HIV-related tuberculosis (HIV-TB) received unprecedented attention at the 44th Union World Conference on Lung Health, held in Paris. This report will attempt to summarise some of the key clinical findings from the HIV-TB related sessions and highlight a few of the most important presentations and issues discussed at the conference and the STOP TB Symposium preceding it. Note, most of the presentations are now available online for anyone wishing to investigate a particular talk in more detail.
Screening for TB and HIV
TB rare in HIV-positive children on ART in Johannesburg
Dr Shobna Sawry of the University of the Witwatersrand reported that repeated routine intensified TB case finding had a low yield in a cohort of HIV-infected children on ART in Johannesburg, South Africa.1 The children, aged from 0-8 years, were enrolled in a prospective cohort study (the THINK study) investigating the incidence of TB and BCG IRIS in children living with HIV starting ART at the clinic. First, children were screened for TB by routine clinic staff using standard of care procedures, and those not diagnosed with TB were subsequently re-screened on the day of starting ART, and at their clinic visits thereafter. 1357 TB screens were performed in 221 children while not receiving TB treatment, yielding 71 (5.2%) positive TB screens in 55 children. Only 5 (9%) however, were started on TB treatment on the basis of X-rays, culture or clinical presentation.
It should be noted that half the children presented to the site were already on TB treatment at the time of initiating ART — and were thus excluded from the study — which may largely explain the low prevalence of TB symptoms at baseline. In the remainder, however, Dr Sawry proposed that the low incidence of positive TB screens could be due to the protective effect of ART-related immune reconstitution.
She also suggested that in young children on ART, routine TB screening might not be necessary, and that it might actually add an unnecessary burden to clinicians managing the children. However, while TB may not have been common in this particular subset of children, children with symptoms could have had other conditions that needed management. TB symptom screening does not take long and flags children who are unwell, which remains important to do, even with ART, particularly in settings with high infant mortality.
However, it may not be necessary to order an exhaustive laboratory and clinical evaluation for TB every time a child on ART develops a cough or fever. Nurses and their supervisors need to develop and employ good clinical judgment for what actions are necessary in their own local context.
TB screening in antenatal clinics in Nigeria feasible, but few cases identified
Similarly, Dr Tosin Idaboh of FHI360 reported that although it was possible to integrate intensified TB case finding into three antenatal clinics in different regions of Nigeria offering services to prevent vertical transmission of HIV, almost no cases were identified.2
However, there were at least a few ways this pilot programme could have missed cases. First, it is important to point out that the TB screen was incorporated into the HIV counselling and testing client intake form — all women were screened for TB regardless of their HIV status (the percentage of the women who were actually HIV-positive was not reported — presumably, most were not). In addition, the TB screen was not the WHO 4 symptom screen for people living with HIV (with any cough, weight loss, fever or night sweats) but a more standard screen using cough of more than two weeks and weight loss of more than 3 kg in the last four weeks. Consequently, only 189 out of 2793 women screened as positive for TB symptoms. Of these, only 103 had a productive cough.
At this point, the diagnostic services were not optimal, relying on smear microscopy to look for TB in 64 sputum samples, while Xpert MTB/Rif was used on only 39 samples. Only one pregnant woman was found to have TB.
TB may indeed have been uncommon at these particular clinics. However, diagnosing TB among pregnant women has previously been shown to be quite difficult — in many cases, it may be necessary to also perform chest x-ray or culture. On the final day of the conference, there would be further presentations on the topic (see below).
Having a dedicated TB nurse improves TST screening and IPT uptake at ART sites
Dr E Soares presented data from Brazil showing that the uptake of tuberculin skin testing (TST) was improved significantly over what had been reported in CREATE’s THRio study, from 33% to 86%, by including a skilled TB nurse with specific TB-related duties in HIV clinics.3 This also led to a decreased time to initiating IPT (from a median of 3 weeks down to one week). Dr Soares said further analyses were needed to see whether it was cost effective. In addition, “it is important to compare the costs of this model, which targeted those who really benefit from IPT (those who are TST+) to the cost effectiveness of providing universal IPT,” she concluded.
Integrating HIV counselling and testing (HCT) and TB screening into both stand-alone and mobile services reaches more people and provides access to services for a wider cross-section of the community
Dr Sue-Ann Meehan of the Desmond Tutu TB Centre reported on a study comparing stand-alone and mobile HCT services in nine areas around Cape Town — using routine data looking at HIV and TB related indicators — which showed that having both was complementary.4
Having HCT and TB screening in stand-alone facilities is of course essential, and seems to reach sicker patients — with a higher proportion of people testing HIV positive and people presenting with lower CD4 cell counts and AIDS-related conditions, including TB.
