Continuous isoniazid preventive therapy (IPT) better at preventing TB than short-course in people with HIV

Taking isoniazid preventive therapy (IPT) for 36 months prevents significantly more cases of tuberculosis (TB) in people living with HIV in a setting with a high burden of TB than simply taking a short course of IPT for six months, according to the preliminary results of the Botswana IPT trial, presented during a special session of the 40 Union World Conference on Lung Health held in Cancún, Mexico from December 4th - 7th.

The study found that the protection provided by the short course of IPT wore off within six months of completing treatment, probably, researchers theorised, because people were at a high risk of re-exposure to, and reinfection with, TB.

In fact, preliminary observations (not presented) suggest that TB rates also go up after the completion of 36 months of IPT, “so it really looks like continuous IPT may be needed,” said Dr Taraz Samandari of the US Centers for Disease Control (CDC) in Botswana.

Overall, 36 months of IPT reduced the risk of TB by 56% in the cohort that began the randomised portion of the study, which included 1655 people, but almost all of the benefit was experienced by the 400 people with a positive tuberculin skin test (TST+) at study entry — these had a 92% reduction in risk of TB (a profound benefit).

People who have a negative TST — either because they were not infected with MTB or because their immune system was so weak they couldn’t mount a reaction on the TST (anergic) didn’t seem to be protected by IPT (and over the course of the study, they had a rather high rate of developing TB).

Only antiretroviral therapy (ART) reduced the risk of TB substantially in the TST-negative group, but somewhat paradoxically, ART only added marginally to the benefit experienced by people with positive TSTs taking continuous IPT.

IPT was generally well tolerated by the study participants, but it did cause some serious side effects — mainly liver toxicity and mostly in the first six months. While the benefit of continuous IPT certainly outweighed its risks in people with positive TSTs, “TST-negatives may be unnecessarily exposed to harm from IPT,” said Dr Samandari.

Background

There is no question that something must be done to reduce the burden of TB in people with HIV, who have a 5-10% annual risk of TB disease once infected with TB bacilli compared to a 5% lifetime risk in HIV-negative people with latent TB infection. Moreover, people with HIV have a much higher risk of dying of TB disease.

For instance, in Botswana, TB has spiralled out of control since the emergence of the HIV epidemic (with a TB case notification rate of 620 per 100,000 in 2002 — among the highest in the world). About a quarter of sexually active adults are believed to be HIV-positive but they make up a much greater proportion of the TB cases (80%). At least 40% of hospital deaths in people with HIV are due to TB.

Numerous studies have shown that IPT can reduce the risk of TB by between 30-60% and the World Health Organization recommends it for people with HIV who are TST-positive or who live in settings with a greater than 30% risk of mTB infection.

However, as HIV & AIDS Treatment in Practice, NAM's electronic newsletter on HIV treatment in resource-limited settings, has described in a number of articles (published in November 2007, in June 2008 and most recently in July 2009), many clinicians and national programmes have been reluctant to roll out IPT.

The notable exception has been the Botswana National IPT Programme, which offers six months of IPT to anyone who tests HIV positive (not bothering with TSTs as per WHO policy).

However, as the programme was being launched, Botswana and the CDC decided that there were some unresolved questions about IPT that would best be addressed by a double blind randomised clinical study, such as:

 

• How durable is the effect of IPT, and should it be given continuously in settings with a high risk of reinfection?
• Do TSTs make a difference in a high TB burden setting?
• Does antiretroviral therapy add to TB prevention?
• What is the risk of isoniazid resistance and severe adverse events or death?

 

The trial design

The study was designed to enrol roughly 2000 subjects who would all start treatment with six months of open-label IPT (the national standard) and then be randomised either to continue IPT for a further 30 months (referred to as 36-IPT since it involved 36 months of IPT)) or a matched placebo group (referred to as 6-IPT).

The study was conducted at eight sites: five in Gaborone and three in Francistown. These were government clinics where IPT and ART were available. IPT was given as 300 mg isoniazid plus 25 mg vitamin B6 daily (or matching placebo), and patients came back every month for refills from study nurses.

The researchers maintained very high clinical trial standards with ongoing review by an external Data and Safety Monitoring Board, and an external Endpoints Committee (which reviewed and approved TB cases, examined adverse events and deaths (blinded to treatment arm). In addition, a clinical research organisation audited the trial for adherence to standards of good clinical practice.

The study included reasonably healthy adults with proof of HIV infection (and whose laboratory tests were within reasonably normal parameters), but excluded anyone with signs or symptoms or a physical exam suggestive of TB, AIDS-defining illness or liver disease. In addition, anyone with a history of IPT, active TB in the past three years or a history of poor adherence to chronic treatment was excluded.

The researchers planned to conduct an intent-to-treat analysis (ITT) on all participants who began the randomised portion of the study, as well as a ‘per protocol’, analysis including only those who had 80% or better adherence to clinic visits.

Out of 4331 screened, 1995 were ultimately enrolled into the study. Arms were well matched; roughly 72% were women, and the median age was around 32 years old. The median CD4 cell count at study entry was about 300. Approximately 24% were TST-positive. Of note, antiretroviral therapy (ART) was begun by almost half the patients, a median of six months after study entry.

Dr Samandari reported good completeness of follow-up with only eleven participants (0.6%) lost to follow-up after 36 months and 176 voluntary withdrawals. However, this is somewhat misleading because later in the presentation, he mentioned that 340 subjects were excluded before the randomised portion of the study for a variety of reasons (including failure to return to clinic, TB or death in the first six months).

