HIV & TB in Practice: Improving clinical management of TB in people with HIV

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South African TB conference looks at improving the clinical management of TB-HIV

“If HIV and tuberculosis (TB) are both treatable diseases, why do some patients with HIV-associated TB require hospital admission and die?” asked Dr Graeme Meintjes, of GF Jooste Hospital in Cape Town, during his plenary talk at the 2nd South African TB Conference held last week in Durban. “Primary care doctors say that these cases are more complex to manage and consultations take longer. There are frequent side effects … and if a patient is deteriorating and losing weight, is this because of TB treatment failure or because of HIV-related causes?”

The best way to improve clinical care for the majority of coinfected people is to get and keep them on appropriate TB treatment and antiretroviral therapy (ART) — and much of the 2nd South African TB Conference, held in Durban last week, was focused on how to better integrate TB and HIV services to make this process as efficient and convenient for the client as possible.

However, some people with HIV present with TB cases that are particularly challenging — and a few presentations at the conference focused on ways to improve the clinical management of some of the difficult cases of HIV-related TB, including one on the management of smear-negative TB, while Dr Meintjes shared his considerable clinical expertise on how to better tackle some of the more complicated cases where TB-IRIS, drug toxicity and other concurrent conditions lead to clinical deterioration.  

WHO’s smear-negative TB algorithm saves lives

One long-standing challenge for HIV-infected people with smear-negative TB has been the difficulty in obtaining timely diagnosis and treatment — but one study presented at the conference provided dramatic evidence that clinicians who follow the 2006 WHO smear-negative TB diagnostic algorithm can “drastically reduce mortality in seriously-ill, HIV-infected, sputum smear-negative TB suspects in South Africa,” said Dr Thuli Mthiyane of the South African Medical Research Council (MRC).

Glossary

antibiotics

Antibiotics, also known as antibacterials, are medications that destroy or slow down the growth of bacteria. They are used to treat diseases caused by bacteria.

clinician

A doctor, nurse or other healthcare professional who is active in looking after patients.

adverse event

An unwanted side-effect of a treatment.

encephalopathy

A disease or infection affecting the brain. HIV-encephalopathy (also called AIDS dementia complex) is the result of damage to the brain by advanced HIV disease.

jaundice

A yellowing of the skin and whites of the eyes associated with liver or gall bladder problems.

In a coinfected person, HIV doesn’t just change the clinical course and nature of TB, it can make it extremely difficult to detect TB by the usual methods, such as smear microscopy and chest x-rays. Smear microscopy involves using a microscope to look for TB bacilli in a sample of sputum (or other biological specimen) that has been stained with a special dye — but specimens from people with HIV and TB are frequently ‘smear-negative.’

According to Dr Mthiyane, in South Africa, the incidence of smear-negative TB has increased 35-fold from 1990-2010 (since the HIV epidemic). Unfortunately, under the previous guidelines for the diagnosis of smear-negative TB — which required performing microscopy on at least three sputum specimens, most of these cases were diagnosed late if at all, resulting in delayed or no treatment, and increased mortality.

In 2006, WHO released revised guidelines for the diagnosis of smear negative pulmonary TB (SNPTB) in countries with a significant burden of HIV. There were a few key changes.

First, in people with or strongly suspected of having HIV, a diagnosis of TB could be made even if only one smear was positive after performing microscopy on only two specimens. A diagnosis of SNPTB could be made in anyone with a cough for two weeks or more if both smears were negative, and there was evidence consistent with TB on chest x-ray and the clinician had decided to treat and monitor. A specimen should be sent for cultural confirmation but treatment should not wait for results.

Likewise, although a short trial with antibiotics (to check for effectiveness against other possible causes of the illness) could be useful during the three-five day period of the initial TB investigations, clinicians should not wait for a week or two for antibiotics to fail before initiating TB treatment. The guidelines also suggest that a diagnosis of SNPTB can be made in, and empiric TB treatment offered to, people with HIV who are dangerously ill with suspected TB even if chest x-ray does not suggest TB, if they do not respond to the antibiotics (including treatment for Pneumocystis jirovecii pneumonia ) after three to five days .

WHO acknowledged that the guidelines were, in some areas, based on expert opinion rather than a strong body of clinical evidence because of the urgency of responding effectively to TB in HIV prevalent settings. In light of this, WHO encouraged operational research to strengthen the evidence base of the guidelines.

