily orally, with dose adjustment

through treatment as necessary. All other drugs are dosed according to South

African national guidelines. All HIV-infected patients are fast tracked for ART regardless of CD4 count, and ART regimens are modified according to known or

possible interactions with second line TB drugs.

Summary

•Addition of linezolid to individually tailored treatment regimens for DR-TB results in high sputum culture conversion and an improved chance of potential

cure.

•Adverse events were significant but manageable with close treatment monitoring. HIV infection and ART do not appear to reduce the efficacy of

linezolid nor result in increased adverse events.

•Restricted access to linezolid due to prohibitively high cost limits the number of patients who may be offered a potentially effective treatment regimen, thereby

leaving a majority of DR-TB patients with an extremely poor prognosis; high risk

of mortality; and ongoing transmission of highly resistant TB strains in the communities where they live.

Acknowledgements

• City of Cape Town Health

• Western Cape Province

• Stellenbosch University

ADVERSE EVENTS:Candidates for linezolid are identified among patients diagnosed with DR-TB in any of the 10 primary care clinics

in Khayelitsha and the following inclusion criteria:

• diagnosis of (pre)-XDR-TB (i.e. MDR-TB with additional

fluoroquinolone and / or second-line injectable resistance)

• failure of standard MDR treatment regimen despite good adherence to treatment (i.e. no culture conversion after 6

months or culture re-conversion to positive anytime)

• National Health Laboratory Service

• Busisiwe Beko (DR-TB counsellor)

• Lizo Nobanda TB Centre staff

Adverse Event Patient Description Outcome

ANAEMIA

2 patients, both

HIV negative

• One mild (Hb drop from 11.2 to 9.7 over one month)

• One severe (Hb drop from 13.8 to 6.1 over two months)

• Resolved without dose change; (Hb 12.0 two months

later)

• Blood transfusion; LZD dose reduction to 300mg; (Hb

maintained >11.0 over next five

months)

NEUROPATHY

2 patients, both

HIV positive

• Peripheral neuropathy after 3 months on LZD (also on

D4T)

• Possible optic neuropathy

after 5 months on LZD (also

insulin-dependant diabetic)

• LZD withdrawn and D4T changed to TDF; symptoms

resolved 5 months later

• LZD withdrawn after 8

months, ophthalmology review

pending

therapy (ART). positive)

both now deceased

treatment ongoing

581

503

92

140

100

200

300

400

500

600

700

No. MDR cases diagnosed

No. MDR with second line DST done

No. pre-XDR, XDR, and MDR Tx failure

Started Linezolid

Num

ber

of patients

Potentially

eligible to receive

linezolid

Figure 2: Khayelitsha DR-TB patients diagnosed 2010 – 2013