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Impact of HIV co-infection on the evolution and transmission of multidrug-resistant tuberculosis.

ABSTRACT: The tuberculosis (TB) epidemic is fueled by a parallel Human Immunodeficiency Virus (HIV) epidemic, but it remains unclear to what extent the HIV epidemic has been a driver for drug resistance in Mycobacterium tuberculosis (Mtb). Here we assess the impact of HIV co-infection on the emergence of resistance and transmission of Mtb in the largest outbreak of multidrug-resistant TB in South America to date. By combining Bayesian evolutionary analyses and the reconstruction of transmission networks utilizing a new model optimized for TB, we find that HIV co-infection does not significantly affect the transmissibility or the mutation rate of Mtb within patients and was not associated with increased emergence of resistance within patients. Our results indicate that the HIV epidemic serves as an amplifier of TB outbreaks by providing a reservoir of susceptible hosts, but that HIV co-infection is not a direct driver for the emergence and transmission of resistant strains.

SUBMITTER: Eldholm V

PROVIDER: S-EPMC4978521 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Impact of HIV co-infection on the evolution and transmission of multidrug-resistant tuberculosis.

Eldholm Vegard V Rieux Adrien A Monteserin Johana J Lopez Julia Montana JM Palmero Domingo D Lopez Beatriz B Ritacco Viviana V Didelot Xavier X Balloux Francois F

eLife 20160809

The tuberculosis (TB) epidemic is fueled by a parallel Human Immunodeficiency Virus (HIV) epidemic, but it remains unclear to what extent the HIV epidemic has been a driver for drug resistance in Mycobacterium tuberculosis (Mtb). Here we assess the impact of HIV co-infection on the emergence of resistance and transmission of Mtb in the largest outbreak of multidrug-resistant TB in South America to date. By combining Bayesian evolutionary analyses and the reconstruction of transmission networks u ...[more]

PMID: 27502557

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Project description:BackgroundMultidrug-resistant tuberculosis (MDR-TB) in HIV infected individuals is a serious threat to global efforts to combat tuberculosis. Inconsistent findings on the association between HIV infection and MDR-TB were present in many studies. We aimed to review existing data on the relationship between HIV infection and MDR-TB systematically to assess the contribution of HIV on MDR-TB worldwide. We also investigated the patterns of MDR-TB by age, country-wise income, study designs, and global regions.MethodsWe utilized PubMed, Google Scholar, and ScienceDirect databases to select eligible studies for meta-analysis that were published between January 12,010, and July 30, 2020. The random-effects model was used to obtain the pooled odds ratio of the crude association between HIV and MDR-TB with a 95% confidence interval. We investigated the potential publication-bias by checking funnel plot asymmetry and using the Egger's test. Moreover, we assessed the heterogeneity using the I2 statistic. Sensitivity analysis was performed based on sample size and adjustment factors. The protocol was registered with PROSPERO-CRD42019132752.ResultsWe identified 1603 studies through a database search, and after subsequent eliminations we selected 54 studies including 430,534 TB patients. The pooled odds of MDR-TB was 1.42 times higher in HIV-positive patients than HIV-negative patients (OR=1.42,CI=1.17-1.71, I2=75.8%). Subgroup analysis revealed that the estimated pooled odds for South-East Asian countries was 1.86, which is the highest in WHO regions (OR=1.86,CI=1.30-2.67, I2=0.00%), followed by Europe and Africa. The effect estimate was found to be higher for primary MDR-TB (OR=2.76,CI=1.70-4.46, I2=0.00%). There was also a trend towards increased odds of MDR-TB for HIV patients older than 40 years (OR=1.56,CI=1.17-2.06). The association was found to be significant in high-burden TB countries (OR=1.75, CI=1.39-2.19) and in high-income countries (OR=1.55, CI=1.06-2.27).ConclusionSuch findings indicate that HIV infection raises the risk of MDR-TB, and after contrasting it with the results of the earlier pooled study, it appeared to be an upward risk trend. Moreover, we found that the risk is the highest in the South-East Asian region. A balanced allocation of resources is needed to halt both primary and secondary MDR-TB, particularly in HIV infected people with 40 years of age and older.

