As reported here on aidsmap, a major clinical trial has now shown that a 12-week course of rifapentine (900 mg) plus isoniazid (900 mg) once weekly treatment for latent tuberculosis is just as effective as a 9-month course of daily isoniazid—in countries with a low to moderate burden of TB. The regimen has additional advantage in that it only needs to be dosed once a week.
The Prevent TB study included close to 8000 participants and took ten years to complete. The results were reported last month at the American Thoracic Society’s International Conference in Denver—and have been lauded as being a major advance by the press, global health advocates, and public health officials.
“New, simpler ways to prevent TB disease are urgently needed, and this breakthrough represents one of the biggest developments in TB treatment in decades,” said Dr Thomas Friedman, who is the Director of the US Centers for Disease Control.
Indeed, a short three-month regimen that could cure latent TB would be welcome news— particularly in countries where TB is epidemic and/or wherever there is a high burden of HIV — given that HIV dramatically increases the risk of latent TB becoming active disease.
Unfortunately, there’s a hitch. At this point, this ‘breakthrough’ is not recommended, and may not be appropriate in the very settings or populations that most urgently need new and simpler ways to prevent TB disease.
The spin on this study could have unintended consequences in many settings with a high burden of HIV-related TB, where many programme managers and communities are considering, or now embarking upon the roll-out of isoniazid preventive therapy (IPT) for people living with HIV.
In some settings, according to recent WHO guidelines, IPT may even need to be given continuously when the risk of exposure to TB is especially great. There’s a danger the buzz about a shorter combination regimen may make some consider putting existing IPT plans on hold, even though the new regimen has not been adequately tested in their settings.
This dilemma was noted at the end of the press release put out by the CDC, which said that the researchers had cautioned, “that these results are only directly applicable to countries with low-to-medium incidence of TB.”
During a teleconference last week to discuss the study findings, Dr Kenneth Castro, Director of the CDC's Division of TB Elimination expanded on these concerns.
“It's important to note that the study was conducted in countries which carry a low to medium incidence of tuberculosis. That is primarily in the United States and Canada, and the results can therefore only be applied to these settings. The trial did not include countries with high tuberculosis incidence where the increased risk of re-infection could affect the effectiveness of this regimen,” he said (more on this below).
In fact, 89% of the participants were from the US and Canada (both very low burden countries), with a small number of patients coming from Spain (which also has a low burden of TB) and Brazil (medium burden). Furthermore, there were very few people with HIV included in the trial — an important omission given that HIV is the key driver for the TB epidemic in most of the world.
In its press release, the CDC stressed that additional studies “will likely be needed before this new regimen can be recommended in countries with a high incidence of TB, especially those with high HIV prevalence and where the risk of TB re-infection is greater.”
Yet the wording makes it sound as though this ‘breakthrough’ could still be just around the corner for the rest of the world — once just a little more research is conducted. But the inevitability of this advance in resource-limited settings is far from guaranteed. In fact, until studies demonstrate otherwise, particularly where resistance to TB drugs is increasing, there is a chance the approach could even be dangerous.
At the same time, however, some of the concerns about the regimen’s potential limitations in high-burden settings may not be entirely warranted.
This article attempts to put the results from the Prevent TB study in context of other recent data on TB preventive regimens, including but not limited to IPT, in order to determine just how promising shorter TB preventive regimens might be in resource-limited settings.
Unpublished trial results are preliminary and often incomplete data
First and foremost, it should be stressed that there has only been one short report on the study findings, a conference call to discuss these data and a press release that was rather scanty on details. Clinical trial results presented at conferences are preliminary until they are peer reviewed for publication, but this may be more true than usual in this particular case partly because, despite the large number of participants in the study, there were rather few study endpoints reached.
To review, the study endpoints in this case were culture-confirmed TB cases in adults (and clinically confirmed TB in younger participants), seven in the combination arm and 15 on the isoniazid arm in a modified intent-to-treat analysis (which can be inferred to mean that the analysis included virtually all of those enrolled in the trial). The study was designed to show the combination was ‘non-inferior’ to the 9-month isoniazid arm. This condition appeared to be easily met, with a high statistical significance. While the combination arm may look superior, the study was not designed or powered in such a way to draw this conclusion.
