- Category: Tuberculosis (TB)
- Published on Tuesday, 18 March 2014 00:00
- Written by Theo Smart
Replacing 2 drugs in standard tuberculosis (TB) regimens may shorten therapy and experimental drugs look good in early studies, but a promising diagnostic test did not lead to improvements in mortality, researchers reported at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) this month in Boston.
Only 10 years ago -- when TB was the most common cause of death among people living with HIV globally -- relatively little about the disease was presented at CROI. However, with increased TB activism and research into new treatments, preventive therapies, and diagnostics, the space devoted to TB at the conference has increased substantially.
The efforts of the Global TB Program at the World Health Organization (WHO), which began hosting a pre-conference satellite symposium at CROI 8 years ago, is at least partly responsible for getting cutting-edge HIV/TB research presented at the meeting.
Latency in HIV and TB
This year’s HIV/TB research satellite meeting focused on latency in TB and HIV, examining what can be learned from the study of latent infection -- how the immune system can contain or control either infection -- as well as why that control breaks down. The meeting was aimed at exploring whether there could be alignments or synergies between the basic science research efforts in both disease areas, particularly in the context of HIV cure research.
As a number of presenters noted, the understanding of latency in TB disease -- and how the immune system interacts with the TB microbe Mycobacterium tuberculosis -- is undergoing an evolution, necessitated by the fact that a number of observations about the disease don't add up.
For instance, some experts have said that in high TB burden settings, virtually everyone who is exposed to TB will eventually become infected -- but current evidence suggests that this simply isn't the case. W. Henry Boom of Case Western Reserve University presented data from Uganda showing that, among household contacts of people with active TB, only 41.5% seemed to show signs of acute infection (evidenced by conversion to positive on a tuberculin skin test, usually within 3 to 6 months of exposure), while 31.9% seemed to be relatively resistant to TB infection.
Boom believes that much of what he called "the latent TB infection dogma" is unproven. For instance, latent TB is thought to occur after the immune system contains an acute infection, walling TB microbes in small cysts called granulomas, made up of immune cells in the lungs. But no one really knows whether all people with "latent" TB actually harbor live TB bacteria, according to Boom -- which could at least partly explain why so many people with latent TB never progress to active disease.
Nevertheless, it is clear that many people with positive tuberculin skin tests do harbor TB granulomas that can become reactivated, and that HIV infection dramatically increases the risk of TB reactivation. But why do people living with HIV in some settings seem to be cured of latent TB with a relatively short course of isoniazid preventive treatment (IPT), while people in other settings seem to require continuous treatment? Re-exposure to TB may be part of the reason, but models have shown that reinfection with the TB microbe cannot explain all of the disease that occurs when people go off of IPT in settings with a high TB burden.
Latent TB has traditionally been thought to be something of a fixed state, but researchers now suspect that "latency" is far more complex than originally thought. Sarah Fortune of Harvard School of Public Health presented data from animal models showing that there can be a spectrum of TB granulomas or lesions present in both latent and active disease even in a single individual. These lesions may be variable in pathology and course, some may contain persistently non-replicating microbes, while others may be on the verge or in the midst of reactivation.
Notably, isoniazid, which targets the microbe’s cell wall synthesis, is bactericidal when TB microbes are rapidly replicating, but it does not sterilize all lesions with microbes in more dormant states, particularly if there is a very high level of dormant microbes -- as one might expect in countries where there is a high burden of TB infection and people are likely to have been repeatedly re-infected over the years. As long as individuals' immune systems have not fully recovered from HIV, they could have remaining TB lesions that are at risk of reactivation.
This suggests that there may be important similarities between strategies to target latent reservoirs in HIV and TB, and a need to foster ties between HIV and TB eradication efforts, according to Fortune; the rest of the satellite symposia was focused on exploring those opportunities.
Other sessions at the conference also focused on how best to deal with latent TB infection. Petros Karakousis of Johns Hopkins University presented further data from a macaque model showing a variety of TB replication states -- even in latent TB lesions.
"These data and other similar findings have led to this idea that perhaps it is incorrect to see TB as a dichotomy [either latent or active TB]. Perhaps it is more accurately represented as a spectrum, all the way from dormant infection to sepsis," he said. Even so, he added, "it is the persistence of [the dormant or slowly replicating TB] that makes it so difficult for isoniazid to eliminate the infection."
