Isoniazid And Rifampicin Resistance And Patient Treatment Response In A Tuberculosis And Hiv-1 Co-Endemic Population In Western Kenya In 2012-2014

ABSTRACT

In 2015, 10.4 million people worldwide had tuberculosis (TB) and 1.4 million deaths occurred,

400 000 of whom were HIV-positive, Sub-Saharan Africa (SSA) accounted for 81% of these

cases. In 2015, 480 000 new cases of multi-drug resistant TB (MDR-TB) were detected globally.

In Kenya, in 2015, 107 000 people had TB and 36 000 were HIV co-infected. In western Kenya,

the prevalence of TB and HIV in 2015 was 39.2% and 15.1%, respectively and in 2008, 10 cases

of MDR-TB occurred. Patients with HIV have a deficient immune system and are likely to be

TB co-infected. As a result of the pill burden of anti-retroviral and TB therapy, poor adherence

may occur. Rifampicin (RIF) and isoniazid (INH) are first-line anti-TB drugs. Resistance to INH

is associated with mutations on the kat G and inh A genes while rpo B gene mutations lead to

RIF résistance. Multi-drug resistant TB arises after acquisition of either INH or RIF resistance

followed by resistance to the companion drug. Patients with resistant TB require admission

which increases transmission. Methods for determining drug resistant TB includes drug

susceptibility tests (DST), GeneXpert, Line probe assay (LPA) and sequencing. In western

Kenya, current data on the distribution of RIF and INH mutations is not available. In addition,

the association of drug resistant mutations with HIV and the treatment response of HIV infected

and uninfected patients with TB are not known. As such, the objectives of the current study were

to determine the proportion of drug resistant Mycobacterium tuberculosis in sputum isolates and

investigate the association of RIF and INH gene mutations with HIV status and monitor

treatment response in a TB/HIV co-endemic population in western Kenya. The present study was

longitudinal in which enrollment was done between 2012 and 2014 after the revision of the TB

treatment regimen and patients with confirmed drug resistant TB were followed up for one year

to establish the TB treatment response as confirmed by sputum smear microscopy. Random

sampling of 415 facilities that support routine TB diagnosis in 13 counties in western Kenya was

done. Patients with suspected TB symptoms and Ziehl-Neelsen (ZN) positive patients were

targeted for enrollment. A total of 1381 new and 18 previously treated TB patients were enrolled.

HIV infected patients accounted for 61% of the enrolled participants. Sputum samples were

cultured on Mycobacteria growth indicator tubes (MGIT), DST and LPA performed to identify

drug resistance and specific mutations on the rpo B, kat G and inh A genes. Discordant samples

were sequenced. Conversion rate was calculated by finding the percentage of smear negative and

positive patients at follow-up and initial visit, respectively. Proportion of mutations as estimated

by LPA and DST was as follows: MDR-TB, 0.95%, 1.53%; RIF mono-resistant TB, 0.88%,

0.66%; INH mono-resistant TB, 1.83%, 1.97%, respectively. Regression analysis showed that

RIF resistance was associated with HIV status (P = 0.025). Mann-Whitney tests revealed that the

conversion time of HIV infected and uninfected patients with TB drug mutations was

comparable (P = 0.180). The results of the study showed that INH mono-resistance was

common. Detection of INH mono-resistance in TB endemic areas should be scaled-up as well as

TB contact investigation studies to increase early detection of resistant strains.