Together, the services reached over 96,000 patients between January 2008 and June 2012 — 94% of whom accepted HIV diagnostic services (overall 7% were HIV-positive). 15% of those testing HIV-positive had symptoms of TB. Most (77%) then received diagnostic services, and 12% of these were found to have TB.
Mobile services reached more people — almost four times as many as the stand-alone services in this study. Mobile services reach as many men as women (men are less likely to present to the stand alone facilities for HCT). Even though a lower percentage of people test HIV-positive in the mobile clinics, overall, they delivered about two thirds of the HIV diagnoses. However, a higher proportion of those presenting to the stand-alone clinics were HIV-TB-coinfected.
“The mobile service was able to access a more “well” population and provide early case detection, referral and linkage to care for a higher number of HIV infected clients,” said Dr Meehan. “The stand-alone service was able to access more coinfected clients and link them to care. I’d like to call upon policy makers who would like to expand access to HCT to consider such an integrated community model for improved coverage.”
Engaging informal health care providers increases case detection for TB and HIV in rural Malawi
Dr George Bello of the Research for Equity and Community Health (REACH) Trust of Lilongwe, Malawi, reported the results of the Triage Plus cluster-randomised trial. It evaluated the implementation of an intervention to engage informal healthcare providers in integrated TB and HIV case detection among the rural poor in Malawi.5
The informal healthcare providers were trained to recognise disease patterns for TB and HIV, to assist in specimen collection for TB, and to refer individuals appropriately for TB and HIV services, while sensitising the community on TB and HIV. At the same time, the health services and community leaders were engaged to support the intervention, and training was provided to front-line public health personnel to support the informal healthcare providers.
After a year of observation during which baseline data were established, six large clusters (matched for population and proximity to urban areas) were randomised to the intervention, either beginning at month 13 and continuing for two years, or delayed until month 25 and continuing a year. Repeated measurements — Poisson regression models —were used to maximise statistical power. The outcomes measured were TB and HIV diagnostic uptake rates and TB and ART treatment initiation rates.
The intervention increased HIV testing (with a 61% increase in the early arm, p<0.001), and initiation of ART (with a 37% increase in patients initiating ART, p=0.048). It also led to an increase in the proportion of presumptive TB cases accessing diagnosis (p=0.003).
However, although there was an increase in the proportion of TB patients starting TB treatment (18%) it did not reach significance.
“There may be reasons for this. We don’t feel stigmatisation explains it in this case. On the other hand, during our intervention period, ART treatment initiation was decentralised to primary health care facilities — but similar decentralisation was not happening in TB. TB treatment initiation was still localised to district level facilities and big hospitals. Meaning that people with TB had to walk further to access these services and due to socioeconomic barriers, most patients were not as able to access TB treatment initiation,” he said. “Treatment initiation requires decentralisation of services, so if the services are not decentralised, people will not be able to access them.”
HIV testing among presumptive TB cases in India
Despite some shortcomings in implementation, HIV testing among presumptive TB cases in India identifies large numbers of people living with HIV, including many who qualify for immediate ART. Providing HIV counselling and testing services to people with TB is a universal guideline. However, in India, the policy since January 2012 has been to offer provider initiated testing and counselling to all people with presumptive TB in the six high-HIV prevalence states.6
Dr Balaji Naik, a consultant to the RNTCP (India’s national TB programme) presented findings of a study evaluating how this policy is working in routine implementation in Karnataka, India. Karnataka has a large population of people living with HIV (around 250,000) and began implementing HIV-TB collaborative activities in 2008. There are 640 TB microscopy sites in 31 districts, 90% of which are supposed to have co-located HIV testing facilities, and more than 50 ART sites in the state.
The recording and reporting registers were modified to capture HIV testing data, and this study evaluated data for the first year of the policy: January-December 2012.
The performance shows that the policy is feasible, but there are some challenges to implementation.
Out of almost 500,000 presumptive TB cases in 2012, only 47% were offered PITC — with HIV testing rates ranging from 10%-83% across the districts.