However, Karakousis presented some in vitro and animal model data showing that it may in fact be possible to "wake up" the dormant TB and expose hidden TB reservoirs to the bactericidal effects of isoniazid -- and thus shorten the duration of TB treatment. His findings suggest one good way to do this would be to knocking out a bacterial enzyme, RelA, which helps regulate replication. He thinks RelA might be a good target for drug development because it is TB-specific as opposed to other broad-spectrum immunological approaches that could activate the TB reservoirs but also have undesirable effects, increasing the risk of other infections or cancers.
Rifapentine and Isoniazid for Latent TB in People with HIV
Another solution to curing latent TB would simply be to treat people coinfected with HIV and latent TB with a standard course of TB treatment for active disease. However, this would expose a lot of people to over-treatment and would be unnecessary when shorter, simpler regimens -- containing a drug that gets to the microbes isoniazid can't kill -- may work just as well.
One option, a 3-month course of rifapentine plus isoniazid -- previously shown by the Prevent TB study to be as effective as taking 9 months of isoniazid in HIV negative individuals with latent TB -- has now been shown to be similarly effective in people living with HIV, according to a poster presentation by Timothy Sterling of Vanderbilt Universityand colleagues.
Rifapentine is a drug that is closely related to the standard TB drug rifampin, but with a much longer half-life that allows for once- or twice-weekly dosing.
The data presented at CROI came from an extension phase of the Prevent TB study, which was a prospective, randomized, open-label, non-inferiority trial comparing rifapentine (900 mg) plus isoniazid (900 mg), both taken once-weekly under direct observation for 3 months, versus 9 months of daily isoniazid. The trial was extended to enroll people living with HIV in the U.S., Brazil, Peru, Spain, Canada, and Hong Kong who were at least 2 years old and either tuberculin skin test positive or close contacts of people with TB (in the end, however, the study only included a handful of children).
The endpoint of the study was culture-confirmed TB in adults and culture-confirmed or clinical TB in children, as assessed by a 3-member expert panel. Antiretroviral therapy (ART) was not permitted until 3 months after enrollment (partly because rifapentine has the potential to affect drug levels of some antiretrovirals -- see below).
The study enrolled 208 participants in the rifapentine/isoniazid arm and 195 in the isoniazid arm, 206 and 193 of whom were eligible for the modified intent-to-treat analysis. A significant number of subjects dropped out before the end of treatment, leaving only 183 and 123 people in the 2 arms, respectively, who were evaluable in a per protocol analysis. Baseline characteristics were well matched.
- In the modified intent-to-treat analysis, there were 2 TB cases in the rifapentine/isoniazid arm (a cumulative TB rate of 1.01%) vs 6 in the isoniazid arm (a cumulative TB rate of 3.50%) -- a difference of -2.49 in the cumulative TB rate.
- In the per protocol population, there was 1 case of TB in the rifapentine/isoniazid arm (a cumulative TB rate of 0.56%) vs 2 on isoniazid (a cumulative TB rate of 1.81%) -- a difference of -1.25 in the cumulative rate of TB.
- Significantly more patients completed the 3-month course of rifapentine/isoniazid than the 9-month course of daily isoniazid.
- The number of adverse drug reactions leading to discontinuation, grade 3/4 adverse events, or death was similar in both arms, though there was a significantly higher rate of liver toxicity leading to discontinuation on isoniazid.
Note that while this study was not conducted entirely in the U.S. and included some sites with a higher burden of TB, it was not performed in the highest TB burden settings in southern Africa. Thus, it is not clear whether the TB preventive effects would prove as durable in that context (however, another ongoing study may provide some evidence about this -- see below)
Rifapentine Can Be Taken with Efavirenz for HIV
One question about the rifapentine-containing regimen is whether it can be taken with antiretroviral drugs, given that -- like rifampin -- it is an inducer of drug-metabolizing P450 enzymes in the liver (CYP 1A2, 2C9, 2C19, and 3A4). However, a couple presentations suggest that, at the very least, it can be safely given with the world’s most commonly used first line regimen efavirenz (Sustiva or Stocrin), tenofovir, and emtricitabine (the drugs in the Atripla single-tablet regimen, and the latter 2 in the Truvada coformulation).