Project description:On the Tibetan Plateau, most tuberculosis is caused by indigenous Mycobacterium tuberculosis strains with a monophyletic structure and high-level drug resistance. This study investigated the emergence, evolution, and transmission dynamics of multidrug-resistant tuberculosis (MDR-TB) in Tibet. The whole-genome sequences of 576 clinical strains from Tibet were analyzed with the TB-profiler tool to identify drug-resistance mutations. The evolution of the drug resistance was then inferred based on maximum-likelihood phylogeny and dated trees that traced the serial acquisition of mutations conferring resistance to different drugs. Among the 576 clinical M. tuberculosis strains, 346 (60.1%) carried at least 1 resistance-conferring mutation and 231 (40.1%) were MDR-TB. Using a pairwise distance of 50 single nucleotide polymorphisms (SNPs), most strains (89.9%, 518/576) were phylogenetically separated into 50 long-term transmission clusters. Eleven large drug-resistant clusters contained 76.1% (176/231) of the local multidrug-resistant strains. A total of 85.2% of the isoniazid-resistant strains were highly transmitted with an average of 6.6 cases per cluster, of which most shared the mutation KatG Ser315Thr. A lower proportion (71.6%) of multidrug-resistant strains were transmitted, with an average cluster size of 2.9 cases. The isoniazid-resistant clusters appear to have undergone substantial bacterial population growth in the 1970s to 1990s and then subsequently accumulated multiple rifampicin-resistance mutations and caused the current local MDR-TB burden. These findings highlight the importance of detecting and curing isoniazid-resistant strains to prevent the emergence of endemic MDR-TB. IMPORTANCE Emerging isoniazid resistance in the 1970s allowed M. tuberculosis strains to spread and form into large multidrug-resistant tuberculosis clusters in the isolated plateau of Tibet, China. The epidemic was driven by the high risk of transmission as well as the potential of acquiring further drug resistance from isoniazid-resistant strains. Eleven large drug-resistant clusters consisted of the majority of local multidrug-resistant cases. Among the clusters, isoniazid resistance overwhelmingly evolved before all the other resistance types. A large bacterial population growth of isoniazid-resistant clusters occurred between 1970s and 1990s, which subsequently accumulated rifampicin-resistance-conferring mutations in parallel and accounted for the local multidrug-resistant tuberculosis burden. The results of our study indicate that it may be possible to restrict MDR-TB evolution and dissemination by prioritizing screening for isoniazid (INH)-resistant TB strains before they become MDR-TB and by adopting measures that can limit their transmission.

Project description:BackgroundWe aimed to determine the relationship between common pre-existing comorbidities in patients with tuberculosis (TB) (including human immunodeficiency virus [HIV], diabetes, and hepatitis C virus [HCV]) with rates of all-cause mortality after TB treatment.MethodsWe conducted a retrospective cohort study among patients treated for rifampicin-resistant and multi/extensively drug resistant (RR and M/XDR) TB in the country of Georgia during 2009-2017. Eligible participants were >15 years of age with newly diagnosed, laboratory-confirmed drug resistant TB who received second-line treatment. Exposures included HIV serologic status, diabetes, and HCV status. The primary outcome was post-TB treatment mortality determined by cross-validating vital status with Georgia's national death registry through November 2019. We estimated hazard rate ratios (HR) and 95% confidence intervals (CI) of post-TB mortality among participants with and without pre-existing comorbidities using cause-specific hazard regressions.ResultsAmong 1032 eligible patients included in our analyses, 34 (3.3%) participants died during treatment and 87 (8.7%) died post-TB treatment. Among those who died post-TB treatment, the median time to death was 21 months (IQR 7-39) after TB treatment ended. After adjusting for potential confounders, the hazard rates of mortality post-TB treatment were higher among participants with HIV co-infection (adjusted hazard ratio [aHR]=3.74, 95%CI 1.77-7.91) compared to those without HIV co-infection.ConclusionsIn our cohort, post-TB mortality occurred most commonly in the first three years after TB treatment ended. Additional post-TB care and follow-up, especially among patients with TB and comorbidities (especially HIV co-infection), may reduce rates of mortality post-TB treatment.SummaryOur findings provide evidence that TB patients with comorbidities, especially HIV, may have a significantly increased risk of post-TB mortality compared to those without comorbidities. We also found that most post-TB mortality occurred within three years after TB treatment completion.

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Impact of HIV co-infection on the evolution and transmission of multidrug-resistant tuberculosis.

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Impact of HIV co-infection on the evolution and transmission of multidrug-resistant tuberculosis.

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