Use of linezolid for complicated drug-resistant TB: experience in HIV infected and uninfected patients in Khayelitsha, Cape Town
Jennifer Hughes msfb-khayelitshatbdoc@msf.org.za
Jennifer Hughes1, Helen Cox1,2, Johnny Daniels1, Vivian Cox1 1Médecins
Sans Frontières, Khayelitsha, South Africa; 2University of Cape Town, South Africa
Background
Results
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 (XDRTB), resulting in even worse outcomes and significant early mortality, particularly among HIV-infected individuals.
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)
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.
Of the four HIV-infected patients:
Percentage Alive
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.
CD4 count at LZD initiation: • CD4 >350 in 3 patients • CD4 113 in the fourth patient
INTERIM TREATMENT OUTCOMES:
100 80
69 69
60
On ART at linezolid initiation: • 3 on first-line ART (d4T or AZT, 3TC, EFV) • 1 on second line ART (TDF, 3TC, Aluvia)
60
40
41
20
Rif mono
MDR, no SL res
13 patients (4 HIV positive) on linezolid >3 months
MDR plus SL res
0 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
Months from diagnostic sputum sample Figure 1: DR-TB mortality rates, Khayelitsha 2009 cohort
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).
10 (77%) culture converted and still culture negative; treatment ongoing (3 HIV positive)
1 (8%) potential treatment failure: (HIV negative), no culture conversion after 5 months on LZD; treatment ongoing
2 (15%) treatment failure after: - 8 months (HIV negative) -9 months (HIV positive) both now deceased
Methods 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) 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. 700
Number of patients
600
581 503
500
Potentially eligible to receive linezolid
400 300 200
92
100
ADVERSE EVENTS: Adverse Event
Patient Description
Outcome
ANAEMIA
• One mild (Hb drop from 11.2 to 9.7 over one month)
• 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)
2 patients, both HIV negative
NEUROPATHY 2 patients, both HIV positive
• One severe (Hb drop from 13.8 to 6.1 over two months)
• Peripheral neuropathy after 3 months on LZD (also on D4T)
• LZD withdrawn and D4T changed to TDF; symptoms resolved 5 months later
• Possible optic neuropathy after 5 months on LZD (also insulin-dependant diabetic)
• LZD withdrawn after 8 months, ophthalmology review pending
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.
14 0
No. MDR cases diagnosed
No. MDR with second No. pre-XDR, XDR, and line DST done MDR Tx failure
Figure 2: Khayelitsha DR-TB patients diagnosed 2010 – 2013
Started Linezolid
• City of Cape Town Health • Western Cape Province • Stellenbosch University
Acknowledgements • National Health Laboratory Service • Busisiwe Beko (DR-TB counsellor) • Lizo Nobanda TB Centre staff