Christine Farenc of Sanofi and colleagues presented a poster describing a small study looking at whether rifapentine has an effect on efavirenz/tenofovir/emtricitabine levels in 12 people with HIV on stable ART following a single 900 mg rifapentine dose and repeated weekly dosing. The first dose increased Cmax (maximum concentration) of tenofovir by 23% and repeated weekly dosing resulted in a modest reduction (15%) in tenofovir Cmin (minimum concentration between doses) and both efavirenz Cmin and AUC0-24 (exposure over time). However, these differences were not seen as being substantial and resulted in no clinically significant changes in CD4 cell counts or HIV viral loads.
Another presentation, by Anthony Podany of the College of Pharmacy at the University of Nebraska, looked at the effect of daily rifapentine administration on efavirenz. This was a pharmacokinetic (PK) substudy of a Phase 3 trial, ACTG A5279, which is evaluating an even shorter course of daily rifapentine/isoniazid (10 mg/kg and 300 mg, respectively, daily for 4 weeks) vs 9 months of daily isoniazid in 3000 HIV positive individuals.
The substudy enrolled the first 90 subjects who, were already taking an efavirenz-based regimen when they entered the trial. Substudy participants came from South Africa (43%), Thailand (36%), the U.S. (14%), Botswana (6%), and Peru (2%). PK sampling was performed at baseline and weeks 2 and 4 after starting rifapentine (12 hours post-dose sample). The researchers estimated that optimal efavirenz levels at that time point needed to be around 1 mg/L, and the study sought to establish that at least 80% or 72 of the participants maintained efavirenz levels above that threshold.
While there were some variations in efavirenz levels, these were seen not only at weeks 2 and 4 but also at baseline in different patients. Critically, however, 81 participants at week 2 and 78 at week 4 had efavirenz concentrations above 1 mg/L, and the oral clearance of efavirenz with or without rifapentine was equivalent. Assessments of viral load pre- and post-rifapentine dosing are ongoing.
These data "provide support that daily rifapentine/isoniazid can be co-administered with efavirenz containing ART for 4 weeks," said Podany.
Whether the more intense daily regimen will be tolerated as well as weekly dosing is another question. One dose-ranging study that was trying to identify the upper limits of rifapentine dosing was stopped early because of safety and tolerability concerns, according to a poster presentation by Kelly Dooley of Johns Hopkins and colleagues. The doses in the study were twice as high (20 mg/kg once-daily or divided in 2 doses) and in some cases with food, which increases bioavailability -- but about half the subjects dropped out due to hypersensitivity reactions to rifapentine.
Optimizing Treatment of Active TB: Isoniazid Concentrations
Isoniazid concentrations may be more important for good treatment outcomes after the intensive phase of TB treatment than had previously been thought, according to another study.
This analysis, evaluating the pharmacokinetics of standard TB drugs (rifampin, isoniazid, pyrazinamide, and ethambutol) in people living with HIV came to a conclusion that the researchers did not expect: when treating active TB in populations with a high burden of HIV coinfection, it may be more important to optimize the plasma concentrations of isoniazid, rather than rifampin.
"We all acknowledge that 6 months of therapy is too long for effective control of drug-susceptible TB, and we believe that the search for shorter therapy may be well informed by an improved understanding of the relationship between anti-TB drug exposure and treatment response," said Derek Sloan of the Malawi Liverpool Wellcome Trust Clinical Research Programme.
But there are limited PK data on TB drugs, particularly in populations with a high burden of HIV/TB coinfection. What data there are have suggested a wide range of interpersonal variability in drug exposure. Plasma drug concentrations are often much lower than have been reported in PK studies in "healthy, normal populations," and variability of the PK of some TB drugs may be linked to poorer treatment outcomes.
Sloan and colleagues conducted a rigorous PK study looking at the relationship between PK and treatment response in Malawian adults with pulmonary TB and a high level of HIV coinfection. The study recruited 169 participants who were eligible at baseline, 133 of whom completed the trial. 57% were HIV positive (and a little under one-third of these were on ART) but did not have symptoms suggestive of other opportunistic infections that could have affected drug bioavailability. 11% of the study participants failed treatment or relapsed within a year of follow-up.
