Two experimental drugs for the treatment of MDR TB have completed phase II clinical trials. While neither is ready yet to be registered with a regulatory authority, bedaquiline (formerly TMC207, manufactured by Tibotec) is already better tested than most second-line TB drugs and has a good side-effect profile. The results of a Phase II trial of delamanid (formerly OPC-67683, manufactured by Otsuka Pharmaceuticals) are expected to be published soon.

Bedaquiline

HTB previously reported the development of bedaquiline and Phase II trial results [1,2]. Tibotec reported further results at a Critical Path to TB Drug Regimens meeting in Arlington in November. In this trial of 160 MDR TB patients, that compared an optimised background regimen plus either placebo or bedquiline, there was faster culture conversion in the bedaquiline arm by 24 weeks (p=0.003). This was the primary endpoint. In secondary analyses, median time to culture conversion was 12 weeks vs 18 weeks. And at 24 weeks 79% of bedaquiline patients vs 58% of placebo ones had converted to sputum-negative (p=0.008). Side effects were distributed evenly over the two groups. There were no serious study drug-related side effects nor were there clinically significant differences in laboratory results. QT prolongation was seen on the bedaquiline arm, but there were no adverse events associated with this nor were there any prolongations greater than 500 milliseconds. [3]

In an ongoing open-label study (C209) that is assessing safety, efficacy and tolerability over two years of bedaquiline in smear-positive MDR TB patients, there was an 80% response rate at 24 weeks. Resistance to more drugs was associated with poorer response rates (56% for XDR, 77% for pre-XDR and 87% for MDR; p=0.0006). Patients with no cavitations also responded better (p=0.0157), as did patients on three or more potentially active drugs (p=0.0376). The most frequent side effects were nausea (11%), arthralgia (12%) and hyperuricaemia (14%). About 2% of the patients stopped bedaquiline due to an adverse event.

Tibotec has planned a Phase III superiority study (C210) with 600 subjects. The primary endpoint is intended to be relapse free cure at 15 months and a final analysis will also be done at 21 months.

The company is also considering a paediatric trial of 60 children to examine PK and safety.

The company has a compassionate use/expanded access programme. In countries that have a mechanism to authorise pre-approval access of unregistered medicines, patients with pre-XDR or XDR TB at what the company describes as validated centres can obtain bedaquiline. In countries where this is not feasible, such as China, Russia and Lithuania, an expanded access trial is planned. But at the time of the Critical Path meeting when this was presented, fewer than 30 patients had accessed the drug via compassionate use or expanded access.

Delamanid

In a phase II trial (Trial 204), about 480 patients with MDR TB were divided into three arms, stratified by disease severity. All patients received optimised background regimens. The first group received placebo, the second delamanid 200mg/day and the third delamanid 400mg/day for eight weeks. Patients were followed for an additional four weeks for safety and to confirm sputum conversion. The trial took place at 15 sites in 9 countries. Those patients who successfully completed Trial 204 were eligible to enroll in a 26 week open label protocol. Those who participated in Trial 204 and received placebo therefore had 26 weeks exposure to delamanid and those who received delamanid in trial 204 had a total of 34 weeks exposure to delamanid. [4]

Otsuka is currently recruiting for a Phase 3 trial to test the safety and efficacy of delamanid 200mg daily. [5]

comment

These two drugs are the furthest along in the pipeline to treat drug-resistant TB. It is essential that they soon be tested together, so that if or when they are approved clinicians do not have to grapple with whether or not to add a single drug to failing regimens.

TB drug development is painfully slow. Consider that rilpivirine (TMC278), an antiretroviral of minor importance, was presumably discovered after bedaquiline (given that TMC278 signifies a chronologically later drug than TMC207). Yet the rilpivirine phase III trial started in 2008 and the FDA approved the drug last year. In contrast, bedaquiline is not expected to be registered in the very near future. This is not to single out Tibotec: indeed their TB development is the most advance. But this example shows the comparative lack of resources invested in getting TB drugs to market. Regulatory hurdles specific to TB worsen the situation. For example, some regulators want to see two-year relapse rates before granting approval.

Pre-regulatory approval expanded access should be a priority. Tibotec has committed to this but because of regulatory hurdles, lack of knowledge about the programme and perhaps lack of urgency from the company, we remain far from significant expanded access. It is unclear what commitment Otsuka has to expanded access.

Activists and patients must increase the pressure on Otsuka, Tibotec, health ministries and service providers to make these drugs available more widely for pre-approval access. More pressure must be put on the entire industry to develop more drugs, though as recent TAG/i-Base pipeline reports show, this is starting to improve.

References:

1. Geffen N. 2009. TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB. HTB 10(7) July/August 2009.
   http://i-base.info/htb/4403
2. Clayden P. 2011. Faster conversion rates with TMC-207 versus placebo plus OBT for the treatment of MDR-TB. HTB 12(1-2) January/February 2011.
   http://i-base.info/htb/14441
3. Presentation by Tibotec to Global TB Community Advisory Board at CPTR 2011.
4. Otsuka. A Placebo-controlled, phase 2 Trial to Evaluate OPC 67683 in patients with pulmonary sputum culture-positive, multidrug-resistant tuberculosis (TB).
   http://www.clinicaltrials.gov/ct2/show/NCT00685360 5.
5. Otsuka. Safety and efficacy trial of delamanid for 6 months in patients with multidrug resistant tuberculosis.
   http://www.clinicaltrials.gov/ct2/show/NCT01424670

The event at the World Lung Conference in Lille that generated the most media was the ZAMSTAR study results, presented by Peter Godfrey-Faussett of the London School of Hygiene and Tropical Medicine. [1] [2]

Four interventions were randomly assigned to six communities each, from a pool of 24 communities. The randomisation was also balanced across two regions comprising the study – Zambia and the Western Cape in South Africa – and high versus low TST levels, drawn at baseline from a sample of children in grades one to three. There were just under a million people altogether in the communities. Each community had a minimum of 25,000 people and a TB notification rate of more than 400 per 100,000 per year.

The primary endpoint was prevalence of active TB in a randomised sample drawn from the population.

The four interventions were as follows:

• Clinic based TB and HIV interventions (clinic, or control arm), which included TB and HIV programme collaboration, testing TB clients for HIV and voluntary HIV counseling and testing for clients screened for TB.
• Enhanced case finding (ECF), which included using community- based interventions to improve awareness of TB and HIV, fast track sputum collection for smear microscopy at a nearby health centre, a schools education campaign and mobile sputum collection points with community advocacy using local youth drama groups. Guiding principles of this intervention were that every person should be able to give sputum within a 30 minute walk and sputum smear results would be available within 48 hours.
• Household interventions (HH) which included, households of people with active TB being visited for active case finding, IPT for asymptomatic HIV-positive people and children less than six years old in the household, access to HIV counseling and testing and discussion with households to try to reduce risk of HIV-negative people contracting HIV, as well as counseling and referral for care.
• All of the above.

The study was run from 2006 to 2009. The ECF intervention attracted TB cases. Overall, 4.6% of the communities in ECF sites gave a sputum sample through ECF and 24% of smear-positive cases (20,630 people, of whom 14,130 were in the Zambian sites and 6,500 in South Africa) were detected via ECF. Interestingly, the South African sites, despite dealing with a smaller number of sputa, had far less efficient turnaround times on microscopy and more missing samples. The costs ranged from $17,137 to $24,455 per ECF site per year, which is equivalent to $0.31 to $0.71 per person per year.

In the HH sites, just over 9,350 households were visited, containing nearly 37,000 people, about 6% of the population. About 27,000 people experienced all three of the study’s scheduled visits. The cost ranged from $24,126 to $34,661 per site per year, or $0.48-$0.8 per person per year. Nearly every household individual received HIV education and group counseling, 67% had HIV tests and 38% (7,029 people) were HIV-positive. Godfrey-Faussett noted that 4,000 people were accessing ART and he described IPT as challenging.

The sample sizes in the prevalence survey at the end of the study were designed on the assumptions that there was a TB prevalence of 1% in the control arm and that a reduction of 30% in arms two and three would be detected. This turned out to be optimistic. On the basis of these assumptions the sample size was 4000 adults per community in each of the 24 communities. Geographically based cluster sampling was used based on standard census enumeration areas. All households in randomly selected enumeration areas were visited. A total of 55,450 households were visited including 123,790 individuals. Of these 90,600 were present and consented to a questionnaire, respiratory sample, HIV test and blood sugar test. Of these, 64,430 had evaluable TB cultures, of which 884 were positive for active TB. Overall prevalence in the Zambian sites was 542/100,000 adults, ranging from 221 to 1,096. Overall prevalence in the South African sites was 2,319/100,000 adults, ranging from 1,489 to 3,054.

The primary outcome was that prevalence for communities with the HH intervention was 746/100,000 versus 883/100,000 in communities without HH. The adjusted risk ratio was 0.78 [95%CI: 0.61-1.00]. The presentation is not clear here but this result appears to be adjusted for age, sex, TST prevalence, HIV prevalence, socio- economic status, education, marital status and smoking. Prevalence for communities with ECF was 927/100,000 versus 711/100,000 without ECF. The adjusted risk ratio was 1.11 [95%CI: 0.87-1.42].

Some secondary endpoints were also presented in Lille. From the presentation it appears that a baseline TST study was done in kindergarten children and then repeated on the TST-negative children at the end of the study four years later, in order to calculate infection incidence. A new infection was defined as a change in induration from 0mm to 15mm. Incidence in the HH arms was 0.87 per 100 person years versus 1.71 for the non HH arms. The adjusted rate ratio was 0.45 but this was non-significant [95%CI: 0.20-1.05]. For ECF this was 1.41 versus 1.05 for non ECF communities, for an adjusted rate ratio of 1.36, also non-significant [95%CI: 0.59-3.14].

Interestingly, incidence in Zambia was 1.2 per 100 person years versus 4.5 per 100 person years in South Africa.

No statistically significant effects were found for any of the interventions on TB treatment outcomes for index cases, cumulative TB incidence or HIV prevalence or incidence.

comment

The ZAMSTAR study has produced many interesting results, not least the differences between TB incidence and systems in Zambia and South Africa. Many interesting papers should come out of it.

Unfortunately there was only one statistically significant
endpoint presented: a lower prevalence at the end of the study in communities, which had the household (HH) intervention. But even this effect was modest. With a longer time period, the effect might have been greater. Moreover, since no baseline prevalence survey was done we cannot be sure that the differences in prevalence did not exist at baseline, but perhaps this concern will be allayed when the study results are published in a journal.

The household intervention appears to be affordable and certainly not harmful, so it might be worth implementing on a larger scale.

References:

1. Godfrey-Faussett P. Do we need to go beyond the clinic to control TB? 42nd Union World Conference on Lung Health, Lille, France (2011)
   http://uwclh.conference2web.com/content/1060
2. Ayles HM et al. ZAMSTAR, The Zambia South Africa TB and HIV
   Reduction study: Design of a 2 × 2 factorial community randomized trial. Trials 2008, 9:63 doi:10.1186/1745-6215-9-63.
   http://www.trialsjournal.com/content/9/1/63

Simon Johnstone-Robertson and colleagues at Cape Town and Stellenbosch universities have published the results of a model that calculated a TB transmission probability of 90% per year for awaiting trial prisoners in a large South African prison. They found that by implementing the national cell occupancy recommendation, the transmission probability could be reduced by 30%. And by implementing international recommendations, transmission probability could come down by 50%. They also found that implementing any one of improved passive case finding, modest ventilation increases or decreased lock-up times according to national or international standards would have a minimal effect. But by implementing all of these measures together including reduced occupancy, transmission could be reduced by 50% if national guidelines were adhered to and by 94% if international guidelines were used. [1]

The authors explain that South Africa has the fourth highest global incarceration rate, with more than 165,000 prisoners in 237 prisons. There is rapid turnover of awaiting-trial prisoners with 79% being imprisoned for less than 12 months and the number of people passing through the system annually exceeding 368,000. There are at any time about 3,200 prisoners awaiting trial in Pollsmoor, the 3rd-largest facility with awaiting trial prisoners in the country. Awaiting trial prisoners are mostly kept in communal cells of 40 to 60 prisoners each.

The South African Constitution’s Bill of Rights says “Everyone who is detained, including every sentenced prisoner, has the right … to conditions of detention that are consistent with human dignity, including at least exercise and the provision, at state expense, of adequate accommodation, nutrition, reading material and medical treatment”. [2]

A 2011 court judgment showed how far the country is from attaining this right. From November 1999 to 27 September 2004 Dudley Lee was an awaiting trial prisoner in Pollsmoor prison complex in Cape Town, except for a four month period in 2000 during which he was out on bail. In June 2003, while he was in prison, he became ill and was diagnosed with pulmonary TB. He later sued the Minister of Correctional Services because the state’s conduct caused him to become ill with TB.

Conditions in Pollsmoor Prison

In his court action, Lee’s legal team claimed that:

• It was common for prisoners in the prison, including Lee, to be in close proximity to one another and to be housed in mass cells;
• A considerable proportion of prisoners were infected with active TB and that it was inevitable that some of the prisoners with TB would infect non-infected prisoners in close proximity to them;
• The Department of Correctional Services was aware of the presence of TB in the prison and the risk of non-infected prisoners becoming infected;
• The Department failed to adhere to prisoners’ requests for adequate treatment to prevent and/or treat and/or cure people;
• The Department could have eliminated or reduced the spread of TB by creating conditions in the prison which made it impossible or difficult for tuberculosis to be spread by separating prisoners sick with TB from healthy prisoners, regular and effective checkups of prisoners to see whether or not they were actively infected with tuberculosis, and by providing regular and effective treatment for the control and elimination of the disease;
• The defendant’s actions towards the plaintiff were unlawful because the Department violated the Constitution and the Correctional Services Act 8 of 1959 including sections that deal with respect and protection of physical integrity.

The court judgment describes overcrowded cells in which inmates typically spend 23 hours a day and an hour in an overcrowded recreational area. The environment is engulfed in tobacco smoke and fumes and coughing. There is a chronic shortage of nurses and staff and so the DOTS system that is supposed to be used is implemented inconsistently at best. TB data in the prison is poorly kept and inconsistent. For example, one doctor testified that treatment cases had to be recorded in a treatment register, which was held in quadruplicate. One copy was to be sent off to the Medical Officer of Health but documents, which were supposed to have been forwarded to the Medical Officer, were still in the register. Another example: A schedule of TB cases covering the period 1998 to 2009 had been prepared by the prison but other records in the prison showed the schedule was wrong. The total number of TB cases for 2001, according to the register, was 177 but the schedule recorded 69 cases with no cases provided at all for April to October.

South Africa has an extraordinarily high crime rate and there is not much public sympathy for prisoners. Dostoevsky’s comment that a “society should be judged not by how it treats its outstanding citizens but by how it treats its criminals,” is not a widely held view, in spite of Constitutional guarantees and legislation protecting prisoner rights. It is therefore notable that Mr Lee was acquitted and therefore arguments lacking empathy for criminals are irrelevant to his case. Moreover, as Johnstone-Robertson and colleagues point out, high TB transmission rates in prison contribute to a high TB burden in the general population.

The judge explained the effect of prison conditions on Mr Lee’s testimony, “Given that prisoners who were awaiting trial spent approximately 23 hours out of every 24 in their cells, there must clearly have been little to distinguish one day from another. Indeed, the plaintiff himself said that one day was much like the next. The plaintiff spent approximately four and a half years in prison awaiting trial and attended court on approximately 70 occasions during that time. In these circumstances it does not appear to me to be surprising that the plaintiff became confused at times.”

The judgment describes a justice system that is under-resourced, cruel and careless.

It is difficult for current or former state employees to testify against the state. The South African state, both during and post-apartheid has a record of ostracising health workers who stand up for patient rights. During the Tshabalala-Msimang era, some doctors were dismissed for providing antiretroviral treatment. So it is worth mentioning that the judge depended on testimony by doctors Paul Theron and Craven, who had been employed as part-time district surgeons at the prison, as well as a male nurse, Frans Muller, formerly employed at the prison. The judge described their testimony of the problems at the facility and their attempts to bring these problems to the attention of authorities as reliable. All three described their frustrated attempts to get the authorities to improve prison conditions.

On the other hand, experts who provide dubious testimony to defend indefensible state policies act without concern for the consequences of their actions. Therefore it is also worth noting the judge’s views of one such witness. Prof. Paul van Helden, who is described on the website of Stellenbosch University’s Division of Molecular Biology and Human Genetics, as the 4th highest ranked scientist in the world in the field of tuberculosis, gave astonishing testimony for the state. He argued that the plaintiff’s acquisition of TB was primarily a consequence of genetics and re-activation, not the prison environment. Dr Theron rebutted his testimony. The judge pointed out a salient problem with it:

“Prof Van Helden also appeared to fall into the trap of losing his objectivity. So, for example, he used statistical evidence which was obtained in lower socio-economic areas such as Ravensmead and Masiphumelele to justify his opinion that the plaintiff, who came from a middle class environment, had probably been infected with TB prior to coming into the prison, in circumstances where he himself had admitted that those statistics would not be applicable in middle and higher socio-economic areas. Indeed, Prof Van Helden went so far as to say that the plaintiff’s chances of having been infected with TB prior to entering prison were ‘exceptionally high’.”

The judge concluded, “There is no doubt that Prof Van Helden is an expert is his field, but he is not a medical doctor and has had no experience in the diagnosis and treatment of TB. His experience relates to research. On the whole, Prof Van Helden’s evidence was tainted with bias and misinformation. As a consequence, his evidence is, in my view, in many instances unreliable and inaccurate.”

The judge drew several conclusions, “On the totality of the evidence, I am accordingly satisfied that it is more probable than not that the plaintiff contracted TB as a result of his incarceration in the maximum security prison at Pollsmoor.”

She also found “that a reasonable person in the position of the defendant would have foreseen that the prevailing conditions in the maximum security prison at Pollsmoor would reasonably possibly spread TB amongst inmates and cause inmates, such as the plaintiff, who had not previously been ill with TB, to succumb to the disease.”

She further wrote, “… the crisp answer to the question as to whether the defendant took reasonable steps to guard against the spread of TB, or to curb its spread in the maximum security prison, is no. There is no evidence that the defendant … took any steps whatsoever to guard against the spread of TB in the maximum security prison”.

And she found that “a reasonable person in the defendant’s position would, in my view, have taken steps to guard against the spread of TB in the maximum security prison, because it is such a formidable disease which is easily spread. More particularly, a reasonable person would have ensured that sufficient numbers of nursing staff were employed to perform the various tasks involved in the control and prevention of TB in the said prison.”

The judge found the state’s actions unlawful. She found the Minister liable to the plaintiff for having become ill with TB and ordered the state to pay costs. The damages amount was scheduled for a separate hearing.

Technical aspects of the model

Johnstone-Robertson and colleagues used data presented in the court case to construct their model. The court record provided several inputs into the model including TB incidence rate (5.5/100 person prison years, derived from 177 cases in a prison population of 3,200), period of infectiousness (1 to 180 days), ventilation (one air change per hour in a cell of 195m3) and floor area per prisoner (1.42m2). Other input parameters were infectious particles produced (1 per hour, a conservative estimate) and respiratory volume (360 litres per hour). The model was also run using other ventilation values: 3 air changes per hour (minimum international recommended ventilation), 8 (intermediate ventilation); and 12 (optimal ventilation), as well as different cell dimensions and floor areas per prisoner (3.34m2, a Red Cross recommendation and 5.4m2, WHO recommendation). The floor space per prisoner parameter corresponds to cell occupancy levels of about 250% (situation in Pollsmoor), 100% (South African recommendation) and 50% (international recommendation).

The authors explain that the model’s main equation is the number of TB infections (C) occurring in a prison cell with susceptible prisoners (S). This was assumed to be a function of the number of infectious cases (I), their infectivity (q, quanta of infectious particles produced per hour), time of exposure (t, minutes), respiration rate (p, litres per hour), and germ-free ventilation (Q, litres per hour):

C = S ( 1-exp( -Iptq/Q ) )

This is known as the Wells-Riley equation.

The authors further explain that the prevalence (P) of infectious adults at any time is the annual smear-positive incidence rate (M, per cent) and the period of infectivity (D, days) as

P = M/[365/D].

The risk of contact with an infectious adult was modeled using a Poisson distribution.

The model is restricted to calculating the risk of infection, not the risk of active disease. Calculating the latter is extremely complex.

Interpret the transmission rate with caution. It is the annual risk of transmission, but Johnstone-Robertson and colleagues explain that 79% of prisoners awaiting trial are incarcerated for less than a year. Also the Wells-Riley model averages the effect of several complex variables. The model is useful for showing that awaiting trial prisoners are at high risk of acquiring infection, but the 90% estimate is an approximation without a confidence interval and should not be cited as the definitive calculation of risk.

The annual risk of TB transmission in the Western Cape in poor communities is also extremely high. One of the authors has pointed out to me that reaching adulthood in the province carries a similar risk of TB acquisition as being incarcerated as an awaiting trial prisoner in Pollsmoor for a year.

Recommendations

The horrendous conditions are not confined to just one prison. We only have detailed information on the situation in Pollsmoor because of this court case.

Johnstone-Robertson and his colleagues explain that there are many strategies to deal with the high transmission rate. They suggest that ventilator grills should not be closed at night. Communal cells can be cross-ventilated by using barred rather than solid doors and using corridor ventilator extraction systems. Carbon dioxide monitoring should be implemented. There should be active case finding and new fast TB diagnosis methods, such as the Gene Xpert presumably, should be introduced. They also say that TB notification data for South African prisons should not be considered secret or restricted information and that accurate data should be made available to the Judicial Inspectorate of Prisons to include in the annual report on the state of our prisons.

The problem, acknowledged by the authors, is that sensible recommendations for improving the situation have been made repeatedly by the Judicial Inspectorate. These can be found in the annual reports. [4] Dr Theron, Dr Craven and Mr Muller testified about the efforts they made to get the authorities to act. In 2000 the Department of Health set up a special task team to deal with TB. But its recommendations were either followed only temporarily, too little or not at all.

A further problem apparent from the case and several cases that the Treatment Action Campaign has been involved in is the sheer inefficiency of the court system, which creates a bottleneck that results in large numbers of awaiting trial prisoners. This is evidenced by the large number of trial hearings Lee attended and that, despite being acquitted, he spent the amount of time in prison reserved for serious crimes.

There is clearly a lack of political will to address TB in South African prisons. The steps to address TB have been identified but are not being implemented. Perhaps more cases of infected prisoners or former prisoners suing the state, such as this one, and protests are the only way to address this ongoing public health crisis.

References:

1. Johnstone-Robertson S, Lawn S, Welte A, Bekker LG, Wood R. Tuberculosis in a South African prison – a transmission modelling analysis. South African Medical Journal, Vol 101, No 11 (2011). http://www.samj.org.za/index.php/samj/article/view/5043
2. Constitution of the Republic of South Africa, No. 108 of 1996.
   http://www.info.gov.za/documents/constitution/1996/a108-96.pdf
3. Lee v Minister of Correctional Services (10416/04) [2011] ZAWCHC 13; 2011 (6) SA 564 (WCC); 2011 (2) SACR 603 (WCC) (1 February 2011.
   http://www.saflii.org/za/cases/ZAWCHC/2011/13.html
4. Judicial Inspectorate for Correctional Services annual reports.
   http://judicialinsp.pwv.gov.za/Annualreports/annualreport.asp

Thank you to Alex Welte for advice.

The benefits of initiating antiretroviral treatment (ART) in TB co-infected patients with CD4 counts below 350 cells/mm3 have been demonstrated in a number of recent studies. [1-2]

Now an open-label randomised controlled trial by Nanteza and colleagues has been published that looks at patients with higher CD4 counts. The trial, run in Uganda, compared 6 months of ART concurrent with TB treatment versus only TB treatment in patients with CD4 counts > 350 cells/mm3. The trial was small, but it provides some evidence that there is clinical benefit to placing patients with high CD4 counts on ART. [3]

From October 2004 through September 2008, 4,951 people were screened. Of these 250 patients co-infected with TB and HIV and with CD4 counts >350 cells/mm3 were enrolled. Of these 232 were randomised and 214 remained on the trial and eligible for analysis. The final control and intervention arms each had 107 patients. Patients in the intervention arm were given ART (abacavir, lamivudine and AZT) for six months. Participants were followed up for 24 months. The trial was designed and approved before several studies demonstrated that structured treatment interruptions are not a viable treatment option. The authors explained that the rationale of the study was that a punctuated course of antiretroviral therapy in patients with high CD4 cell counts would suppress viral replication during therapy for tuberculosis, block the effects of immune activation on T cells harboring HIV, slow the pace of HIV disease progression, and improve clinical outcomes.

The baseline characteristics of the patients were mostly well matched. There were slightly more men in the control arm (63% versus 52%). Nearly all patients had at least one TB symptom, especially cough. Median age was 31 years. Nearly 90% of patients were both smear and culture-positive. Interestingly 8% of patients were smear-positive and culture-negative, while only 3% were smear-negative and culture-positive. The intervention and control arms had similar median CD4 counts (between 500 and 550 cells/mm3) and median viral load (4.6 and 4.7 log10 copies/mL).

The primary endpoint was a composite of CD4 cell count <250 cells/mm3, clinical AIDS, or death. In the intervention arm, 17 people reached this endpoint versus 25 in the control arm (p=0.17). Most people reached the endpoint on the basis of CD4 count, 15 in the intervention arm and 18 in the control arm. They initiated lifelong ART. Although not statistically significant, there were consistently fewer endpoint events in the intervention arm throughout the trial. At 12 months of follow-up the difference between the arms reached significance (98% and 90%, respectively; p=0.02), but became non-significant by the end of the follow-up period.

There were two deaths in the ART arm and no clinical endpoints. There were three clinical endpoints and four deaths in the control arm. Despite the tiny numbers, this was significant (p=0.048).

In the intervention arm, 86% of participants achieved a viral load <400 copies/mL at three and six months. Viral load rebounded upon discontinuation of treatment to near baseline. The average viral load of the control group did not change significantly over the 24-month period.

There were 45 versus 28 adverse events in the control and intervention groups respectively. When considered individually, the risk of a grade 3 or 4 adverse event was 76% greater in the control arm than in the intervention arm (rate ratio, 1.76; 95% CI: 1.24–2.53). About half the adverse events took place during the six months treatment (ART or TB) stage of the study. Neutropenia was high and not significantly different in both arms (17 versus 25% in the intervention and control arms respectively). The authors therefore concluded that neutropenia is common in patients with tuberculosis, even when CD4 counts are >350 cells/mm3 and that treatment with concurrent antiretroviral therapy only partially mitigates the effect of HIV infection on bone marrow suppression. As would be expected in a trial of people with relatively high CD4 counts, no Immune Reconstitution Syndrome was detected.

No patients were culture-positive after six months of TB therapy. The average time to culture conversion was 37.5 days in the intervention group versus 29 in the control, but this was not significant (p=0.37).