So between 2008 and 2009, researchers in South Africa conducted a prospective observational study at three hospitals in KwaZulu Natal (McCord, St. Mary’s and Stanger Hospital) comparing whether people suspected of having TB who were managed under the WHO algorithm for smear-negative TB fared better than those who were managed under current standard practice.1

The study included seriously ill people with HIV over the age of 15 with cough for more than two weeks, a chest x-ray suggestive of TB and at least two negative smears. Researchers assessed whether there was a significant difference in the proportion of TB suspects alive at 8 weeks after admission (about the time it takes to get culture results back). A secondary outcome was whether there was a significant difference in the proportion of patients discharged from the hospital, due to clinical improvement (according to the clinician’s reports in the medical records) at one week after admission.

The study enrolled 351 subjects into the standard practice cohort, and 187 subjects in the WHO algorithm cohort. Demographic characteristics were well matched in both groups, with the exception that subjects in the WHO algorithm group were more severely ill (with more WHO stage IV disease). At admission, most participants had a CD4 cell count below 200, although some had CD4 cell counts that were much higher, and a few patients were already on ART.

Seven days after admission, 37% of patients were still in hospital in the standard practice group, compared to the WHO algorithm group [Odds Ratio (OR) 0.61, 95% confidence interval (CI) 0.41-0.90, p=0.01.] There wasn’t a significant difference in the number who died in hospital; but after 8 weeks, a significantly greater proportion of subjects were alive in the WHO algorithm group (84%) compared to the standard practice cohort (68%) [OR 2.5, 95% CI 1.6-3.8, p=0.001].

“There was a huge difference,” said Dr Mthiyane. This was driven by the success of the WHO algorithm at getting people onto appropriate treatment sooner — less than half (47%) of SNPTB suspects in the standard practice cohort were started onto TB treatment either before or after discharge.

“There was high mortality among those in whom appropriate TB treatment was delayed or not given at all due to a trial of antibiotics,” said Dr Mthiyane. “Eight week survival was highest in those in whom appropriate TB treatment was started within three days in patient’s meeting WHO criteria for SNPTB.”

Some in the audience were left wondering whether such a prospective study was truly necessary.

“How many lives would have been saved if the WHO Guidelines should simply been followed when they came out? We’ve known for years that there is little time to waste in getting a severely ill TB suspect with HIV onto TB treatment,” one doctor told this reporter. “In a high burden setting like this, it is extremely likely that the person has TB. In fact, as long as the clinician keeps an eye out for other possible causes, we should probably put all advanced people with HIV and symptoms of TB onto TB treatment.”

Clinical deterioration on TB treatment

While this may be true, according to the plenary talk by Dr Meintjes, it is a good idea to watch out for other conditions in a person with TB and HIV anyway — as they are often the cause when there is clinical deterioration despite TB treatment.2

“Clinical deterioration during treatment for TB remains a common reason for hospital admission,” said Dr Meintjes. To learn why and how common this is, Dr Meintje and colleagues conducted a prospective observational study during the first quarter of 2007 at GF Jooste Hospital, collecting data on every case with clinical deterioration (clinical worsening or failure to stabilise after 14 or more days treatment for TB) that required hospital referral.3  

Over a three-month period, there were 352 patients who met this definition of clinical deterioration, and 296 were admitted (accounting for 17% of the hospital admissions during this period). 83% were known to be HIV-infected with a median CD4 cell count of 89. The median duration of hospital admission was 9.5 days, more than twice what was normal for this setting. 16% of the patients died.

While most people would assume resistance to treatment to be the cause of deterioration in a country with a growing TB drug resistance problem, the majority of cases actually had another illness in addition to TB. Among the 291 TB-HIV coinfected patients, rifampicin-resistant TB was only found in 10%. Other causes of deterioration included an alternative illness other than TB (in other words, a mistaken diagnosis) in 4%, poor adherence in 7%, TB-IRIS in 21%, and an additional illness in 72%.

Most of the additional illnesses were AIDS-defining conditions (pneumocystis pneumonia (n=20), cryptococcal meningitis (n=18), HIV encephalopathy (n=14), toxoplasmosis (n=6), oesophageal candidiasis (n=6), non-Hodgkin’s lymphoma (n=5), Kaposi Sarcoma (n=4) etc). The single most common additional illnesses were bacterial infections (n=53), twelve of which were resistant organisms (e.g., MRSA), gastroenteritis (n=37), drug induced toxicity (n=35) including drug-induced hepatitis. Deep vein thrombosis was found in 12 cases.