The researchers collected multiple sputum samples, looking at sputum colony counts (to estimate the TB bacilli load) as well as time to positivity on liquid culture (a faster time to positivity would suggest more TB bacilli in the specimen). In addition, they looked at traditional clinical measures: time to culture conversion and long-term favorable outcomes.
They found a high amount of inter-patient PK variability, which was highest on rifampin -- 87% of patients had low rifampin levels compared to previously reported references. And yet this did not seem to have to a clear effect on TB colony counts or clinical outcomes.
"The only significant correlation we found was with isoniazid -- which is not generally thought to be a sterilizing drug -- but from the colony counting, those with a higher AUC for isoniazid had a higher rate of elimination of bacilli during the later sterilization phase of the [TB elimination] curve," Sloan said. Similarly, only isoniazid levels were significantly associated with delayed time to positivity on culture, sputum culture conversion by 2 months, and more favorable long-term outcomes in terms of stable cure.
This finding was considered surprising because isoniazid has long been thought to be important for initial clearance of actively replicating TB in the early phases of treatment -- but perhaps not so important later during treatment. Some mouse studies have even suggested that it is antagonistic after the first couple of days to the sterilizing effects of rifampin and pyrazinamide, and, consequently, some clinical trials have been moving to actually eliminate isoniazid from TB treatment regimen after the first few doses.
"I was under the impression that isoniazid was important over the first 5 to 7 days, and then it was a less important component of bacilli clearance," said Sloan. "I think the only thing I can say with confidence from our data is that that may not be the case, and we may have to think about it a little more."
Substituting Rifapentine and Moxifloxacin
A regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol during the initial phase of therapy may be more effective than standard TB treatment, according to a study by Susan Dorman of Johns Hopkins and colleagues.
According to mouse-model data, the combination of rifapentine, moxifloxacin, and pyrazinamide is particularly potent, so the researchers conducted a Phase 2 trial in Rio de Janeiro to evaluate the effects of swapping rifapentine (7.5 mg/kg daily) and moxifloxacin (400 mg/day) for rifampin and ethambutol during the intensive phase, or first 8 weeks, of TB treatment, with standard treatment (rifampin/isoniazid) thereafter.
The trial's primary endpoints were the proportion of patients with negative sputum cultures at the completion of the intensive phase of therapy, as well as safety and tolerability. The secondary endpoint was time to sputum culture conversion. While the trial was open-label, the microbiologists were blinded to the treatment assignments.
The trial intended to enroll a couple hundred participants, but was terminated early because of slow enrollment and other operational challenges. Nevertheless, 121 patients were enrolled and randomized to treatment. Several were excluded, leaving 53 on the standard therapy arm and 61 on the experimental arm.
Rates of reported severe adverse events were similar between arms, though liver toxicity was more common on standard therapy and allergic-type events more common in the experimental arm. More people on the experimental arm withdrew consent or were lost to follow-up, however (6 vs 1).
In the modified intent-to-treat analysis, the percentage of participants who were culture negative on solid culture at the end of the intensive phase of treatment was similar between the 2 groups, though there was a trend toward a higher response on the experimental arm in the per protocol analysis.
Using more sensitive liquid culture, however, there was a trend toward greater efficacy for the experimental arm in the modified intent-to-treat analysis. There was also a statistically significant difference on the per protocol analysis, with 71.4% culture negative on standard treatment vs 94.4% in the rifapentine/moxifloxacin arm. Time to stable culture conversion (liquid culture) was also significantly faster in the experimental arm.
Dorman noted that the dose of rifapentine used in this study would be considered to be low (and without food guidance). Other studies are looking at higher doses, but nevertheless the activity of the rifapentine-containing arm was at least as good as that of the standard regimen.
"That said, the antimicrobial activity of the [experiental] regimen was at least that of the control regimen," said Dorman. "Therefore, we believe that investigational regimens that include the dual substitution of rifapentine and moxifloxacin warrant additional study in clinical trials."
Novel Combination with Bedaquiline and PA-824
A novel drug combination showed potent anti-TB activity in early human studies, while clofazimine -- a drug purported to be useful for multidrug-resistant TB (MDR-TB) did not, according to another study presented at the conference.