The authors state that the trial provides limited further support for early initiation of treatment.

comment

Although small and despite the outdated and short treatment intervention, this study does provide limited support for initiating all HIV-positive patients with TB on ART, even at high CD4 counts.

The World Health Organisation (WHO) recommends that treatment be provided to all patients with TB irrespective of CD4 count. The South African government has recently announced that it will treat all patients with CD4 counts <350 cells/mm3. This study offers some evidence, albeit not compelling, that South Africa should go further and implement the WHO recommendation. It seems likely that South Africa’s new HIV and TB National Strategic Plan for 2012-2016 will provide for this.

Also interesting was that in this Ugandan setting 25% of the TB and HIV co-infected patients who screened for the trial had CD4 counts above 350 cells/mm3.

In Khayelitsha, Cape Town, nearly one in five HIV-positive patients presents with a CD4 count >500 cells/mm3 (communication with MSF). These statistics show that the question of determining the optimal starting point affects many people and is an important one.

We look forward to the results of the TEMPRANO and START trials that have been designed to answer this question.

References:

1. Abdool Karim SS et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010; 362:697–706.
   http://www.nejm.org/doi/full/10.1056/NEJMoa0905848
2. Blanc FX et al. Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. Vienna: International AIDS Society, 2010:284–5.
   http://pag.aids2010.org/Abstracts.aspx?AID=17091
3. Nanteza MW et al. 2011. A randomized trial of punctuated antiretroviral therapy in Ugandan HIV-seropositive adults with pulmonary tuberculosis and CD4+ T-cell counts >= 350 cells/uL. JID 2011:204 (15 September)
   http://jid.oxfordjournals.org/content/204/6/884.abstract

The World Health Organisation (WHO) has updated its guidelines for drug-resistant TB. [1]

The guidelines were last published in 2008. [2]

The guidelines make eleven recommendations. All of them were supported by very low quality evidence.

1. Rapid drug susceptibility testing of isoniazid and rifampicin or rifampicin alone is recommended if there are resources to do it and if rifampicin resistance is not rare in the patient group. Currently the line probe assay and the GeneXpert are the only diagnostic tools to meet the WHO criteria for rapid diagnosis (two days or less).

2. Sputum smear microscopy and sputum smear culture, rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR TB during treatment.

This is a change from the 2008 guidelines that recommended monthly sputum smear microscopy and culture examination prior to culture conversion to negative and quarterly culture, with monthly smear examination after conversion.

Data pooled from 10 observational studies indicated that monthly sputum smear microscopy and culture performed best at identifying treatment failures early. This is conditional recommendation because of the resources required to implement it.

3. MDR TB patients should be treated with a flouroquinoline. This is a strong recommendation.

4. MDR TB patients should be treated with a late-generation flouroquinolone (levofloxacin, moxifloxacin, gatifloxacin and sparfloxacin) rather than an earlier-generation one. This is a conditional recommendation.

5. MDR TB patients should be treated with ethionamide or prothionamide. This is a strong recommendation.

6. In the treatment of MDR TB patients, four second-line drugs likely to be effective (including an injectable, kanamycin, amikacin or capreomycin) as well as pyrazinamide should be included in the intensive treatment phase. This is a conditional recommendation.

7. MDR TB patients should be treated with at least pyrazinamide, a fluoroquinolone, an injectable, ethionamide (or prothionamide) and cycloserine (or PAS if cycloserine cannot be used). This is a conditional recommendation.

Recommendations 3 to 7 were based on the results of three systematic reviews of observational data. Bias was likely substantial because some drugs may have been used for sicker patients. Nevertheless, this is the best available evidence.

Analysis showed that in the intensive phase a regimen with at least four drugs was likely to be effective. The analysis did not show any injectable to be superior to any other, so kanamycin is recommended because of its lower cost.

Fluoroquinolones were significantly associated with cure and this association was greater with later-generation ones. The recommendations gave higher weight to interventions that increased the risk of cure and reduced the risk of failure, relapse and death. Consequently fluoroquinolines were strongly recommended despite potential long-term serious adverse events. The recommendation for later-generation fluoroquinolines was conditional because of the unknown long-term side effects of these drugs. Ciprofloxacin may have some anti-TB activity but it should not be used.

For oral bacteriostatic drugs the association with cure was higher for ethionamide than cycloserine which was higher than PAS. PAS is only recommended if there is no other effective drug available to make up the four-drug regimen. No significant association between cure and any of the following was found: amoxicillin/clavulanate, azithromycin, clarithromycin, clofazimine, roxithromycin and thiocetazone.

There were too little data on linezolid and high-dose isoniazid. Pyrazinamide showed slight benefit in one analysis.

Patients with XDR TB were excluded from this analysis so these recommendations do not necessarily apply to them. Nevertheless, the WHO recommends that the same principles used to design MDR TB regimens should be used for XDR TB regimens.

The regimen composition recommendations differ only in small nuances from the 2008 guidelines. Ethambutol has been removed as an alternative to pyrazinamide in the new guidelines, albeit that the new guidelines acknowledge that the decrease in efficacy associated with ethambutol in their analysis could be due to confounding.

8. The intensive phase of treatment for MDR TB patients should be at least eight months. This is a conditional recommendation.
9. A total treatment duration of at least 20 months is recommended.

The evidence base for recommendations 9 and 10 is the same as recommendations 3 to 7 and subject to confounding and bias. There was an association between treatment success and the length of treatment and the length of the intensive phase.

The 2008 guidelines recommended at least six months intensive phase treatment and at least 18 months of total treatment.

10. ART is recommended for all HIV-positive patients with MDR TB irrespective of CD4 count, starting within eight weeks after TB treatment. This was a strong recommendation.

Ten studies, none of them randomised controlled trials, informed this recommendation. The quality of evidence varied from low to very low quality. The recommendation is based in part on evidence from studies for any patients with TB and HIV (ie majority non DR patients).

11. Patients with MDR TB should be treated using mainly ambulatory care rather than models of care based on hospitalisation. This is a conditional recommendation. The data for this recommendation came from published and unpublished studies in Estonia, Peru, Philippines and Russia, but none of these were randomised controlled trials. Nor did these studies allow direct comparisons of effects between models of care. The key considerations informing this recommendation was that the cost per disability adjusted life-year was generally lower in outpatient models and that these models appear to reduce exposure to infectious drug-resistant patients. However, the guidelines warn that ambulatory care can shift the burden of cost from the service provider to the patient (eg increased travel and food costs). Therefore implementation of ambulatory care models must be accompanied by provision of what the document calls “appropriate enablers”.

The guidelines state that important gaps in knowledge should be addressed in future research, particularly in the context of large-scale expansion of treatment for patients with drug-resistant TB. The document further calls for randomised controlled trials to determine the best combination of drugs and optimal treatment duration. Further research on (1) paediatric MDR TB treatment, (2) best regimens for patients with isoniazid resistance, (3) prophylaxis for contacts of MDR TB and (4) therapy for relief from adverse reactions due to second-line drugs is needed.

comment

A common theme throughout these guidelines is the lack of evidence to support the recommendations.

The development of new TB drugs like TMC207 and OPC-67683 needs to be completed. The phase IIB trial results of TMC207 suggest that it is already better tested than many second-line TB drugs and therefore should be available to patients.

MSF has pioneered outpatient MDR TB care in South Africa. It would strengthen recommendation 11 if they published more data on this.

References:

1. WHO. Guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.
   http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf
2. WHO. Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update 2008, WHO, Geneva, 2008.
   http://www.who.int/entity/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/index.html

The 2011 edition of the World Health Organisation’s Guidelines for Intensified Tuberculosis Case-finding and Isoniazid Preventive Therapy for People Living with HIV in Resource-Constrained Settings has 12 recommendations. [1]

The fourth recommendation says that adults and adolescents living with HIV who have an unknown or positive tuberculin-skin-test (TST) status and who are unlikely to have active TB should receive at least 36 months of Isoniazid Preventative Therapy (IPT). Furthermore, IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women. The WHO says this is a strong recommendation with moderate quality of evidence to support it. The third recommendation is identical except that six months instead of 36 months of IPT is recommended and this is ranked as a strong recommendation with high quality of evidence.

The Guidelines for Tuberculosis Preventative Therapy Among HIV Infected Individuals in South Africa, published in 2010, are consistent with recommendation three. They further state, “Clinical trials have shown that the benefit of TB preventive therapy is greatest in HIV-infected persons with a positive tuberculin skin test. Where tuberculin tests are feasible and can be performed, IPT should only be offered to those who are TST positive. However, the practicalities and logistics of doing a tuberculin skin test are often an obstacle for provision of TB preventive therapy. Therefore the tuberculin skin test is no longer required to identify HIV infected people eligible for IPT.” [2]

This article deals solely with adults who are not pregnant, who are not health-workers with HIV and not in special high-risk settings such as mines or prisons. The removal of the necessity of the Mantoux test to determine TST status from IPT guidelines is concerning, as the data summarised here demonstrates.

Cochrane Review of IPT trials

A Cochrane Review of short-course chemotherapy trials (6 to 12 months) to prevent TB was published in 2010. [3]

Twelve trials met the strict criteria for inclusion in this meta-analysis. In all, 4811 participants were TST positive, 2030 were TST negative. Of these, 1,640 were known to be unable to mount an immune response to the Mantoux test (ie they were anergic). The TST status in 1737 participants was unknown. No differences were found in trials that compared effectiveness of different combinations of drugs, but all regimens significantly reduced the risk of TB as shown in Table 1.

Using INH alone reduced the incidence of confirmed, probable or possible TB by 32% (RR: 0.67 95%CI: 0.51-0.87, n=4136).

However, when analysed by TST status, the effect was only significant for TST positive participants as table 2 shows.

IPT showed no mortality benefit (RR: 0.95; 95%CI 0.85-1.06). When analysed by TST status, the benefit only just reached significance in TST positive participants (RR: 0.74; 95%CI 0.55-1.00) and there was no benefit to TST negative (RR: 1.02; 95%CI: 0.90-1.16) or TST status unknown participants (RR: 0.81; 95%CI: 0.52-1.27).

Botusa Trial

The Botusa trial has previously been reported in HTB South. [4]

Since then it has been published in the New England Journal of Medicine. The results of the trial, contrary to the way it has been reported, are not a resounding success for long-term IPT; on the contrary the trial raises difficult questions. [5]

In this double-blind randomised controlled trial in Botswana, 989 HIV-positive participants were randomised to receive six months of isoniazid and 1,006 were randomised to receive 36 months of isoniazid. All participants received open-label isoniazid for the first six months, after participants either took placebo or isoniazid for 30 months. Only 2% of participants were on ART at the start of the trial. At the end of the open-label phase, 821 participants continued in the placebo group and 834 in the isoniazid arm.

TB incidence between the two groups diverged at 200 days after the open-label phase, indicating not unexpectedly that the benefits of short-course IPT were transient.

The protocol defined definite, probable and possible TB as follows:

• Definite: one or more culture was positive M tuberculosis or if two or more sputum smears were positive for acid-fast bacilli
• Probable: one sputum smear or one biopsy specimen was positive for acid-fast bacilli
• Possible: if smears and cultures were negative or not done. A death defined as possibly related to tuberculosis was one that had clinical or verbal autopsy evidence consistent with tuberculosis as the proximate cause of death.

In an analysis of participants that actually remained on the study after the open-label phase ended, the only statistically significant result in favour of long-term IPT was the reduced incidence of definite, probable and possible TB, and here the confidence interval was wide (25 on placebo versus 12 on isoniazid; HR: 0.47; 95%CI: 0.24-0.94). No significant difference between the arms could be found when only definite and probable cases were counted (18 versus 10; HR: 0.55; 95%CI: 0.25-1.18). Nor was there significant difference if TB (definite, probable and possible) and deaths were combined (41 versus 37; HR 0.89: 95%CI: 0.57-1.39). However there were more deaths in the long-course arm, although this was not significant (16 versus 25; HR 1.54; 95%CI: 0.82-2.88).

When analysed by TST status, TST positive participants benefited from 36 months IPT. There were 11 cases versus only 1 case of definite, probable and possible TB (HR: 0.08; 95%CI 0.01-0.61). There were 10 cases versus only 1 case of definite and probable TB (HR:0.09; 95%CI 0.01-0.67). TB (definite, probable and possible) and all deaths were also significantly better (20 versus 4; HR: 0.17; 95%CI: 0.06-0.50). When just deaths were looked at, the 36 month arm did better though this was not significant (9 versus 3; HR: 0.28; 95%CI: 0.08-1.03).

However, the results for TST negative participants were surprising and worrying. There were no significant differences or even trends with respect to TB. But there were 21 deaths on the 36 month arm versus 7 on the short-course arm and this was significant (HR: 2.99; 95%CI: 1.27-7.04).

The reasons for this are unclear. Only one death, due to hepatic encephalopathy, appeared to be due to a known isoniazid side-effect. The adverse event rates between the arms were almost identical (1% versus 1.3%). Nevertheless, this was a double-blinded RCT and the significantly higher deaths in TST negative people in the 36 month arm should not be ignored.

comment

The findings of the Cochrane Review and the Botusa trial show that TST status is relevant. There is no evidence that TST negative people benefit from any form of IPT prophylaxis.

In the case of long-term prophylaxis, which is now recommended by WHO guidelines and likely where other guidelines are heading, TST negative people could be put at risk of harm unnecessarily.

Guideline writers appear to be focusing on reduced TB incidence demonstrated by IPT studies. But mortality is surely a more important measure from the perspective of patients than TB incidence.

Overall, the short-course IPT studies show no significant mortality benefit when TST status is not taken into account. And in the one major long-course IPT trial there is unequivocally no mortality benefit if TST status is not taken into account. The Mantoux test should therefore not be removed from guidelines.

There is a concern that implementing the Mantoux test is too burdensome for many health facilities. If that is the case, then we need to ask if such facilities should be implementing IPT, especially long-course IPT.

References:

1. WHO. 2011. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings.
2. South African Department of Health. 2010. Guidelines for tuberculosis preventative therapy among HIV infected individuals in South Africa.
3. Akolo C et al. 2010. Treatment of latent tuberculosis infection in HIV infected persons.
   http://www2.cochrane.org/reviews/en/ab000171.html
4. Geffen N. Botswana IPT trial: Continuous isoniazid superior to 6 months short course. HTB South, April 2010.
5. Samandari T et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011 May 7; 377(9777):1588-98.
   http://www.ncbi.nlm.nih.gov/pubmed/21492926

Polly Clayden, HIV i-Base

Physiological changes in pregnancy can affect drug disposition. Plasma concentrations of several PIs – including lopinavir, atazanavir and saquinavir – currently prescribed to HIV-positive pregnant women, are decreased during this period. Pharmacokinetcs (PK) for darunavir (DRV) and fosamprenavir (FPV) in pregnancy are not well characterised. Two posters presented at the paediatric workshop and IAS 2011 showed data from PK studies of these antiretrovirals in pregnant women. [1, 2]

Darunavir

Edmund Capparelli and colleagues from the IMPAACT P1026s study group presented PK and safety data of DRV dosed twice-daily (BID) and once-daily (QD) during the third trimester of pregnancy, at delivery and post partum. These data were shown at the paediatric workshop in Rome.

IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral PK in pregnancy. It comprises of two groups of women receiving ritonavir-boosted DRV either as 600/100mg BID, or 800/100 mg, QD, as part of an ART regimen during pregnancy and 6-12 weeks postpartum (PP).

All women had received at least two weeks of ART at the time of the evaluation. Intensive steady-state 12 or 24-hour PK profiles were performed during the 3rd trimester and PP. Cord blood and maternal samples were taken at delivery when possible. DRV concentrations were measured by HPLC (limit of detection 0.09 mcg/mL). The minimum exposure targets were DRV AUC0-12 or 24 of 43.6 or 56.5 mcg*hr/mL, for BID or QD, respectively. This represents >70% median for non-pregnant adults.
PK data were available for 31 women (19 BID, 12 QD). Two PP PK evaluations (1 BID and 1 QD) were excluded for non-adherence with no detectable DRV concentrations. Geometric mean 3rd trimester/PP ratios were 0.74 (90% CI 0.54-0.92) and 0.76 (90% CI 0.64-0.91) for AUC and 1.42 (90% CI 1.09-1.84) and 1.31 (90% CI1.10-1.55) for CL/Fs with BID and QD dosing respectively.

For the PK parameters presented below for 3rd trimester and PP the investigators indicated values with p<0.05 compared to PP with an asterisk (*). They found, AUC0-12 were median 50.7 (range 23.8-102)* mcg*hr/mL for 3rd trimester and 70.0 (range 40.3-175.5) mcg*hr/mL PP for women who received DRV/r 600/100mg BID. Of those with PK parameters available, 13/19 (68%) and 11/13 (85%) met the AUC-12 target. CL/F was 11.82 (range 7.58-26.4)* L/h and 8.57 (range 3.42-14.89) L/hr. C12h was 3.13 (range 0.78-8.85) mcg/mL and 2.81 (range 1.61-5.50) mcg/mL.

AUC0-24 were 67.7 (range 30.3-105.5) mcg*hr/mL and 87.9 (77.5- 150.2) mcg*hr/mL, for the women who received DRV/r 800/100mg QD. Of these 8/12 and 7/7 met the AUC0-24 target. CL/F was 11.82 (7.58-26.4) L/h and 9.10 (5.33-10.32) L/hr. C24h was 1.37 (0.15-3.49) mcg/mL and 2.59 (<0.09-3.96) mcg/mL.
A total of 20 paired samples of maternal delivery and cord blood were collected. Of these, 6 pairs had concentrations below the limit of detection. For the remainder (n=14) median cord blood DRV concentrations were 0.19 (<0.09-1.1) mcg/mL. Maternal delivery plasma DRV concentrations were 1.42 (<0.09-5.62) mcg/mL. The median ratio of cord blood/maternal delivery plasma concentrations was 0.24 (0.062-0.58) indicating limited transplacental transport of DRV.

The investigators concluded that lower troughs and AUC with QD compared to BID dosing combined with pregnancy lowering DRV exposure suggests BID dosing should be used in pregnancy and higher doses may be required.

Of note, not all women achieved viral suppression in both dosing groups (at delivery overall, 57% and 79% <50 and <400 copies/mL respectively), and there was at least one vertical transmission among 24 (77%) infants with data available at the time of this analysis.

Fosamprenavir

There are limited data describing safety and outcomes of FPV in pregnancy or plasma concentrations of FPV’s active metabolite, amprenavir (APV), during pregnancy, PP and in cord blood.

Michelle Cespides and colleagues from New York University School of Medicine showed findings from a phase I, open-label, single-centre study to evaluate APV PK following dosing of ritonavir boosted FPV 700/100mg BID in pregnant women. The investigators evaluated steady-state PK in the second and/or third trimesters and 4-12 weeks PP. Maternal plasma and cord blood samples were taken at the time of delivery. APV concentrations were measured by LC-MS/MS, and PK were determined using WinNonlin. This study was presented at IAS 2011.

The study evaluated 10 women receiving DRV/r based regimens. Cord blood samples were available from six deliveries. The median ratio of cord blood/maternal APV concentrations was 0.27, again, indicating limited transplacental transfer of this PI. Individual APV AUC was 22-34% lower, Cmax 9-41% lower and C12 27-28% lower in pregnancy than PP. See Table 1: Amprenanvir concentrations during pregnancy.

The investigators noted that although APV C12 was 27-28% lower in pregnancy, HIV was well suppressed for all subjects at delivery. Maternal and cord blood concentrations were above mean protein binding-adjusted IC50 (0.146 ug/mL) for wild-type virus.

Safety and outcomes data showed that FPV was well tolerated in this small study with no hepatic, renal, or adverse events attributed to ART.

At delivery, all women had viral loads < 400 copies/mL and nine women had <50 copies/mL. All infants were HIV PCR negative.

comment

The recommendation from the first study that higher doses of DRV may be required is consistant with US recomendations with other PIs such as lopinavir and atazanavir.

BHIVA guidelines do not recommended a dose increase.

References

1. Capparelli E et al. Pharmacokinetics of Darunavir Once or Twice Daily During and After Pregnancy. 3rd International Workshop on HIV Pediatrics. 15-16 July, 2011. Rome, Italy. Poster abstract P_72.
2. Cespedes M et al. Pharmacokinetics, cord blood concentrations, and tolerability of boosted fosamprenavir (FPV) in pregnancy. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TUPE278.

Interactions between rifampicin and protease inhibitors makes treating patients coinfected with HIV and TB more complicated.

Rifabutin is an alternative rifamycin, which can be used in patients receiving a protease inhibitor. Recent findings suggest that the current recommended dose of lopinavir/r (LPV/r) is suboptimal. There are limited data regarding the newer formulation of LPV/r.

Investigators from University of Cape Town, International Union Against Tuberculosis and Lung Disease and WHO evaluated the pharmacokinetics (PK) of rifabutin in co -infected patients on a first line TB regimen before and after the initiation of LPV/r-based ART.

Suhashni Naiker and colleagues showed findings from this study in a poster at CROI 2011.

A group of 16 patients on stable rifabutin-containing TB regimens were initiated on LPV/r-containing HAART. At HAART initiation they were randomised to receive either: rifabutin 150 mg daily for 1 month followed by 150 mg 3 times weekly, or 3 times weekly doses followed by daily doses.

The investigators measured serial rifabutin and 25-O-desacetyl rifabutin concentrations during a dose interval after 4 weeks of rifabutin 300 mg daily, after 4 weeks of 150 mg rifabutin daily with LPV/r-based HAART, and after 4 weeks of rifabutin 150 mg 3 times a week with LPV/r-based ART.

At baseline the participants were a mean (SD) of 31.6 (5.5) years, 59.0 (9.4) kg, 160.1 (7.1) cm and 147 (43) CD4 cells/mm3. Ten were men. Two were not included in the analysis due to poor adherence.

The investigators reported median AUC0-24 and Cmax, for participants receiving 300 mg rifabutin daily, 150 mg rifabutin three times a week, and 150 mg rifabutin daily, respectively, of 3026 ng/mL.h and 297ng/mL, 2307 ng/mL.h and 168 ng/mL, and 5010 ng/mL.h and 311ng/mL.

They found that rifabutin was well tolerated at all dosing strategies. There was one case of uveitis that occurred before  LPV/r was initiated, and one grade 2 transaminitis and one grade 2 neutropenia were also reported.

They concluded that rifabutin 150 mg daily used with LPV/r produces Cmax concentrations within the recommended target range of 300 to 900 ng/mL.

Reference

Naiker S et al. Pharmacokinetic evaluation of different rifabutin dosing strategies in African TB patients on lopinavir/ritonavir-based ART. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 650.

The complex question of the optimal time to start antiretroviral therapy (ART) in HIV-positive patients co-infected with TB was the subject of two important presentations at a plenary session of the 18th Conference on Retroviruses and Opportunistic Infections. Diane Havlir presented the findings of ACTG’s Stride trial and Salim Abdool Karim presented the results of the SAPIT trial. [1, 2]

Stride

Havlir and colleagues conducted an open label international trial to confirm their hypothesis that in patients starting TB treatment, ART initiated within 2 weeks (immediate initiation) could reduce mortality and morbidity compared to patients starting ART within 8-12 weeks (early initiation).

Patients were randomised to immediate (405 patients) and early (401 patients) ART treatment arms. Patients had confirmed or presumed TB and a CD4 cell count <250 cells/mm3. The ART regimen for 97% of patients was efavirenz and tenofovir/emtracitabine. The TB treatment was country approved. Nearly half of the patients had confirmed TB with a median CD4 count of 77 cells/mm3 (IQR: 36-145).

The primary endpoints of the study were all cause–mortality and new AIDS-defining illnesses by 48 weeks. No data is available for after 48 weeks as patients were not followed beyond this endpoint. Secondary endpoints were safety, CD4, HIV RNA changes, TB IRIS and TB outcomes.

The proportion of AIDS or death between the immediate (12.9%) and the early (16.1%) arms were not statistically significant (p=0.45). However, a pre-specified analysis that considered patients with a CD4 cell count <50 cells/mm3 found that the proportion of patients with AIDS or death was 26.6% in the early arm compared to 15.5% in the immediate arm and this was significant (p=0.02). The majority of AIDS or death events occurred within the first 24 weeks after randomisation, with the highest proportion amongst the early arm with a CD4 count <50 cells/mm3. There was barely any difference in endpoints in the higher CD4 strata (11.5% versus 10.3% for the immediate versus early arms respectively; p=0.67).

Thirteen cases of cryptococcal disease made it the most common AIDS primary endpoint (n=63) The next two most common AIDS illness included oesophageal candidiasis (n=12) and Kaposi’s Sarcoma (n=11).

There were 31 deaths in the immediate arm versus 37 deaths in the early arm. TB was the largest contributor to deaths (21 out of 68 patients). During question time, Havlir was asked if the 14 TB-related deaths on the immediate arm versus seven in the early arm were indicative of fatal TB IRIS. She pointed out that these cases were reviewed and that they were a consequence of TB progressing in contrast to patients with IRIS who get better and then become ill again.

Twenty-one cases of AIDS-related deaths were reported and 16 non-AIDS related deaths (respiratory, renal and hepatic disease being most common). The frequency of TB IRIS in the immediate arm was 11% and 5% in the early arm (p=0.002).

In summary the investigators found that immediate ART did not overall reduce AIDS-defining disease overall and death compared to early ART, but for patients with CD4 counts < 50 cells/mm3 immediate ART reduced AIDS and mortality. Grade 3 or 4 toxicities, HIV RNA suppression rates or CD4 increase did not differ between the arms. TB IRIS was higher in the Immediate arm although it did not increase mortality. They concluded that in patients with CD4 counts <50 cells/mm3 ART should be started within two weeks.

SAPIT

Salim Abdool Karim and colleagues conducted a 3-armed open label trial called SAPiT. The sequential arm, in which patients first completed their TB treatment course and then initiated ART was stopped by the DSMB due to the significantly higher mortality in that arm. We have previously reported on this aspect of the trial. [3] This report is confined to the results of the remaining two arms.

HIV-positive patients with smear-positive TB and CD4 counts <500 cells/mm3 were randomised into an early integrated therapy arm (214 enrolled and ART initiated within four weeks of starting TB treatment) and a late integrated therapy one (215 enrolled and ART initiated within four weeks of completing the intensive phase of TB treatment). Baseline characteristics for age, gender and CD4 count were similar in both arms.

All participants attended the TB-DOTS programme at eThekwini Clinic in Durban and the study’s primary endpoints were death and AIDS defining illness.

Both arms had similar rates of AIDS defining illness or death with 18 deaths in the early arm and 19 in the late arm. The Incidence Rate Ratio (IRR) was 0.89 (95% CI: 0.44 to 1.79; p=0.73).

When the results were stratified for CD4 count of <50 cells/mm3, a 68% reduction of AIDS or death was found in the early and this approached significance (IRR: 0.32 [0.07-1.13], p=0.06). For participants with CD4 counts >50 cells/mm3 no discernable differences in AIDS/Death were noted (IRR: 1.51 [0.61-3.95], p=0.34).

