AIDS 2016: New WHO Algorithm Aims to Prevent TB Deaths in People with Advanced HIV


The World Health Organization (WHO) has released a new diagnostic algorithm to reduce the likelihood of seriously ill people with HIV dying of undiagnosed and untreated tuberculosis (TB). The algorithm was presented at a scientific workshop at the 21st International AIDS Conference last month in Durban.

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"Despite being preventable and curable, TB is still the leading cause of morbidity and mortality, even in the era of antiretroviral therapy (ART) going to scale. In fact, in 2014, it accounted for nearly a third of HIV-related deaths," said Annabel Baddeley of WHO’s Global TB Program, who moderated the session dedicated to discussing the need, evidence base, and application of the algorithm and other strategies to reduce mortality from HIV-associated TB.

The Persistent Dilemma of TB and HIV

Although people with HIV starting treatment earlier -- data from some large cohorts show that the median CD4 cell count at treatment initiation has doubled -- the proportion who present for care with very advanced disease has remained relatively unchanged, and "mortality is largely, in most parts of the world, due to the same problems," said Nathan Ford of WHO, who presented data on the enduring burden of TB morbidity and mortality among people living with HIV.

Ford's team did a global systematic review last year to assess the main causes of morbidity and mortality among people with HIV presenting at emergency wards and being hospitalized. They found that while there has been some increase in non-AIDS defining illnesses such as viral hepatitis and non-AIDS cancers, AIDS-defining illnesses continue to be the leading cause of hospitalization, and nearly 1 out of 5 are hospitalized because of TB.

Importantly, 30% of HIV-positive people who were hospitalized were only diagnosed with HIV at the time of hospitalization -- underscoring the challenge of reaching people living with HIV earlier in the course of infection. The median CD4 cell count at diagnosis was 131 cells/mm3. Another systematic review which looked at post-mortem data on causes of death found that in resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths.

But "late presenters" are not the only ones at risk of being hospitalized with advanced HIV disease and TB. A South African study of medical admissions found that more than a third (36%) of the HIV-positive people admitted to a public sector district hospital in Cape Town had not yet started ART, 45% reported being currently on ART, and 19% reported that they had initiated therapy but for one reason or another had interrupted treatment. Here too, the most frequent primary diagnosis was TB (34%). Outcomes in the cohort were poor: in 90 days of follow-up, 30% required readmission and 13% had died, with TB being the most common cause of death (in 37%).

Case fatality rates among people being treated for TB are more than 3 times greater if they are HIV-positive than if they are HIV-negative -- and even higher if they are not put on ART as soon as possible after starting TB treatment. According to Ford, this often does not happen.

There are major challenges in diagnosis and putting HIV/TB coinfected individuals on ART despite almost 10 years of recommending immediate HIV treatment for all patients who are coinfected with TB, Ford said.

The reasons why TB can be difficult to diagnose in people with advanced HIV disease have changed little, even with current tests. People with HIV are often unable to provide sufficient and high-quality sputum specimens for lab tests, even when they can produce sputum the amount of TB bacilli in the specimen may be very low, and people with HIV have high rates of extrapulmonary (outside the lung) TB.

However, Yohhei Hamada of WHO’s Global TB Program, who presented the new algorithm, said there are some tools that can help expedite TB diagnosis and treatment.

The Xpert MTB/RIF assay is much more sensitive than smear microscopy (looking for bacilli in a sputum sample under a microscope). In some studies Xpert MTB/RIF detected up to 79% of pulmonary TB in people living with HIV. The test is automated and rapid and theoretically can generate results in less than 2 hours. It may also be used rather than conventional tests (culture) for testing extrapulmonary specimens. However, the equipment that runs the test is expensive, severely limiting access in many resource-limited settings.

The lateral flow urine lipoarabinomannan (LAM) test can speed TB diagnosis in some of the most seriously ill individuals. The LAM assay is routinely used at the point of care, generating results in 25 minutes. Unfortunately, the sensitivity of the test is limited in patients who are not hospitalized and in people with CD4 counts higher than 200 cells/mm3. Of note, at the TB 2016 pre-conference meeting before AIDS 2016, Robin Wood from the University of Cape Town noted that positive urine LAM results may in fact indicate TB disease in the kidneys.

The New Algorithm

WHO has long recognized the need to respond more effectively to prevent deaths from undiagnosed TB in HIV-positive people. In effect, the new algorithm is descended from the algorithm for diagnosis of smear-negative TB in HIV-prevalent settings, updated in light of the latest technology and data on presumptive treatment and targeted to the most seriously ill people at greatest risk of dying of TB.

