Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.

These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.

Background Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. Methods A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. Conclusions These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.

Resistance to antituberculosis drugs was found in all 35 countries and regions surveyed, suggesting that it is a global problem.

No abstract

The emergence of strains of Mycobacterium tuberculosis that are resistant to antimycobacterial agents is a worldwide problem whose global magnitude is not well described. We reviewed and tabulated 63 surveys of resistance to antituberculous drugs that were performed between 1985 and 1994. Rates of primary resistance to isoniazid, administered as a single agent, ranged from 0 to 16.9% (median rate, 4.1%); to streptomycin, 0.1%-23.5% (median, 3.5%); to rifampin, 0-3.0% (median, 0.2%); and to ethambutol, 0-4.2% (median, 0.1%). The rates of acquired resistance to these agents, which were higher than those of primary resistance, were as follows: isoniazid, 4.0%-53.7% (median rate, 10.6%); streptomycin, 0-19.4% (median, 4.9%); rifampin 0-14.5% (median, 2.4%); and ethambutol, 0-13.7% (median, 1.8%). The highest rates of multidrug-resistant tuberculosis have been reported in Nepal (48.0%), Gujarat, India (33.8%), New York City, (30.1%), Bolivia (15.3%), and Korea (14.5%). The WHO (World Health Organization) and the IUATLD (International Union Against Tuberculosis and Lung Disease) have established a global project of drug resistance surveillance that is based on standard epidemiological methods and quality control through an extensive network of reference laboratories. Accurate drug resistance surveillance data can be used to assess and improve national tuberculosis programs.

Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. Am J Respir Crit Care Med 161:S221‐S247, 2000). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens for treatment of LTBI among persons who live in the United States. The systematic literature review included clinical trials of regimens to treat LTBI. Quality of evidence (high, moderate, low, or very low) from clinical trial comparisons was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. In addition, a network meta‐analysis evaluated regimens that had not been compared directly in clinical trials. The effectiveness outcome was tuberculosis disease; the toxicity outcome was hepatotoxicity. Strong GRADE recommendations required at least moderate evidence of effectiveness and that the desirable consequences outweighed the undesirable consequences in the majority of patients. Conditional GRADE recommendations were made when determination of whether desirable consequences outweighed undesirable consequences was uncertain (eg with low‐quality evidence). These updated 2020 LTBI treatment guidelines include the NTCA‐ and CDC‐recommended treatment regimens that comprise three preferred rifamycin‐based regimens and two alternative monotherapy regimens with daily isoniazid. All recommended treatment regimens are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to isoniazid or rifampin. These updated guidelines do not apply when evidence is available that the infecting M tuberculosis strain is resistant to both isoniazid and rifampin; recommendations for treating contacts exposed to multidrug‐resistant tuberculosis were published in 2019 (Nahid P, Mase SR Migliori GB, et al Treatment of drug‐resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93‐e142). The three rifamycin‐based preferred regimens are 3 months of once‐weekly isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily isoniazid plus rifampin. Prescribing providers or pharmacists who are unfamiliar with rifampin and rifapentine might confuse the two drugs. They are not interchangeable, and caution should be taken to ensure that patients receive the correct medication for the intended regimen. Preference for these rifamycin‐based regimens was made on the basis of effectiveness, safety, and high treatment completion rates. The two alternative treatment regimens are daily isoniazid for 6 or 9 months; isoniazid monotherapy is efficacious but has higher toxicity risk and lower treatment completion rates than shorter rifamycin‐based regimens. In summary, sh...

Background HIV-infected men are at increased risk for anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types. Methods AIDS Malignancy Consortium Protocol 052 is a single-arm, open-label, multi-center clinical trial to assess the safety and immunogenicity of the quadrivalent HPV (types 6, 11, 16, 18) vaccine in HIV-infected men. Men with high-grade anal intraepithelial neoplasia or anal cancer by history or by screening cytology or histology were excluded. Men received 0.5 mL intramuscularly at entry, week 8, and 24. The primary endpoints were seroconversion to vaccine types at week 28, in men who were seronegative and without anal infection with the relevant HPV type at entry, and grade 3 or higher adverse events related to vaccination. Results There were no Grade 3 or greater adverse events attributable to vaccination among the 109 men who received at least one vaccine dose. Seroconversion was observed for all 4 types: type 6 (59/60, 98%), type 11 (67/68, 99%), type 16 (62/62, 100%), type 18 (74/78, 95%). No adverse effects on CD4 counts and plasma HIV-1 RNA were observed. Conclusions The quadrivalent HPV vaccine appears safe and highly immunogenic in HIV-infected men. Efficacy studies in HIV-infected men are warranted.