Other details about when and where the TB cases occurred have yet to be released. However, Jennifer Horvath of the CDC’s news media team told HATIP that there were no TB cases during treatment in the arm that received the combination regimen — which suggests that some of the cases did occur during the first nine months of the isoniazid monotherapy arm. However, in an intent-to-treat analysis, this could include TB cases that occurred in participants who may have discontinued treatment, for instance, due to toxicity.
Differences in endpoints by site were not presented, but when there are such a small number of events, it is possible that small differences in baseline characteristics and other variables could influence interpretation of the results.
Notably, the per protocol analysis (which excludes patients known to have discontinued study treatment for a number of possible reasons) only included 5,858 of the 8053 participants recruited to the study. Of those who remained, there were eight cases of active disease diagnosed in those taking isoniazid monotherapy and four on combination treatment. These are small numbers, but what is perhaps more important is that this means that overall ~45% of the reported active TB cases occurred in people who prematurely discontinued treatment, perhaps due to toxicity, or due to other protocol violations, such as missing data.
Easier adherence — but can isoniazid adherence be improved?
Another critical variable is adherence to treatment—in other words, were there differences between the study arms in how well participants took their pills? In the Prevent TB study, differences in adherence support were built into the protocol.
This was, of course, half the point of the study — adherence was expected to be better on the much shorter, once-weekly, supervised combination arm than a pill that had to be taken daily for nine months. Dr Timothy Sterling of Vanderbilt University, who presented the Prevent TB results in Denver, said that around 82% stayed on treatment and made their study visits through to 33 months of follow-up in the combination arm compared to 69% study completion on the isoniazid arm.
But with better adherence support the isoniazid monotherapy arm might have been significantly more effective. According to the recently published results from the BOTUSA study comparing 6 months of IPT to 36 months of IPT, the largest decrease in tuberculosis was seen in TST-positive participants with the “strongest adherence to continued isoniazid treatment."1
On the conference call, though, Dr Castro stressed that adherence has long been a key weakness of IPT.
“Even among those who do begin treatment, up to 60% never complete their treatment,” he said. “In study conditions, people are usually at their best performance — and I would argue that the 69% completion that we saw for nine months of isoniazid is as good as it gets. Without the study conditions, I would expect much fewer individuals to complete treatment during nine-month regimens.”
Indeed, this has historically been the case.2, 3, 4 However, since the Prevent TB study started, adherence support interventions for IPT have improved as experience of using IPT in people living with HIV has grown. In particular, lessons learned from supporting people taking antiretroviral therapy have increased confidence in supporting people through a long course of IPT.
In clinical trials, at least, the idea that 69% adherence to IPT is as good as it gets could be a bit outdated. For instance, in the Thibela TB study, which includes over 27,000 South Africans working in the mining industry, retention was initially fairly low, but it has steadily improved to around 75% in the latest clusters of participants to be enrolled.5
In another recent study by the Tuberculosis Research Centre (TRC) in Chennai, rates of adherence were also very high. Of those randomised to IPT (36 months) 93% were judged to be taking at least 80% of their pills, as gauged by unannounced home visit pill counts.6 Researchers at the TRC stressed that people living with HIV liked the quality of care they received at the site, and continued coming to them even after the study had completed. Adherence in the other arm of that study, ethambutol plus isoniazid for six months, was similar.
Meanwhile, in the BOTUSA study, adherence, or retention in care, was defined as ‘making 80% or more of their clinic visits’.7 A number of participants dropped out during the initial six months when everyone received IPT, but after that, during the blinded part of the study, adherence remained rather good: falling from a high of 85% to 78% in those who continued making more than 80% of their clinic visits. A subset analysis looking at the level of isoniazid in spot urine tests in 200 randomly selected subjects suggest that 80% actually continued taking the medication for seven months to one year, and 74% were still taking it between months 25-30.
Note this was in marked contrast to the IPT programme in Botswana, where large numbers of patients were lost to follow-up at least partly because the population is highly mobile there.8 However, as described in HATIP #175, people living with HIV and civil society organisations in the southern Africa region have since been taking up the challenge to better educate and support people in the community to adhere to IPT.
Would the combination regimen in the study have performed as well without each dose being directly observed? Perhaps not, so a subsequent study is being performed to answer the question.
Side-effects - now or later?
When the endpoints being averted are so rare (in low TB burden countries at least), one has to ask whether the benefits of treatment outweigh its risks.