For the remaining subjects who completed the first six months of treatment, adherence remained rather good, falling from a high of 85% to 78% who continued making more than 80% of their clinic visits. Spot urine tests in 200 randomly selected subjects found only slightly lower percentages of isoniazid in the urine (a mean of 74-80% were actually taking the medication).

Results

Because of losses in the first six months, 1655 people were included in the final ITT analysis, 1318 in the per protocol analysis. Overall, 36 month (continuous) IPT reduced the risk of TB by 56% compared to six months of IPT followed by placebo. See details in table.

 

TB incidence by treatment arm

	Intent to treat		Per protocol
	6-IPT	36-IPT	6-IPT	36-IPT
Number analysed	821	834	665	653
TB
Definite TB	16	9	12	6
Probable TB	2	1	2	0
Possible TB	7	2	5	5
All incident TB	25	12	19	8
TB rate per 100py	1.39	0.61	1.1	0.51
Hazard ratio	0.44		0.43
P value (<0.05)	0.029		0.039
	56% reduction		57% reduction

 

One of the key questions that the study intended to answer was how long people remain protected from TB after finishing a six month course of isoniazid. The answer, unfortunately, is not very long. After about 200 days (six months), people who were randomised to placebo began developing active TB at a rate that was significantly higher than seen in the 36-IPT arm.

Another key study objective was to determine whether treatment TST status affected outcomes in this setting. To the consternation of many policy makers in the room, it did.

Of the 1594 subjects for whom TST results and data were available, 400 were TST positive. In the 6-IPT arm, there was a TB rate of 2.53 cases per 100 person years (12 cases of TB) vs 0.19 (or one case) in the continuous IPT arm. This yielded a hazard ratio of 0.08 (p = 0.015). In other words, there was a 92% reduction in TB on continuous IPT.

The 1194 people with negative TST results had a TB case rate of 0.92 (13 cases) in the 6-IPT arm versus 0.78 (11 cases) in the 36-IPT arm — for a hazard ratio of 0.86, (p-value non-significant). In other words, treating almost 1200 TST-negative people with IPT for an additional 30 months reduced TB cases by only 14%, resulting in two fewer cases) and even this apparent reduction may have been a chance result.

Many of the TST-negatives probably had relatively high CD4 cell counts and had probably never been infected by mTB and/or may have had relative lower risks of MTB infection. IPT would be expected to have less of an impact in that population.

More worrisome are the TB cases that occurred despite treatment. Most of these cases in TST negatives were probably in people who were anergic, in other words, exposed to MTB but unable to mount an adequate immune defence to it. However, no data on median CD4 counts in TST-positive and negative groups were presented, nor the median CD4 count in TB cases in the TST-negative group).

In a conversation after his presentation, Dr Samandari posited that without support from the immune system, IPT may not be up to the task of fighting off TB on its own. However, there may be other mechanisms as well due to differences isoniazid metabolism and bioavailability in people with very advanced immune suppression. Also a subset of people with very low CD4 cells may have established TB infections somewhere in their body without clinically apparent symptoms — meaning that IPT in these people was simply suboptimal treatment.

ART (which was initiated at different times but evenly distributed in the two arms of the study) however had an impact on risk in people who were TST negative. A Cox regression model, including the interaction of IPT, baseline CD4 and TST, looked at the affect of ART over time and how it interacted with TST and IPT.

The model found that for each extra day on ART, the risk of TB decreased by 0.23 percent (p=0.04). When provided for 360 days, the risk of TB was reduced by 50% when IPT was not included. However, the addition of ART to IPT didn’t seem to add much benefit - around 4% in TST positives taking IPT.

More importantly, the addition of IPT to ART in TST-negative participants only seemed reduce the risk of TB by an additional 4% (54%) — so ART did not seem to restore their ability to respond to IPT.

Adverse events, resistance and mortality

The study found a relatively low rate of severe adverse events after the first six months of IPT that were at least possibly associated with study medication, with seven (0.9%) events in the 6-IPT arm (placebo) and eleven (1.3%) in the 36-IPT arm.

However, one was a case of hepatic encephalopathy leading to death in month 9 (another case occurred during month six).

In addition, it should be noted that there were 20 severe cases of hepatitis (grade 3 or above) in the first six month of open-label IPT — though most had no clinically recognised symptoms. Coadministration with ART may have increased the risk of liver toxicity somewhat (relative risk 1.59 [0.63-4.0]). The risk was greater on nevirapine (RR 2.09 [0.74 - 5.87]) as opposed to efavirenz (RR 0.96 [0.21 - 4.31]).

IPT did not lead to a substantial increase in isoniazid resistance in this study. The background prevalence of isoniazid resistance among new TB patients in Botswana was 9%. In the IPT study 17% of incident TB cases had mono or MDR resistance in the 6-IPT arm and 14% in the 36-IPT arm.

The data on mortality were less clear-cut. Overall there was a death rate of 1.4% per annum (2% in the first year). “This is comparable to mortality in rich nations,” said Dr Samandari.

However, in this clinical trial setting (where TB cases were probably detected and treated earlier than would happen in the field), 36-IPT did not reduce mortality compared to 6-IPT — in fact, there was a slightly higher risk of mortality (25 deaths versus 16 deaths) but this difference was not statistically significant (p = 0.17)

Implications

The CDC clearly seem to think that the Botswana IPT trial is a game changer. They asked for and were, granted a special session in a highly unusual move by typically conservative conference organisers, not just to share the preliminary results, but to discuss the policy implications.

“The results of this trial are of great public health significance,” said Professor Gavin Churchyard of South Africa — though he noted that the findings also raise many questions.

The public policy implications of the study will be reviewed in a future edition of HIV & AIDS Treatment in Practice.