In patients with CD4 counts <50 cells/mm3, the reduction in AIDS/death in the early arm overshadowed the 5-fold higher risk of IRIS (95% CI; IRR 4.7 [1.5-19.6]; p=0.01) and the increasing trend in drug switches.

HIV suppression was greater than 90% after 18 months irrespective of CD4 status. Similarly TB treatment was successfully completed in about 80% of patients with no significant differences across groups.

On the other hand in patients with CD4 counts > 50 cells/mm3 there was an IRIS rate of 15.8 person years and 7.2 in the late arm; CI: 95%; IRR: 2.2 [1.1-4.5]; p=0.02) and this was significant. Rates of drug switches were 7/100 patient years in the early arm and 1 in the late arm (CI: 95%; IRR: 6.8 [0.8-551.1]; p=0.04). The lower rates of IRIS and drug switches in the late therapy arm indicated a slight benefit to starting ART during the continuation phase of TB treatment in patients with CD4 counts >50 cells/mm3.

comment

The main results of both studies were similar. Immediate ART is warranted in patients with CD4 counts <50 cells/mm3 while ART for patients with CD4 counts >=50 cells/mm3 can be postponed until the continuous phase of TB treatment, but not beyond.

These studies have implications for some guidelines in high incidence countries. For example, he South African Guidelines for Antiretroviral Therapy in Adults state with respect to patients co-infected with TB state:

“[For patients with] CD4 count <200 cells/mm3: commence ART after it is clear that the patient’s TB symptoms are improving and that TB therapy is tolerated. The suggested time period to commence ART is between 2 and 8 weeks after starting TB therapy.

CD4 count 200 – 350 cells/mm3: delay ART until after the intensive phase of TB therapy (2 months) unless the patient has other serious HIV-related illness. The longer delay before commencing ART in this group is recommended to reduce the risk of shared toxicity (as the patient will then only be on fewer TB drugs) and to reduce the risk of the immune reconstitution inflammatory syndrome (see below).

CD4 count >350 cells/mm3: defer ART.”

When the guidelines are updated, the drafters will have to consider:

• Whether the recommendations be modified to explicitly state that patients with CD4 counts <50 cells/mm3 must be started immediately on ART, or does the current framing sufficiently cover that?
• Whether the recommendations be modified to initiate ART to patients with CD4 counts of 50-350 cells/mm3 only after the intensive phase?

The answers to these questions are not clear.

While the SAPIT trial included patients with CD4 counts <500 cells/mm3, there is not yet enough data on patients with CD4 counts of 350 to 500 cells/mm3 to justify a change in guidelines. Hopefully the START and TEMPRANO trials, scheduled to complete in 2015 and 2013 respectively, will help answer this question. [5, 6]

References:

1. Havlir D et al. 2011. International randomized trial of immediate vs early ART in HIV+ patients treated for TB: ACTG 5221 STRIDE study. 18th Conference on Retroviruses and Opportunistic Infections, 27 Feb to 2 March, Boston.
   http://www.retroconference.org/2011/data/files/webcast_2011.htm
2. Abdool Karim S et al. 2011. Optimal timing of ART during TB therapy: findings of the SAPiT trial. 18th Conference on Retroviruses and Opportunistic Infections, 27 Feb to 2 March, Boston.
   http://www.retroconference.org/2011/data/files/webcast_2011.htm
3. Geffen N. 2009. HIV and TB from CROI. HTB South. April 2009.
   http://i-base.info/htb-south/589/
4. Southern African HIV Clinicians Society and Department of Health. 2008. Guidelines for antiretroviral treatment in adults.
   http://sahivsoc.org/index.php?option=com_docman&task=doc_download&gid=40&Itemid=67
5. INSIGHT. Strategic Timing of Antiretroviral Treatment (START).
   http://www.clinicaltrials.gov/ct2/show/NCT00867048
6. ANRS. Early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in HIV-infected adults (ANRS 12136 TEMPRANO).
   http://www.clinicaltrials.gov/ct2/show/NCT00495651

The theme this year was “TB, HIV and Lung Health: From Research and Innovation to Solutions” pointing to the need for new drugs and vaccines, but also for the resources and policies required to put these new tools to use to help some of the poorest citizens, where demand and need is the greatest.

Approximately 2500 delegates attended from over 100 countries.

An impressive programme of webcasts from the meeting ensure that most of the oral sessions can now be viewed online, including slide presentations.

http://uwclh.conference2web.com/content/all#/?groups=3

The programme and abstract book from this meeting can also be downloaded from the conference website.

http://www.worldlunghealth.org/confBerlin/index.php?lang=en

Articles from this conference in this issue of HTB include:

• Faster conversion rates with TMC-207 versus placebo plus OBT for the treatment of MDR-TB
• Xpert MTB-RIF validation study from Tanzania
• Gene Xpert demonstrates good sensitivity and specificity but at high cost

TMC207 is the first in a new class (diarylquinoline) of anti-tuberculosis (TB) drugs to inhibit mycobacterial ATP synthase. It has the potential to improve treatment of both drug-sensitive (DS) and multidrug- resistant (MDR) TB.

In an oral presentation, David McNeely first provided some background information on this drug. [1] TMC-207 previously increased culture conversion by approximately 40% in MDR TB patients in an 8-week trial (see below). These findings were published in the NEJM and we reported them in the August 2009 issue of HTB. [2, 3]

He also showed several key pharmarmacokinetic findings from the phase 1 trials. These were: a positive food effect with TMC-207 giving a two-fold increase in drug exposure when taken with a meal; coadministation of rifampicin lowers TMC207 levels by 50% and coadministartion of lopinavir/ritonavir (LPV/r) modestly increases TMC-207 exposure by 22%. Unpublished information on nevirapine shows a similar interaction. These data suggest the potential to administer the drug with antiretrovirals. Dr McNeely noted that this did not occur in the early trials in patients, as this information was not available. The drug also has a long terminal half-life and does not reach steady state by day 14.

He reported that, to October 2010, 595 participants had received TMC-207 in all trials: 217 healthy volunteers; 147 DS and MDR-TB patients (79 for 24 weeks). There is also an open label trial (Breathe) in which 231 MDR TB patients have been enrolled that is ongoing.

In the second part of this presentation, Andreas Diacon showed findings from TMC-207 C208 stage 2. This randomised, double-blind, placebo-controlled trial is in two stages. It is conducted in patients with newly diagnosed smear positive pulmonary MDR-TB. Following a one-week washout period, patients were randomised to receive optimised background therapy (OBT) plus TMC-207 or placebo.

TMC-207 was dosed at 400mg once daily for 14 days and then 200mg TIW (three times a week).

In Stage 1, conducted in South Africa, 47 patients received 8 weeks of TMC207 (n=23) or placebo (n=23). They then continued their MDR-TB treatment with background regimen alone. All stage 1 patients have completed the trial. Stage 1 found a significant increase in the proportion of culture negative subjects among those who received TMC207 compared to placebo (48% vs. 9% at week 8). There was a 58% reduction in mean time to culture conversion in those who received TMC-207 compared to placebo.

In Stage-2, 161 patients were randomised to receive 24 weeks of either TMC207 or placebo added to the same 5-drug background regimen. All stage 2 patients have completed 24 weeks of TMC207/placebo plus OBT. They are now completing 18–24 months treatment with 2nd line TB drugs (without TMC207/placebo).

Stage 2 was a multi country trial conducted in Brazil, India, Latvia, Peru, Phillipines, Russia, South Africa and Thailand.

The objective was to demonstrate superiority of TMC-207 compared to placebo at 24 weeks. The primary endpoint was time to sputum culture conversion (MGIT). Participants who discontinued during 24 weeks were considered failures irrespective of their culture status at time of discontinuation.

The secondary endpoint was culture conversion rates at 24 weeks.

At baseline about 65% of patients were men, with a median age of 33 years, 85% were HIV-negative and they weighed about 53kg. Patients had confirmed resistance to isoniazid and rifampicin and had not received second line TB treatment previously. HIV-positive patients had a CD4 count greater than 300 cells/mm3 and were not receiving antiretroviral treatment. No patient had significant extrapulmonary TB or other illness.

Of the total randomised patients (80 TMC-207, 81 placebo), 160 were included in the ITT analysis (one patient randomised to the TMC-207 arm, did not receive study drug). The researchers also conducted a modified ITT analysis of 132 patients. Exclusions included, non-MDR patients (4 TMC-207 and 8 placebo), XDR patients (3 TMC-207 and 4 placebo) and patients, for whom, culture results were not evaluable.

OBT was a 5-drug standardised background regimen: ethionamide, pyrazinamide, ofloxacin, kanamycin and terizodone/cycloserine.

Dr Diacon noted that there were high rates of baseline resistance to kanamycin at baseline among patients from European sites. He also noted worryingly high rates of resistance to pyrazinamide across all sites. In vitro evidence suggests there may be good synergy between TMC-207 and pyrazinamide.

Adverse events were similar across both groups. None were serious and discontinuations were unrelated to the study drug.

He reported that the addition of TMC-207 to a 5-drug OBT regimen resulted in faster culture conversion within 24 weeks, p=0.003. It also gave a shorter median time to 50% culture conversion of 12 vs 18 weeks. And there was a higher sputum conversion rate at 24 weeks of 79 vs 58%, p=0.008.

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These results are very promising and phase 3 trials will begin this year. Discussions between Tibotec and regulatory authorities in the US and Europe are ongoing and data should be submitted to the FDA and EMA for accelerated or conditional approval this year.

Demand for early access to this drug is already considerable. Activist organisations published an open letter to Tibotec calling for expanded access. This letter was handed over at the beginning of the World Lung conference at which the presentations discussed here were made. The company has committed, both in a teleconference on 7 January and in the OpenForum meeting in Addis Ababa in August 2010, to accelerate access. In countries that have a regulatory framework for pre-registration access, such as South Africa, this will be the preferred method. Although expanded or accelerated access has been the norm for HIV drugs, TMC 207 could set precedence for these strategies with TB drugs. Tibotec needs to maintain a balance between making it available fast to those in greatest need and ensuring it is used judiciously.

Tibotec intends to carry out a trial that will collect safety data in countries that do not provide for pre-registration access and this will allow drug-resistant patients with limited options to access TMC207. Quite reasonably, Tibotec is concerned that it only partners with health-delivery institutions that are capable of ensuring high adherence. There are also plans to include TMC207 in studies with the investigational drug in development from Otsuka Pharmaceuticals, OPC-67683. This is a nitroimidazole and is in phase 2b. It is especially important that OPC-67683 or other drugs under investigation for DR-TB, such as PA-824, become available soon after TMC207, so as to reduce the risk of continuously adding TMC207 to potentially failing second-line regimens and consequently risking a high rate of TMC207 resistance.

References:

1. McNeeley D et al. TMC-207 versus placebo plus OBT for the treatment of MDR-TB: a prospective clinical trial. The International Journal of Tuberculosis and Lung Health. S3 41st Union World Conference on Lung Health. 11-15 November 2010.
   http://uwclh.conference2web.com/content/187
2. Diacon AH et al. The diarylquinoline TMC207 for multidrug-resistant Tuberculosis. NEJM. 2009 June 4. 360, 2397-2405. (4 June 09).
   http://content.nejm.org/cgi/content/abstract/360/23/2397
3. Geffen N. TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB. HIV Treatment Bulletin. August 2009.
   http://i-base.info/htb/4403

The Xpert MTB-RIF assay (Xpert, described in detail in the article below) gained a lot of attention at this meeting.

This is a cartridge-based, real-time PCR test with automated sample processing, amplification, detection of M. tuberculosis and resistance to rifampicin (RIF).

Andrea Rachlow presented data from an evaluation study of this test performed in Tanzania.

This study enrolled 292 consecutive symptomatic patients. These patients were classified as TB positive or negative following results of sputum smear, culture on solid and liquid media on three different sputum samples (plus chest X-ray and HIV test), and sustained recovery after two months follow-up.

Stored samples were then tested with the Xpert (three frozen, untreated sputum samples per patient).

The investigators reported, that of 69 culture-positive TB cases, Xpert detected 88.4% (95% CI 78– 95%). Sensitivity was notably different between smear-positive and only culture-positive patients, with sensitivities of 98% and 61% respectively.

Among all TB negative patients, Xpert detected one positive result (99% specificity). One of the samples from 45 patients that were culture-positive for non-tuberculous mycobacteria (NTM) also tested positive with Xpert.

Additionally, the test performed well in HIV-positive patients (n=50) with 88% sensitivity and 89% specificity.

The investigators noted that the test is easy to use and the short time to a result could mean avoidance of loss to follow up during the diagnostic process, which could result in a 5-15% decrease in TB deaths worldwide.

They added that further studies are required to confirm the tests performance on fresh sputum samples and on other clinical material.

Reference:

Rachlow A et al. Detection of TB using the Cepheid Xpert MTB/RIF® Assay: a clinical validation study from Tanzania. The International Journal of Tuberculosis and Lung Health. FA-101098-13
http://uwclh.conference2web.com/content/667

Further information:

http://www.treatmentactiongroup.org/press.aspx?id=4320

http://www.tac.org.za/community/node/2962

We published a report on the Gene Xpert in the April 2010 edition of HTB South. [2] Catherine Boehme of FIND and her colleagues have since published the test results of Cepheid’s Gene Xpert TB diagnostic technology in the NEJM. [1] This device aims to diagnose TB and determines rifampicin resistance in less than two hours. Preliminary results have been good. This study confirms that this device has high sensitivity and specificity in a variety of settings in both HIV-positive and HIV-negative patients and in culture-positive sputum-negative patients.

Over 1,800 patients were screened at five sites located in Lima, Baku, Cape Town, Mumbai and Durban. 1,730 patients were able to provide three sputum samples with sufficient volume and were consequently eligible for the study. Of these, 268 were excluded from final analysis, 115 because they were culture-negative and suspected of MDR TB while receiving treatment, 28 because three or more of their cultures were contaminated, 23 because they had growth of non-MTB only, 10 because they had indeterminate phenotypic rifampicin results, 39 because they were smear-positive but culture-negative, seven because they had suspected culture cross-contamination and 46 because they died or were lost to follow-up.

Of the 1,462 included in the main analysis 741 were culture-positive, of whom 567 were smear-positive and 174 were smear-negative. Of the 721 culture-negative cases, 105 had clinical TB and 616 did not have TB (as determined by a clinical review committee).

As explained in our previous article the Gene Xpert consists of a computer installed with Cepheid’s proprietary software and a machine –the smallest of which is about the size of a desktop computer– that takes cartridges loaded with sputum and reagents. The cartridges consist of a syringe barrel, a sonicator dome, a reverse-transcriptase PCR tube and a rotary valve. The smallest version of the machine takes four cartridges. The highest capacity one apparently contains 100 cartridges. As explained below, two or even three cartridges might be needed for a patient.

The screening results and consequent inclusion and exclusion criteria of patients in various analyses is complicated in this study. Table 1 presents an overview that readers can refer to when reading the remainder of this summary.

Table 1: Screening results. Adapted from Boehme et al.

TB sensitivity and specificity

With one sputum sample, the Gene Xpert had a sensitivity of 92% for all culture-positive specimens. This increased to 96% for two samples and 98% for three. Specificity on non-TB cases was 99% with one sputum sample, declining marginally to 98% with three samples. However, for culture-positive, sputum-negative specimens, sensitivity using one sputum sample was 73% rising to 90% with three samples. No site had a sensitivity lower than 83% for culture-positive, sputum-negative specimens.

Further details including confidence intervals are provided in Table 2.

Table 2: Sensitivity and specificity of Gene Xpert on culture-positive patients and culture-negative patients not treated for TB. Adapted slightly from Boehme et al.

Sensitivity was 94% in HIV-positive patients with pulmonary TB versus 98% in HIV-negative patients (p=0.02). Of the 105 patients with culture-negative samples excluded from the main analysis but who had clinical signs of TB, 29.3% had positive results on the Gene Xpert.

Rifampicin sensitivity and specificity

Of the 723 culture-positive patients correctly identified as having TB by the Gene Xpert, 720 were tested phenotypically for rifampicin resistance (for the remaining three, the Gene Xpert gave indeterminate resistance results). The Gene Xpert identified 200 out of 205 rifampicin resistant specimens correctly for a sensitivity of 98%. It identified 505 out of 515 rifampicin sensitive specimens correctly for a specificity of 98%.

Details of resistance testing with confidence intervals are presented in table 3.

Table 3: Sensitivity and specificity of Gene Xpert on phenotypically determined rifampicin susceptibility. Adapted from Boehme et al.

The authors also did a second analysis that included the results of gene sequencing of the 15 discrepant results between phenotyping and the Gene Xpert. After three of these were excluded from analysis because sequencing gave indeterminate results, sensitivity was 99.1% [95%CI: 96.6-99.7] (209/211 correct) and specificity was 100% [95%CI: 99.2–100.0] (506 correct).

Importantly, 195 out of 200 of the rifampicin resistant specimens were also resistant to isoniazid. This suggests that rifampicin resistance is a good predictor of MDR TB in practice.

In 115 patients, excluded from the main analysis in the study, who were culture-negative but who were diagnosed with MDR TB and consequently received treatment, 51 had positive results on the Gene Xpert. Rifampicin resistance was detected in eight. Interestingly, the authors note that all eight patients were later started on second-line therapy by physicians unaware of the results of the Gene Xpert results.

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These results are promising. The Gene Xpert is much easier to use than sputum microscopy. It has a high sensitivity and specificity and appears to be better than culture in a subset of patients who are culture-negative but nevertheless have TB. It has high sensitivity and specificity for detecting rifampicin resistance. The diagnostic can be used in facilities that offer consistent electricity supply. One drawback, as with most TB diagnostics, is that patients need to provide sputum and preferably as many as three samples.

But the main obstacle to wider use of the Gene Xpert will be its price. The cheapest machine reportedly costs $20,000. Each cartridge costs approximately $20. There is a great need for better TB diagnostics primarily in poor communities. Pressure needs to be exerted on Cepheid to bring down the price of this system, which was in any case developed with substantial public investment. Conversely pressure needs to be placed on international TB bodies to fund the implementation of diagnostics such as this one in resource-poor settings.

References:

1. Geffen N. 2010. Cepheid Gene Xpert diagnostic technology for TB. HTB South April 2010.
   http://i-base.info/htb-south/960/
2. Boehme C et al. 2010. Rapid Molecular Detection of Tuberculosis and Rifampin Resistance. NEJM September 2010.
   http://www.nejm.org/doi/full/10.1056/NEJMoa0907847

Lopinavir/ritonavir (LPV/RTV) is first line treatment for young children in South Africa. Concomitant treatment for TB is common in children with HIV. There is a complicated interaction between this boosted protease inhibitor and the first line TB drug, rifampicin (RIF), which reduces the bioavailabilty and Cmin of LPV by approximately 75% and 99% respectively.

Two strategies are possible to increase the LPV levels when it is dosed with RIF – either increasing the dose of RTV to a LPV:RTV 4:4 ratio or doubling the dose to a LPV:RTV ratio 8:2.

Chao Zhang and colleagues from the University of Cape Town showed a population pharmacokinetic (PK) model developed to describe the interactions between LPV, RTV and RIF in children. They used this to look at the effect of various factors (age, BSA, weight, gender, haemaglobin, albumin, ALT) on LPV and RTV PK, and make dosing recommendations for HIV/TB coinfected children receiving these drugs concurrently. [1]

In this study, 39 children with HIV only received the standard dose of LPV/RTV, 4:1, (control group); 15 coinfected children received the super-boosted dose, 4:4; and 20 the double dose, 8:2. Then 11 coinfected children received the standard dose following RIF-based treatment. Repeated sampling was performed (4-6 from each child) up to 12 hours post dose.

The children were a median age of 21 months (range 6 months to 4.5 years) and a medium weight of 10.2kg (range 5-17kg).

Using a one-compartment model with first order absorption for LPV and a one-compartment model with transit absorption for RTV, the investigators modelled the effect of RTV concentration on LPV clearance as direct inhibition with an Emax model.

The investigators found that, during concomitant treatment with RIF, the relative oral bioavailability of LPV was reduced by 79% in children receiving the twice the standard dose of LPV/RTV. RTV clearance was 18 L/h with RIF and 13L/h without.

The estimated baseline clearance of LPV, when there was no detectable RTV was 4.34 L/h. As the concentrations of RTV increased, the clearance of LPV decreased in a sigmoid relationship (EC 50, 0.051 mg/L). They found volume of distribution for LPV and RTV were 11.7 and 102 L respectively.

When the investigators performed simulations for dose optimisation during RIF-based TB treatment with a target of LPV concentrations with Cmin >1mg/L in 95% of children, they predicted doses of LPV/RTV as described in Table 1. They noted that smaller children required higher mg/kg doses of LPV/RTV, in both 4:1 and 1:1 ratios, than larger children.

Table 1: Simulation for dose optimistion of LPV/RTV during RIF-based TB treatment

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The same group previously presented data to show that the double dose LPV/r is not sufficient for children when coadministration with rifamipicin. [2]

The current median LPV dose using double dose strategy in this study is 23 mg/kg,

The investigators suggestion for dose adjustment in this study is much higher than double dose. Or they suggest switching to an 8 hourly dose strategy considering the adverse effect slinked to higher doses. [3]

References:

1. Zhang C et al. Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Oral abstract O24. Published in Journal of the International AIDS Society 2010 13(Suppl 4). O223.
   http://www.jiasociety.org/content/13/S4/O24
2. McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.
   http://www.retroconference.org/2009/Abstracts/34615.htm
3. Personal communication with the author.

Blanc and colleagues presented the results of CAMELIA, a randomised open-label controlled trial in Cambodia. The trial’s purpose was to determine when to initiate ART in patients with TB with low CD4 counts. They randomised patients to either receive treatment at two weeks after commencing TB treatment (ie during the intensive phase) or eight weeks (ie during the continuation phase). [1] The SAPIT trial, also discussed in this issue, is still examining this question but the SAPIT cohort has a much higher mean CD4 count.

CAMELIA was designed as a superiority trial to answer the question of the best timing for the introduction of ART in patients with TB with CD4 counts ≤ 200 cells/mm3. All patients were ART-naive at trial entry. The primary endpoint was survival at the end of the trial.

661 patients with suspected TB were randomised, 332 to the early arm and 329 to the late arm. A high proportion of patients turned out to be culture positive for tuberculosis in both arms (282 in the early arm and 294 in the late one).

The patients were all very sick with no difference between the two arms. The median CD4 count was 25 cells/mm3, median viral load was 5.60 log copies, and the median BMI was 16.7. Of the 645 patients, 587 had (at least) pulmonary TB and 13 cases (2%) of MDR TB were identified.

There was a 34% reduction in mortality in the early arm: 59 deaths versus 90. The mortality rate in the early arm was 8.28 per 100 person years (IQR: 6.42 – 10.69) and 13.77 per 100 person years (IQR: 11.20 – 16.93) in the late arm (p=0.002).

IRIS occurred more frequently (p<0.0001) in the early arm, 4.03 per 100 person-months, (IQR 3.34-4.86) compared to the late arm, 1.44 per 100 person-months (IQR 1.09 – 1.91). It occurred about 2 to 3 weeks after starting ART in both arms, but was easily managed.

More than 95% of patients had an undetectable viral load at week 50. The median CD4 cell count at week 50 had increased by 114 cells/mm3 and this had increased to 200/mm3 by the end of the trial.

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This trial provides convincing evidence that patients with TB with low CD4 cell counts should be placed on treatment immediately upon diagnosis. One of the main concerns with early initiation of ART in such patients is the concern about IRIS. Since the patients in this trial are on average more immuno-compromised than those in SAPIT and would therefore be expected to have higher rates of IRIS, it is not clear if they can be any valid reason left for delaying ART in any group of patients with TB with CD4 counts <350 cells/mm3. The DSMB for the SAPIT study should meet to consider the implications of this data on SAPIT.

Reference:

F.X. Blanc et al. Cambodian Early vs. Late Introduction of Antiretrovirals. XVIII International AIDS Conference, Vienna, July 18-23. Late Breaker Session B-1.
http://pag.aids2010.org/PAGMaterial/aids2010/ppt/113126_10013/final.pptx

A late breaker at the International AIDS Conference by Shapiro and colleagues presented the results of a project to trace the contacts of patients with TB in Northwest Province, South Africa. Based on an aerial photograph in the presentation, data was collected from five sites separated by a total approximate distance of 50km. [1]

The authors studied whether intensified case-finding (ICF) in household contacts of known TB patients is a feasible strategy for a high-TB, high-HIV prevalence settings. They also compared the strategy of testing for TB in the households of contacts versus randomly selected households. By way of background, a meta-analysis by Morrison and colleagues in 2008 of household contact tracing in low and middle-income countries found that 4.5% [95%CI: 2.1-2.5] of household contacts of known TB patients also had active TB. Just over 51% had latent TB [95%CI: 50.6-52.2]. But there was substantial heterogeneity across the studies.

In this study by Shapiro, 800 people were screened. Of these, 723 patients with active TB were enrolled over seven months. These are referred to as the index cases. Of these, 607 (84%) were HIV-positive and the HIV statuses of another 28 (4%) were unknown. The basis for TB diagnosis was as follows: 163 had tested smear-positive, 16 were smear-negative but culture-positive and the remainder were diagnosed using clinical criteria and chest x-rays. Three (0.4%) had MDR TB. Each index had an average of four household contacts. A total of 2 812 household contacts were screened for TB.

The mean age of the index cases was 38 (IQR: 18-91) compared to the mean age of 23 (IQR: 0-92) in the household contacts (p<0.01). Of the index cases, 78% were unemployed versus 61% of the household contacts (p<0.01). There were no significant differences between the two groups in sex (about 43% female). A quarter of participants lived in shacks.

A total of 2 146 (76%) household contacts gave sputum for analysis and 164 (8%) were diagnosed with TB. Of these, 95 were confirmed and 69 were probable cases. Of the 666 (24%) who did not give sputum, 60 were already on TB medication. The TB statuses of the other 606 were unknown.

Amongst the household contacts, 205 (7%) were already known to have HIV and of these, 99 were already on ART. Another 1 610 (57%) agreed to voluntary counselling and testing and 164 (10%) tested HIV-positive. Of these, 32 (19%) of these had a CD4 below 250 cells/mm3 and were referred for ART.

154 (94%) of the 164 household contacts with TB were smear-negative and culture-positive. Only 18 (11%) of these had TB symptoms. Five (3%) had MDR TB, 22 (13%) were HIV-positive and four (18% of HIV-positive cases) had CD4 counts <250 cells/mm3 (p<0.01 for all of these compared to the index cases).

A random sample of 350 households was compared to the contact households. Table 1 below shows that they were significantly less likely to have TB. At least one case of TB was found in 138(19%) contact households versus 4(1%) in the randomly selected households.

