d4T toxicity risk seven-fold higher when started with TB treatment

In patients receiving treatment for TB, initiating antiretroviral treatment that contains d4T results in a greatly increased risk of d4T-related toxicity during the first two months of antiretroviral treatment, US and South African researchers report. They say that all TB patients should be screened for pre-existing neuropathy before starting antiretroviral treatment, and that alternatives to d4T should be considered for antiretroviral treatment (ART) alongside TB treatment.

The findings are published in the June 1^st edition of the journal Clinical Infectious Diseases by researchers from the University of North Carolina and the Clinical HIV Research Unit of the University of the Witwatersrand, Johannesburg.

First-line antiretroviral treatment regimens containing d4T (stavudine) remain the norm in many developing countries due to the low cost of fixed-dose combinations containing the drug.

However d4T has a number of serious potential toxicities including lactic acidosis, peripheral neuropathy and lipoatrophy. Lactic acidosis is life-threatening if early symptoms are not recognised, and nerve damage caused by the drug may exacerbate existing neuropathy caused by HIV, leading to irreversible, extremely painful, harm to the nerves in the feet and legs.

For many patients receiving TB treatment there is a need to initiate antiretroviral treatment either concurrently or after TB treatment has begun, due to a low CD4 count and the consequent high risk of further opportunistic illnesses. In South Africa at least 20% of people with HIV who start a course of TB treatment need to initiate antiretroviral treatment at the same time as TB treatment.

But TB treatment contains isoniazid, a drug also known to cause peripheral neuropathy.

This study was designed to examine the extent to which d4T use alongside TB treatment results in termination of d4T use and substitution with another drug, the most concrete marker of unacceptable toxicity available for measurement.

The researchers reviewed data on 7066 patients who initiated d4T-containing ART at the Themba Lethu clinic in Johannesburg between April 2004 and March 2007. Of this group, 1845 patients received treatment for active TB that coincided with the period of d4T treatment: 1272 were already receiving TB treatment when they began ART, 224 commenced TB treatment at the same time as ART and 349 required TB treatment after beginning ART.

Of all patients who initiated ART, regardless of TB history, 3.7% died, 17.7% were lost to follow-up and 17.3% (1219) switched from d4T to another drug (of whom 69% changed only d4T). The overall rate of substitution was 12.1 per 100 person years of follow-up, with the rate of substitution increasing with the duration of d4T treatment from 7.9 per 100 person years in months zero to six, to 18.1 per 100 person years beyond year one.

The analysis controlled for the effects of sex, age, previous history of peripheral neuropathy or TB, haemoglobin, body mass index, CD4 count, WHO disease stage and stavudine dosage on the risk of switching from d4T during TB treatment.

Among patients who received TB treatment, hazard ratios for d4T substitution compared to those who did not receive TB treatment were:

Forty-three per cent of single-drug d4T substitutions were due to peripheral neuropathy, 24% to lipodystrophy and 20% to lactic acidosis or symptomatic hyperlactataemia. The dose of d4T received did not appear to affect the risk of substitution. Patients who received TB treatment were more likely to switch due to peripheral neuropathy.

“Our results show that initiation of TB treatment and stavudine-based HAART within a 2-week window puts patients at a nearly 7-fold increased risk of stavudine substitution in the first 2 months of HAART,” the authors note.

They suggest that their results may, if anything, understate the frequency with which concomitant d4T and TB treatment is leading to serious peripheral neuropathy, due to the fact that South African patients receive vitamin B6 alongside isoniazid to reduce the risk of peripheral neuropathy. In addition, patients with peripheral neuropathy often receive amtriptyline to manage neuropathic pain.

Without these interventions, severe peripheral neuropathy could lead even more frequently to switches from d4T, they say.

The study was unable to assess the extent to which milder peripheral neuropathy is emerging as a result of concomitant TB and d4T treatment.

In South Africa at least 20% of people with HIV who start a course of TB treatment need to initiate antiretroviral treatment while taking isoniazid, highlighting the public health relevance of these findings. The authors say that screening for peripheral neuropathy is important in all patients receiving TB treatment and d4T, especially those who start TB treatment and d4T within a short time of each other. In addition, “where additional antiretroviral drugs are available,” they say, ”we may wish to reconsider the use of stavudine in first-line HAART for patients with ongoing or concurrent initiation of TB treatment.”

Further information

NAM’s electronic newsletter HIV & AIDS Treatment in Practice recently published an extensive clinical review on the management of peripheral neuropathy in people with HIV in resource-limited settings. Download the pdf here.