WHO defines "seriously ill" as individuals with HIV or unknown HIV status presenting with one or more of the following danger signs:

  • Unable to walk unaided;
  • A respiratory rate over 30/min;
  • A fever of more than 39oC (102oF);
  • A pulse rate of over 120/min.

The new algorithm, published in WHO’s 2016 edition of the Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection, is specifically designed to provide earlier access to TB treatment to seriously ill people with HIV or unknown status in resource-limited settings, particularly peripheral settings where access to TB diagnostics is limited.

1) If a person with HIV or unknown HIV status who visits a peripheral health facility -- such as a primary health clinic or outpost -- is suspected of having TB and has danger signs, they should be immediately referred to a higher level medical facility if possible.

2) Often referral is not possible, and in those cases the algorithm recommends performing an Xpert MTB/RIF test and LAM urine test for people with CD4 counts <100 cells/mm3 and for seriously ill individuals regardless of CD4 count. Meanwhile, the patient should be given intravenous antibiotics to treat any possible bacterial infections and treatment for Pneumocystis pneumonia should also be considered. If available, a chest X-ray should be performed.

3) If any of the TB tests come back positive, TB treatment should be initiated.

4) If the TB tests are negative or not available, then if there is improvement of symptoms after 3 to 5 days, TB is unlikely and the care provider should look for other HIV-related diseases, consider starting ART as soon as possible, provide isoniazid preventive therapy and cotrimoxazole preventive therapy, and complete the course of IV antibiotics.

5) If there is no improvement or symptoms worsen after 3 to 5 days, presumptive TB treatment should be started, as well as ART and cotrimoxazole preventive therapy. The clinician should perform further tests for TB (such as culture) and other diseases and complete the course of IV antibiotics.

A graphic representation of the WHO TB algorithm is available here.

Presumptive TB Treatment

In certain cases WHO recommends presumptively treating suspected TB, which it defines as initiation of TB treatment for people with HIV seen at peripheral facilities,based exclusively on clinical suspicion of TB in seriously ill patients with respiratory distress based on the judgment of the clinician.

Some recent trials of empirical or presumptive TB treatment failed to show a benefit. The REMEMBER trial found no benefit to providing empirical TB treatment over providing isoniazid preventive therapy to HIV-positive people with less than 50 cells/mm3. However, the study only included participants in whom TB had been ruled out by extensive investigations and was therefore not suspected.

More recently the TB Fast Track Trial evaluated empirical treatment for individuals with CD4 counts of 150 cells/mm3 or below who were suspected of having TB (a positive LAM test or low hemoglobin or low body mass index). Those considered to have a high probability of TB were more likely to receive an eventual confirmed TB diagnosis, but there was no significant benefit to empirical treatment. This may have been due to the fact that, contrary to expectations, empirical TB treatment was associated with delayed ART initiation.

However, Hamada stressed that these study protocols did not meet WHO's definition of presumptive treatment, in particular they did not target individuals meeting the algorithm’s definition of seriously ill.

The failure of these particular empirical therapy strategies to improve survival does not mean other presumptive TB treatment approaches will not work. In fact, in one recently published study empirical TB treatment was associated with a statistically significant 44% reduction in 8-week mortality among seriously ill HIV-positive inpatients with WHO’s "danger signs."


Clearly, access to better and more reliable diagnostics would lead to more expeditious TB treatment for seriously ill coinfected individuals, but it is hoped that until such tools become available, use of this algorithm could minimize delays in TB treatment initiation and prevent early mortality. In the meantime, programs are urged to "adopt rapid TB diagnostic tools to increase earlier diagnoses of TB," Hamada concluded.  



Maximizing Survival from Tuberculosis in Late Presenters: the Answer Lies in the Algorithm! 21st International AIDS Conference. Durban, July 18-22, 2016. Session THWS03.

N Ford. Review of the evidence on mortality from HIV-associated TB and blocks in the cascade of care through from early case detection to timely treatment. 21st International AIDS Conference. Durban, July 18-22, 2016. Presentation THWS0302.

Y Hamada. Overview of the new algorithm to expedite diagnosis, to include elements such as the use of rapid diagnostics, LF-LAM and presumptive TB treatment. 21st International AIDS Conference. Durban, July 18-22, 2016. Presentation THWS0303.