Dr Meintjes noted that both HIV and TB have been postulated to be risk factors for deep vein thrombosis and pulmonary embolus. In 2005, a systematic review found a 2-10 fold increased incidence of deep vein thrombosis in people with HIV compared to matched healthy controls,4 while another study found that TB was associated with several risk factors for deep vein thrombosis.5

Subsequently, a similar study was conducted at a primary care TB clinic (the site B clinic in Khayelitsha, South Africa).6 This prospective study followed the outcomes of 292 people with TB over a three-month period in 2008, 71% of whom were HIV-infected. 40% had an episode of clinical deterioration, again mostly due to similar concurrent illnesses. Among those who were HIV-positive, there was a clear increasing risk of clinical deterioration as CD4 cell counts decreased. 15 of the 17 deaths were in people with HIV. A multivariate analysis found that both HIV infection and a low CD4 count at the time of TB diagnosis were significant risk factors for clinical deterioration and death.

Several other studies in Africa have also found TB case fatality rates that are two to eight-fold higher in people with HIV.7, 8,  9, 10, 11  In addition to TB-related causes of death, such as severe disease due to delayed diagnosis and treatment, TB drug resistance and neurological TB, Lawn et al in 2008 and Martinson et al both reported finding concurrent illnesses including AIDS-related opportunistic infections, bacterial infections and pulmonary embolus.12

The course of TB to severe disease and death is much more rapid in people with HIV. Martinson et al conducted a post-mortem study at Chris Hani Baragwanath Hospital near Johannesburg of 47 people diagnosed with TB who died within 2.4 weeks on TB treatment. 10 subjects were found not to have TB, while additional illnesses were common in the rest.13

In light of these findings, Dr Meintjes recommended the following approach to managing people who are clinically deteriorating:

 

Managing clinical deterioration

Checklist question

Action

Is the diagnosis of TB correct?

Review the TB results

Is the patient adherent

Review history

Exclude MDR-TB

Drug susceptibility testing (preferably with rapid test)

If rapid deterioration or clinical suspicion of bacterial infection

Blood culture

Other bacterial cultures

Antibiotics

Exclude other opportunistic infections/malignancies

Examine for Kaposi’s Sarcoma

Serum cryptococcal antigen

Mycobacterial blood culture

Tissue Biopsy

Chronic gastro-enteritis

Stool for stains

Endoscopy and biopsy

 

Dr Meintjes reminded the audience that many of the conditions that cause clinical deterioration in TB-HIV coinfected patients can be prevented by cotrimoxazole prophylaxis. A recent paper on TB-HIV by Harries et al reviewed the evidence for cotrimoxazole use in TB, which reduced mortality by as much as 48% in settings with a low background of cotrimoxazole resistance, and by 22-45% in settings where resistance is much more common.14

Likewise, getting TB-HIV coinfected patients onto ART as quickly as feasible can dramatically reduce the risk of death.15 As a result of the SAPIT study, which demonstrated a 56% reduction in mortality in patients who started ART while on TB treatment, it is now policy in South Africa that ART should be initiated in TB coinfected patients with CD4 cell counts below 350.

Dr Meintjes mentioned a couple of other measures that might be considered in some patients including heparin prophylaxis in hospitalised patients, especially if they are bedbound, unless contraindicated (due to thrombocytopaenia for example). In extremely ill people with HIV who present with disseminated TB, it can also be important to take a blood culture and then to put the person on a broad-spectrum antibiotic.

 

TB immune reconstitution inflammatory syndrome (TB-IRIS)

Paradoxical TB-IRIS occurs when a person who is diagnosed with TB and improving on TB treatment has a recurrence of TB symptoms and new or recurrent clinical manifestations of TB after they have started taking ART (usually within one to four weeks). Dr Meintjes has found this to be relatively common in Cape Town, where 25% of people starting ART are on TB treatment, with TB-IRIS occurring in 8-43% of people on TB treatment who start ART.

TB-IRIS may present as new lymphadenopathy, worsening pulmonary symptoms, effusions, or with neurological manifestations. There can also be liver involvement, with hepatomegaly, jaundice, nausea and vomiting that may be difficult to distinguish from drug-induced hepatitis. 16, 17

“There is no confirmatory diagnostic test,” said Dr Meintjes. “Diagnosis relies on clinical deterioration with features of TB, the temporal relationship to ART initiation and exclusion of alternative diagnoses.” Other possible diagnoses include drug-resistant TB, adverse drug reactions, or other infections or cancers.