The authors conclude that undetected TB and HIV are highly prevalent in the households of known TB patients. The undetected TB in contacts is more likely to be in HIV-negative and asymptomatic individuals than in patients who present to care for TB diagnosis and treatment.

The authors suggest that intensified case-finding in household contacts of TB patients resulted in accelerated detection of both TB and HIV in undiagnosed contacts. They explain that their study demonstrated that household contact-tracing is feasible and acceptable in a high TB/HIV burden setting and should be considered as an approach to addressing the co-epidemics.

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This is an excellent study that shows the feasibility and usefulness of contact tracing. The contacts on average appear to have been in an earlier stage of active TB. Consequently, an additional advantage of tracing contacts is that they would be treated earlier thereby potentially preventing significant TB transmissions.

The authors are planning to present a cost-effectiveness analysis. It would be surprising if contact-tracing were not cost-effective compared to random household selection. What will be particularly interesting to see is the cost per TB case diagnosed. Interestingly, 81% of contact households did not have TB. It would be very useful if criteria could be found that identify contact households with a higher probability of having someone with TB. If such criteria could be found, an algorithm for contact-tracing could potentially be found that reduces the cost of contact-tracing and requires fewer human resources to speedily identify people with TB.

The meta-analysis by Morrison and colleagues indicates that there is significant heterogeneity amongst contacts. Therefore it would be useful if this study was replicated in several other communities in Southern Africa, possibly as part of a pilot contact-tracing programme.

While contact-tracing will cost money and require an additional intervention to be placed on health systems, the extensive benefits that are likely to accrue from it probably make it worthwhile. Southern African governments should give serious consideration to massive contact-tracing operations.

References:

1. Shapiro AE et al. Targeting at-risk households: intensified case-finding for TB and HIV in contacts of TB patients in South Africa. XVIII International AIDS Conference, Vienna, 18–23 July 2010. Late breaker poster FRLBC106.
   http://pag.aids2010.org/Abstracts.aspx?SID=643&AID=17517
2. Morrison J et al. Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Infect Dis. 2009 Jan; 9(1):3-4.
   http://www.ncbi.nlm.nih.gov/pubmed/18450516

Taraz Samandari of the CDC presented the results of a randomised double-blind placebo-controlled  Isoniazid Preventative Therapy (IPT) trial at CROI. This trial took place in Botswana and randomised HIV-positive patients to either six months of IPT, the standard of care, or continuous therapy, ie the 36 month duration of the trial. [1]

Botswana began implementing a country-wide IPT programme in 2001. The protocol provided for six months of IPT and no Tuberculin skin testing. The rationale for this trial was that evidence has been emerging that the effects of 6-month IPT decrease with time.

For the first six months, the entire cohort –after screening– of 1,995 patients was initiated on open-label 300mg once-daily isoniazid. After six months patients were randomised to either receive placebo or continue receiving isoniazid. There were 989 in the six-month arm (6H) and 1,006 in the continuous one (36H). Patients also received 25mg vitamin B6 daily.

Patients were excluded from the trial if they had current weight loss or an AIDS-defining illness, a history of IPT, TB in the last three years, an abnormal chest x-ray, signs of TB based on a physical examination or the following laboratory criteria: Hgb<6.6gm/dl, neutrophil count <1,000 cells/mm3, platelets <75,000/mm3, AST(SGOT) >2.5 times the upper limit of normal, ALT (SGPT) >2.5 times upper limit of normal, total bilurubin >1.5 times the upper limit of normal, creatinine >1.5mg/dl and negative beta-HCG.

There were no significant differences between the 6H and 36H arms at baseline.  Females comprised 72% of the cohort. Median age was 32. Median CD4 count was approximately 300 cells/mm3. Just under 4% had a history of TB. In 6H, 23% of participants were TST-positive (>=5mm) and in 36H, this was 26%. By six months about 45% of the cohort had initiated ART.

Only 11 people were lost to follow-up. There were 176 withdrawals and 36 deaths. Adherence was good: at 36 months, 78% of participants had attended more than 80% of their visits (where pills were provided).  In a random sample of 200 people on 36H, 74% had detectable INH in urine at 25-30 months.

In intention-to-treat analysis, there were 34 incident TB cases in the 6H arm and 20 in the 36H arm (HR:  0.57, p=0.047). In a modified intention-to-treat of 1,655 people who were enrolled after six months there were 25 TB cases in the 6H arm and 12 on the IPT arm (HR: 0.47, p=0.033).  In a per protocol analysis of people who had attended least 5 out of 6 clinic visits (ie >=80% adherent), there were 19 and 8 TB cases in 6H and 36H respectively (HR=0.043, p=0.045).

In an analysis of TST-positive patients, the results were even more compelling. There were 13 incident TB cases in 6H and 4 in 36H (HR:0.26, p=0.019).  In the modified intention-to-treat it was 11 cases in 6H and 1 case in 36H (HR: 0.08, p=0.015) and in the per-protocol analysis 8 and zero cases respectively (HR: 0.0, p=0.007).  However, in TST-negative patients the reduction was slight and not significant (incidence rate of 0.98 versus 0.78 per 100 patient years; HR: 0.86; p=0.69).

The effect of 6 months IPT remained the same as the 36H arm for nearly six months after the completion of the open-label part of the study, but then TB cases escalated in the 6H arm.

ART initiation was evenly distributed between the two arms. Increasing ART use decreased TB incidence for all participants. By one year, the risk was reduced by half.

Compared to 6H patients not on ART:

• 6H TST-negative patients on ART had a TB hazard ratio of 0.5 (95%CI: 0.26-0.97).
• This was identical for 6H TST-positive patients.
• 36H TST-negative patients not on ART had a TB hazard ratio of 0.92  (95%CI: 0.4-2.1).
• 36H TST-positive patients not on ART had a TB hazard ratio of 0.08 (95%CI: 0.01-0.06).
• 36H TST-negative patients on ART had a TB hazard ratio of 0.46 (95%CI: 0.16-1.3).
• 36H TST-positive patients on ART had a TB hazard ratio of 0.04 (95%CI: 0.01-0.36).

After month 6, there were seven possibly drug-related adverse events in the 6H arm and 12 in the 36H arm. The difference was not significant. There was one death possibly due to isoniazid in the 36H arm (hepatic encephalopathy), though the patient also had severe herpes. There were 20 cases of severe hepatitis in the first six months (across both arms) and 15 subsequently (6 on 6H and 9 on 36H).

DST was available for 24 samples in the 6H arm and 14 in the 36H arm. There were three cases of INH mono-resistance in 6H and 1 in 36H. One patient on each arm had MDR TB.

Mortality was 1.4% per annum.  Interestingly it was non-significantly higher in the 36H arm (HR: 1.55; p=0.17). However, for TST-positives, the HR was 0.28 (p=0.06) and for TST-negatives, the HR was 2.99 and this was significant (p=0.01).

Samandari concluded that:

• The benefit of 6 months of IPT was lost in less than 6 months after treatment completion.
• Continuous IPT reduced TB incidence by 43% compared to 6 months of IPT.
• TST-positive patients were at high risk of TB after six months of IPT, even on ART.
• Continuous IPT was 92% effective in reducing TB in TST-positive patients.
• ART’s effect was smaller than continuous IPT in reducing TB, but additive.
• However, only ART reduced TB in TST-negative people.
• Provision of IPT did not increase isoniazid resistance.
• TST-negative patients may be unduly exposed to harm by IPT.

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This is one of the largest and best-conducted IPT studies to date. The finding that the benefit of IPT can only be maintained with continuous therapy is important. This study makes a strong case for scaled up IPT rollout. The new South African treatment guidelines provide 6 months IPT in all patients who are not indicated for ART.

However, the significantly higher mortality in TST-negative patients in the intervention arm is cause for concern. It suggests that Tuberculin skin testing must be done before initiating patients on IPT.

Ref: Samandari T et al. Randomized, placebo-controlled trial of 6 vs 36 months isoniazid TB preventive therapy for HIV-infected adults in Botswana. Oral abstract 104LB. 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco.

http://retroconference.org/2010/Abstracts/39555.htm

http://retroconference.org/2010/Sessions/027.htm

Several presentations at this conference indicated that there is progress in TB drug development and diagnostics. For example, at least three drugs for the treatment of TB and drug-resistant TB are in advanced clinical trials, including moxifloxacin, TMC207 and OPC-67683. We include reports on:

• Cepheid Gene Xpert diagnostic technology for TB
• Adherence of TB patients on self-administered treatment
• High mortality and poor record-keeping for in-patients in Kwazulu-Natal Hospital
• Factors affecting survival of XDR TB patients

Many delegates from African countries struggled to get visas for the conference, because the only Mexican consulate in Southern Africa is in Pretoria. Cancun is primarily known as a holiday resort and it was not an appropriate venue for this conference. Hopefully in future years it will be held in venues easily reached by people most affected by TB.

Current State of TB Testing

Current diagnostics for active TB are limited by cost, complexity, long diagnostic time, poor sensitivity or poor specificity. A point of care, affordable, easy-to-use, highly sensitive and specific test for active TB, analogous to HIV rapid tests, is urgently needed. Sputum microscopy is the standard technique used to diagnose TB in many developing country health facilities but has poor sensitivity especially in immune-compromised patients. It also requires a skilled health worker or technician.

The closest to a current gold standard for an active TB diagnosis is to perform both a liquid and solid culture test. These, however, have median turnaround times measurable in weeks.

Nucleic acid amplification techniques such as the FAST Plaque TB assay and PCR give results much faster but still take days and are much less sensitive and specific. They are also expensive. All these methods are compromised by the fact that some patients struggle to provide quality sputum samples.

Cepheid Gene Xpert

Mark Perkins of FIND presented data at the International TB conference in Cancun on a new nucleic acid amplification diagnostic technology for TB, the Cepheid Gene Xpert. The key data he presented has subsequently been published in the Journal of Clinical Microbiology by a group of researchers from FIND; New Jersey Medical School; Cepheid; Pham Ngoc Thach Hospital, Ho Chi Minh City and Makerere University, Kampala.  [1, 2]

The Clinical Microbiology paper describes the Cepheid Gene Xpert as an integrated hands-free sputum-processing and real-time PCR system with rapid on-demand, near-patient technology, to simultaneously detect M. tuberculosis and rifampicin resistance. The device consists of a computer installed with Cepheid’s proprietary software and a machine –the smallest of which is about the size of a desktop computer– that takes cartridges loaded with sputum and reagents. The cartridges consist of a syringe barrel, a sonicator dome, a reverse-transcriptase PCR tube and a rotary valve.

The molecular beacon-based PCR assay that the system uses was shown to have high sensitivity and specificity on MDR isolates from the US, Spain, Mexico and India but without the machine is complex and labour-intensive to carry out. Rifampicin resistance is detected by mutations in the 81-base pair rifampicin resistance-determining region of the rpoB gene, which according to research cited by the authors occurs in 95 to 98% of rifampicin-resistant strains and are usually absent in rifampicin-susceptible ones. The authors indicate that rifampicin resistance is a good proxy for isoniazid resistance (and consequently MDR-TB, which is defined as resistance to both drugs).

The cartridges contain liquid sample-processing, PCR buffers and freeze-dried (lyophilized) PCR reagents. To prepare a cartridge, (1) PCR buffer is added to the sputum sample (ratio of 2 to 1), (2) the mixture is shaken for 5 seconds, (3) then allowed to stand for ten to 15 minutes, (4) 2 to 3 ml are transferred to the cartridge and (5) the cartridge is loaded into the machine, at which point the test can begin. It takes approximately two hours to give a result. Up to four cartridges can be loaded into the smallest machine.

Validation tests

The researchers report results of several tests to measure the machine’s accuracy. Only some are described here. They found that the device has a limit of detection (LOD, defined as the number at which there is a 95% probability of a positive result) in clinical samples of 131.0 colony forming units (CFU) per ml of sputum (95% CI: 106.2-176.4).  By way of comparison, the gold standard BACTEC 960 MGIT culture test has a LOD of 10-100 CFU/ml and fluorescent microscopy has  a LOD of 10,000 CFU/ml. [3]

Sputum samples from Vietnamese patients were used to validate the clinical efficacy of the device. The assay detected TB bacteria in all 29 smear-positive samples (95% CI: 85.4-100%) and 38 of 53 smear-negative samples that were culture-positive (71.7%; 95% CI: 57.4-82.8%).

To validate rifampicin resistance detection, 64 Ugandan cases were studied, in which the patients were being retreated for TB and therefore had a higher probability of rifampicin resistance. The device detected resistance in all nine known rifampicin resistance cases, giving a sensitivity of 100% (95% CI: 63.0-100%) and in 1/55 rifampicin-susceptible cases giving a specificity of 98.2%. (95% CI: 89.0-99.9%). The authors sequenced the rpoB gene of this discordant isolate and found a mutation commonly associated with rifampicin resistance. They therefore suggest that the Gene Xpert gave the correct result and the current standard rifampicin resistance test gave the wrong one. They point out that similar errors have been reported in other studies and furthermore that in this case the isolate was known to be resistant to both isoniazid and ethambutol, increasing the likelihood of rifampicin resistance. Furthermore, the device detected M. tuberculosis in 63 of the 64 sputum samples from culture-positive Ugandan patients (98.4%; 95% CI: 90.5 to 99.9%). Twenty laboratory control sputum samples from patients not suspected of having tuberculosis were negative.

The researchers measured the time required to analyse one and eight sputum samples, beginning at the moment that a sputum sample was given to a laboratory technician. The time-to-result for one sputum sample processed alone was just under two hours. The time-to-result for eight samples processed together was two hours. Total hands-on time was about five minutes.

Perkins indicated that sensitivity and specificity are greatly improved if more than one cartridge is used per patient instead of one, but this is not discussed in the Clinical Microbiology article.

Cost

Cepheid has not responded to a question about the cost of the device and its reagents. Based on informal discussions it appears the cheapest complete machine costs between US$25,000 and US$30,000 and handles four cartridges. The cartridges are $22 each. If three cartridges are needed per patient, then the cost per test is $66. This all needs to be confirmed, however. Cepheid’s website indicates that developing country public health systems will qualify for substantial discounts.

comment

A largely hands-off automated test that produces highly sensitive and specific results in less than two hours would greatly improve patient-care. However it remains unclear that the Gene Xpert can be widely used in resource-poor settings, including most of Southern Africa.

Opinion about the device is cautious, with concern about its cost and lack of validation.

The machine is being tested in a National Health Laboratory Systems laboratory at the Site B Community Health Centre in Khayelitsha, Cape Town, with the assistance of Medecins Sans Frontieres. While this is a resource-poor setting, the health centre is relatively well resourced compared to the kinds of health facilities usually found in this kind of neigbourhood. The staff at this facility found the device convenient and easy to use, especially compared to smear microscopy. It is conceivable that at facilities with this kind of infrastructure, the machine will have a useful place.

There are several caveats about the machine:

• Unless the prices of both the machine and the cartridges come down dramatically, this device will     not be rolled out beyond advanced laboratories and academic hospitals. If the machine proves useful in practice, there is potential for an activist-driven campaign to drive prices down, with the argument for price reductions perhaps strengthened by the fact that substantial public money was used to develop the device. The authors of the Clinical Microbiology article indicate that cost and cost-effectiveness studies are planned.
• It is unclear how complex the process of preparing the cartridge is and how much training is  required for health workers to operate it, though the Khayelitsha technician operating the machine found it easy and quick to use. It will be important to validate the specificity and sensitivity of the device in pilot operational settings before it is made generally available.
• The authors point out that freezing may alter sputum viscosity and improve nucleic acid recovery from mycobacteria. They therefore state that the results need to be confirmed in larger prospective studies with fresh samples. (They did however document similar LODs regardless of whether the assay was performed with fresh or frozen sputum samples in analytic studies using spiked sputum.)
• The clinical test sample sizes are quite small with consequent large confidence intervals. Further validation, preferably from an operational setting such as Khayelitsha, is needed.
• It is unclear if Cepheid is or has obtained CE mark (demonstrating that it has met European Union consumer safety, health or environmental requirements) or FDA approval for the device.
• If the device does prove itself in practice a further question that will arise is to what extent rifampicin resistance should be used as a proxy for assuming isoniazid resistance and consequently MDR TB. Should isoniazid-resistance testing still be done if rifampicin resistance is detected? If so, what clinical decisions must be taken while waiting for results?
• Even in the best-case scenario, ie the Gene Xpert proves itself to be a robust highly specific and sensitive TB diagnostic tool in operational settings and its price is made affordable, we remain short of the holy grail point-of-care test for active TB. Nevertheless, it is possible that this device will have a useful place in the current TB diagnostic arsenal.

Thank you to Julian Duncan, Helen Lee, Gregg Gonsalves, Cheryl McDermid, Helen Cox and the Khayelitsha NHLS staff.

References

1. Perkins M. Xpert MTB/RIF: Automated molecular detection of TB and MDR at point of treatment. Presentation at 40th Union World Conference on Lung Health, December 2010.

http://www.finddiagnostics.org/export/sites/default/resource-centre/presentations/iualtd_40th_union_conf_cancun_2009_FIND_Forum/XpertMTB_MarkPerkins.pdf

2. Helb D et al. Rapid Detection of Mycobacterium tuberculosis and rifampin Resistance by Use of On-Demand, Near-Patient Technology. Journal of Clinical Microbiology, Jan. 2010, p. 229–237.

http://jcm.asm.org/cgi/content/full/48/1/229

3. Roscigno G. Drug resistant TB and new diagnostics for people living with HIV: emerging results from FIND. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July, Cape Town.

http://www.stoptb.org/wg/tb_hiv/assets/documents/DRUGRE~1.PDF

In the October 2009 issue of HTB South, we described a pilot study by Atkins and colleagues in which TB patients self-administered treatment. [1] At the World Lung Conference, a poster by MSF examined self-administered treatment at a site in Homa Bay, Kenya. [2] This is in contrast to direct observation of treatment recommended by the World Health Organisation (WHO).

This cross-sectional study consisted of a survey of 279 potentially eligible patients taken from the TB register in November 2008 and June 2009. Of these, 67 (24%) did not participate because five never started treatment, 20 defaulted before the survey, 11 were dead, four were hospitalised, 13 refused to consent to the home visits necessary to carry out the survey and 14 were not found. Patients received education on TB treatment. They had to collect their medicines weekly during the intensive phase and monthly during the continuation phase.

The survey consisted of four measurements: an interviewer-administered questionaire, visual analogue scale in which the patient estimated adherence in the last month, pill counts and an isoniazid urine strip test. For those who participated the median age was 35 years, 46% were female, 79% had pulmonary TB and 69% were HIV-positive. Of those who were HIV-positive, 73% were on ART.

The interviewer-administered questionaire asked questions about pill intake over the past four days. If patients responded that they had taken all their pills, their adherence was described as exact. If they took 75% of their pills, their adherence was described as satisfactory, else their adherence was described as unsatisfactory. 95% were exact, 3% satisfactory and 2% unsatisfactory.

On the Visual Analogue Scale assessment, patients were asked: “How much of your prescribed TB medications have you taken in the last month?” 93% answered 90-100%. 7% answered 80-90% and only one patient answered less than 80%.

Overall, 98% of patients tested positive for isoniazid. Pill counts results were described as exact if 100% of pills were taken, satisfactory if at least 80% of pills were taken and unsatisfactory otherwise. 84% were exact, 10% satisfactory and 6% unsatisfactory. However pill count data was unavailable for 64 patients.

There was no significant difference observed between the intensive and continuation phases for any of the four measures of adherence nor were there significant differences between HIV-positive and HIV-negative people, nor between people on ARVs and people not on ARVs.

Reasons given for non-adherence varied with 17 patients giving 36 reasons, the most common being “ran out of pills” (8 patients), followed by “away from home” (7 patients), followed by, “forgot to take medication” (6 patients).

The Kappa coefficient measures agreement between qualitative assessments. A Kappa < 0.4 is moderate or poor agreement, 0.4 – < 0.75 is fair to good agreement and ≥ 0.75 is excellent agreement. The only combination of assessments that had fair to good agreement was INH positivity and the questionaire (Kappa = 0.43). All other binary comparisons of the assessments had poor to moderate agreement.

The authors pointed out that the INH test was expensive and needed a cold chain and that pill counts had poor reliability and inconsistent data. Therefore they state that in routine settings, the questionaire and visual analogue scale should be the preferred adherence measurement tools. They also state that adherence measurements should not be based on just one tool.

The authors concluded that adherence was high among surveyed patients but acknowledged that the study was limited by several factors including that only patients who consented to home visits were surveyed, the adherence visit was sometimes too close to the last visit and patients who defaulted before the survey were not included.

comment

At the time of the conference, data was not yet available to adequately compare patient outcomes and adherence. Hopefully the researchers will publish this soon.

While this study has some serious limitations–particularly that it does not examine patients who were not adherent before the survey started–observational data is accumulating that self-administered treatment for TB can compete with the directly observed treatment model promoted by the WHO. A randomised open-label trial to compare these methods is warranted. Such a trial should compare health outcomes and adherence, but also perceptions of patient dignity, travel costs incurred by patients and cost to the health system.

References

1. Geffen N. 2009. Overview of TB-related studies at IAS.

http://i-base.info/htb/5919

2. Huerga H et al. 2009. Adherence to self-administrated tuberculosis treatment in Homa Bay, Kenya. 40th World Lung Conference, Cancun, December 2009.

A poster by Cudahy and colleagues examined mortality and record-keeping of TB in-patients in Edendale Hospital in Kwazulu-Natal.  [1]

The researchers conducted a cross-sectional audit of patient charts in medical wards for a 4 week period in early 2009. These records were compared with the hospital TB register. Patients who were prescribed TB treatment and lived longer than 24 hours from admission were included for analysis. They identified 79 such patients. All were on first-line TB medication, but some were retreatment cases (ie they also received streptomycin). There were 40 pulmonary and 39 extra-pulmonary TB cases.  HIV status was known for 68 (86%) of patients, of whom 58 were HIV-positive and 43 had CD4 counts < 200 cells/mm3, but only 13 patients were on ART. The mean CD4 count for HIV-positive patients was 95.

Of the 79 TB patients, 24 died as inpatients. None were recorded as deaths in the hospital register submitted to the district TB control programme. Five were recorded as transferred to a local clinic for follow-up in the hospital register. The remaining 19 were unrecorded.  16 had TB as the recorded cause of death on their death certificates.

Two of the 79 left hospital against medical advice, but they were unrecorded in the TB register.

Five of the 79 were transferred to a TB hospital. Four of them were unrecorded in the TB register and one was recorded, incorrectly, as transferred to a local clinic for follow-up.

The remaining 48 were discharged to home to be followed up at their local clinics. Only 66% of them reported to their local clinic within 30 days. The register recorded only 36 patients transferred to local clinic for follow-up. The other 12 were unrecorded.

The authors note that a similar audit was conducted seven years ago with similar results. However, the poor recording of deaths is a new finding. One positive finding is that in the previous audit 30% of patients did not have an HIV test result, while now it was only 14%.

The authors conclude that “these results add to the conclusion reached elsewhere that patients, often HIV-positive, present late for care directly to hospitals and sick enough to require admission. This has left medical wards overcrowded and overworked leading to the poor outcomes seen in this audit. More resources need to be directed to TB care at hospital sites and better systems need to be implemented to track patient outcomes once discharged.”

comments

These are disturbing findings and action by the Kwazulu-Natal Provincial Department of Health is necessary to rectify the discord between hospital and patient records. While the authors’ conclusion is accurate, the death reporting system worked better seven years ago. It is possible that years of mismanagement of health in Kwazulu-Natal, has led to worsening systems.

Nevertheless, it is unlikely that the findings about record keeping of TB mortality at Edendale are exceptional. Nor are the problems likely to be peculiar to South Africa. This has implications not only for the accuracy of statistics kept for the Millenium Development Goals as pointed out by the study’s authors, but also for Statistics South Africa’s mortality data.

The accuracy of TB and HIV data supplied by the National Department of Health are ultimately dependent on the quality of data at health facility level. Given these findings about TB statistics at one of the larger Kwazulu-Natal health facilities, it raises questions about the quality of data of HIV patients generally and consequently the quality of the statistics provided by the National Department of Health on numbers of people on ART.

Elsewhere in this issue and in several previous HTB-South issues we have described high mortality in cohorts of drug-resistant patients. But this small study demonstrates very high mortality in HIV-positive hospitalised TB patients generally. It underscores the importance of early TB screening and ensuring HIV-positive people with TB are prioritised for ART. It is disturbing that only 13 out of 43 patients with AIDS were on ART, though it is possible that all or some of those were still in the intensive phase of TB treatment and consequently not eligible for ART if their CD4 counts were about 50 cells/mm3.

Ref: Cudahy P et al. 2009. TB Case Outcomes at a Large Public Sector Hospital in Kwa-Zulu Natal, South Africa. 40th World Lung Conference, Cancun, December 2009.

A poster by Shenoi and colleagues at the World Lung Conference examined survival characteristics of people with XDR TB in Tugela Ferry, Kwazulu-Natal. [1]

This was a case controlled study. It included patients registered at Tugela Ferry with new active TB. Patients also had had culture and drug susceptibility testing demonstrating resistance to isoniazid, rifampin, ciprofloxacin, and kanamycin. Survivors were defined as patients who were alive at least six months from sputum collection. Non-survivors were defined as patients who died within six months from sputum collection. Non-survivors were matched to survivors by year of XDR TB diagnosis.

The researchers found records of 460 patients with XDR TB from 2005 to 2008. Of these 122 were confirmed alive at time of receipt of DST results and referred for XDR TB treatment. Of these, 68 met the definition of survivors and 74 met the definition of non-survivors. Remarkably, only one patient in each arm was HIV-negative.

The XDR TB regimen used in Tugela Ferry was ethambutol, pyrazinamide, ethionamide cycloserine or Terizidone, Para-aminosalicylic acid (since 2007) and capreomycin for at least six months followed by an 18 month continuation phase that excluded capreomycin. Amoxicillin/clavulanate and clarithromycin were added to the regimen if one of the above was discontinued due to toxicity or if patients were still TB-culture positive after 12 months of treatment. Patients were also treated with antiretrovirals if there CD4 count was lower than 200 cells/mm3.

Survival was associated with several factors. The most significant and intuitively sensible of the treatment characteristics associated with survival were having started XDR TB treatment (97% v 28%, p<0.0001), having ever received ART (82% v 42%, p<0.0001) and having a higher baseline CD4 count  at XDR diagnosis (162[IQR:72-260] v 84 [IQR:40-157] cells/mm3, p=0.004). Being smear negative also predicted survival (37% v 79%, p<0.0001). The majority of patients on ART initiated therapy prior to diagnosis of XDR TB. The authors indicate that ART may have unmasked XDR TB IRIS in some patients.