After years with little to no activity in TB drug development, there are now 2 new recently approved TB drugs -- bedaquiline and delaminid. Other agents with anti-TB activity such as moxifloxacin are being repurposed, plus a handful of experimental compounds with anti-TB activity are in clinical development. Since the number of potential TB combination regimens is now quite large, it has been proposed that preclinical and mouse studies direct which combinations should be tested first in clinical trials. However, according to the results from a Phase 1 antibacterial activity study presented at CROI by Andreas Diacon of Stellenbosch University, there may be no substitute for human studies.
Mouse models of TB have predicted that bedaquiline and the experimental compound PA-824 would have potent bactericidal and sterilizing activity when used in combination with clofazimine -- which is currently being used in regimens to treat MDR-TB, even though its efficacy has never been established in controlled clinical trials -- and the standard TB drug pyrazinamide. One of the potential advantages of the combination is that it should be effective regardless of whether TB is sensitive to the standard regimen or not.
A 7-arm study that included 15 participants with TB in each arm was performed in Cape Town to evaluate the early bactericidal activity over 14 days of the following regimens:
- Clofazimine alone
- Pyrazinamide alone
- Bedaquiline + clofazimine + pyrazinamide
- Bedaquiline + PA-824 + clofazimine
- Bedaquiline + PA-824 + pyrazinamide
- Bedaquiline + PA-824 + clofazimine + pyrazinamide
- Standard TB treatment (rifampin, isoniazid, pyrazinamide, and ethambutol)
Although the combination of bedaquiline plus PA-824 and pyrazinamide performed the best, the study found a significant difference between the combination arms in early bacterial activity measured by counting colony-forming units (the TB load) on solid culture and time to culture positivity on liquid media. Notably, however, clofazimine seemed to add nothing to the combination -- which was perhaps not surprising, given that it also seemed to have no activity in the monotherapy arm, in contrast to pyrazinamide monotherapy.
This is a matter of some concern, because clofazimine is being widely used in MDR-TB treatment, but as Diacon said, "We don’t really know if it works or not."
Use of clofazimine can be traced to a report of it being part of the "Bangladesh Regimen" -- a combination with gatifloxacin and several other drugs -- that was reported to effectively treat MDR-TB in 9 months (as opposed to the 18-24 months that it usually takes to treat highly resistant TB). But clofazimine had never previously been evaluated on its own against TB.
Although Diacon's team showed that the dosing regimen for clofazimine in the study achieved concentrations that inhibit TB in vitro, in humans the drug is highly protein-bound, and Diacon believes that it may not be possible to deliver levels of unbound drug that would be high enough to be bactericidal.
"So either it doesn't work in people, or we gave too little, or we didn't give it long enough, or it does something we didn't measure, which is possible," he said. "Clofazimine has an anti-inflammatory effect, which may be important."
And as for why the 4-drug combo looked superior in the mouse model but not in the human study?
"It is important to test these things in people, and perhaps spend a little less time in the mouse," concluded Diacon.
Perhaps the biggest piece of TB news at the conference concerned the failure of the advanced GeneXpert technology and the Xpert MTB Rif test to make any difference at all in mortality, TB cases treated, or losses to follow-up in South Africa -- despite the hundreds of millions of dollars spent by the South African government and its development partners (including USAID) on the test's national rollout -- according to 2 presentations based upon the XTEND trial, a large scale cluster-based study that was nested in the South African program.
Mostly, this was not the fault of the technology per se. Xpert MTB is indeed an important diagnostic advance that picks up many more TB cases faster and more reliably than the much older diagnostic technique, smear microscopy, which does a particularly poor job of catching cases of TB among people living with HIV.
According to Gavin Churchyard and Katherine Fielding, the Xpert rollout failed to make a significant difference in these critical outcomes because of "health system weaknesses." And yet that explanation was not really proven, and probably only partly true.
What is true is that the cost and complexity of the technology affected how it could be implemented in the developing world context. It was cost-prohibitive to install Xpert machines on site at each clinic, which could have diagnosed many cases while the patients were waiting and put them on treatment immediately.