Corticosteroids are increasingly being used to manage the TB-IRIS but carry a number of potential risks, including increasing the risk of Kaposi’s sarcoma, reactivating herpes virus infections, and worsening undiagnosed drug-resistant TB.18 Other treatments include NSAIDS, and aspiration of lymph nodes and other surgical procedures.

A placebo-controlled study conducted by Dr Meintjes and colleagues demonstrated that a four-week course of prednisone (1.5 mg/kg/d for 2 weeks, then 0.75 mg/kg/d for two weeks), could improve outcomes when given to people who develop TB-IRIS. The study found that there was a reduction in the combined endpoint of days hospitalised and outpatient therapeutic procedures. There was also consistent significant benefit across a range of secondary outcomes including symptom score, quality of life, chest radiology and a reduction in C-reactive protein levels (a marker of inflammation). While there were more mild infections occurring in the prednisone-treated group, there was no increase in severe reaction or metabolic steroid side-effects.19

Dr Meintjes highlighted one problem that can be found in these patients: prolonged TB lymphadenitis. In people who develop this condition he said that it is important to exclude MDR-TB by sending specimens for culture and drug sensitivity testing. Management of the adenopathy may require taking repeated wide bore needle aspirates, but surgical drainage can result in the formation of large sinuses, and TB treatment may need to be extended until the swelling resolves.

Drug toxicities

As already noted, drug toxicities are a common cause of clinical deterioration, and the problem is compounded in people on TB and ART because of shared toxicities.

Drug rash and hepatitis can be caused by ART, TB treatment or cotrimoxazole. A number of studies have found the risk of adverse events on TB treatment to be much greater in people with HIV. Yee et al reported that people with HIV were 3.8 times more likely to experience a significant drug-related adverse event; while Dean et al reported that people on TB treatment and ART were 1.9 times more likely to have an adverse event.20,21  Dr Meintjes added that unpublished preliminary data from a study conducted last year at GF Jooste Hospital, by Schutz et al, found that 45 out of 255 (22%) patients with hepatitis (ALT>200 or bilirubin>44) were on TB treatment, with or without ART.

 

Shared toxicities

 

TB medication

ART

Hepatitis

Rifampicin, isoniazid, PZA

Efavirenz and nevirapine

Protease inhibitors (especially boosted)

Drug Rash

All TB drugs

Efavirenz and nevirapine

Neuropathy

Isoniazid

D4T, ddI

Kidney toxicity

Aminogycosides, rifampicin

Tenofovir

Nausea and vomiting

All TB medications

AZT, ddI, protease inhibitors

 

The severity of a drug reaction (hepatitis or rash) must be assessed because reaction can be fatal. Markers of severity in rash include systemic symptoms, mucosal involvement, extensive skin involvement, blistering, desquamation, and angio-oedema. For hepatitis, subjects with jaundice, very high ALT/AST, coagulopathy and encephalopathy could be at risk of hepatic failure and death.

In such cases, there may be little option but to interrupt treatment, but in a person with TB-HIV this of course carries “the risk of resistance and a delay in optimal treatment, which could result in increased morbidity and mortality,” according to Dr Meintjes.

Furthermore, regimens to re-challenge a patient can be complex. Local guidelines vary regarding how to re-start TB treatment. With ART, there is the possibility of substituting a less hepatotoxic drug, such using efavirenz rather than nevirapine.

Peripheral neuropathy is also a risk in people taking TB treatment containing isoniazid and ART containing d4T — with a 7-fold higher risk of d4T substitution reported in one study.22  D4T should be avoided in such people if possible, and supplementation with vitamin B6 is recommended.

There may be problems coadministering tenofovir with aminoglycosides in people on MDR-TB treatment as these drugs can cause renal tubular toxicity (predominantly in the proximal tubules) especially if there is underlying renal impairment.23 Current recommendations are to avoid tenofovir in people on an MDR-TB regimen containing an aminoglycoside, and instead to switch to AZT (or d4T).