The authors emphasise that laboratory diagnostic delay is a major impediment to detecting XDR TB. They also suggest that smear negativity and better multi-organ functioning suggested less disease severity at baseline. They state that concurrent therapy for both XDR TB and HIV coinfection is feasible and associated with successful XDR TB outcomes.

comment

Although this is a small case controlled study, this research is important for understanding how to improve survival in XDR TB patients. The new South African HIV treatment guidelines, in line with these findings, now provide for ART for all HIV-positive patients with drug-resistant TB, irrespective of CD4 count. The new guidelines are described in this issue of HTB South.

Notable is the apparent extremely high mortality rate. From the 460 patients identified, only 128 were confirmed alive. While this does not mean that all of the remainder died, it is very probable that most of them did. Furthermore, of the confirmed survivors, less than half lived six months. The likely availability of new TB drugs in the next few years will probably help reduce the drug-resistant mortality rate. But, even more important is finding ways to diagnose drug-resistant TB quicker, primarily by getting DST results back to clinics and hospitals faster. This will probably have the greatest short to medium-term impact on reducing drug-resistant TB mortality.

It would be useful if the authors clarified some of their findings in greater detail (some of the data on their poster is unclear or counterintuitive) and published this valuable study in a journal.

As the authors recommend, prospective studies to examine their findings in greater detail are needed.

Ref: Shenoi SV et al. 2009. Comparison of characteristics of XDR TB survivors with those of non-survivors in rural Kwa-Zulu Natal, South Africa. 40th World Lung Conference, Cancun 2009.

A simple, reliable and affordable algorithm to identify if a patient can safely be initiated onto isoniazid preventative therapy (IPT) would be very useful. It is important to reduce the risk of initiating patients with active TB on IPT so that they are not effectively given monotherapy with the prospect of developing resistance to isoniazid. Furthermore, it is important that patients with active TB are initiated onto TB treatment. Research published by Cain and colleagues in the NEJM examines this problem. Their large prospective study of HIV-positive antiretroviral-naive patients in Cambodia, Thailand and Vietnam examined 80 million unique combinations of one to five predictors of TB in order to identify the most effective TB screening algorithm. They also identified the most effective TB diagnostic algorithm for patients who were received positive screening results. [1]

Cohort

A total of 1,836 HIV-positive antiretroviral-naive people from eight out patient facilities were screened for eligibility for the study. Of these, 1,768 were eventually enrolled. Three samples of sputum and one each of urine, stool, blood, and lymph node aspirate for patients with lymphadenopathy were obtained for TB culture testing. Patients who were culture-positive for TB were assumed to have TB. Twenty patients could not have their TB status classified and were excluded from the analysis. TB was diagnosed in 267 (15%) of patients.

The sensitivity of screening and diagnostic algorithms was determined based on the results of the culture tests. Sputum smears from and chest radiographs of patients were also taken.

At baseline, the median CD4 count was 242 cells/mm3 (IQR: 82 to 396). Median age was 31 years (IQR: 7 to 72) and just over half were male.

Screening

The challenge for a screening algorithm is to find the best combination of signs, symptoms and history of exposure, easily determined at any level health facility, that maximises the number of negative patients correctly diagnosed as negative but also minimises the number of patients who are suspected of being positive and consequently require microscopy and culture. For example, an algorithm that simply assumes everyone does not have TB might result in too many patients with active TB being inadvertently prescribed isoniazid monotherapy resulting in unnecessarily high isoniazid resistance, as well as many patients with active TB going untreated. On the other hand an algorithm that assumes everyone needs diagnostic testing might be impractical and too expensive in most settings.

The study found that requiring more than one symptom present for a positive diagnosis resulted in too low sensitivity. Also, considering only one or two symptoms was too insensitive. On the other hand, considering four or more symptoms conferred no substantial additional benefit over three symptoms but added complexity to the algorithm. The best screening algorithms therefore were ones, which required the presence of one or more of three symptoms. These were:

• Cough or fever of any duration or drenching night sweats for three weeks out of the previous four weeks: This algorithm has a sensitivity of 93%, specificity of 36% and negative predictive value of 97%.
• Cough, drenching night sweats, or loss of appetite of any duration in previous four weeks: This has the same sensitivity and negative predictive value as above, and a specificity of 35%.
• Cough in previous 24 hours or fever of any duration or drenching night sweats for three weeks in previous 4 weeks: This has a sensitivity, specificity and negative predictive value of 90%, 43% and 96% respectively.
• Cough in previous 24 hours or drenching night sweats or loss of appetite of any duration in previous 4 weeks: This has a sensitivity, specificity and negative predictive value of 89%, 44% and 96% respectively.

The authors show the benefit of three symptoms over two by giving this example: As compared with two symptoms (cough or fever of any duration in the previous four weeks) a combination of three symptoms (the addition of night sweats for three weeks or more) reduced by five the number of patients with false negative screens but increased by 18 the number of patients who needed diagnostic evaluation.

Using the recommended three criteria screening algorithm, 1,199 of the 1,748 participants would have needed diagnostics, but there would have been 18 patients with false negatives not referred for diagnostics. By comparison, the WHO screening approach of only referring patients for diagnostics if they have had a cough for more than two or three weeks would have resulted in only 355 patients being referred for further diagnostics, but 179 false negatives.

Diagnostics

For patients who receive a positive screen, the researchers recommend the following algorithm:

• Start with AFB microscopy of two sputum smears. Patients with at least one positive sputum result should be initiated on TB therapy in most cases.
• For patients with two smear negative results, conduct a chest x-ray. If the x-ray is abnormal, clinical judgment should be used to determine if the patient should be treated, followed by confirmatory mycobacterial culture.
• For patients with a normal x-ray but a CD4 count below 350 cells/mm3, clinical judgment should be used to determine if the patient should be treated, followed by confirmatory mycobacterial culture.
• The authors state that for patients with a CD4 count ≥ 350 cells/mm3 it is unclear what to do. Remember, these are patients with at least one symptom associated with TB.

Applying the screening/diagnostics algorithm to this cohort, the results were as follows:

• Of the 1,199 patients with a positive screen for TB using the screening algorithm described by the authors, 113 had at least one sputum positive result from two sputum smear microscopy examinations. Of these, 98 (87%) had culture-confirmed TB.
• Of the 1,086 with two sputum-negative results, 250 had an abnormal chest x-ray, of whom 83 (33%) had TB.
• Of the 836 with normal chest x-rays, 558 had a CD4 count < 350 cells/mm3. Of these, 55 (10%) had TB.
• Of the 278 with a CD4 count ≥ 350 cells/mm3, 13 (5%) had TB.
• A total of 808 culture tests would need to be done (comprised of the 250 patients with abnormal chest x-rays and the 558 patients with CD4 counts below 350 cells/mm3)

Using this algorithm, the number of false negative results in the screening and diagnostic steps combined was 31, far fewer than the WHO methodology. The authors also compared their combined screening/diagnostic algorithm to one in which all patients underwent chest x-rays and microscopy of two sputum smears, without symptom screening or culture confirmation. This method would have yielded 75 false negatives; ie patients who had tuberculosis but nevertheless had normal x-rays and two negative smears.

The study also found that patients who had false negative results with the screening/diagnostic algorithm tended to have higher CD4+ cell counts than patients who had false negative results with the other two approaches.

The authors conclude by recommending validation of the algorithm in Africa and other parts of the world. They also argue that policy changes should be considered based on their findings.

comment

This excellent paper is the most detailed analysis of how to diagnose TB in HIV-positive antiretroviral-naive patients, a critically important challenge. The sample size is large and the methodology sound. Furthermore, although the cohort is Asian, the high rate of TB in this cohort means it has some applicability to southern African settings. However, the authors are right that validation of the algorithm is needed. This study could and should be carried out in southern Africa.

Even for well-resourced settings, this study is important. It takes a few weeks for the gold-standard TB diagnostic, a liquid medium culture test, to return a result. In the meanwhile clinicians need to decide whether or not to commence treatment or isoniazid preventative therapy.

However, the study also shows how costly, slow and difficult TB diagnosis is. Even the authors’ algorithm, albeit an improvement on the WHO’s current one, has a large number of false negatives (cf HIV testing). It is also more expensive to carry out than the WHO one. Many health facilities do not have the resources to carry out the diagnostic part of the algorithm, which involves far more sputum smears and chest x-rays than the WHO one. Indeed, the shortcomings of all current TB screening and diagnostic algorithms makes it difficult to implement isoniazid preventative therapy in many health facilities.

The findings of this study remind us again of the need for faster, cheaper and more sensitive and specific TB diagnostics.

Ref: Cain K et al. An algorithm for tuberculosis screening and diagnosis in people with HIV. NEJM 362;8 February 25, 2010.

http://content.nejm.org/cgi/content/full/362/8/707

A prospective study of workers with TB in a South African gold mine that was published in Emerging Infectious Diseases provides useful data on the emergence of drug resistant TB. Calver and colleagues found that drug resistant TB was developing in this setting despite stringent treatment adherence. Much of this resistance was probably nosocomial, but also occurred in the work and living environments. The authors found that diagnosis delay and inappropriate therapy facilitated disease transmission and drug resistance. [1]

An over two-fold increase in drug-resistant TB cases at the mine was noted in 2003. The study was carried out at the mine from January 2003 to November 2005. Mine employees as well as any of their dependents who were diagnosed during the study period with drug-resistant TB were included in the study. The researchers found that 3,003 patients were diagnosed and notified with TB. Of these, 1,443 (48%) had new pulmonary TB cases, 755 (25%) were retreated for pulmonary TB and 805 (27%) patients had extrapulmonary TB.

Patients were identified either via an active screening programming that included biannual chest radiographic screening (30%) or because they sought care because they had TB symptoms (70%). The cure rate was high, 87%, and 12% of patients died. The remainder (less than 2%) defaulted or had an unsuccessful treatment outcome. Adherence was high, in the region of 95 to 98%.

Drug resistance

Drug-resistant TB was diagnosed in 128 mine workers, of whom 124 were male. All had worked at the mine for at least 6 months (median 15 years) and had passed a pre-employment physical examination that ruled out active TB. Of these 13 (10.2%) had isoniazid-resistance, 7 (5.6%) had poly–drug-resistant TB and 108 (84.4%) had MDR TB. Among patients with MDR TB, 26 had pre-XDR TB (ie resistance to either ofloxacin or kanamycin but not both) and 5 had XDR TB. HIV status was know for 91 drug-resistant patients, of whom 84 were HIV-positive and 7 were HIV-negative. 57 patients, including three with unknown HIV status, had CD4 counts below 200 cells/mm3.  Most patients, 95 (74%) were smear-positive. This was 70% for HIV-positive patients, approximately consistent with other findings of 65%. Seven patients started ART before TB diagnosis and 22 after. Median time to initiation for the latter was 172 days (range 41 to 1,425 days).

Outcomes for drug-resistant patients were poor: 40 completed treatment or were cured; one patient failed treatment; 45 died; 32 were transferred out and 10 were lost to follow up. Median time to death was 5 months (range 1-24 months).

Clustering of drug-resistant isolates

The researchers conducted genetic clustering analysis of the drug-resistant TB isolates to try to determine patterns of infection. They analysed isolates from 124 of the 128 patients. Of these, 74 were clustered into 11 clusters ranging in size from 2 to 42. At least 63 isolates had primary drug resistance. Among the 50 unclustered isolates, 25 were from first-time TB patients at this facility, also suggesting primary infection. Clustering was more frequent amongst MDR than mono or poly-resistant TB strains (adjusted OR 14.13, p = 0.002 – unadjusted rate was almost identical). The same was true for XDR isolates compared to mono and poly-resistant ones (unadjusted OR 27.42, p<0.001). The pre-XDR and XDR isolates were strongly clustered with the MDR ones (24 of the 30 isolates were in MDR clusters). 59% of clustered patients had a previously documented TB episode.

The researchers analysed the types of contacts patients in the largest cluster had. They found most patients had multiple different contacts that put them at risk:  32 of the 42 had a non–MDR TB hospitalization at the same time another patient in the cluster was admitted for MDR TB, 39 worked in a shaft in which another MDR TB patient in the cluster had worked and 36 resided in the same residential unit where another MDR TB patient had lived.

Phylogenetic analysis indicated that resistant pyraziamide resistance occurred on two separate occasions. Then ethambutol resistance evolved independently. Ofloxacin resistance later evolved on six separate occasions, of which one of these isolates evolved into XDR causing disease in a single patient. The authors state that the “evolution of resistance to ethambutol and pyrazinamide represents the further amplification of drug resistance in the context of patients with undiagnosed MDR TB initially being given standard therapy”. They further explain that, “an MDR TB case-patient with a strain resistant to isoniazid, rifampin, ethambutol, and pyrazinamide could then spread disease to persons who were cohospitalised for drug-susceptible TB or illnesses other than TB.  Disease may develop in these persons, and they can then spread MDR TB to their contacts at their place of work or residence, thereby unintentionally perpetuating the drug- resistant TB outbreak. We believe that this observation is not unique to this setting.”

The authors claim that although the mine’s TB control programme was effective at preventing acquisition of resistance to first-line drugs, it was unable to prevent transmission of pre-existing MDR TB. Their study also confirms other findings that a prior TB episode increases the risk of a later episode through reinfection.

The authors concluded with several recommendations: integration of DOTS and HIV management programmes to ensure wider ARV availability, public awareness raising of TB symptoms to encourage earlier diagnosis, active screening of all patients making contact with the public health system, aggressive case finding, more frequent sputum smear examinations, more frequent culture-based diagnoses to identify cases before they become infectious, development and implementation of rapid drug susceptibility testing diagnostics, studies to optimise drug regimens and dosages and more rigorous control measures in health facilities to reduce nosocomial transmission.

comment

This excellent study provides data that can be used for better modelling the development and spread of drug-resistant TB, at least within high-risk mine settings. Two other studies in community settings referenced by the authors are worth noting. In a 1999 study by van Rie and colleagues they used genetic analysis to determine that two patients treated for drug-susceptible TB contracted MDR TB outside hospital, leading the researchers on that study to state that transmission of MDR TB is not limited to HIV-positive patients in institutional settings. [2] More recently, a 2007 study by Victor and colleagues found a cluster of 64 patients –out of 450 with drug-resistant TB– that shared a rare mutation, indicating the spread of this drug-resistant strain within the cluster. They concluded that factors leading to the “development and spread of this drug-resistant genotype were inappropriate chemotherapy, poor adherence to treatment and prolonged periods of infectiousness due to delays in susceptibility testing.” [3]

The conclusions and recommendations of Calver and colleagues must be supported. In particular, that 12 patients with drug-resistant TB died while receiving first-line therapy indicates the need for investigating how to optimise the process of diagnosing drug-resistant TB, including analysis of the National Health Laboratory Service’s systems. Methods to reduce delays in health-seeking behaviour by people with symptoms of TB also need investigation. To implement all of Calver and colleagues’ recommendations will require a massive investment of state, corporate and donor funds into TB. This is clearly necessary.

The authors also state that the “incidence of drug-susceptible TB has continued to rise, an increase that reflects both the rising HIV prevalence in this community and the occupational risks specific to the mine setting such as silicosis, congregate living, and working conditions.” Pressure should be put on mining companies both by unions, civil society organisations and government to address these unacceptable living and working conditions in order to reduce the spread of TB, especially drug-resistant strains.

Much of the Department of Health’s messaging aimed at promoting the reduction of drug-resistant TB emphasises patient adherence. This study adds to the body of evidence showing that this is only one part of the problems. Despite excellent adherence, drug-resistant TB continued to emerge because of poor technology and sub-optimal systems as well as working and living conditions conducive to the spread of TB.

References

1. Calver et al. 2010. Emergence of increased resistance and extensively drug-resistant tuberculosis despite treatment adherence, South Africa. Emerging Infectious Diseases Vol. 16, No. 2, February 2010.

http://www.cdc.gov/eid/content/16/2/264.htm

2. Van Rie A et al. Transmission of a multidrug-resistant Mycobacterium tuberculosis strain resembling “strain W” among noninstitutionalized, human immunodeficiency virus-seronegative patients. J Infect Dis. 1999;180:1608–15. DOI: 10.1086/315054

http://www.jstor.org/pss/30110459

3. Victor TC et al. Spread of an emerging Mycobacterium tuberculosis drug-resistant strain in the western Cape of South Africa. Int J Tuberc Lung Dis. 2007;11:195–201.

http://www.ncbi.nlm.nih.gov/pubmed/17263291

Khan and colleagues published a systematic review and meta-analysis in Clinical Infectious Diseases that evaluated the impact of three factors on failure, relapse and death during treatment of TB/HIV co-infected people. These were duration of rifampicin or rifabutin treatment, (2) daily versus intermittent dosing and (3) ART during TB treatment. [1]

Out of 5,128 titles identified by a literature search, 30 articles were ultimately included in the review. These described 26 studies, of which only six were randomised trials. All reported failure and death during TB treatment and 17 reported relapse rates. Only one study examined rifabutin, so the authors considered all rifamycins together.

The authors compared the findings of three trials with internal head-to-head comparisons of rifamycin treatment strategies, but pooling the results was impossible because all three used different durations of rifampicin treatment.  In one of the trials, relapse and failure were similar in patients receiving 6- versus 9-month regimens. In another relapse rates were significantly lower after 12 months of rifampicin versus 6 months. In the third, patients who received rifampicin for 6 months of an eight month regimen had lower failure and relapse rates than those receiving it for only two months of an eight month regimen.

A pooled analysis of all 27 studies found that longer duration of rifamycin (≥ 8 months v 6 months v 2 months) was associated with less failure (1.9% v 2.6% v 2.9%), less relapse (3.3% v 9.8% v 10.8%) and less death during treatment (11.7 v 10.5 v 16.6), but the confidence intervals are very wide on all of these data and none reached significance because there were too few studies with too few participants. There were approximately 2,500 subjects in the studies that considered treatment failure, 1,300 in the studies that considered relapse and 3,000 in the studies that considered death during treatment.

However, in an analysis adjusted for a range of potentially confounding factors, rates of relapse and death were significantly higher among patients who received rifamycin for only two months compared to patients who received it for at least 8 months (relapse RR for two month rifamycin: 3.6 95%CI 1.1-11.7; death RR: 1.8 95%CI 1.0-3.1).

In studies where some patients were on ART during TB treatment there were significantly lower rates of failure (3.2% [95%CI 2.0-4.5] v 0.8% [95%CI 0-1.8]) and relapse (15.5% [95%CI 4.5-25.5] v 0.5% [95%CI 0-1.7]). But after adjustment this was non-significant.

Daily treatment was non-significantly better than three times weekly. However in adjusted analysis it resulted in significantly better relapse and failure rates during the intensive (or initial) phase of treatment (failure RR of intermittent treatment: 4.0 95%CI 1.5-10.4; relapse RR: 4.8 95%CI 1.8-12.8).

The authors describe several limitations of their analysis: there was only one randomised trial that assessed the schedule of treatment administration and only three trials that compared rifamycin duration. Because the pooled analysis mainly used observational data it was subject to confounding and selection bias. There was substantial variability in settings, patient characteristics, interventions and outcomes assessed.

comment

This study suggests the need for a clinical trial to determine the optimal duration of rifamycin during TB treatment. It also underscores the lack of compelling data on how to optimise TB treatment, contrasted with the large number of trials that have been done on ART. As the authors say, “the most important and striking finding of this review is the paucity of well-designed and adequately powered randomised trials of HIV-TB co-infection treatment.”

Reference

Khan F et al. 2010. Clin Infect Dis 2010:50 (1 May)

Other recommendations include provider initiated TB testing, and drug susceptibility testing (DST) for all previously treated TB patients at or before the start of treatment.

All HIV-positive patients with active TB should receive antiretrovirals.

World Health Organisation. Treatment of tuberculosis guidelines. Forth edition:

http://www.who.int/tb/publications/tb_treatmentguidelines/en/index.html

Some useful TB research has been published since the last issue of HTB. With approximately 120 TB-related abstracts at IAS2009, we summarise some of the most important.

Epidemiology

The most interesting TB research presented at the IAS conference dealt with the epidemiology of TB/HIV co-infection.

A presentation by Keren Middelkoop and colleagues analysed the association between the introduction of HAART in a community and active TB rates. [1]

They collected TB notification data, prior to HAART (1998 to 2004) and after HAART was introduced (2004 to 2008), in Masiphumelele township in Cape Town. HIV prevalence was estimated to be 23% in the township. Pre-ART adult TB notifications increased by an average of 212 cases per 100,000 people per year (p =0.005 for trend). Post-HAART, adult cases decreased by 116 per 100,000 people per year (p=0.16, NS for trend).

TB rates in HIV-negative people did not change substantially over the period and averaged 697 cases per 100,000 per year. TB rates in HIV-positive people increased by an average of 826 cases per 100,000 per year over the same period (p value for trend 0.08), but after the introduction of HAART, declined by 600 cases per 100,000 per year (p=0.16, NS for trend). For HIV-positive people not on HAART, the average decline in the post-HAART era was 421 cases per 100,000. For people on HAART, it declined by 1,394 cases per 100,000 and this trend was significant (p=0.05). The authors concluded that wide-scale HAART implementation and the community’s well-functioning TB programme were associated with modest TB declines.

Masiphumelelo’s population is only 20 to 30,000 which might explain a lack of power to detect statistically significant trends. But another study in Masiphumelelo also conducted by Middelkoop and colleagues makes the argument for the effect of ART on a declining TB rate more compelling. [2]

In 2008 they repeated a randomly sampled cross-sectional survey that was first performed in 2005. About 30% of HIV-positive adults were estimated to be on HAART in 2008. Two sputum samples were obtained from each participant. Participants also filled in questionnaires on TB history. Those who were not being treated for TB and had two TB-positive sputum or culture tests were considered to have undiagnosed TB. The survey measured a significant decline in the TB rate in HIV-positive people since 2005 (all testing was anonymous), including a significant decline in undiagnosed TB in this group. No such decline was seen in HIV-negative people. The study also found that after adjusting for age, sex and HIV status, the overall 2008 TB prevalence was significantly lower than the overall 2005 prevalence (p=0.02). See Table 1.

Shortly after the conference, members of this research group published an article in AIDS that examined the association between current CD4 count and risk of TB. [3]

They analysed TB incidence in 1480 patients receiving ART for up to 4.5 years. Updated CD4 cell counts were measured 4-monthly. During 2785 person-years of observation, 203 cases of TB were diagnosed, giving an overall incidence of 7.3 cases/100 person-years. TB incidence by CD4 count strata is described in Table 2 (p<0.001).

Table 1: Results of surveys in 2005 and 2008 in Cape Town township

Table 2: TB incidence by CD4 count strata (from Lawn et al.)

The authors found that updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk. They concluded that updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. They also found that among those with baseline CD4 cell counts less than 200 cells/mm³, the excess adjusted risk of TB during the first four months of ART was consistent with unmasking of disease missed at baseline screening. They noted that TB incidence at CD4 cell counts of 200-500 cells/mm³ remained high and concluded that TB prevention would be improved by ART policies that minimised the time patients spend with CD4 cell counts below 500 cells/mm³.

These studies provide evidence that widespread ART implementation can reverse the growth in active TB rates in Southern Africa.

A study by Van Rie and colleagues analysed risk factors for TB in patients who had been on HAART for greater than six months in a prospective cohort from the Themba Lethu clinic in Johannesburg. [4]

This study provided quantitative data on TB incidence and its relationship to patients failing treatment. Of 5934 adults, 217 (4%) developed TB after six months. Median time to TB was 418 days (IQR: 276-672, incidence of 2.3 cases per 100py). The incidence was four times lower than in the first six months of ART. Significant risk factors associated with active TB were BMI <18.5 compared to BMI ≥25 (HR: 6.52, 95%CI: 3.60-11.80) history of TB treatment (HR: 1.50, 95%CI: 1.09-2.50), current viral load >10,000 copies/mL (HR: 2.44, 95%CI: 1.57-3.79) and CD4 count ≤ 50 cells/mm³ (HR=0.84, 0.45, and 0.34, for CD4 51-100, 101-200, and 201-350 respectively).

In a study from Khayelitsha, Pepper and colleagues examined patients in their cohort who had clinical deterioration. [5]

They enrolled 298 people with who had initiated TB treatment from June to August 2008 and then followed them for six months. In this group, 209 (71%) were HIV-positive, with a median CD4 count of 129 cells/mm³ (IQR: 62-277). At TB diagnosis, 35 (17%) HIV-positive patients were receiving HAART. This rose to 112 (54%) on HAART six months later.

Within 6 months, 117 patients (39%) experienced 208 episodes of clinical deterioration. Of these, patients, 71% were HIV-positive. There was an escalating risk of clinical deterioration in HIV-positive patients as CD4 counts decreased (CD4>350: RR:1.4; 95%CI=0.7-2.9; CD4 200-350: RR:2.0, 95%CI: 1.1-3.6; CD4< 200: RR=3.0, 95%CI=1.9-4.8).

AIDS-defining illnesses (n=30), TB-IRIS (n=22) and MDR-TB (n=10) were important causes for clinical deterioration. The number of deaths was 17, of whom 15 were HIV-positive with a CD4 count <200 cells/mm³ at TB diagnosis. The authors also noted that health-care use was significantly higher in HIV-positive patients with low CD4 counts. They pointed out that starting HAART initiation at higher CD4 counts is likely to reduce this clinical burden.

De Bruyn and colleagues presented data from Soweto that showed an association between ART and neutrophil count. [6]

They explain that neutrophil granules contain antimicrobial peptides that kill M.tuberculosis. In HIV-negative people exposed to TB, neutrophil count is inversely associated with risk of latent TB infection and positively associated with ability to contain mycobacterial growth in vitro. However, neutrophil functional defects occur in HIV-positive patients. The authors therefore examined the association of incident TB with neutrophil count.

They followed a prospective cohort of almost 2700 HIV-positive adults for over 5500 person-years. Median age was 32. Women comprised 79% of the cohort. Median CD4 count was 282 cells/mm³. The median neutrophil count was 2.46 copies/nL. TB incidence was 5.2/100py (95%CI: 4.6-5.8). ART was associated with a reduced risk of TB (HR: 0.26; p<0.001), as was increasing CD4 count. Increasing neutrophil count was also associated with increased risk of TB (HR: 1.18; p=0.02). For patients on ART, there was a trend showing that risk of TB was reduced by 75% per nL increase in neutrophil count (HR: 0.25, p=0.08).

The authors conclude that the association between neutrophil count and risk of tuberculosis in HIV-positive adults varies according to whether HAART is administered. Their results suggest that HAART critically influences the relationship between neutrophils and the risk of TB.

COMMENT

The potential role of earlier ART in reducing the epidemiological impact on TB is encouraging.

This supports the recommendation to start HAART at CD4 counts over 350 cells/mm³ in patients coinfected with TB.

Drug resistance

Research on drug-resistant TB continued to be a concern.