In the case of some preventive regimens such as rifampin/pyrazinamide, the answer has been no (see below). Rifapentine/isoniazid performs better, but it was not necessarily better than IPT. Data on adverse events in the study were mixed — there were significantly more mild adverse events reported on the isoniazid arm, which was not surprising given that the longer course of treatment provided more opportunities for complaints to arise. However, the trend was reversed for more serious events. 4.7% of those in the rifapentine-containing regimen permanently discontinued treatment due to an adverse event versus 3.6 percent in the isoniazid arm. There was no significant difference between the arms in terms of serious grade 3 or 4 adverse events or death. However, the side effects on the combination regimen occurred over a short course of time — so the toxicity on the regimen is more, up front.
Of note, the only major study so far to look at the rifapentine/isoniazid preventive regimen in people living with HIV in a high burden setting also suggested it was fairly well tolerated.9 The Soweto study compared four arms, 1) the three-month rifapentine/isoniazid regimen to 2) rifampin 600 mg plus isoniazid 900 mg twice weekly for 12 weeks, to 3) daily isoniazid 300 mg for 6 months, and finally a smaller number were randomised to 4) continuous isoniazid for the course of the study. Over the course of follow-up, there were no significant differences in adverse events between the rifapentine regimens, except for a significantly higher rate of adverse events on the continuous isoniazid arm. However, this markedly higher rate of adverse events on continuous isoniazid was not observed in either the BOTUSA study, or the study in Chennai.
Shorter TB preventive regimens: not new, but still not widespread
Though the Prevent TB study was by far the largest to address the question, it is not the first study to report that other TB preventive regimens are as effective as isoniazid. A few of these alternative regimens, rifampin plus pyrazinamide, rifampin plus isoniazid, and rifampin or rifabutin alone were described as early as 1997, by one of the champions of IPT, Dr Richard Chaisson and his colleague Dr William Bishai of Johns Hopkins University.10 In addition to the perceived problems with toxicity and adherence on isoniazid, Bishai and Chaisson wrote that “bacteriologic models suggest that, in their persistent form, tubercle bacilli are relatively resistant to isoniazid but become more sensitive to other drugs.” In other words, isoniazid was simply not the most effective TB drug to use to clear latent TB (although studies have clearly shown that IPT works, particularly, in this writer’s opinion, if you give it long enough). Rifampin, on the other hand, has much greater sterilising activity and could theoretically clear an infection faster.11
But in the fourteen years that have passed since that paper was published, and despite numerous studies, uptake of these alternative regimens has been limited for several reasons.
The first was toxicity, particularly with the rifampin plus pyrazinamide regimen that proved to be profoundly disappointing. Initially there was great excitement about this even shorter course regimen of rifampin plus pyrazinamide (taken for two months) after it was found to be as — if not more — effective than IPT (for up to 12 months).12 Most of the early studies had been conducted in people living with HIV, who seemed to tolerate the regimen adequately. In people without HIV however, the results ‘were radically different,’ according to a recent review of the different treatments of latent TB infection by Lobue and Menzies.13 [Much of this section is drawn from this review (which is exhaustive); citations for the key studies of these regimens can be found in their paper]. Rates of grade III/IV liver toxicity were dramatically higher than on nine months of isoniazid.14
Other options seem much safer. For instance, several randomised trials have reported that the rifampin/isoniazid regimen, taken twice weekly for three to four months, has similar completion rates, comparable toxicity and effectiveness as six or more months of IPT (again, the adverse events may be more common while taking the combination treatment). In many ways, the rifapentine plus isoniazid regimen is a variation on this theme, since rifapentine is essentially a rifamycin, like rifampin but with a five-fold longer half-life. However, because of the difference in dosing, half-life and adherence, the drug exposure achieved by the two regimens is not necessarily equivalent. (And there are questions about the adequacy of once weekly rifapentine/isoniazid in other contexts (see below).
A couple of studies have previously looked at rifapentine/isoniazid to prevent TB. One was a Brazilian study in HIV-negative individuals that found it to be somewhat less effective than rifampin/pyrazidamide — though given the low event rate the study was underpowered for this finding to reach significance.15 What was clear was that rifapentine was associated with far fewer adverse events.
The other study was the SOWETO study, which stands out for being conducted in a high burden setting and in people with HIV. The study involved 1150 participants and found no differences in efficacy across the four arms. “The proportion who had active TB (or died) was the same in all,” SOWETO’s chief investigator, Dr Neil Martinson told HATIP.
(Another preventive option, six months of ethambutol/isoniazid, is discussed later in the article).
