6.0 Overlapping toxicity profiles of antiretroviral drugs with anti-tuberculosis therapy

Adverse reactions to drugs are common among patients with HIV-related tuberculosis especially if taking HAART concomitantly.

Rash, fever and hepatitis are common side effects of antituberculosis drugs especially rifampicin, isoniazid and pyrazinamide.  The NNRTI and co-trimoxazole may also cause similar features.  The co-administration of these drugs can lead to difficult clinical management decisions if these side effects occur especially when HAART and TB drugs are started concurrently.

A total of 167 adverse events were recorded in 99 (54%) of the 183 patients for whom data on therapy were available in a study from the South East of England.57

Adverse events led to cessation or interruption of either their TB or HIV therapy in 63 (34%) of the 183 patients. The most common side effects usually occurred in the first 2 months of treatment and were peripheral neuropathy 38 patients (21%), rash 31 patients (17%), gastrointestinal intolerance 18 patients (10%) hepatitis 11 patients (6%) and neurological events in 12 patients (7%).

The majority of adverse reactions occurred within the first 2 months of starting concurrent therapies. Rifampicin was frequently implicated by the treating physicians, and was responsible for almost 2/3 of adverse events.

6.1 Hepatotoxicity

Hepatotoxicity is a common and potentially serious adverse event. It is defined as:

  1. A serum AST or ALT level of more than three times the upper limit of normal in the presence of symptoms, or
  2. A serum AST or ALT greater than five times the upper limit of normal in the absence of symptoms.

Hepatotoxicity due to isoniazid in the general population increases with age, occurring in less than 0.3% of those under 35 years versus about 2.3% in those older than 50 years.  It is also more likely in those with a heavy alcohol intake, with hepatitis C co-infection and in those who are receiving therapy with rifampicin.  High rates of adverse reaction requiring changes in therapy have been reported in HIV infected patients who are likely to have some or all of the other risk factors noted above.  The rates of adverse reaction were 26% in one HIV cohort compared with 3% in the HIV uninfected group. Other studies have shown similar results. 144, 145,146

If hepatitis develops then all potentially hepatotoxic drugs including isoniazid, rifampicin, pyrazinamide and others eg antivirals and co-trimoxazole, should be stopped immediately.

Serological testing for hepatitis viruses A, B, and C, if not already done, should be performed and the patient asked about any exposure to other possible hepatotoxins, especially alcohol.

As resolution of the hepatitis may be prolonged and until the cause of the hepatitis is identified then, if necessary, it would be reasonable to treat with two or more antituberculosis medications without significant risk of hepatotoxicity, such as ethambutol, streptomycin, amikacin/kanamycin, capreomycin, or a fluoroquinolone.

Monitoring of serum AST (or ALT) and bilirubin and any symptoms should be performed frequently and once the AST level drops to less than two times the upper limit of normal and symptoms have significantly improved, then first line medications can be restarted using a reintroduction regimen [Table 4].

If the drugs cannot be restarted or the initial reaction was life threatening then an alternative regimen can be used (see below).

6.2 Pre-existing liver disease

The risk of hepatotoxicity in these patients is greatest with pyrazinamide then rifampicin and then isoniazid. Isoniazid and rifampicin are essential drugs in short course TB treatment regimens and should be used whenever possible even in the presence of pre-existing liver disease.

However if the serum AST is more than three times normal due to chronic liver disease even before starting treatment, then other regimens can be used e.g.

  1. Avoid pyrazinamide and treat with isoniazid and rifampicin for 9 months, adding ethambutol until isoniazid and rifampicin susceptibility are demonstrated [AIII]
  2. Avoid isoniazid and treat with rifampicin, ethambutol, and pyrazinamide for 2 months, followed by 10 months of rifampicin and ethambutol.  [BIII]
  3. Use only one potentially hepatotoxic agent in patients with severe liver disease and treat with rifampicin plus ethambutol, for 12-18 months preferably with another agent, (such as a fluoroquinolone), for the first 2 months however, there are no data to support this recommendation. [CIII] 

In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug induced hepatic injury.

Monitoring should be performed more frequently (at least 2 weekly initially) in those with underlying liver disease. This should include biochemical and hematological assessments and the prothrombin time. Patients should be told to report to their physician if they develop symptoms such as anorexia, nausea, vomiting, abdominal pain or jaundice. 58,59

6.3 Gastrointestinal side effects

These are common especially in the first 2-3 weeks after starting anti-tuberculosis therapy. If patients develop epigastric pain, vomiting or nausea with first line drugs, have no evidence of hepatic disease and are unresponsive to symptomatic treatment e.g. with anti-emetics, then they can:

  1. take their treatment with meals unless on less than 600 mg rifampicin daily. Food delays or decreases the absorption of anti-tuberculosis drugs but these effects are moderate and of little clinical significance or
  2. change the time of dosing.

Patients should avoid dividing doses or changing to alternative drugs if at all possible; however sometimes dividing the dose of e.g. pyrazinamide, can improve tolerability

6.4 Peripheral neuropathy

The nucleoside analogues ddI, ddC  and d4T may all cause peripheral neuropathy and an additive toxicity of isoniazid when used with d4T has been demonstrated. These antiretroviral drugs can be avoided in the HAART naïve population and alternatives should be found if possible in those already on these drugs. [AII]

Pyridoxine 10-25mg daily should be used in all HIV positive patients receiving isoniazid. 57,60