A study by Max O’Donnell and colleagues who have produced excellent data on the drug-resistant TB epidemic, found that health care workers in Kwazulu-Natal had a much higher incidence of TB than the general population. [7]

Based on data from King George V Hospital, MDR-TB incidence was 58.9 per 100,000 people for the province’s health workers and 10.7/100,000 for the province’s general population (OR: 5.53; 95%CI; 4.70-6.50). XDR-TB incidence was 4.0/100,000 among health workers and 1.0/100,000 in the general population (OR: 3.89 95%CI: 2.02-7.11). There were 235 cases of health workers with drug-resistant TB and 3,391 cases for non health-workers at the hospital. About half of drug-resistant patients were HIV-positive and this did not differ between health workers and the general population. The high incidence amongst health workers is clearly related to occupational exposure. The researchers therefore conclude that screening and controlling occupational exposure among health workers is critical to limit nosocomial spread of drug-resistant TB.

In another Khayelitsha study, Helen Cox and colleagues reported on the prevalence of drug-resistant TB. [8]

This team conducted a representative cross-sectional survey of clients attending two clinics suspected of having pulmonary TB between May and November 2008. Of 1,850 TB suspects surveyed, 536 (30%) were culture-positive. HIV status was known for 427 (80%) cases with 261 HIV-positive (61%). Rifampicin resistance was found in 4% of new cases and 10% of previously treated cases (p=0.003), and in 8.0% of HIV-positive and 4.8% of HIV-negative cases (p=0.18). They estimated rifampicin resistance in Khayelitsha to be 50 to 72/100,000 people per year. They concluded that there is extremely high prevalence of drug-resistant TB in the township. Moreover, that it is high amongst HIV-negative people too.

PACTG 1041 was a double-blind placebo controlled trial to test isoniazid preventative therapy (IPT) in perinatally HIV-exposed infants. The primary endpoint was TB disease, infection or death. The DSMB stopped the trial because of futility. Partial results were reported at ICAAC 2008 (covered in HTB Nov/Dec 2008) and CROI 2009. At IAS2009 a poster by Anneke Hesseling and colleagues reported the results of an analysis of the 22 culture-confirmed cases of TB in the trial. [9]

Of these, 18 were sent for drug-susceptibility testing. Five were drug-resistant (one to INH, four MDR-TB). The authors conclude that the high rate of drug-resistant TB in the trial is consistent with the growth of the adult drug-resistant TB epidemic and has potential consequences for the programmatic implementation of IPT.

COMMENT

The growing evidence of a rising drug-resistant TB epidemic that might undermine the benefits of IPT, particularly in infants, is concerning. So too are the high rates of drug-resistance in HIV-negative people beyond nosocomial infection in Khayelitsha. The South African government is still not demonstrating adequate commitment to co-ordinating and prioritising infection control measures and contact tracing. For example, it would be useful to have a project to revamp clinic waiting rooms (along similar lines to the waiting room at the Ubuntu clinic in Khayelitsha, which has heaters and a roof, but no walls allowing a continuous flow of air). A public information campaign to keep windows open in public places (e.g. buses and taxis) is also important.

Izoniazid preventative therapy (IPT)

One concern about community-wide IPT is that it will result in higher isoniazid resistance. A study by Halsema and colleagues provides promising data that will help allay, albeit not completely, this fear. [10]

The Thibela TB study is a large cluster-randomised trial to study IPT strategies in South African gold mines. Individual mine shafts are randomised to receive either standard TB control (IPT to miners with silicosis or HIV infection) or the intervention (IPT to everyone in the mine, from miners to executives).

In this case-controlled study, drug susceptibility data from TB cases among people who received IPT in the Thibela TB intervention clusters were compared to two groups: (1) TB cases in the control clusters and (2) a subset of patients from a laboratory substudy confined to the first TB episodes in the control clusters. The comparison cases were restricted to the same calendar period as the intervention cases. The Thibela TB intervention began in July 2006 and the study included all TB cases in the intervention clusters up to mid-February 2009.

The intervention group included all participants receiving IPT who attended at least one follow-up visit and were subsequently treated for TB, unless they did not have positive TB cultures. Of the 126 individuals who met the inclusion criteria in the intervention arm all but one were male. The median age was 43 years. Of 103 patients with known HIV status, 89 (86.4%) were HIV-positive. Median CD4 cell count was 196 cells/mm³ (n=51). The median time from starting IPT to TB treatment was 316 days (IQR: 174-491). For 75% people (n=94) this was their first TB episode and 25.4% (n=32) were retreated. TB was pulmonary for 87 (69.0%), extra-pulmonary for 22 (17.5%) and disseminated for 17 (13.5%).

Amongst the intervention cases, 96 outcomes had been documented at the time of the analysis: 39 (41%) were cured, a further 23 (24%) completed treatment, 8 (8.3%) died, there was one treatment interruption, one treatment failure, 11 (11.5%) transferred out or were lost-to-follow-up and for 13 (13.5%) cases the outcomes were unknown.

The authors concluded that TB disease after IPT may be largely due to re-infection in this high HIV prevalence group.

Data on drug susceptibility was presented for 58 people in the intervention group, 182 in the control clusters and 32 in the laboratory substudy. Table 3 presents the results of their analysis.

Table 3: Drug-resistance in three groups from Thibela TB study

There were no significant differences between the groups in any of these outcomes. However, the authors noted the very wide confidence intervals (depicted graphically on their poster). In their discussion, they explained that if IPT is more effective at treating isoniazid susceptible latent TB, then an increased proportion, but not absolute numbers, of isoniazid resistant TB cases would be expected among those who have taken IPT. They concluded however, that the proportion of TB episodes in the intervention groups did not differ from the controls, and that these data do not support concerns about IPT induced resistance.

TB treatment

The standard model for the management of TB patients that is promoted by the WHO involves directly observed treatment (DOT). In this model, patients come daily to their health facilities to take their pills under the supervision of a health worker.

Atkins et al. described an alternative model piloted from April 2007 to March 2008 in five health facilities in Cape Town. [11]

In this intervention, adult TB patients received adherence counselling. They also selected a treatment buddy. Lay health workers supported patients’ self-supervised treatment.

Using information stored in a routine electronic TB register, TB data from these five clinics was compared against another five clinics that use DOT. Across the five intervention clinics 75% of new patients were treated using the new model. In these clinics, treatment success was 72.4% (95%CI: 67.4-77.4) and in the control clinics it was 75.9% (95%CI: 70.8 to 80.9), a non-significant difference.

In the previous issue of HTB South, we reported on the results of the CAPRISA trial that compared immediate versus deferred HAART in patients coinfected with TB. It showed significant reduced mortality in the immediate arm. We commented on the importance of integrating TB and HIV services to make this intervention easier to implement. Further evidence of the benefits of integrating TB and HIV treatment comes from a Malawian study.

Malawian TB case notifications have risen dramatically over the last two decades. Chan and colleagues described what happened when the Zomba Central Hospital ART Clinic, which opened in 2004, began integrating TB services. [12]

Zomba district has a population of 670,000 (80% rural). HIV prevalence amongst 15 to 49 year-olds is estimated to be 16.5%. Routine national TB programme data shows that 69% of TB patients are HIV-positive.

Integration of services began in September 2007 through monthly HIV/TB integration days. By April 2008, services were fully integrated with a daily TB/HIV Integration clinic where all patients registered for TB were also tested for HIV and referred for HIV care in the same physical area. Ministry of Health TB patient records and HAART records from September 2007 to December 2008 were reviewed to assess uptake of HAART. Following integration, HAART uptake increased dramatically from 4% to 33% in HIV monoinfected patients and from 25% to 50% in patients with HIV/TB coinfection. See Table 4.

The CARINEMO-ANRS 12146 Trial is a randomised, open-label non-inferiority study comparing 48 weeks virological suppression and safety of nevirapine (400mg daily without leading dose) vs efavirenz (600mg daily) co-administered with rifampicin. The other ARVs in the study regimen were d4T and 3TC. HAART was started four to six weeks after TB treatment. Bhatt and colleagues presented preliminary safety data, covering the period November 2007 to December 2008. [13]

By the end of this period, 236 patients with CD4 counts <250 cells/mm³ and who were co-infected with active TB had been randomised. Of these, 11 (4.7%) discontinued the study (6 due to death, 3 withdrew consent, 1 lost-to-follow-up and 1 other).

Follow-up included weekly clinical assessments for the first eight weeks of HAART and monthly assessments thereafter. Patients also had aminotransferase (ALT) measurements every two weeks during the first eight weeks followed by monthly measurements. 204/236 patients (86.4%) presented at least one adverse event. There were 26 serious adverse events, of which six resulted in death. None of the deaths were drug-related.

Skin-related adverse events were reported in 47 patients (19.9%), but none were severe. Also, 11 (4.7%) patients had an ALT increase (> grade 3). Five patients (2.1%) interrupted treatment due to hepatitis. However, there were no cases of severe rash. The researchers concluded that this plus the relatively low number of cases of severe hepatitis and treatment interruptions due to adverse events were reassuring but needed to be confirmed. Final results are expected at the end of 2010. A study by Kamateeka and colleagues of children taking rifampicin and nevirapine is also reviewed in this issue of HTB.

A study from a Uganda found that efavirenz is associated with a greater decline in TB incidence than nevirapine. Hermans and colleagues reported data from their large cohort of ART patients (n=7,648). [14]

Between May 2002 and January 2009 they identified TB events in patients who had been on HAART for two years or less.

At baseline, median CD4 was 111 cells/mm³ (IQR: 38-179) in the cohort and 85 cells/mm³ (IQR: 30-149) in patients with TB coinfection. For the whole cohort, 30% were in WHO stage I or II, 40% in stage III and 30% in stage IV (the TB patients had similar proportions).

In the first two years of HAART (almost 13,600 PYFU), there were 360 (4.7%) new TB events (2.65 per 100PY; 95%CI: 2.39 ¬ 2.94). Incidence rates declined with time on HAART. For 0-3, 3-6, 6-12 and 12-24 months they were 9.91 (95%CI: 8.51-11.55), 5.14 (95%CI: 4.11-6.44), 2.16 (95%CI: 1.66-2.82) and 0.82 (95%CI: 0.64-1.05), respectively.

Table 4: Numbers of patients (%) in HAART uptake following integration of TB and HIV clinics at Zomba Central Hospital , Malawi

In a multivariate analysis, baseline CD4 count <50 cells/mm³ (HR 1.58; 95%CI: 1.10-2.27; p=0.01) and male sex (HR 1.43; 95%CI: 1.15-1.77; p=0.001) were significantly associated with increased risk for TB.

A key finding of the study is that 100 patients out of 2842 receiving AZT/3TC/efavirenz versus 227 out of 3974 using d4T/3TC/nevirapine developed TB (832 used other regimens). Compared to the d4T/3TC/nevirapine regimen, the HR for the AZT/3TC/efavirenz was 0.7 (95%CI: 0.53-0.89; p=0.003).

This difference could not be explained by differences in baseline CD4, calendar year starting HAART or immune restoration status after 14 months of HAART. In a multivariate analysis, the HR was 0.67 (95%CI: 0.53-0.86; p=0.002). The researchers further point out that this association occurred despite clinician bias towards prescribing efavirenz to patients with any TB symptoms to avoid subsequent switching due to interactions between nevirapine and rifampicin. This has not been previously described.

Is therapeutic drug monitoring needed in people with MDR-TB taking ofloxacin? This was a question that arose in a small proof of technology study reported by Mugabo and colleagues at Brooklyn Chest Hospital in Cape Town. [15]

Previously, PK values for ofloxacin have been obtained primarily using high performance liquid chromatography (HPLC) from cohorts in rich country. This study tested liquid chromatography coupled with mass spectrometry and found it to be simple, specific, accurate, sensitive and reproducible.

The inclusion criteria for their study included adult patients (18-65 yrs old) on ofloxacin therapy for at least two weeks who had TB that was resistant to isoniazid and rifampicin but sensitive to second line anti-TB drugs (i.e. strict definition of MDR-TB). Pregnant or breastfeeding women, patients intolerant of ofloxacin or patients on any drugs, other than ARVs, known to interact with ofloxacin PK were excluded.

They researchers found that the PK values of their eight patients with MDR-TB on ofloxacin differed from previous studies, with reduced AUC and Cmax, and prolonged T1/2 and Tmax.

Five patients were HIV-positive (one was female and four male). The woman and two men were on HAART (d4T, 3TC and efavirenz). All eight patients received kanamycin, ethambutol, ethionamide and pyrazinamide. None were on capreomycin, aminosalicylic acid and terizidone.

Obviously this is a very small study, but the results are concerning because they suggest MDR-TB patients are receiving sub-optimal doses of ofloxacin. The authors therefore recommend ofloxacin plasma monitoring in order to maintain therapeutic plasma levels. Larger studies of patients with MDR-TB taking ofloxacin are also needed to ensure that optimal dosages and timing are determined, taking into account the effects of HIV, liver and kidney dysfunction.

Bhaijee and colleagues reported on a drug-induced life-threatening condition related to the commonly prescribed anticoagulant warfarin. [16]

The incidence of warfarin induced skin necrosis is low (estimated 0.01-0.1%), and by 2000, only 300 cases had been reported. Most of these were in patients receiving treatment for venous thromboembolism. This study was a retrospective review of six cases that occurred in GF Jooste Hospital in Cape Town from April 2005 to July 2008. This is a high concentration at one facility for such a rare condition. All patients were HIV-positive women (aged 27 to 42) with venous thrombosis and with active TB coinfecton. Four died, likely from systemic sepsis when resistant bacteria infected their wounds and one of the survivors underwent bilateral mastectomies and extensive skin grafting at a specialist centre. Median time from skin necrosis to death was 43 days (range 23-45).

No common pattern was detected: three were on HAART, two had TB-IRIS, two had previous TB. While five had low nadir CD4 counts (range 10-56), one of these (on HAART) has a CD4 count of 396 cells/mm³ at the time of the necrosis. The site of skin necrosis included breasts, buttocks, and thighs.

The authors made four recommendations: (a) active prevention and appropriate management of venous thromboses, (b) parallel heparin therapy for at least the first four days of warfarinisation in patients with venous thrombosis (which they suggest may limit the occurrence of skin necrosis), (c) effective infection control measures, and (d) expedited referral to specialist centres for surgical review for patients who develop this warfarin induced skin necrosis.

Wilkinson and colleagues prospectively analysed their cohort to find immunological differences in drug-sensitive and drug-resistant patients with TB IRIS. [17]

They compared 12 rifampicin-resistant cases (nine had MDR-TB) to 27 case controls. They found no significant differences in the median duration of IRIS, days of HAART to development of IRIS, baseline CD4 count or days of TB treatment prior to HAART between drug-resistant and drug-sensitive groups. They also found no difference between the IFN-gamma spot forming cells/ million PBMCs in response to several M. Tuberculosis antigens (ESAT-6, Acr1, Acr2, 38kDa, PPD and heat killed H37Rv). C reactive protein was elevated in both groups, but without significant difference from each other. The authors concluded that both drug-sensitive and drug-resistant TB-IRIS, are clinically and immunologically indistinguishable, and that the occurrence of TB-IRIS is an opportunity to screen for previously undetected drug resistance.

COMMENT

While news on TB treatment is hardly breathtaking, some of the studies described above are important and merit further comment.

The model of care described by Atkins, based on the HAART model, demonstrated that there are workable, more affordable and more convenient alternatives to DOT that give patients greater autonomy. It deserves further study, and ideally a randomised trial.

The increased uptake of HAART following TB/HIV integration at Zomba Central Hospital offers further evidence of the importance of integration. Although the data from this study can be used for advocacy, one caution should be noted: increased uptake could also have been linked to the general improvements in the facility over time.

The Hermans data is important. One limitation of the study is that a complex and potentially error-prone method was used to merge two separate databases containing patient data to determine the number of TB events. Nevertheless, this data offers evidence that efavirenz and AZT reduced the risk of TB compared to d4T and nevirapine. Their findings are worth testing in clinical trials and perhaps the CARINEMO-ANRS 12146 trial will provide more insight, at least regarding nevirapine versus efavirenz. Furthermore, if d4T-including regimens offer less protection against TB, it is another reason to limit their use in southern African countries.

Diagnostics data at IAS were more disappointing. Data on several methods were presented, including, but not limited to, acid-fast stain, urine lipoarabinomannan and the quantiFERON-TB Gold In-Tube assay. In the last of these, one study found an association between indeterminate results and increased risk of disease progression, but these patients also had lower median current and nadir CD4 counts, which are both, probably, better predictors. [18]

However, no studies at IAS showed algorithms with a combination of high speed, sensitivity and specificity.

The problem is global. One Cambodian study analysed sensitivity and specificity of smear and culture of urine, stool and lymph node aspirate as well as blood culture. It found they added little additional value. The authors aptly concluded, “In HIV settings, there is an urgent need for simple methods for mycobacterial cultures to detect earlier smear-negative tuberculosis.” [19]

References
Unless othewise stated, all references are to the Programme and Abstracts of 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town.

1. Middelkoop K et al. Can antiretoviral therapy contain a previously escalating TB epidemic in a high HIV prevalence community? 5th IAS 2009, Cape Town. Poster abstract CDB041.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2932
2. Middelkoop K et al. Widespread ART is associated with decline in TB prevalence. 5th IAS 2009, Cape Town. Oral abstract WELBB105.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3844
3. Lawn et al. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS. 2009 Aug 24;23(13):1717-25.
http://www.ncbi.nlm.nih.gov/pubmed/19461502
4. Van Rie et al. Risk factors for incident tuberculosis six months or more after ART initiation – experience from Johannesburg, South Africa. 5th IAS 2009, Cape Town. Poster abstract TUPEB135.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1933
5. Pepper DJ et al. Clinical deterioration during TB chemotherapy in HIV-1 infected patients. 5th IAS 2009, Cape Town. Poster abstract LBPED07.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3674
6. De Bruyn et al. Neutrophil count and risk of tuberculosis in HIV-infected adults. 5th IAS 2009, Cape Town. Poster abstract CDB038.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1539
7. O’Donnell et al. High incidence of multidrug resistant and extensively drug resistant tuberculosis among South African health care workers. 5th IAS 2009, Cape Town. Poster abstract TUPEB149.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3139
8. Cox H et al. Prevalence of drug resistant tuberculosis and association with HIV in Khayelitsha, South Africa. 5th IAS 2009, Cape Town. Poster abstract MOPEB019.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2902
9. Hesseling A et al. High prevalence of drug resistance amongst HIV-exposed and infected children with culture confirmed tuberculosis enrolled on a tuberculosis prevention trial. 5th IAS 2009, Cape Town. Poster abstract MOPEB019.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1610
10. Van Halsema CL et al. Good tuberculosis treatment outcomes and no evidence of increased drug resistance in individuals previously exposed to isoniazid preventive therapy in a population with high HIV prevalence. 5th IAS 2009, Cape Town. Poster abstract MOPEB021.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1966
11. Atkins S et al. An evaluation of a new tuberculosis treatment support programme: Implications for integrating TB and HIV/AIDS treatment programmes. 5th IAS 2009, Cape Town. Poster abstract WEPED231.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2944
12. Improved uptake of antiretroviral therapy (ART) following integration of TB and HIV services in a district in southern Malawi. 5th IAS 2009, Cape Town. Poster abstract CDD062.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2166
13. Bhatt NB et al. Preliminary safety results of co-administration of nevirapine (NVP) or efavirenz (EFV), and rifampicin (RMP) in HIV-tuberculosis (TB) co-infected patients in Maputo (Mozambique): CARINEMO-ANRS 12146 Trial. 5th IAS 2009, Cape Town. Poster abstract MOPEB032.
http://www.ias2009.org/pag/Abstracts.aspx?AID=589
14. Hermans SM et al. The use of efavirenz is associated with a decreased incidence of tuberculosis after antiretroviral therapy initiation in an urban HIV clinic in sub-Saharan Africa. 5th IAS 2009, Cape Town. Poster abstract TUPEB136.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2109
15. Mugabo P et al. Determination of plasma concentrations using LC/MS and pharmacokinetics of ofloxacin in patients with multi-drug resistant tuberculosis and in patients co-infected with multi-drug resistant tuberculosis and HIV/AIDS. 5th IAS 2009, Cape Town. Abstract CDB101.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1916
16. Bhaijee F et al. Warfarin induced skin necrosis in HIV-1 tuberculosis patients with venous thrombosis: a case series. 5th IAS 2009, Cape Town. Poster abstract CDB115.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1358
17. Wilkinson KA. Immunological analysis of the overlap between Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) and antitubercular drug resistance. 5th IAS 2009, Cape Town. Poster abstract TUPEB130.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1448
18. Aichelburg MC et al. Indeterminate results of the QuantiFERON-TB Gold In-Tube assay indicate an increased risk for disease progression in HIV-1-infected individuals. 5th IAS 2009, Cape Town. Poster abstract TUPEB131.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1546
19. Pe R et al. Diagnostic evaluation of smear microscopy of different samples as screening tool for tuberculosis in HIV patients at Sihanouk Hospital Center of Hope, Phnom Penh, Cambodia. 5th IAS 2009, Cape Town. Poster abstract CDA102.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1714

Tibotec are recruiting for an open label trial called TMC207-TiDP13-C209. Its purpose is to evaluate the safety, tolerability, and efficacy of TMC207 as part of an individualised treatment regimen in patients with sputum smear-positive pulmonary MDR-TB.

Several groups have met with Tibotec to ask the company to facilitate greater access to TMC207 for drug-resistant TB patients with limited options while clinical trial testing of the drug continues (see HTB-South April-June 2009). Tibotec has presented this trial as a first step towards this. The company says it wants to closely monitor safety and tolerability while the compound is still under phase 2 evaluation.

Three sites have opened in South Africa (see Table 1 for details).

Table 1: TMC207-TiDP13-C209 contact details

The trial currently provides for 225 patients to be enrolled in sites in Brazil, Estonia, Hong Kong, Kenya, South Korea, Latvia, Peru, Philippines, Thailand, Turkey and Ukraine and South Africa. XDR TB patients can participate in this trial. Currently the criteria exclude patients on HAART (because of potential interactions) and sputum-negative patients. Negotiations are proceeding with Tibotec to review these limitations and to increase the size of the trial.

Patients who participate in the trial will have to attend many obligatory trial visits at the same study centre at one of these locations over a two-year period. Strict adherence to the drug regimen is a requirement.

Reference

Tibotec. TMC207-TiDP13-C209 trial to evaluate the safety, tolerability, and efficacy of TMC207 as part of an individualized multi-drug resistant tuberculosis (MDR-TB) treatment regimen in patients with sputum smear-positive pulmonary MDR-TB.
http://clinicaltrials.gov/ct2/show/NCT00910871

(Thanks to Helen Cox, Andreas Diacon, Alex Pym and Martin Grobusch for additional information.)

Rifampicin-based TB treatment is recommended for children (there is no formulation of rifabutin for young children nor is it widely available). In South Africa children with HIV who are <3 years old receive lopinavir/ritonavir-based antiretroviral 1st line regimens. Rifampicin reduces
trough concentrations of lopinavir by more than 90%. Additional boosting with ritonavir to a 1:1 ratio during TB treatment provides adequate concentrations in adults and children but this strategy is complex with oral solutions and not always feasible.

Helen McIlleron from the University of Cape Town presented findings from a pharmacokinetic (PK) study using double dose lopinavir/r (LPV/r) (ratio 4:1) with rifampicin in young children who were >6 months of age. This strategy has achieved adequate concentrations in healthy adult volunteers.

In this study, children with TB/HIV (n=17), received 460/115mg/m2 LPV/r +2NRTIs, once established on rifampicin-based TB treatment. Children without TB (n=24) were used as a control group and received the standard dose LPV/r 230/57.5mg/m2 +2 NRTIs.

Table 1. Baseline characteristics and PK of children receiving LPV/r

Baseline characteristics and PK parameters are median (IQR).

Pre-dose sampling was performed at 2, 4, and 8 hours after dose and determined using LC-MSMS method.

Following an interim analysis and DSMB review of plasma levels in 15 children with TB/HIV the study was stopped.

The investigators reported a median (IQR) LPV dose of 486 mg/m2 (478-497) in cases and 234 mg/m2 (228-241) in controls.

Characteristics and PK of the children are shown in Table 1. There were more girls than boys with TB/HIV and children with TB weighed less than controls.

They noted that among a subgroup of 5 cases sampled 12 hours after the observed dose 12-hour LPV concentrations were 0.65 mg/L lower than Cpre showing that adherence to the previous dose is unlikely to be the reason for the low concentrations.

The investigators found high interpatient variability within both groups of children. The median LPV Cpre, Cmax and AUC0-8h were reduced by 82%, 44% and 51% respectively among children receiving double dose LPV/r with rifampicin-based TB treatment; 10(59%) had subtherapeutic LPV/r Cpre (<1mg/L) vs 2 (8%) controls.

They do not recommend this approach in young children and Dr McIlleron concluded: “There is an urgent need to establish safe, effective and feasible co-treatment for young children with HIV associated tuberculosis”.

COMMENT

These data are important to offer guidance for “what not to do” in this population. They also argue for easier to use solid paediatric formulations of LPV/r and RTV.

Ref: McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.
http://www.retroconference.org/2009/Abstracts/34615.htm

South African HIV guidelines recommend PI-based regimens for children <3 years old. Young children mostly receive lopinavir/ritonavir (LPV/r) but in some cases full-dose ritonavir (RTV) is used if a child is also being treated for TB.

Cordula Reitz and co-workers evaluated factors associated with virologic suppression among children receiving protease inhibitors in Johannesburg in the NEVEREST study.

NEVERST enrolled HIV-infected children who had been perinatally exposed to nevirapine (NVP). Children age >6 months to 24 months received LPV/r based ART and children less than 6 months old or receiving TB treatment (rifampicin/isoniziazid for 6 months + pyrazinamide for 2 months) received RTV-based ART. All children received d4T+3TC.

Viral suppression was defined as reducing viral load to <400 copies/mL. Kaplan Meier methods were used to calculate the probability of achieving viral suppression at 9 months or death.

This analysis included 254 children with a median age of 8.75 months (IQR 5.18-13.8), median CD4 percentage 18.95% (IQR 12.8-24.5) and 80.2% were WHO stage III or IV.

Of these, 138 (54.3%) children started ART with a LPV/r-based regimen and 116 (45.7%) a RTV-based regimen. 54 (46.6%) were <6 months old and 62 (54.3%) were receiving TB treatment (by 9 months an additional 37 [14.6%] children began TB treatment).

The investigators reported an overall mortality rate of 14%. Higher mortality was significantly associated with younger age <12 months vs >12 months [AHR 2.9, 95%CI 1.1-7.8], pre-treatment weight for age z-score (WAZ) <-4 vs >-2 [AHR 3.3; 95%CI 1.4-8.2] and higher pre treatment viral load >750,000 copies/mL vs <100,000 copies/mL [AHR 3.1; 95%CI 0.4-23.5.

The probability of viral suppression (<400 copies/mL) was 83.7% at 9 months after starting ART. Children receiving TB treatment were less likely to achieve viral suppression than children never treated for TB, 78.3% vs 94.1% respectively.