Studies also suggest four to six months of rifampin monotherapy is better tolerated, easier to adhere to, and case series suggest it is highly effective.16, 17 A large-scale international trial to assess the effectiveness of 4 months rifampin compared to nine months of IPT is underway. Notably the only study to compare the combination of isoniazid plus rifampin to rifampin alone suggested that the combination actually performed worse (perhaps because of tolerability or pill-burden related adherence problems).18
But there are some downsides of rifamycin-containing TB preventive regimens.
Drug interactions
One of the other problems with preventive regimens containing rifampin or rifapentine is that they are metabolised by the same hepatic enzyme pathway that metabolises the non-nucleoside reverse transcriptase inhibitors and protease inhibitors that anchor antiretroviral therapy (ART). Even efavirenz, which is the preferred option to use in people on ART who must take TB treatment, is somewhat affected — to the extent that you probably wouldn’t want to use rifampin or rifapentine for a preventive regimen. People on ART were excluded from the Prevent TB study.
Rifabutin, which is less likely to interfere with antiretrovirals, might be an alternative in preventive regimens, but hasn’t been studied much for latent TB, though at least one small study suggests it is relatively safe when used in combination with isoniazid (dosed twice weekly).19 Rifabutin is now on the WHO’s essential medicine list so it should be easier to explore these options in resource-limited settings.
Resistance (drug and programmatic)
Given their importance to treatment of active disease, many TB specialists and national TB programmes insist that any regimen that uses a rifamycin should be directly observed or there should be some comparable adherence support given the importance of those drugs for treatment and the fear of encouraging the development of resistance.
It took years to convince national TB programmes to begin to relinquish control of isoniazid in order to allow HIV programmes to begin offering IPT to people living with HIV (some are still ‘resisting’). While Lorub & Menzie suggest that they believe rifampin resistance to be less likely to spontaneously evolve (if active TB has been excluded), this may not reassure those who fear that screening programmes may miss active cases and put them on suboptimal therapy.
One of the reassuring aspects of following the recent WHO guidelines on intensified case finding and IPT is that, if there is a breakthrough case of active TB on IPT, it ought to be quickly detected by monthly screening. Furthermore, data suggest that breakthrough cases on IPT are generally only mildly resistant to isoniazid, and should remain highly treatable with standard TB treatment (although increasing the dose of isoniazid used for treatment may be advisable). The same cannot be said, however, for rifamycin-resistant TB that could develop if active cases are not caught soon enough. In other word, even if less common, the consequences of developing rifamycin resistance are much greater.
One option is to make sure that isoniazid is also part of the regimen as this “does offer theoretical protection against development of resistance if a person with undiagnosed active TB is inadvertently treated for latent TB infection,” according to Lorub and Menzies.
But is this necessarily true if isoniazid is only administered once a week, as is the case with rifapentine/isoniazid?
In the Soweto study, there were a few cases of resistance detected — and more of these were on the weekly rifapentine arm. When initially reported, the study investigators concluded “the development of RIF-resistance and MDR TB in patients in the weekly RPT/INH arm is of concern.”
Today, Dr Martinson is less worried.
“There is always a concern about resistance but we found no real cause for alarm,” he told HATIP, noting they had also found rifamycin resistance in the six-month isoniazid arm. When the researchers looked at the people who had active TB at baseline and were excluded from the study “out of 90 cases there were two with rifamycin resistance. Not that it is ‘scientifically’ significant (given low rates and [the fact that this is] comparing incidence with prevalence). But it suggests that there is circulating rifamycin resistance.”
In other words there is a chance that the resistance was acquired in a reinfection rather than being selected, but Dr Martinson concedes they did not do contact tracing (and phylotyping) to make certain of this.
But the concern might persist particularly in a programmatic setting, where early cases of active TB are more likely to be missed, especially in people living with HIV.
In another context where rifapentine/isoniazid has been used in HIV-positive people, this time in people with active TB — though on maintenance therapy — once-weekly dosing was clearly associated with the emergence of resistance.
This was observed in US Public Health Service Study 22, which included mostly HIV-negative and a smaller number of HIV-positive participants.20 In order to reduce the burden of directly observing doses, the study compared the once-weekly regimen of rifapentine/isoniazid with twice weekly rifampin/isoniazid during the 4-month continuation phase of treatment for pulmonary tuberculosis (after the first two months of intensive treatment which should generally make someone AFB-smear negative).