Instead, the equipment was installed at microscopy centers distributed through the country, and clinics had to take sputum samples and send them out for diagnosis -- just as if they were sending out specimens for microscopy or culture -- and then wait for the results. Once the results came back (a length of time not so different from how long it took to get microscopy results back), the clinic would still have to track down the patients and get them back into the clinic in order to deliver their results and initiate treatment. Clinicians who strongly suspected pulmonary TB sometimes treat patients regardless of whether they have their diagnostic tests back or not.
Meanwhile, it is important to note that most of the deaths in the study occurred among people who did not receive a TB diagnosis. Unfortunately, the Xpert MTB RIF test, as it has been used thus far, has required sputum specimens, which are very difficult to get from many patients -- including most of those who are most ill with smear-negative and extra-pulmonary TB. These harder-to-recognize cases probably accounted for most of the deaths, regardless of whether the site used smear microscopy or Xpert.
It is worth noting, however, that while the roll-out was happening, researchers have refined the use of Xpert to look at other specimens. At least one study presented as a poster at CROI reported high yields diagnosing extra-pulmonary TB.
Meanwhile, Steve Lawn of the London School of Hygiene and Tropical Medicinepresented a late-breaker poster on the use of urine specimens to diagnose TB. Xpert MTB Rif testing of concentrated urine from ill people living with HIV admitted to the hospital could detect 59.0% of the culture confirmed TB cases, compared to 19.4% that were detected by fluorescence smear microscopy, 26.6% detected by Xpert on sputum, and 38.1% detected by Determine TB LAM (a rapid inexpensive TB test with sensitivity that appears to be mostly restricted to people with HIV who become gravely ill with TB). Combined, Determine TB LAM and Xpert testing of concentrated urine detected 69.1% of the culture-confirmed TB cases.
Implementation of rapid TB testing of urine could, thus, make a difference in those cases that are in most dire need of treatment. Since it is an affordable point-of-care test, the dipstick test, by itself, could be used to get a substantial proportion of these HIV positive people with smear negative or extra-pulmonary TB on treatment much sooner -- within hours of testing.
S Fortune. Latency in TB: Opportunities, Challenges and the Way Forward. 8th HIV/TB Research Frontiers Meeting. Boston, March 3, 2014.
WH Boom. Latent M. tuberculosis infection: Perspective from the Host. 8th HIV/TB Research Frontiers Meeting. Boston, March 3, 2014.
PE Karakousis. Is Latent TB Infection Really Latent? 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 108.
T Sterling, C Benson, N Scott, et al. Three Months of Weekly Rifapentine + INH for M. tuberculosis Infection in HIV-Infected Persons. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 817.
C Farenc, A Doroumian, C Cantalloube, et al. Rifapentine Once-Weekly Dosing Effect On Efavirenz, Emtricitabine and Tenofovir PKs. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 493.
AT Podany, Y Bao, RE Chaisson, et al. Efavirenz Pharmacokinetics in HIV+ Persons Receiving Rifapentine and Isoniazid for TB Prevention. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 105.
KE Dooley, R Savic, JG Park, et al. Rifapentine Safety and PK With Novel Dosing Strategies To Increase Drug Exposures for TB: ACTG A5311 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 816
DJ Sloan, A Schipani, D Waterhouse, et al. Pharmacokinetic Variability in TB Therapy: Associations With HIV and Effect On Outcome. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 106.
MB Conde, SC Cavalcante, M Dalcolmo, S Dorman, et al. A Phase 2 Trial of a Rifapentine Plus Moxifloxacin-Based Regimen for Pulmonary TB Treatment. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 93.
A Diacon, R Dawson, C Van Niekerk, et al. 14 Day EBA Study of PA-824, Bedaquiline, Pyrazinamide and Clofazimine in Smear-Positive TB Patients, 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 97LB.
G Churchyard, K McCarthy, KL Fielding, et al. Effect of Xpert MTB/RIF On Early Mortality in Adults With Suspected TB: A Pragmatic Randomized Trial. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 95.
KL Fielding, K McCarthy, H Cox, et al. Xpert as the First-Line TB Test in South Africa: Yield, Initial Loss To Follow-Up, Proportion Treated. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 96LB.
SD Lawn,A Kerkhoff, R Burton, et al. Massive Diagnostic Yield of HIV-Associated Tuberculosis Using Rapid Urine Assays in South Africa. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 811LB.