Dr Naik identified several causes for the low testing rates. The main reason was that even though there are 640 microscopy centres in the state, many people actually provide their sputum specimens to clinics and other sites that send the specimens to the microscopy centres. These sputum collection centres don’t have HIV screening facilities on site. Other reasons included not having HIV test kits on hand at the microscopy centres, lack of staff (on leave or vacancies), and the lack of co-located HIV testing facilities at the microscopy centres (which is the case at less than 7% of the sites now). In addition, some patients opted out of testing.
Despite this, quite a significant number (21,899 or 9%) of those who were tested were diagnosed HIV-positive — with positivity rates ranging from 2% to 29% depending upon the site.
So the policy is feasible and identifies a large number of HIV-positive individuals most of whom are eligible for immediate ART. “The biggest challenge is the lack of HIV screening/testing facilities at sputum collection centres. We are working on this to make the strategy more efficient,” said Dr Naik.
MSF reports experiences with the Gene Xpert MTB/Rif TB diagnosis assay in different epidemic settings
Dr Anne-Laure Page described the experience of MSF in implementing the Xpert MTB/Rif assay in routine conditions into four programmes with different HIV prevalence and risks of MDR-TB. The evaluation assessed per-patient diagnostic results, the effects upon treatment decisions and time to treatment and feasibility (the number of tests per day, turn around time).7
The four sites included Tbilisi in Abkhazia (low HIV, high MDR), Kampong Cham in Cambodia (low HIV, low MDR), Mathare in Kenya, a slum area with high HIV, but low MDR, and Nhlangano in Swaziland, an area with both high HIV and high rates of MDR-TB.
The diagnostic algorithms varied somewhat by setting: in high HIV settings, Xpert and LED-fluorescence microscopy were the initial tests.
Xpert could be repeated in patients who initially tested negative who did not respond to a course of antibiotics. In the low HIV settings, smear microscopy was the initial test, and Xpert was only used in smear-negative cases that did not respond to a course of antibiotics, or in smear-positive cases at high MDR-TB risk.
Notably, Kenya was the only site where the test was conducted on the same day as the patient visit (in over 60% of the cases) — this was associated with a significantly shorter time to treatment initiation.
“Same-day testing is crucial to optimize delay to treatment initiation and decrease loss to follow up,” said Dr Page.
In high-HIV prevalence settings, there were varying relative gains in diagnoses but it was consistently higher in HIV-positive rather than HIV-negative patients.
“This is in favour of using Xpert as the front-line TB test when HIV prevalence is high. However, considering the possibility of an inconclusive result, a second specimen remains useful,” said Dr Page.
In low-HIV prevalence settings, Dr Page noted there was a lack of standardization of Xpert MTB/RIF requests and algorithms were not strictly followed.
“As a result of this as well as the limitations of routine data collection, there was little information available on whether there is an added value of repeating Xpert after a course of broad-spectrum antibiotics in subjects whose first specimen is Xpert negative,” she said.
Two concurrent sessions had further reports on the use of Xpert in a wide variety of settings — and the extent to which it is increasing diagnoses and access to treatment.
Some of the key findings are described in the table below.
HIGH HIV SETTINGS
LOW HIV SETTINGS
Median age (years)
Tested for HIV (%)
- HIV-positive (%)
Tested with Xpert (%)
- Repetition (inconclusive) (%)
- Repetition (algorithm) (%)
Proportion rif resistance among Xpert-positive
Started on MDR empiric treatment
Median delay to treatment initiation (IQR), days
Costs of diagnosis to health system
Some of the presentations focused on how to reduce the costs associated with using the test. In Cambodia, which has a low-HIV prevelance and very low MDR-TB burden, Dr Kosuke Okada of the Research Institute of Tuberculosis (RIT)/Japan Anti-Tuberculosis Association reported that diagnostic algorithms that reserve Xpert as the third-line test (screening only smear-negative patients without clear signs of TB on chest x-ray) would diagnose as many patients and could save the TB programme up to 20-25% in costs over using Xpert as the frontline test.8
Dr Okada did not present data on time to treatment using these algorithms. Also this approach will mean some people with MDR and people living with HIV might fall through the cracks.
Xpert’s use in settings with low access to chest x-ray
In addition, these results won’t be the matched in countries with different epidemiology. Even in India, a country where the HIV burden is low, “upfront testing with Xpert can detect more pulmonary TB cases,” according to Dr Manoj Toshniwal of the World Health Organization-Country Office for India.9 “But it is much more useful in the health facilities which do not have X-ray facilities.”