The overall probability of viral rebound at 4 months was 17.6%. Only TB treatment was associated with viral rebound; 8/15 (53.3%) children who started TB treatment after ART and achieved viral suppression had viral rebound compared to 12% without TB and 2.8% probability among those who started TB treatment before ART, p<0.0001 [AHR 5.2; 95% CI 2.1-12.9].

Although the researchers reported high rates of viral suppression among children <2 years they wrote; “How best to treat HIV-infected children who require TB treatment remains an unsolved problem. There is an urgent need to further evaluate the pharmacokinetics and clinical outcomes in children co-treated for these two diseases so that evidence-based recommendations can be made.”

COMMENT

Once again, we need more PK data in younger children and better PI formulations.

Ref:

Reitz et al. Virologic Response to protease inhibitor-based ART among children younger than 2 Years of age co-treated for TB in South Africa. 16th CROI, February 2009, Montreal, Canada. Abstract 910.
http://www.retroconference.org/2009/Abstracts/34444.htm

Pharmacokinetics of nevirapine (200 mg twice daily) and fluconazole ( 200 mg three times weekly) were determined in 27 HIV+ patients and compared to data from 22 HIV+ subjects receiving nevirapine (200 mg twice daily) and placebo. [1]

Fluconazole increased nevirapine AUC by 33 % (from 34297 ng.h/ml to 45685 ng.h/ml); increases were also observed in median Cmax (5028 vs 6354 ng/ml) and Cmin (3709 vs 5116 ng/ml). Despite the increase in nevirapine exposure, there was no evidence of increased hepatotoxicity.

Nevirapine trough concentrations were determined in 20 Ugandan children (age 1.2-11.3 years), seven of whom were receiving concomitant anti-TB therapy which included rifampicin. [2]

Median concentrations in the non-rifampicin group were 4204 ng/ml (range 834 to 15976 ng/ml). Concentrations in the rifampicin group were lower (2920 ng/ml, range 1668 to 9978 ng/ml), with 57% of the children in this group having subtherapeutic concentrations.

References:
1. Wakeham K, et al. Coadministration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans. 16th CROI, Montreal, 2009. Abstract 703. Abstract 700.
http://www.retroconference.org/2009/Abstracts/34543.htm
2. Barlow-Mosha L, et al. Nevirapine concentrations in HIV-infected Ugandan children on adult fixed-dose combination tablet ART, with and without rifampicin-based treatment for active M. tuberculosis infection. 16th CROI, Montreal, 2009. Abstract 909.
http://www.retroconference.org/2009/Abstracts/35604.htm

There were many studies on TB and HIV at the 16th CROI. While the reports on TB diagnostics were bleak, there have been advances in TB treatment, particularly the use of prednisone in patients with Immune Reconstitution Inflammatory Syndrome related TB. There were also important scientific findings presented on how TB can be managed more effectively using existing technologies. Data on drug-resistant TB continues to be very concerning, with some studies reporting extremely high mortality rates.

Integration of TB and HIV care

Further evidence of the need to integrate TB and HIV treatment was presented. This makes the case for integration incontrovertible.

Salim Abdool Karim and his team at CAPRISA based at the University of Kwazulu-Natal conducted a randomised controlled trial that showed that initiating HAART in HIV/TB-co-infected patients, with CD4 counts <500 during TB treatment significantly improves survival. Over a three-year period, 645 HIV-positive patients diagnosed with TB were given standard TB treatment and cotrimoxazole. Patients were randomised to either receive HAART (lamivudine, didanosine and efavirenz) while on TB treatment (integrated arm) or to defer HAART until the end of their TB treatment course (sequential arm). Participants commenced HAART, on average, 67 days after starting TB treatment on the integrated arm and 261 days on the sequential arm.

The Drug Safety Monitoring Board (DSMB) recommended stopping the sequential arm because mortality was 55% lower in the integrated arm (95%CI 0.26 to 0.79; p=0.0049. 5.1/100 person-years [24 deaths; n=431] versus 11.6/100 person-years [26 deaths; n=214].

Two integration strategies are being tested and this part of the trial is ongoing. The integrated strategy would be simpler to implement if clinics integrate TB and HIV care. [1]

COMMENT

In the sequential arm TB patients (including those with CD4 < 200) had HAART delayed until the end of the TB treatment. The result was substantially increased mortality compared to those who started HAART while on TB treatment. It is important to note that treatment protocols throughout sub-Saharan Africa have for several years advised that TB patients with low CD4 counts (CD4 < 200 in South Africa) start HAART during their TB treatment.

A poster by Geoffrey Fatti and researchers with Absolute Return for Kids (ARK) showed an analysis of 109 facilities treating over 35,000 patients with TB, of which 98 facilities did not provide HAART. In the remaining 11 facilities, ARK introduced HAART. In facilities where ARK operated, TB cure rates averaged 79%, while at the non-HAART facilities, it was 71%. This is a relative increase of 11.3% (95% CI: 9.1-13.6; p< 0.0001)

Default rates at the former were 6% as opposed to 11% at the latter (p<0.0001). The authors speculated that the reasons for this might be that “TB patients are screened for HIV and visa versa, resulting in earlier diagnosis, referral and management.” They also explained that TB patients receiving HAART at ARK-supported sites “receive group education, individual counseling, adherence support tools and community adherence psychosocial support.”

ARK’s high quality of care is obviously a confounding factor in this study. [2]

Andrea Howard and her colleagues analysed 238 PEPFAR funded HIV sites that collectively treat 93,935 patients. They found three key factors associated with a greater number of patients being screened for TB. These were the availability of TB services, the site being located in a rural setting, a greater provider to patient ratio and a greater age of the TB screening programme. Certainly the first of these factors supports integration of TB and HIV treatment. In multivariate analysis, the mean proportion of patients screened for TB if screening took place on site was 76% versus 56% if screening took place off-site (p=0.03). [3]

As a corollary of the above studies, a poster by Stephen Lawn and researchers from the Desmond Tutu HIV Centre at the University of Cape Town showed the need for HAART programmes to screen more pro-actively for TB and to place people on HAART at higher CD4 counts to reduce the risk of TB. They examined their cohort of HAART patients and found, unsurprisingly, that TB rates were much higher at lower CD4 counts and in the first few months of HAART.

They diagnosed 203 cases of TB in during 2,785 person-years of follow-up (7.3/100py). The TB incidence rate per 100 patient-years for CD4 count strata were as follows:

The TB rates within the 0-200 cells/ strata was 1.7 times higher than the rates in corresponding CD4-strata during the first four months of HAART (p=0.026). But this higher risk did not remain significant after four months of HAART.

The authors concluded that the excess adjusted risk of TB during early HAART among those with baseline CD4 counts less than 200 cells/ was consistent with “unmasking” of disease missed at baseline screening. They further explained that TB prevention would be improved by HAART policies that minimised the time patients spend with CD4 cell counts below 500 cells/. In patients whose immune systems had recovered to CD4 counts above 500 cells/, TB rates were much lower, albeit still approximately twice the background population rate. [4]

Diagnostics

There was disappointing news on the diagnostics front. Several research groups showed that symptoms, such as coughing, differentiate poorly between patients with and without active TB. Smear tests, x-rays and PCR tests are also poor predictors of who has TB. The definitive TB culture test takes weeks to return a result (an average of 23 days according to a study conducted in Cape Town [5]⁠, but often much longer, ranging from 6 to 50 days), which is far too slow for determining if a patient should be treated.

At a pre-conference meeting on TB, Peter Godfrey-Fausett and Helen Ayles of the London School of Hygiene and Tropical Medicine presented the results of TB diagnostics used in the ZAMSTAR community based prevalence studies. ZAMSTAR consists of four sites: one peri-urban and one rural in Zambia, and one medium density and one high density urban site in South Africa. This is a massive sample of 14,330 patients, both HIV-positive and HIV-negative.

They showed that coughing and other symptoms are a poor predictor of culture positive TB. The tables below show sensitivity and specificity percentages for various symptoms.

Table 1: Sensitivity of different TB symptoms (sensitivities are percentages)

ADD TABLE

Table 2: Specificity of different TB symptoms (specificities are percentages)

Tables from Godfrey-Faussett et al.

While using the presence of any symptom to diagnose TB is reasonably sensitive, it is very unspecific, resulting in many false positive diagnoses. However, using only a prolonged cough to screen TB is reasonably specific but highly insensitive, resulting in many cases of TB going undiagnosed.

Godfrey-Fausett considered the implications of this for Isoniozid Prophylaxis Therapy (IPT). Despite the preference to avoid providing IPT to people with active TB, there is no accurate mechanism for diagnosing active TB other than the tardy culture test. It is difficult to determine which patients should receive IPT. Godfrey-Fausett discussed various algorithms for minimising the risk of placing someone with active TB onto IPT. He also suggested that it is not necessarily a serious problem to put someone with active TB on IPT. [6]

Ingrid Bassett and her colleagues at McCord Hospital in Durban compared the cost of intensive TB screening for HIV-positive patients starting HAART against the World Health Organisation (WHO) standard of only doing a smear-test on patients who have had a cough for two to three weeks. The intensive TB screening procedure consisted of screening all patients regardless of cough and other symptoms of TB. This involved taking a chest x-ray, collecting a sputum sample, doing an AFB smear test and doing a culture test (liquid (MGIT) and 7H11 solid medium).

They calculated the additional costs incurred by this intervention versus what their costs would have been had they just done smear tests on patients with two to three week coughs. They found that just over 19% (159 cases) of their 824 patients tested positive for TB using a culture test. Using just a cough and smear test (i.e. the WHO recommendation) yielded very poor sensitivity and specificity (52% [95%CI: 44-60] and 63% [95%CI: 55-96] respectively).

The most accurate predictor of culture-positive TB was to consider cough, other symptoms of TB and the chest X-ray combined, but even though this was 93% [95%CI: 88-97] sensitive, its specificity was poor: 15% [95%CI: 13-18] (smear test added no additional sensitivity or specificity). The cost per case identified using the WHO screening criteria was $240. The cost per case identified with intensive TB screening was $300. To identify all 159 cases of active TB cost an additional $360 per case.

They concluded that neither cough nor sputum smear alone were sensitive enough to serve as the trigger for screening HIV-infected patients for TB. They explained that compared to screening based on cough, intensive screening doubles the TB cases identified with only a modest increase in the cost per case identified and that sputum cultures should be performed routinely in all patients prior to HAART initiation in areas of high HIV/TB prevalence. [7]⁠

Shaheen Hassim and her colleagues examined the sensitivity and specificity of PCR testing for determining resistance to isoniazid and rifampicin. Unfortunately, sensitivity and specificity, as with smear testing, was poor. A positive culture test matched a positive PCR result only 55.8% of the time. Specificity was better, 88.3%. [8⁠] See Table 3.

Table 3: Sensitivity and specificity of PCR for determining resistance to isoniazid and rifampicin

Similarly distressing results were found by David Edwards and his group from their cohort in a Cape Town township. They screened 236 patients for TB using a combination of symptoms of cough, weight loss, fever and night sweats. 62 (26.3%) patients were culture-positive. Their screening procedure had a sensitivity of 78%, but specificity was very low (35%). They also found that Chest x-rays were normal in a third of cases. They also found that a Lipoarabinomannan ELISA test had a specificity of 99% but a sensitivity of only 31%.

The sensitivity increased to 51% in patients with a CD4 count <100 cells/. More than a quarter of patients had culture-positive TB. Symptom screening, sputum smears and x-rays were poorly predictors of TB. On the other hand, sputum culture was slow. The authors poignantly concluded that new more rapid diagnostic tests are urgently needed. [5]

COMMENT

The state of TB diagnostics is poor. Until it improves, it is worth considering offering, on a regular basis, a TB culture test to every patient with HIV and offering IPT to those whose culture test is negative. Smear-positive patients as well as smear-negative patients with symptoms of TB should be treated presumptively until their culture tests come back. It appears at least 3 in 10 patients with TB can be correctly diagnosed quickly if the Lipoarabinomannan ELISA test is more widely introduced HTB would be interested in hearing from clinicians what they think of this, how regularly screening should take place and what the cost implications would be.

Treatment: matters look a little more promising for TB treatment

Graeme Meintjes presented the results of a double-blind placebo controlled trial of prednisone for the treatment of patients who develop clinical deterioration of active TB as a consequence of Immune Reconstitution Inflammatory Syndrome (IRIS) after starting HAART. This steroid is used by many clinicians to treat paradoxical TB IRIS but this is the first clinical trial to determine its safety and efficacy.

55 patients were randomly assigned to prednisone and 54 to placebo. The median CD4 count was 53 prior to HAART and 116 at the time they were enrolled on the trial. Average time in hospital spent by prednisone patients was shorter than those on placebo (1 [IQR: 0-3] versus 3 [IQR: 0-11], p=0.05). The cumulative number of hospital days of the prednisone group was 282 versus 463 days for the placebo group. There were also fewer hospital procedures in the prednisone arm (29 versus 38). Further evidence of prednisone’s benefits are that during the four weeks of the study, five patients switched to open-label prednisone in the prednisone arm versus 19 in the placebo arm due to clinical deterioration (p=0.001).

Also, all six patients lost to follow-up were in the placebo arm (p=0.01) Nine patients had potential drug-related side effects in the prednisone arm versus three in the placebo but this was not significant (p=0.07). A 5-point score demonstrated significant symptom improvement in the prednisone arm compared to placebo at 2 weeks (p = 0.003). [9]

COMMENT

This study showed that prednisone reduces hospitalisation and procedures. It also improved symptoms. There was no statistically significant difference in mortality (3 on prednisone versus 2 on placebo), but as Meintjes pointed out this was likely due to the exclusion of patients who had severe IRIS (eg neurological involvement) from the study (they were given prednisone) and the switching of patients to open-label prednisone when their health deteriorated.

Elizbeth Corbett gave a summary of the state of TB research. She showed a slide of the TB drug development pipeline, which looks more promising than a few years ago. There are six drugs in pre-clinical trial stages, two in phase one and three in phase two trials. Three existing drugs are being tested, either for new use or in higher dose, in phase III trials.[9]

The most promising new drug is TMC207. The interim results of a phase II trial comparing MDR TB treatment plus TMC207 versus MDR TB treatment plus placebo were presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy in October 2008. The study showed that the drug was safe and well-tolerated over eight weeks in patients with drug-resistant TB. 47.5% of patients in the TMC207 arm were culture-negative at the end of the eight weeks as opposed to 8.7% in the placebo arm. [10]

COMMENT

In a pre-CROI presentation Charles Flexner of the Division of Pharmacology at John Hopkins University explained the pharmacology of TMC207. He concluded his talk by provocatively suggesting that it should be tested to see if it could eradicate latent TB with a single dose. Flexner’s idea, albeit speculative, is exciting: a large percentage of people in Southern Africa are infected with latent TB with the potential to become active TB if their immune systems are weakened. If TMC207 worked against latent TB, this would be a major breakthrough against the disease. However, Flexner also pointed out the problem that the lack of profitability of TB drugs was a hindrance to pharmaceutical company development.

Also see:  TMC207 reduces time to sputum conversion in phase II trial in patients with drug-resistant TB

Prevention

The standard IPT regimen is 300mg of isoniazid daily for six months. A Cochrane Review has concluded that this reduces the risk of developing active TB in people with HIV, but the review also said that more research was needed to find the best regimen. [12]

Neil Martinson and his colleagues conducted a randomised trial on 1,150 patients to determine if alternative regimens had advantages over standard IPT.

His team compared four regimens:

• Regimen 1: 900mg of rifapentine plus 900 mg of isoniazid once weekly for 12 weeks (n=329)
• Regimen 2: 600mg of rifampicin plus 900 mg of isoniazid twice weekly for 12 weeks (n=329)
• Regimen 3: 300mg of isoniazid daily for the entire trial (an average of nearly 4 years for most of the 164 patients on this arm)
• Regimen 4: Standard IPT regimen (n=328)

There were no statistically significant differences in TB incidence or death between the arms. There was a statistically significant greater number of grade 3 and 4 toxicities in the continuous isoniazid arm (regimen 3). 54 patients were tested for resistance. One had rifampicin resistance (regimen 1), one had streptomycin resistance and three had MDR-TB (one in regimen 3 and and two in regimen 1).(13)⁠

Since none of these regimens proved superior to the standard regimen, it should continue to be the TB prevention regimen of choice. However, the effectiveness of the other regimens was not inferior either and in some settings or with some patients it might make sense to use them.

Drug-resistant TB: news on drug-resistant TB in South Africa continues to be concerning

A poster by Max ‘O Donnell presented data on XDR TB patients at King George V Hospital in Durban. In 2006-2007, 1,771 cases of MDR TB and 242 cases of XDR TB were referred to the hospital. O’Donnell and his team specified a six-month study period, in which they attempted to enrol 72 XDR TB patients. Four refused enrolment, six died prior to starting treatment and two had insufficient data, leaving a cohort of 60. The patients were transferred to the hospital from 26 different health facilities representing seven of the province’s 11 districts. This implies that XDR TB is quite diffuse in Kwazulu-Natal. 25% of patients came from Tugela Ferry, 11% from Durban and 8% from Pietermaritzburg. 43 were HIV-positive, 12 negative and the remainder unkown. 21 were on HAART. At least 11 had never been treated previously for TB and at least 28 had never been treated for MDR TB. Three were health workers.

25 died and 6 defaulted, meaning that less than half were alive and accounted for by the end of the six month study period. Only 12 patients had converted to a negative culture. 17 were still in treatment. Interestingly, HIV disease increased the risk of death but this increase was not statistically significant, quite likely because the sample was too small to detect it. [14]

So while some treatment success was achieved, the outcomes for XDR TB remain very poor.

This was confirmed by a study from Tugela Ferry by Neel Gandhi and colleagues, which found extremely high mortality rates in patients with MDR and XDR TB. They used the local TB register to identify drug resistant cases diagnosed from 2005 to 2007. They found 272 MDR TB cases and 382 XDR TB cases. One-year mortality was 82% and 69% for XDR and MDR cases respectively.

They noted that “40% of MDR and 54% of XDR TB cases died within the first 30 days.” On a promising note, one-year mortality in MDR cases dropped from 87% in 2005 to 45% in 2007 (p=.009). 30-day mortality also improved for MDR TB, from 57% to 32%. Unfortunately no statistically significant improvements in XDR TB occurred.

One-year and 30-day mortality were proportional to the number of resistant drugs (p<0.001) see table 4. [15]

Table 4: 30 day mortality proportional to number of resistant drugs

ADD TABLE

Another study from Tugela Ferry by Palav Babaria and colleagues at Church of Scoland Hospital found alarmingly high rates of TB, including drug-resistant strains, among HIV-positive patients. They screened 263 HIV-positive patients. 52 (20%) were culture-positive for TB. Only 24 tested smear-positive, once more underlining the lack of reliability of this test in HIV-positive patients. Symptoms of TB were not a good predictor of disease, because most patients presented with coughs, night sweats, chest pains, weight loss and fever irrespective of their TB status. 13 patients had at least MDR TB (resistant to both isoniazid and rifampin), of whom 7 met the criteria for XDR TB as well. [16]

COMMENT

The study by Gandhi et al made excellent recommendations on what is needed: a test that can diagnose MDR and XDR TB within one to two weeks, intensified case finding to identify patients at an earlier stage of disease, expansion and decentralisation of second-line TB treatment programmes, creation of integrated HAART and 2nd-line TB treatment programmes and infection control programmes in areas where TB patients congregate.

The first of these, a better quicker diagnostic, is beyond the immediate control of the South African Department of Health, but the remaining recommendations are all achievable with current technologies. If we are to mitigate the effects of drug-resistant TB, the money and resources needed to implement these recommendations must be made available.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 16th Conference on Retroviruses and Opportunistic Infections. 8-11 February 2009, Montreal. Oral abstracts are available as a web cast.

1. Abdool Karim S et al. Initiating ART during TB Treatment Significantly Increases Survival: Results of a Randomized Controlled Clinical Trial in TB/HIV-co-infected Patients in South Africa. 16th CROI 2009. Oral abstract 36a.
http://www.retroconference.org/2009/Abstracts/34255.htm
2. Fatti G et al. Improved TB Treatment Outcomes at Facilities Enhanced by a Non-governmental Organization-assisted ART Program: Western Cape, South Africa. 16th CROI 2009. Poster abstract 591.
http://www.retroconference.org/2009/Abstracts/33694.htm
3. Howard A, Saito S, Nash D, Flam R, Elul B, Scardigli A, Oyeledun B, Cunningham A, Hoos D, El-Sadr W. On-site Location of TB Services Is Associated with TB Screening of HIV-infected Patients at Enrollment in HIV Care Programs: 6 Sub-Saharan African Countries. 16th CROI 2009. Poster abstract 590.
http://www.retroconference.org/2009/Abstracts/36106.htm
4. Lawn S, Myer L, Edwards D, Wood R. Short- and Long-term Risks of TB Associated with CD4 Cell Response to ART in South Africa. 16th CROI 2009. Poster abstract 788.
http://www.retroconference.org/2009/Abstracts/34727.htm
5. Edwards D et al. Baseline Screening for TB among Patients Enrolling in an ART Service in South Africa. 16th CROI 2009. Poster abstract 780.
http://www.retroconference.org/2009/Abstracts/36271.htm
6. Godfrey-Faussett P. et al. Sensitivity, specificity and predictive values of symptoms to detect tuberculosis in the ZAMSTAR community based prevalence studies. Presentation at pre-CROI obtained through personal communication.
7. Bassett I et al. Intensive TB Screening for HIV-infected Patients Ready to Start ART in Durban, South Africa: Limitations of WHO Guidelines. 16th CROI 2009. Poster abstract 779.
http://www.retroconference.org/2009/Abstracts/34392.htm
8. Hassim S. Active Sputum Acquisition Permits Detection of Substantial Rate of Multidrug-resistant TB in a High-risk Population in South Africa. 16th CROI 2009. Poster abstract 781.
http://www.retroconference.org/2009/Abstracts/34089.htm
9. Meintjes G et al. Randomized Placebo-controlled Trial of Prednisone for the TB Immune Reconstitution Inflammatory Syndrome. 16th CROI 2009. Oral abstract 34.
http://www.retroconference.org/2009/Abstracts/34429.htm
10. Corbett E. Prospects for Better Control of HIV/TB: From the Clinic to the Community. 16th CROI 2009. Plenary abstract 19.
http://www.retroconference.org/2009/Abstracts/36637.htm
11. Levin J. Conference Reports for NATAP: Interim analysis of a double- blind, placebo-controlled study with TMC207 in patients with Multi-Drug Resistant (MDR) Tuberculosis: effective and safe. 2008.
http://www.natap.org/2008/ICAAC/ICAAC_95.htm
12. Volmink J et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Review. 2003.
http://www.cochrane.org/reviews/en/ab000171.html
13. Martinson N et al. Novel Regimens for Treating Latent TB in HIV-infected Adults in South Africa: A Randomized Clinical Trial. 16th CROI 2009. Oral abstract 36bLB.
http://www.retroconference.org/2009/Abstracts/36768.htm
14. O’Donnell M. et al. Improved Survival for Patients with Extensively Drug-resistant TB and HIV in South Africa. 16th CROI 2009. Poster abstract 785.
http://www.retroconference.org/2009/Abstracts/34552.htm
15. Gandhi N et al. High Early Mortality among HIV-infected Patients with Extensively Drug-resistant or Multidrug-resistant TB in Rural South Africa. Poster abstract 784.
http://www.retroconference.org/2009/Abstracts/36299.htm
16. Babaria P et al. High Rate of Unrecognized TB and Drug-resistant TB among ART Clinic Patients in Rural South Africa. Poster abstract 782.
http://www.retroconference.org/2009/Abstracts/36257.htm

The results of the first of two stages of a double-blinded phase II Tibotec trial on the new TB drug TMC207 have been published in the NEJM.[1] Its purpose was to evaluate the safety, tolerability, pharmacokinetics, and antibacterial activity of TMC207. 47 hospitalised patients in South Africa aged 18 to 57 with sputum-positive TB and resistant to isoniazid and rifampin – ie they had multi-drug-resistant TB (MDR-TB) – were randomised to receive either TMC207 or placebo as an addition to their MDR treatment. The study was run from 5 June 2007 to 23 January 2008.

Besides standard exclusion criteria, patients resistant to aminoglycosides, other than streptomycin, and fluoroquinolones were excluded. So were patients who had previously been treated for MDR TB, had neurologic or severe extrapulmonary TB, had HIV with a CD4 count lower than 300 cells/, had received ART or antifungal medication or both in the previous 90 days or had significant cardiac arrhythmia.

The dosing regimen was 400 mg once daily for weeks 1 and 2, followed by 200 mg three times a week for weeks three through eight, the length of time patients were enrolled in this stage of the study. The study drugs were provided as TMC207 100-mg tablets (or placebo) and were taken with water immediately after breakfast. The preferred background regimen for all patients was kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizidone. The primary efficacy end point was the time to the conversion of sputum cultures from positive to negative, defined as two consecutive negative cultures. Cultures were performed weekly.

23 patients were in the study drug arm and 24 in the placebo one. 74% of the patients were male, 55% black and 87% HIV-negative. Median age was 33.Three patients were excluded from the final analysis, two because they met study exclusion criteria and one because his or her culture test (MGIT) gave a negative result throughout the study despite originally being smear-positive. 41 patients (20 and 21 in the TMC207 and placebo groups respectively) completed the study.

There were no significant differences in adverse events except for nausea (six cases in the TMC207 arm versus one in the placebo arm; 26% vs 4%; p=0.04). There were two grade four events, one in each arm. These were considered unrelated to TMC207.

The majority of patients achieved average steady-state plasma TMC207 concentrations above the target of 600 ng per milliliter throughout the dosing period. Sputum culture conversion did not predict average steady-state plasma concentrations of TMC207.

TMC207 resulted in 11.8 times quicker conversion to sputum-negative culture (95%CI: 2.3-61.3; p=0.0003). The proportion converting to negative culture during the 8 weeks was 48% for TMC207 (10 of 21 patients) versus 9% in the placebo group (2 of 23 patients). Treatment responses were similar irrespective of trial centre and lung cavitation.) At week four 57% in the placebo group and 77% in the TMC207 group had negative sputum smears (acid-fast bacilli). At week eight these proportions were 68% for the placebo group and 84% for the TMC207 group. The change from baseline in the log10 count of colony-forming units (CFUs) in the sputum TB culture were also measured in a sub-group of 22 patients (9 TMC207 vs 13 placebo). The median log10 CFU decreased to zero by week four in the TMC207 arm and week eight in the placebo arm.