 

Starting ART

One final clinical challenge that remains in managing TB-HIV is when exactly to start ART, according to Dr Meintjes, keeping in mind the need to balance the risk of mortality from TB-IRIS against mortality from delaying ART.  According to the new South African DOH guidelines, all people with TB-HIV and CD4 cells under 350 are eligible, though we are still awaiting the clinical trial evidence of whether to start ART two weeks or two months after TB treatment. WHO’s guidelines suggest starting as soon as possible and within 8 weeks.

But in practice, because of the many steps to ART initiation in the health system, as soon as possible may be too late. A lot of time can pass between starting TB treatment, receiving an HIV test and diagnosis, then getting a CD4 cell count, being referred for ART, waiting for an appointment, attending counselling sessions and then starting ART. During each step, there can be delays, according to Dr Meintjes, and people will be lost to death and lost to follow-up.

“But despite these challenges, the majority of patients with HIV-related TB will have a good outcomes with appropriate TB treatment, co-trimoxazole prophylaxis, antiretroviral therapy (ART), close monitoring and early diagnosis and treatment of complications and co-morbidities,” Dr Meintjes concluded.

 

References

[1] Medical Research Council South Africa, U.S. Centers for Disease Control. Patient outcomes and management practices: a comparison of proposed 2006 WHO guidelines for the diagnosis of smear-negative pulmonary tuberculosis against current practice in KwaZulu-Natal, Republic of South Africa. 2nd South African TB Conference, Durban, 2010.

[2] Meintjes G. Challenges in the clinical management of HIV-associated TB. 2nd South African TB Conference, Durban, 2010.

[3] Pepper DJ et al. Clinical deterioration during antitubercular treatment at a district hospital in South Africa: the importance of drug resistance and AIDS defining Illnesses. PLoS ONE 4(2): e4520, 2009. doi:10.1371/journal.pone.0004520

[4] Klein SK et al. Is chronic HIV infection associated with venous thrombotic disease? A systematic review. The Netherlands Journal of Medicine, 63(4):129-136, 2005.

[5] Robson SC et al. Acute-phase response and the hypercoagulable state in pulmonary tuberculosis. Br J Haematol. 1996 Jun;93(4):943-9.

[6] Pepper DJ et al. Clinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors. BMC Infectious Diseases 2010, 10:83. 

[7] Mukadi YD, Maher D, Harries A. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa.AIDS;15(2):143-52, 2001.

[8] Malkin JE et al. Tuberculosis and human immunodeficiency virus infection in west Burkina Faso: clinical presentation and clinical evolution. Int J Tuberc Lung Dis. 1(1):68-74, 1997.

[9] van den Broek J et al. Impact of human immunodeficiency virus infection on the outcome of treatment and survival of tuberculosis patients in Mwanza, Tanzania. Int J Tuberc Lung Dis. 2(7):547-52, 1998,

[10] Elliott AM et al. The impact of human immunodeficiency virus on mortality of patients treated for tuberculosis in a cohort study in Zambia. Trans R Soc Trop Med Hyg. 89(1):78-82, 1995.

[11] Lawn SD et al. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS 22(15):1897-908, 2008.

[12] Martinson NA et al. Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study. AIDS 21(15): 2043-50, 2007.

[13] ibid

[14] Harries AD et al. The HIV-associated tuberculosis epidemic - when will we act? Lancet. 375(9729):1906-19, 2010.

[15] Lawn SD, Kranzer K, Wood R. Antiretroviral therapy for control of the HIV-associated tuberculosis epidemic in resource-limited settings. Clin Chest Med. 30(4):685-99, 2009.

[16] Lawn SD et al. Immune reconstitution and "unmasking" of tuberculosis during antiretroviral therapy.  Am J Respir Crit Care Med.;177(7):680-5, 2008.

[17] Lawn SD, Wood R. Hepatic involvement with tuberculosis-associated immune reconstitution disease. AIDS  21(17):2362-3, 2007.

[18] Meintjes G  et al. Novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance. Clin Infect Dis. 48(5):667-76, 2009.

[19] Meintjes G et al. Randomized placebo-controlled trial of prednisone for the TB immune reconstitution inflammatory syndrome. Sixteenth Conference on Retrovirus and Opportunistic Infections, Montreal, abstract 34, 2009.

[20] Yee D et al.  Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 167(11):1472-7, 2003.

[21] Dean GL et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS. 16(1):75-83, 2002.

[22] Westreich D et al. Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy. Clin Infect Dis 48: 2009.

[23] Gitman MD et al.  Tenofovir-induced kidney injury. Expert Opin Drug Saf. 6(2):155-64, 2007.

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