TB & HIV in Practice

This regular feature on TB/HIV integration is kindly supported by the Stop TB department of the World Health Organization.

Continuous isoniazid preventive therapy (IPT) better at preventing TB than short course — but only in those with a positive tuberculin skin test (TST)

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 4^th - 7^th.

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 HATIP 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).

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.

One of the key questions that the study was 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.

TB incidence by treatment arm

 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 relatively low 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 in 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)

References

Samandari T et al. Preliminary results of the Botswana Isoniazid Preventive Therapy (IPT) Clinical Trial (6 months vs 36 months). 40^th Union World Lung Conference, Cancun, 2009.

Interpretation and policy implications of the Botswana IPT trial

Although there is no question that the use of IPT could reduce the burden of TB in people with HIV overall, the results from the Botswana IPT trial pose almost as many questions as they answered. So after the findings were presented, researchers, policy makers and patient advocates debated how the results should be interpreted, and expressed somewhat diverging views how they should affect policy.

WHO currently recommends that isoniazid should be provided to people with HIV when active TB is excluded, and IPT is one of the three I’s at the heart of its TB/HIV strategy, along with intensified case finding and infection control.

However the results of the Botswana study are likely to influence WHO recommendations very swiftly.

Policy in the works

“The results of the Botswana IPT trial are very timely because we are currently revising the policy of intensified case finding (ICF) and isoniazid preventive therapy (IPT) to re-conceptualise the implementation of IPT — not as a stand-alone intervention but intimately linked to ICF,” said Dr Haileyesus Getahun of WHO’s STOP TB Department.

WHO is holding a meeting in the last week of January 2009 to reformulate the ICF/IPT policy. As one of the most rigorous trials on IPT to date, the Botswana IPT study will have a significant impact on the new recomendations.

“Clearly the Botswana study, a randomised controlled trial, definitely falls into the strongest area,” said Dr Getahun, describing how the WHO currently weighs evidence in its guideline development process. “Once we’ve graded this evidence, we will consider the strength of the recommendation. But it’s not only the evidence but also the operationality, the implementation and other issues that will be considered.”

Numerous studies have shown that six to nine months of IPT can lower the risk of active TB — but IPT has been a hard sell to national TB programmes, despite the existing WHO recommendation. In fact, even some of the thought leaders in HIV have been questioning IPT.

“I’m not sure IPT is worth the trouble to be quite honest,” said Dr Francois Venter of Johannesburg Hospital at the HIV Implementers’ Meeting in Windhoek Namibia this year. “We really need to critically re-evaluate IPT. It has distracted national governments and TB programmes like nothing I’ve seen before — I believe it is a long time coming that people start questioning whether this is how we should be spending our resources.”

“IPT has not been a very popular intervention,” said Dr Helen Ayles of ZAMSTAR during a session at this year’s Union World Conference on Lung Health.

The short duration of IPT’s benefit: will IPT have to be given continuously?

Previous studies in Africa have reported that IPT’s benefit lasted at least a year and up to two and a half years.^{1, 2}

“Why is the durability so much shorter in the Botswana trial compared to these other two trials?” asked Professor Gavin Churchyard. He pointed out that the two other trials were in the pre-ART era and that after treatment completion, patients were followed only periodically every three to six months (so to some extent the Botswana study may simply have detected cases earlier). But the more frequent clinic visits in the Botswana study might also put people at risk of exposure to TB.

“It makes one wonder whether transmission within the health services is contributing to more rapid loss of durability in the Botswana trial,” Prof Churchyard said, “which underscores the need for having infection control in our health services.”

The smaller study by Martinson et al found no difference between continuous IPT and short course preventive therapy in the intent-to-treat analysis. However, adherence was an issue in that study and the per-protocol analysis suggested that continuous IPT was more effective than any of the other preventive therapy arms.

Another study that could have a bearing on how this finding is interpreted has just been completed by the Tuberculosis Research Centre in India. The study compared a six-month course of isoniazid/ethambutol to continuous IPT — but the results will only be presented at the Conference on Retroviruses and Opportunistic Infections next February.

One downside of continuous IPT could be an ongoing risk of toxicity. While the Botswana IPT study suggested IPT was fairly well tolerated, and that most severe adverse events were seen in the first several months of IPT, Dr Getahun noted that Martinson et al reported a higher rate of severe toxicity in the continuous IPT arm.

Does the study provide reassurance to national programmes that have been reluctant to roll out IPT?

“Five years ago, I got tuberculosis... I had to suffer from TB disease when this might have been prevented,” said Carol Nyirenda, a patient advocate living with HIV and working with the Community Initiative for Tuberculosis, HIV/AIDS and Malaria plus other related diseases (CITAM+) in Zambia. But she said that national programmes are even refusing to provide IPT on an opt-out basis (when people with HIV request it). “I strongly believe this withholding of life-saving drugs is not ethical – we need to move from discussion to implementation urgently. Our lives are at stake.”

“What does it take to actually change practice on the ground?” asked Mark Harrington of the Treatment Action Campaign. “I think that it is obvious [the WHO guidelines] didn’t really have much of an effect on practice, and all the same issues are brought up no matter what the data say.”

But this study may change things, according to Dr Jeremiah Chakaya, formerly the national TB programme manager in Kenya and presently co-chair of the STOP TB Partnership.