In the HIV-positive people with TB, slightly more people who were randomised to rifapentine/isoniazid relapsed than those on rifampin/isoniazid though this was not statistically significant given the small size of the subset. What was significant, and frightening however, was that four out of five of those who relapsed on the once-weekly regimen had developed rifamycin-resistant TB — compared to none on the twice-weekly rifampin regimen (p=0.05). In contrast, there was no rifamycin-resistant relapse among the HIV-seronegative patients on rifapentine.21
A subsequent analysis concluded that this was not the fault of rifapentine, at least not directly. Instead, it was the low isoniazid concentrations achieved with once-weekly dosing that were associated with failure/relapse.22
“Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine,” the authors of that analysis concluded. In other words, weekly dosing really requires a drug with a longer halflife.
The risk of resistance developing in people living with HIV on a once weekly TB preventive therapy in programmatic settings is one reason why further research of this combination could be necessary.
Reinfection
Another reason, as Dr Castro mentioned, is the potential for reinfection, particularly for people who are more susceptible to TB (due to poor health, nutrition and HIV), in places where they are more likely to be repeatedly re-exposed to TB. In such settings, anything short of continuous therapy might appear to be wrong-headed.
Or is it?
Although clearly people do become reinfected, even in high-burden settings, the risk varies from setting to setting, person to person, difference in CD4 cell count and tuberculin skin test status. Data to support the benefits of continuous IPT as being worth the costs (side effects, financial and other health system resources) are, at present, far from unequivocal.
Only a few studies have looked at the durability of TB preventive therapy, with variable results. Most of the older IPT studies in high TB burden countries suggest that HIV-positive people who are put on six months of IPT continue to have a reduced incidence of TB compared to those who were untreated for awhile after discontinuing treatment, though the effect diminishes gradually over time.23 One study in Zambia suggested that the protective effect could last up to three years.24 while a study from Uganda found the effect only lasted one year.25 These studies have to be interpreted with caution however as there was substantial loss to follow-up.26
On the basis of these data, one of the ‘old questions’ about IPT was how often HIV-positive people in regions with a higher risk of TB exposure should have to repeat a course.
This changed somewhat when the BOTUSA study results came out. Again, everyone in that study got six months of IPT and was then randomised to either placebo (stopping IPT) or continuing IPT out to 36 months. Much to their surprise, the investigators found that the protection provided by the short course of IPT in their study wore off more quickly than they expected in those randomised to placebo — within six months of completing treatment. The researchers theorised this was probably because people were at such a high risk of re-exposure to, and reinfection with, TB in Botswana. They may be right, or at least partly right, but there are a number of possible explanations. For instance, in the one of the studies mentioned above. Quigley et al wrote that “the diminishing effect of preventive therapy over time in HIV-infected Zambian adults may be explained by the high risk of new infection or by inadequate sterilization of dormant tubercle bacilli in the absence of immunity.”
It is odd that the BOTUSA investigators don’t consider that this last idea, that six months of IPT doesn’t entirely clear the infection in all individuals, is at least part of the explanation for what happened in their study. After all, most studies and a meta-analysis suggest that in tuberculin skin test positive patients, six months of IPT reduces the risk of TB by only around 60%. The remaining cases will still happen — without more preventive therapy.
Instead, the BOTUSA investigators give two primary reasons why they think reinfection is what is occurring. One, they note that there have been high rates of clustering and reinfection of successfully treated cases of tuberculosis reported in Botswana — and there is no denying this. Then they claim that short-courses of isoniazid preventive treatment have a durable protective effect for people with HIV and positive tuberculin skin tests in areas of low tuberculosis incidence.” But the study that they cite to support their argument involved 12 months of isoniazid — not six months — and 12 months of IPT may have a better chance of clearing the bacilli if there is good adherence.
This was very clearly suggested in an on-treatment analysis of the pivotal IPT study conducted by the International Union Against Tuberculosis Committee on Prophylaxis including over 28,000 people in the late 1970s.27 The preventive effect became evident after the first 12 weeks on treatment with a 31% reduction in incidence of active disease, but the effect increased to 69% after 24 weeks of IPT. But in adherent patients, the benefit increased to over 93% at 52 weeks.