In India (and presumably in other countries as well), people with presumptive TB who are smear-negative by microscopy must travel to a higher centre for a chest x-ray to receive a diagnosis.
Following WHO’s recommendation of the Xpert MTB/RIF, RNTCP, WHO and FIND collaborated on pilot studies with Xpert in facilities at sites in India. Dr Toshniwal described findings of introducing Xpert into one district in Amravati Municipal Corporation comparing diagnoses at facilities before and after Xpert was introduced in 2012.
A similar number of suspects were screened each year, but in 2012, there was a 27% increase in pulmonary TB diagnosed — smear-negative diagnoses increased by 61%. The increase was even more substantial in the labs that did not have an x-ray facility, where a 7-fold rise in case diagnoses was observed.
“Diagnosis of pulmonary TB cases can be ensured by sputum specimen collection and transportation to a laboratory having Xpert instead of referring the TB suspect to the X-ray facility. The TB Control Programme should emphasise upfront testing of TB suspects with such tests in district microscopy centres that do not have X-ray facility. The availability of Xpert at district level improves diagnosis of MDR-TB,” he concluded.
Introducing Xpert where access to diagnostics is limited
Similarly, a study in the Central Karoo, South Africa also demonstrated that introducing Xpert substantially improved the diagnosis of TB and patient care in an area with poor access to diagnostics and a high case fatality rate despite having a relatively low HIV co-infection rate (around 11.4%) and low burden of MDR-TB.10
“We aimed to assess the impact of Xpert implementation on patient care in the Central Karoo [in Laingsburg, Prince Albert, Murraysburg] – a rural, sparsely populated area with poor access to laboratory and radiology,” said Dr Theo Van Den Handel of Right to Care.
The three health care facilities were selected for their remoteness from laboratory and x-ray services, and a before and after analysis of routinely collected data was performed to assess the impact on time to treatment and proportion of cases with bacteriological confirmation.
Over the course of 1020 observation days (half before and half post Xpert implementation), 959 people were assessed (584 by smear microscopy and 375 by Xpert).
“The number of patients assessed for TB was 17%, 28% and 53% lower after Xpert implementation, due to stricter adherence to the criteria for defining TB suspects and we feel that the perception of higher cost played a role in this. But despite the lower number of suspects assessed for TB, we still found the number of TB cases diagnosed increased by 4%,” said Dr van den Handel.
There was also a 12% increase in bacteriological confirmation, a 9% increase in treatment initiation rate, and an 11-day reduction in time from first sputum collection to initiation of TB treatment.
Xpert clearly improved the quality of diagnosis and health care in these remote sites and also capacitated clinical staff in supporting treatment and management decisions, according to Dr van den Handel.
“As far as the policy implications, when determining the optimal placement and roll-out strategy for Xpert MTB/RIF countries may need to consider characteristics of places — taking into consideration access to diagnostics, diagnostic turn around time, poverty— in addition to the currently recommended characteristics of people,” Dr van den Handel concluded.
Costs of diagnosis to the patient
One potential reason for the improved access to diagnosis and improved uptake of and time to treatment with Xpert in some contexts could be the cost of diagnosis to the patient. According to Dr Anete Trajman, of Gama Filho University, Rio de Janeiro, even though TB care is free-of-charge, there are significant costs for patients including the cost of obtaining a TB diagnosis.11
She reported the results of a study that compared the costs from the patients’ perspective of Xpert MTB/RIF as a replacement test versus that of the standard of care (two smears) for the diagnosis of tuberculosis. The study was performed at six primary care sites in Rio de Janeiro and 14 primary care sites in Manaus from October 2012 – June 2013.
Adult patients were interviewed up to four months after their diagnosis using a standardised questionnaire, asking them about their sociodemographics, out-of-pocket expenditures, food and transportation costs and time spent during the diagnosis process, focusing on the bacteriological tests. Their indirect costs were calculated based on the time invested multiplied by their hourly income, based upon their current job activity. For those without formal work, minimum wage was calculated at US$1.50 (around 3.5 Real) per hour.
218 patients were interviewed, with no significant difference between those who received a smear microscopy diagnosis and those who received an Xpert diagnosis — other than age (those receiving a smear diagnosis were slightly older but age did not appear to effect relative costs).