“In Kenya, even though a lot of study indicated that IPT was useful, a lot of us clinicians did not believe in it, we thought it was too difficult, we thought it was impossible. But like some of the people in this room here, I’m a very recent convert of IPT,” said Dr Chakaya.  “Many of us were concerned that in routine programme settings it may be difficult to exclude active tuberculosis and that in fact a lot of TB could leak through the TB screening procedures and inadvertently lead to isoniazid monotherapy and increased isoniazid resistance. What this study has shown us, is that in fact isoniazidresistance does not seem to increase in this study.”

In addition, he said that the study addressed several other key concerns of programme managers by showing that fairly high adherence was possible, and that IPT appears relatively safe.

But the study wasn’t designed to address operational concerns of managing ‘well’ patients, as noted by Dr Francois Venter at the HIV Implementer’s Conference in Windhoek this year.

“Wellness programmes are so shocking, not just in developing countries but in developed countries. We know that we cannot retain people within the system unless we have them on antiretrovirals — study after study tells us that — and yet we take these people, we diagnose them and we try to insert them into a system where all we have to offer them is isoniazid. And outside of very specialised programmes, every programme I see seems to haemorrhage people out of the system unless you put them on antiretrovirals — and we need to engage with that before we start offering IPT in my opinion.”

Dr Chakaya suggested that programmes might instead have to think about delivering IPT at another level of the health system — moving IPT out to the community and relying much more heavily on “community health care workers, patient support groups and things like that. But we need to remember that the more complex the intervention the less likely that the intervention will be taken to scale.”

The role of tuberculin skin tests

But the Botswana IPT findings showing no significant benefit of IPT in people with negative TSTs could wind up making IPT much more complex.

“I think one of the take-home messages - at least for me is: it would be difficult to justify the continual provision of IPT without a TST or an alternative to identify patients most likely to benefit,” said Dr Themba Moeti (the man who launched the Botswana IPT programme). 

“I think it is clear that if TST-negatives do not benefit - and study after study shows that TST-negatives do not benefit from IPT - then TST-negatives should not be given IPT,” said Dr Chakaya. “It doesn’t seem right for us to know what science is telling us and do different things just because they are easier to do.”

Javid Syed of the Treatment Action Group argued that even a small benefit to TST-negatives could justify the routine prescription of isoniazid to people living with HIV, regardless of TST status.

“In fact, 15% of protection was provided to TST-negatives. And for HIV-positives, 15% is not a figure we can ignore,” he said.

However, the study did not demonstrate that degree of benefit with any level of confidence, nor did a Cochrane Group meta-analysis.

 “All of us would have wished that the data would have shown incontrovertibly that everyone benefited and we don’t have to bother with TST, but the data are what they are… and to disregard this is scientifically and intellectually somewhat dishonest,” said Dr Ken Castro of the CDC.  “And we’ve been reminded not to disregard the 14% who may have benefited from IPT if TST-negative but [this ignores] the higher side effects in that group — so where’s the balance in terms of risk-benefit?”

The bigger problem is that TSTs do appear to be difficult to implement in many resource-limited settings.

“TST is an obstacle to IPT," said Dr Kerrigan McCarthy of Johannesburg’s Reproductive Heath and HIV Research Unit earlier this year at the South African AIDS Conference.³

“Firstly there’s the hassle of the supply chain management of TST - quality tuberculin, syringes, PPD RT23, cold chain management.”

In addition, Dr McCarthy said that Johannesburg clinics reported wide variations in the proportion of TSTs interpreted as positive, indicating lack of consistency in performing and interpreting the test. Health care workers arrived at different conclusions about whether the size of the skin reaction, or induration, indicated a positive result or not.

“Quality control of TST is impossible! If the quality of a test cannot be controlled, that test should not be used.”

Indeed, many programmes have had difficulty keeping tuberculin for the tests in stock, nurses have to be trained on how to correctly interpret the result (especially in people with HIV), and people have to return to the clinic within a few days to have it read —which can be a challenge in settings where the clinic is far away, transport is limited, and people have to work to survive and can’t spend much time going to, and waiting in, a busy clinic. In fact, data suggest at least a quarter never come back for their readings — which means that many people who could benefit never come back for treatment. This is why WHO currently recommends that IPT be given to everyone with HIV if they live in a setting with a very high burden of TB.

“Tuberculin (for the TSTs) needs a cold chain and refrigeration. With HIV care and treatment being decentralised into the most peripheral facilities, how are we going to reconcile that?” said Dr Getahun.

“TST is a real barrier to the implementation of IPT,” agreed Professor Churchyard. “In South Africa, as an example, we had absolutely negligible IPT uptake when we had TST as a criteria for enrolling. A year ago, we took IPT out of the revised guidelines, which have now been rolled out and in the last year the number of people put on IPT has tripled.”

Requiring TSTs will mean more expense, training and supervision — and could simply become the new excuse not to offer IPT.

It’s a conundrum, especially for treatment advocates, who are put into the awkward situation of having to weigh the risk-benefit for the HIV community overall versus the benefit for the individual. Treating everyone would reduce the risk of TB by around 56% (marginally higher than the benefit offered by ART in the study) — but it would also result in treating three quarters of the population unnecessarily, and placing them at risk of toxicity. Perhaps that choice (preferably informed) ought to be left up to each individual.

References 

[1] Quigley MA et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS 15(2): 215-222, 2001.

[2] Johnson JL et al. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS 15: 2137-2147, 2001.

[3] McCarthy K et al. INH prophylaxis: Lessons learned during implementation in Inner City Johannesburg: 2008. CREATE Three I’s symposium, 4^th South African AIDS Conference, Durban, South Africa, 2009.