Background on TMC207

In July 2003, Janssen Pharmaceutica, a subsidiary of Johnson & Johnson (J&J) filed a patent application for quinoline derivative drugs for the treatment of mycobacterial diseases including TB. The patent was published in February 2004.[2] One of these drugs, TMC207 was first described in Science in December 2004 by Andries et al.[3] It was originally called R207910 but it was renamed to reflect that Tibotec, another J&J subsidiary, is developing it. Andries et al. examined a class of drugs called diarylquinolines which were chemically optimised from a lead compound. They announced that they had found 20 molecules with an in vitro minimum inhibitory concentration (MIC) below 0.5 µg/ml against a strain of TB, H37RV. This strain was derived from a human-lung TB isolate in 1934 and is used extensively in biomedical research as a standard [4] TMC207 was the most effective of three of these drugs which were effective against TB in vivo.

The chemical name for TMC207 is 1-(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol. The molecular formula is C32H31BrN2O2 and the molecular weight is 555.51 daltons.

Andries et al. ran experiments to select TB bacteria resistant to TMC207. They then genetically sequenced these resistant strains and found that only one gene was affected on three independent strains. This gene codes a part, F0, of ATP synthase. This is a protein that uses protons to convert ADP to ATP. F0 is a membrane proton channel. Researchers have therefore determined that TMC207 works by inhibiting the proton pump of ATP synthase. This is a different mechanism to current anti-TB drugs. This together with Andries et al.’s laboratory experiments indicates that if TMC207 is effective it will not be cross-resistant with other TB drugs.

In the Andries et al. study TMC207 appeared to be selectively active against TB; much higher MICs were required for laboratory efficacy against other bacteria (a subsequent study indicated activity against Buruli ulcer and leprosy in mice [5] [6]). At appropriate concentration (10 times MIC) the drug reduced bacterial load by 3 log units after 12 days. The effect was not improved with higher concentrations, suggesting, the authors say, that the effect is time-dependent rather than concentration dependent.

Another Tibotec study showed that TMC207 has in vitro activity against latent (or dormant) TB.[7] This is because, according to the authors, dormant TB bacteria have residual ATP synthase activity.

In another phase II study 75 treatment-naïve patients with newly diagnosed smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in effect to INH and RIF over the same period. The authors concluded that TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.[8]

Ongoing TMC207 trials

There are five TMC207 trials registered with clinicaltrials.gov of which one is complete [9-12]. The four incomplete ones are:

• TMC207-TiDP13-C208: This is a phase II, placebo-controlled, double-blind, randomized trial to evaluate the anti-bacterial activity, safety, and tolerability of TMC207 in subjects with newly diagnosed sputum smear-positive pulmonary infection with MDR-TB. This is the second stage of the study discussed in this summary and is currently recruiting patients including in six South African hospitals. The second stage consists of a 24 week treatment period for 150 patients. All patients will be followed for 96 weeks after the last dose of TMC207 or placebo. It is planned to complete in May 2011.
• TMC207-TiDP13-C110: This will be a phase I study to examine, in 16 healthy volunteers, the interactions between TMC207 and lopinavir/ritonavir. Recruitment has not begun.
• TMC207-TiDP13-C117: This will be a phase I study in 16 HIV-positive people to examine the interactions between TMC and nevirapine. Recruitment has not begun.
• TMC207-TiDP13-C209: This will be a phase II, open-Label trial with TMC207 as part of an MDR-TB treatment regimen in 225 patients with sputum smear-positive pulmonary infection with MDR-TB. The estimated study completion date is June 2012. Recruitment has not begun.

COMMENT

There is a pressing need for new TB drugs globally for several reasons: to improve treatment outcomes for patients with drug resistant TB, to shorten the course of standard TB treatment, to improve and shorten the treatment of latent TB and to allow options for patients who develop toxicities that make them intolerant of the currently used drugs.

Several new TB drugs are in development. It is too early to say with certainty if any of these are safe and effective for the treatment of TB in humans. TMC207 is the most promising of these, especially since it has in vitro activity against dormant TB.

Pharmaceutical companies do not consider TB drugs particularly profitable. Consequently there are relatively few in development in relation to the pressing global need. Those that are will take a long time to get through the drug development cycle. TMC207’s history goes back to at least 2004, possibly even 2003, and yet, if it proves safe and effective, it is unlikely to be registered anywhere before 2011, perhaps even 2012. This is a much longer development period than for many ARVs, even though the need for new TB drugs is at least as great.

In the meantime compassionate access for TMC207 should be considered for patients with DR-TB and no other options.

References

1. Diacon AH et al. The diarylquinoline TMC207 for multidrug-resistant Tuberculosis. N Engl J Med. 2009 June 4. 360, 2397-2405.
http://content.nejm.org/cgi/content/abstract/360/23/2397
2. Guillemont J Patent (International publication number: WO 2004/011436.
http://www.wipo.int/pctdb/en/wo.jsp?IA=EP2003050322&wo=2004011436&DISPLAY=STATUS
3. Andries K et al. A diarylquinoline drug active on the ATP synthase of mycobacterium tuberculosis. Science. 2005 January 14. 307, 223-227.
http://www.sciencemag.org/cgi/content/abstract/307/5707/223
4. Sanger Institute mycobacterium tuberculosis H37Rv project.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=224
5. Ji B et al. Bactericidal activities of R207910 and other newer antimicrobial agents against mycobacterium leprae in mice. Antimicrob. Agents Chemother. 2006 April 1. 50, 1558-1560.
http://aac.asm.org/cgi/content/abstract/50/4/1558
6. Ji B et al. In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against mycobacterium ulcerans. Antimicrob. Agents Chemother. 2006 June 1. 50, 1921-1926
http://aac.asm.org/cgi/content/abstract/50/6/1921
7. Koul A et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J. Biol. Chem. 2008 September 12. 283, 25273-25280.
http://www.jbc.org/cgi/content/abstract/283/37/25273
8. Rustomjee R et al. Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob. Agents Chemother. 2008 August 1. 52, 2831-2835.
http://aac.asm.org/cgi/content/abstract/52/8/2831
9. NIH TMC207-TiDP13-C208: Anti-bacterial activity, safety, and tolerability of TMC207 in patients With multi-drug resistant mycobacterium tuberculosis (MDR-TB).
http://clinicaltrials.gov/ct2/show/NCT00449644
10. NIH TMC207-TiDP13-C110: Interaction study in healthy volunteers with lopinavir/ritonavir.
http://clinicaltrials.gov/ct2/show/NCT00828529
11. NIH TMC207-TiDP13-C117: Interaction study in Human Immunodeficiency Virus-Type 1 (HIV-1) infected patients with nevirapine (NVP).
http://clinicaltrials.gov/ct2/show/NCT00910806
12. NIH TMC207-TiDP13-C209: Trial to evaluate the safety, tolerability, and efficacy of TMC207 as part of an individualized multi-drug resistant tuberculosis (MDR-TB) treatment regimen in patients with sputum smear-positive pulmonary MDR-TB.
http://clinicaltrials.gov/ct2/show/NCT00910871

Graeme Meintjes et al. have published a detailed analysis of 100 prospectively evaluated patients with suspected TB IRIS from February 2005 to July 2006 at GF Jooste Hospital in Cape Town. The authors’ analysis elucidates the relationship between TB IRIS and drug-resistant TB. [1]

The TB incidence rate in the Western Cape province is 1,031 per 100,000 population and more than 10,000 people have initiated HAART in the catchment area for GF Jooste Hospital. Many patients initiate late and TB and HIV co-infection is high. Consequently, as the authors explain, hundreds of TB IRIS cases have been seen.

Paradoxical TB-IRIS occurs in patients who are diagnosed with TB prior to ART initiation. These patients are typically improving on TB treatment, but then 1-4 weeks after starting ART develop new or recurrent TB symptoms and clinical manifestations, such as enlarging TB lymph nodes or worsening radiographic pulmonary infiltrates. There are many other reasons for clinical deterioration in such patients and because there is no diagnostic test for TB IRIS, the diagnosis of the condition can be difficult. Diagnosis requires exclusion of TB treatment failure due to resistance or suboptimal drug concentrations, as well as alternative opportunistic infections (OIs).

During the diagnostic work-up of patients with suspected TB-IRIS in the study the authors found a high prevalence of unsuspected drug-resistant TB in their cohort, with implications for the diagnosis and management of TB IRIS. In particular, prednisone, which is an effective adjunctive treatment for TB IRIS, and other corticosteroid therapies may worsen outcomes if used in patients on incompletely efficacious TB treatment or with other untreated OIs. The 100 patients in this report were being assessed for the clinical trial that ultimately determined the efficacy of prednisone against placebo in patients with mild and moderate TB IRIS (reported on in this issue). 38 of these 100 patients were enrolled in that study and 25 received corticosteroids outside the study, usually for severe TB IRIS.

Baseline data and subsequent diagnoses

66 patients were female and 34 male. The median age was 31 [IQR: 26-35]. Patients were initially diagnosed with TB using culture tests (41 people), smear microscopy (31) and clinical and radiological data (24). Subsequent tests showed that the remaining four patients were incorrectly diagnosed with TB despite receiving TB treatment (3 had NTM infections and 1 had lymphoma). Of the patients clinically and radiologically diagnosed with TB at baseline, seven were later confirmed with smear or sputum tests.

After presentation with suspected TB-IRIS the following diagnoses were made after work-up and sending samples for TB culture and drug susceptibility testing;

• 80 patients were diagnosed with TB IRIS and no resistance.
• Nine patients were diagnosed with TB IRIS and then discovered to have rifampicin resistance, seven of whom were also found to have INH resistance (ie. MDR TB).
• Four patients were known with rifampicin resistance at presentation, of whom three were known to have MDR TB.
• Seven patients with suspected TB IRIS were diagnosed not to have TB-IRIS but received a diagnosis of an alternative OI.

The first two groups initially fulfilled the case definition of TB IRIS. There were no statistically significant differences in baseline data except a shorter duration from initiation of TB treatment to HAART in the first two groups compared to the third.

The median baseline CD4 count was 50 cells/ (IQR: 26-94). Follow-up CD4 counts were available for 77 patients. CD4 counts increased by a median of 139 (IQR: 64-241) from their pre-HAART values in 73 patients. They declined in the remaining four. In 65 of 74 patients with viral load performed on HAART it was below 400 copies/mL. In four patients with viral loads > 1000, CD4 cell counts nevertheless increased during HAART.

The paper describes a wide variety of methods, procedures and mechanisms used to diagnose TB, diagnose TB IRIS and determine drug susceptibility results, including use of cultures performed on sputum (55%), lymph node or abscess aspirate (18%), pleural fluids (8%), CSF (8%) and other specimens (11%); radiographs and FASTplaque assays (rapid rifampicin susceptibility test), to name a few. It also gives case histories for the nine patients subsequently diagnosed with rifampicin resistance and clinical data for the 80 patients without resistance. The most frequent TB-IRIS symptoms in this latter group were constitutional (68 people), including night sweats, anorexia, malaise, and weight loss; respiratory (48 people) and abdominal (47 people) including abdominal pain, nausea, vomiting and diarrhea. The symptoms for the nine rifampicin-resistant patients were similar Blood tests were also similar between the two groups although the median C-reactive protein level was higher in the resistant group (179mg/L [IQR: 100-212] vs 96mg/L [IQR:70-152]; p=0.05). There was evidence of immune activation using ELISpot in both groups, albeit less so in the resistant group.

Drug resistance and IRIS not mutually exclusive

The nine patients with subsequently detected rifampin-resistance improved while receiving standard TB treatment prior to HAART and then deteriorated during the weeks after HAART initiation (3-48 days which is characteristic of TB IRIS). The same occurred in the additional four patients with known rifampicin resistance although they were on MDR treatment prior to HAART. The authors ask whether the condition of these 13 patients deteriorated because of sub-optimally treated TB, TB IRIS or both. They propose that based on their clinical observations that TB IRIS and TB drug resistance may overlap and are not mutually exclusive. They suggest that patients with rifampicin resistance might be at greater risk of TB IRIS because of higher mycobacterial loads. This has implications for the case definition of TB IRIS.

COMMENT

This study’s detailed clinical histories and descriptions of diagnosis may be useful for clinicians who need to diagnose TB, drug-resistant TB and TB IRIS. However, the complexity of this work is not replicable in the public health system outside research and referral hospital settings especially when the intensity of investigation and wide variety of diagnoses that were made are taken into account. Yet these findings are important because the proportion of drug-resistant cases and initial misdiagnoses was substantial. Two conclusions follow from this: (1) TB diagnostics need to be improved and simplified. This is not a new observation, but this paper exemplifies this need. (2) It is urgent that Meintjes et al.’s findings, both in this paper and their work on prednisone, be used to update the TB treatment guidelines in the South African public health system, taking into account constraints on health worker time and the need for simple protocols.

Ref:

Meintjes G. et al. Novel Relationship between Tuberculosis Immune Reconstitution Inflammatory Syndrome and Antitubercular Drug Resistance. Clinical Infectious Diseases 2009;48:667–676
http://content.nejm.org/cgi/content/abstract/360/23/2397

Daniel Westreich and colleagues have examined the risk of stavudine substitution for patients on TB treatment in the Themba Lethu clinical cohort. [1] This cohort comprises adults at one of the largest public clinics providing HAART in South Africa. Stavudine is part of the first-line regimen used in the South African public health system and most of sub-Saharan Africa. It has a poor side-effect profile compared to other currently used ARVs and is associated with lactic acidosis, lipid disorders, lipodystrophy and peripheral neuropathy, but it is also the cheapest ARV which is why it is so widely used. Westreich et al. report that more than 20% of patients in this cohort required substitution of stavudine because of toxicity –primarily lipodystrophy or peripheral neuropathy– by 36 months after treatment initiation.[2]

Westreich et al. examined four groups among over 7,000 patients on HAART from April 2004 to March 2007:

• patients not on TB treatment (n=5,226);
• patients on ongoing treatment, i.e. those who started TB treatment at least 15 days before initiating HAART (n=1,272);
• patients on concurrent treatment, i.e. those who started TB treatment and HAART within 14 days of each other (n=224); and
• patients who needed TB treatment at least 15 days after commencing HAART (incident treatment group, n=344).

All TB regimens contained isoniazid, which is also associated with peripheral neuropathy. The outcome was all-cause stavudine substitution, defined as the substitution of stavudine with another ARV, usually AZT, while the remainder of the regimen was unchanged. Patients were followed up until they substituted stavudine, contracted a second episode of TB while receiving HAART, died, were lost to follow up, had multi-drug substitution or until the end of the follow-up period. Results were adjusted for sex, ethnicity, employment, age, history of HAART, history of TB treatment, pregnancy, peripheral neuropathy at HAART initiation, hemoglobin level (adjusted for sex, altitude and pregnancy), BMI, CD4 count, WHO stage, calendar date, whether treatment was initiated after consultation fees were abolished in October 2006 and stavudine dosage.

260 (3.7%) patients died, 1,252 (17.7%) were lost to follow-up and 1,219 were changed off stavudine, of whom 203 had multi-drug substitutions, 172 were switches to second-line HAART and 842 had single stavudine substitutions. The crude rate of single stavudine substitutions was 12.4 per 100py [95%CI: 11.6-13.3] with a median time to single-drug stavudine substitution of 347 days [IQR: 175-535].

The absolute rate of stavudine substitution increased with time from HAART initiation:

• months 0-6: 7.9/100py (95%CI: 6.9-9.1),
• months 6-12: 12.3/100py (95% CI, 10.8-14.0),
• rest of follow-up: 18.1/100py (95%CI: 16.4-20.0).

Peripheral neuropathy was the main cause of substitution (362 out of 842, 43%). Lipodystrophy was responsible for 205 (24%) switches. Lactic acidosis or symptomatic hyperlactatemia was responsible for 168 (20%). 21 (2%) were due to a combination of toxicities and 86 (10%) had no reason recorded.

The ongoing and concurrent TB treatment groups were significantly associated with stavudine substitution in the first two months of TB treatment, but not the incident group, when compared to those not on TB treatment. The hazard ratio for the ongoing group remained significant in months 3 to 6 of TB treatment. The adjusted hazard ratio for the three TB-treatment groups compared to the no-TB treatment group is given in Table 1, broken down by number of months on HAART.

ADD TABLE

Table 1. Adjusted HR for stavudine substitution by months on HAART and 95% CI

The study found that patients who switched because of peripheral neuropathy were 1.53 times more likely to have TB at HAART initiation or during follow-up (95%CI: 1.33-1.75). This suggests that the risks of stavudine and isoniazid for neuropathy compound each other. Interestingly, those who switched because of lactic acidosis or lipodystrophy were less likely to have TB (RR: 0.58; 95% CI: 0.48-0.71).

The results were not sensitive to stavudine dose, multi-drug substitutions, or TB treatment lasting nine months rather than six months. However if only patients without a history of TB were considered, the hazard ratios in the ongoing and concurrent groups in the first two months of treatment rose to 3.56 and 7.57 respectively. The authors suspect that lingering peripheral neuropathy from previous drug exposures in those with a history of TB treatment included in the no TB treatment group might therefore have resulted in the true impact of current TB treatment on stavudine substitution being underestimated.

The authors also suggest that they underestimate peripheral neuropathy because most TB patients in SA receive vitamin B6 for the prevention of this INH-related neuropathy. Also amitriptyline is prescribed to patients who develop peripheral neuropathy. Take these two two treatments away and the number of substitutions would likely increase. The authors did not analyse low-level peripheral neuropathy not requiring substitiution. They explain therefore that the impact of TB treatment on the risk of stavudine toxicities may be higher than the impact of TB treatment on the risk of stavudine substitution. They further explain that the surprising lack of stavudine substitution in the incident group might be because of a decrease in susceptible patients or because the risk of stavudine toxicity is reduced with low viral load they hypothesize.

Overall, one in 18 of all patients with TB at baseline (the ongoing and concurrent groups) need a stavudine substitution versus one in 42 for patients who do not receive TB treatment. The authors state that because more than 20% of patients who commence HAART are on or need TB treatment, this has considerable public health implications.

Several confounding factors might have biased the analysis. Patients with TB might be more exposed to other drugs that increase the risk of peripheral neuropathy. Further, health workers might be more likely to look for peripheral neuropathy in patients taking isoniazid and stavudine.

COMMENT

This is yet another study which demonstrates the need to replace stavudine with tenofovir in sub-Saharan African first-line regimens, at least for patients at risk of TB. The large difference in price between the two drugs, the fact that the only readily available three-in-one combination pill (Triomune) contains stavudine (a factor important outside of South Africa, because Triomune is not used in the public sector in SA) as well as the long delays in updating and publishing the South African Department of Health guidelines remain barriers to this happening.

As the authors recommend, regular monitoring for peripheral neuropathy in patients taking stavudine, especially if they are on isoniazid, is essential. In particular, patients should be asked about sensations of pain, numbness or tingling in the toes and feet.

References

1. Westreich DJ et al. Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy. Clinical Infectious Diseases. 2009; 48:1617-23
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)60492-4/fulltext
2. Boulle A et al. Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort. Antivir Ther 2007; 12:753­60
http://www.ncbi.nlm.nih.gov/pubmed/17713158

The report found a total of 9.3 million new TB cases in 2007, 1.4 million of which occurred in people living with HIV/AIDS. Kevin De Cock, HIV/AIDS director at WHO said that these new estimates do not reflect an increase HIV/TB coinfections or in TB deaths among HIV patients, but rather “better analyses, better data and better methodology”. In addition, increased HIV testing among TB patients has revealed cases of HIV that previously went undetected. In previous reports, WHO used data on HIV/TB coinfection from 15 countries; however, the new report includes data from 64 countries, several of which are in sub-Saharan Africa.

According to the report, 55% of recorded TB cases occurred in Asia in 2007, while 31% occurred in Africa. India had the highest number of recorded cases at two million, followed by China with 1.3 million and Indonesia with 530,000.

There were about 1.3 million TB deaths among HIV-negative people and about 456,000 among HIV-positive people in 2007. TB was the primary cause of death among people living with HIV/AIDS in 2007 and HIV-positive people are about 20 times more likely to develop TB than HIV-negative people in countries with high HIV prevalence and are between 26 and 37 times more likely to develop TB in countries with lower HIV prevalence.

The report found a significant increase in the number of HIV tests that are administered to people with TB, particularly in Africa. About 4% of TB patients in Africa were tested for HIV in 2004, compared with 37% in 2007. In several countries, more than 75% of TB patients received an HIV test, according to the report. Although efforts to address HIV/TB coinfection have improved, such efforts are inadequate in many developing countries. De Cock noted that only one in seven HIV-positive people receive preventive treatment for TB. In addition, more than one-third of TB cases worldwide are undiagnosed, increasing the risk of transmission. The report recommended that HIV-positive people receive TB screenings and medications to reduce their risk of developing the disease.

The report also found an increase in drug-resistant strains of TB in recent years. According to the report, more than 500,000 people worldwide have been diagnosed with multi-drug resistant TB. Fewer than 1% of people with MDR-TB were receiving WHO-recommended treatment in 2007. In addition, at least one case of extensively drug-resistant TB has been reported in 55 countries and territories worldwide. XDR-TB is resistant to two of the most potent first-line treatments and at least two of the classes of second-line drugs. Mario Raviglione, director of WHO’s STOP TB department, added that the actual prevalence of XDR-TB likely is higher because many developing countries do not conduct tests to determine the extent of drug-resistance in TB patients.

The report also documented concern over funding in the current economic downturn, noting that 94 countries that account for 93% of all TB cases worldwide have a funding shortfall of $1.5 billion to meet the targets in the Global Plan to Stop TB 2006-2015.

Wafaa El-Sadr, a professor of medicine and epidemiology at Columbia University said the report’s findings “demonstrate that one cannot think of tackling or controlling the TB epidemic globally without thinking of how we’re going to do it in HIV-infected populations”.

Source: Edited from Kaiser Daily News. About 25% of TB deaths occur among HIV-positive people, WHO Global TB Control Report says. (25 March 2009)

http://www.kaisernetwork.org/daily_reports/rep_hiv.cfm#57660

The WHO report, together with supporting documents, is available online:
http://www.who.int/tb/publications/global_report/2009/en/index.html

In an oral presentation, Andrew Boulle from the University of Cape Town showed findings from a prospective cohort study of adults receiving rifampicin based TB treatment with either nevirapine or efavirenz containing ART.

The study was conducted in Khayelitsha, a township outside Cape Town with a 30% HIV antenatal prevalence and TB case finding above 1500/100,000. The aim was to look at outcomes, in patients initiating NNRTI-based ART, who were already receiving rifampicin containing TB treatment.

The cohort were treatment naïve adults >/= 14 years of age, </=250 cells/mm³ enrolled between 2001 and June 2006. If they were receiving TB treatment there must have been 14 days overlap of TB and HIV treatment.

The analysis looked at four different treatment scenarios: people without TB starting either nevirapine or efavirenz and people receiving rifampicin-based TB treatment when starting nevirapine or efavirenz.

The investigators identified 4117 patients starting on ART during the study period. Of those, 2687 patients were without TB when they initiated HIV treatment; 1726 started on nevirapine and 961 efavirenz. The remaining 1283 started ART while receiving TB treatment, of these, 209 started with nevirapine and 1074 efavirenz.

The four treatment groups had similar baseline characteristics. There were however more women in the nevirapine vs efavirenz groups: 73.7% vs 62.1% (p<0.001) with TB treatment, and 80% vs 51.7% (p<0.001) without TB. Also in the TB treatment group, the patients receiving nevirapine had been receiving TB treatment for longer, a median of 87 days vs 73 days in the efavirenz group (<0.001). And the patients receiving nevirapine had higher median CD4 counts than those receiving efavirenz: 80 vs 61 cells/mm³ (p=0.002) in the TB treatment group and 116 vs 93 cells/mm³ (p<0.001) in the group without TB at baseline.

Viral load results were available for a subset of patients. The investigators defined a suboptimal response to HAART as failure to suppress viral load to less than 400 copies/mL. This occurred for approximately 15% at 6 months of the patients receiving nevirapine with TB treatment at 6 months vs between 6-9% for the patients receiving nevirapine (n=141) without TB treatment or efavirenz. The same analysis at 18 months showed failure to suppress in approximately 20% vs 8-13% in the nevirapine with TB treatment (n=80) and the other groups respectively.

The odds ratios for viral load >400 copies/mL at 6, 12, 18 months and all time points combined, for patients receiving TB treatment were 2.1, 1.6, 1.4 and 1.7 respectively for those receiving nevirapine and 1.2, 0.9, 1.1 and 1.1 for those receiving efavirenz.

In multivariate analysis combining all four groups the odds ratios (with efavirenz and no TB treatment as reference) were: efavirenz/TB treatment at start 1.1 (95% CI 0.7-1.7); nevirapine/no TB 1.5 (95% CI 1.0-2.1); nevirapine, TB treatment at start 2.9 (95% CI 1.8-4.7), p<0.001.

In this analysis age and gender were not significant but baseline CD4 (per 25 cell increase) 0.9 (95% CI 0.9-1.00), p<0.001; baseline weight (per 10kg increase) 1.2 (95% CI 1.1-1.3), p=0.001 and baseline viral load (per 1 log) 1.3 (95% CI 1.1 -1.6), p=0.001 were found to have an effect.

Additionally duration of ART (with 6 months as reference): 12 months 1.5 (95% CI 1.2-1.8) and 18 months 1.8 (95% CI 1.5-2.3), p<0.001 were significantly associated with viral load >400 copies/mL.

The study also looked at ART and TB treatment in patients who developed TB while receiving ART. The findings are limited by the small number of patients developing TB while on ART, but in this study there was no increased risk of viral load >400 copies/mL with TB treatment: Adjusted HR 1.00 (0.5-2.00) for nevirapine, p=0.995 and 1.2 (0.6-2.4) for efavirenz, p=0.703.

Dr Boulle summarised that receiving rifampicin-based TB treatment at the start of NVP-based ART was associated with an up to a two-fold increased risk of a viral load >400 copies/mL in the first 18 months on ART. There was no increased risk with incident TB on nevirapine-based ART, but this analysis was limited by small numbers. He said that the most likely explanation for this is lead-in dosing of nevirapine in patients with pre-existing hepatic induction due to rifampicin. He suggested to always include a 400mg/day induction arm in the nevirapine/rifampicin groups in future research.

He noted there were more nevirapine substitutions due to toxicity in patients already on TB treatment but this difference was not significant after adjustment for potential confounders.

Overall the analysis is limited by small numbers in the nevirapine/rifampicin group which he explained is “unlikely to change as local policy no longer recommends nevirapine use whilst on rifampicin.”

He described these findings as giving a “complex message” and recommended that if efavirenz is available a strong case can be made for using it for people receiving rifampicin based TB treatment in preference to nevirapine. “However, in spite of differences, 85% of patients on NVP/Rif at the start of ART achieved a viral load < 400 copies/ml at 6 months and 80% at 18 months – still highly effective in the absence of alternatives.”

Ref: Boulle A, Van Cutsem G, Cohen K et al. Antiretroviral treatment outcomes in patients who received rifampicin together with nevirapine or efavirenz. 38th World Conference on Lung Health of the Union against Tuberculosis and Lung disease. December 2007. Cape Town. Abstract TS 1893-12.