People may be putting too much faith in early studies of IPT in people living with HIV that found there were no differences in efficacy between six versus 12 months in HIV-positive patients (in intent to treat analyses). This could be due to the rampant adherence problems or other issues. It is difficult for this writer to ignore the weight of the Union’s study. Furthermore, it seems rather paradoxical that the WHO guidelines review committee concluded that twelve months isn’t more effective than 6 months, and yet gave a conditional recommendation of continuous IPT, on the basis of a study that reported the loss of benefit so shortly after discontinuing six months of IPT.
One of the BOTUSA study’s findings undermines their argument somewhat: continued IPT only reduced TB incidence in people who, when they first entered the study, were TST positive (the clearest measure of having a pre-existing latent TB infection). Note, that only 23% of the study participants were TST positive and therefore showing clear evidence of previous exposure to TB.
If ongoing exposure to TB is so widespread, why didn’t the study see a big increase in the number of TB cases in the rest of the study population on placebo? One would have expected to see some slight trend of difference in the remaining participants, who made up roughly 77% of the study population. The fact that breakthrough cases only occurred in someone who was TST positive at baseline is suggestive of an infection that wasn’t cleared, although it is possible that people who were already latently infected (as the TST shows) are somehow more susceptible to becoming infected again.
But there is limited evidence, such as the study previously mentioned in Uganda —that the benefit of 6 months of IPT is relatively short-lived. However, in the same study, the benefit of shorter more potent combination regimens is sustained out to three years.28 Similarly, in the TRC study in Chennai, there did not appear to be any statistically significant rebound of TB after the six-month ethambutol/isoniazid regimen concluded, (though the event rate was higher than in those randomised to three years of IPT).
If it does take a longer course of isoniazid to clear the infection (if indeed it is possible some of the more advanced people living with HIV), then it may be possible that a more potent regimen may better clear latent TB in less time. If this is true, then there will be less loss of effect — a longer window period free from the risk of TB — even in the higher burden settings. This will need to be demonstrated by further clinical research but it is certainly worth investigating.
If rifapentine/isoniazid, or another short course regimen is effective and safe, then the question of when to give people living with HIV a repeat course may become pertinent again. Dr Martinson doesn’t believe it will be necessary.
“In HIV-positive people the "real sterilising" effect is getting ARVs and restoring immunity soon after receipt of preventive treatment,” he said. “I think few people would be diagnosed soon enough, with a high CD4 count, to receive a short course twice prior to ART initiation. ARVs are the key. IPT has no impact on mortality and has a low durability — get people on ARVs!”
Cost and access issues
But another very simple reason why the Prevent TB study probably won’t soon affect policy in resource-limited settings is that rifapentine is not widely available or on the market in much of the world.
In addition, at current prices, the cost of the rifapentine/isoniazid regimen is $160 per patient — versus roughly $6 for nine months of isoniazid. If that were the price of preventive therapy, it will be a pretty big ask to put every single person with HIV on it, as current WHO guidelines recommend, particularly in programmes that are already financially strained.
However, it is possible that lower prices can be negotiated, and during the conference call, Dr Castro reminded the participants that there were other costs in a preventive programme besides the cost of the drug.
“We are developing some updated estimates. However, I can refer to a cost-efficacy study published by Dr. David Holland and colleagues recently. For the nine months of isoniazid, it's estimated that it would cost about $237 to implement, whereas the three months of isoniazid and rifapentine would cost about $503. Rifapentine is much costlier than isoniazid.” However, he pointed out, there are other cost considerations, including the number of visits and the laboratory tests that would be required to monitor individuals and evaluate safety.
This would be true in resource-limited settings as well. While community-based mechanisms of adherence support — where they exist — may be able to provide adherence support, it is not clear that overburdened HIV clinics that do not have community-based service providers will be able to cope with the repeat ICF screening, and toxicity screening on a monthly basis to roll TB preventive therapy out to all people living with HIV. Shortening the regimen may significantly reduce the burden on the health system.
In the meantime, however, it is important that the buzz about a potential breakthrough treatment not be allowed to confuse and weaken the resolve to implement an existing intervention that we know will reduce the burden of TB among people living with HIV. The efforts to build demand for IPT are not helped when CDC officials describe the regimen as being ‘lengthy and cumbersome’ — after all, people living with HIV take ART medications every day, and must do so indefinitely. Finally, considering how connected the world is, and how the greatest need for TB advances is not in the US or Canada, it is perhaps important not to promote something as a ‘TB breakthrough’ until it has been shown to work in the people and settings where people are most at risk.
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[27]
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