All the costs were higher for those who received smear diagnosis — the cost of transportation, hours lost per visit and total hours lost (smear microscopy diagnosis took a median of one extra visit). Overall, the total cost to the patient of receiving a diagnosis was a median of US $16.44 in the Xpert arm versus $25.24 for those who received a diagnosis by microscopy — a difference of $8.80.
“These costs are high, when you consider their income. Xpert was cost saving in the Brazilian contexts, and we believe that in the future, with routine implementation, Xpert can reduce one of the barriers in accessing TB diagnosis,” said Dr Trajman.
Xpert MTB/RIF may miss some RIF resistance in ‘mixed’ infections, leading to poor treatment outcomes
“Xpert represents a major advance in TB diagnostics and has shown good performance for the diagnosis of TB and RIF resistance in most settings,” according to Dr Nicola Zetola of the Botswana-University of Pennsylvania Partnership. Nevertheless, he believes clinicians should have a high index of suspicion for MDR-TB in patients failing first-line therapy, despite an Xpert result showing RIF-susceptibility.13
Dr Zetola bases this on a study he performed in Botswana to see how sensitive Xpert was at detecting whether someone has a mixed MTB infection. In high TB (and HIV) burden countries, TB may be simultaneously caused by multiple strains. In fact, mixed TB infections have been reported in 1% to 60% of TB cases from endemic settings.
“We hypothesised that mixed TB infections (where at least one strain is rif-sensitive) significantly decreases Xpert’s performance for the identification of sub-populations of rif-resistant strains, leading to poor clinical outcomes,” he said.
So the study enrolled patients who had Xpert testing (using version 4 cartridge of the test) at diagnosis and at least one culture with drug sensitivity testing (processed using the proportion method in MGIT 960 media). Genotyping was then performed to see whether the individual had a ‘mixed’ infection (note however, that the mixed infection could indicate a mixture of drug sensitive MTB strains, a mixture of drug resistant TB strains or a mixture of drug sensitive and drug resistant strains.)
The study included 318 people diagnosed as being drug-sensitive TB by Xpert, and 52 who were diagnosed as drug resistant.
There was a higher proportion of mixed infections than has previously been reported in the literature: 20, or 6.3% among the Xpert ‘drug sensitive’ and 17 (or 32.7%) among the ‘drug resistant.’ Of these 37 mixed infections taken together, 16 (43.5%) were a mixture of drug sensitive strains, 16 (43.5%) were a mixture of drug resistant and drug sensitive strains, and 5 (13%) were a mixture of drug resistant strains.
Roughly the same proportion of drug resistant and drug sensitive cured or completed therapy — but deaths were more common among the Xpert sensitive cases, with 19 (6%) dying, versus only 1 (1.9%) of the drug resistant cases dying so far (some remain on treatment, and some are lost to follow-up).
Looking at whether Xpert and DST agreed on whether patients had mixed infection, Dr Zetola said there was concordance in the results for mixed drug sensitive, and mixed drug-resistant strains. However, Xpert missed four of those which DST found to be a mixture of drug-resistant and drug-sensitive strains. Xpert diagnosed these cases as being drug sensitive, and on the basis of those results, the patients were started on first line TB treatment. All four died.
Looked at overall, only some factors were associated with poor outcomes. Being HIV positive (at any CD4 cell count) — but especially with CD4 cell counts below 100 — is consistently associated with poorer outcomes. But poor outcomes are also strongly associated with having genotypic mixed infection (adjusted OR 6.5, 95% confidence interval (CI) 2.1-20.5) and discordant results with DST (adjusted OR 6.6, 95% CI 1.2-48.2).
“Xpert is not perfect. Given that mixed infections are increasing, clinicians should be aware of the possibility of a false result in patients who are not doing well despite having a sensitive test,” he concluded.
Xpert MTB/RIF is getting more people with drug resistant TB onto treatment earlier — but still not enough
While Xpert MTB/RIF processes specimens very rapidly —and does shorten the time to diagnosis and treatment—there were a number of presentations showing that people (especially those with MDR-TB) are not getting on treatment as rapidly as they should.
For instance, Dr Riziki Kisonga reported that in Tanzania the use of molecular tests (including both Xpert and the Hain line probe assay) cut the median time from MDR-TB diagnosis to start of treatment from 259 days to 34 days — but noted that the benefits were most pronounced among people living with HIV and active TB.14
“Molecular diagnostics should be scaled up to more areas focusing on the burden of TB/HIV, he said.
Xpert MTB/RIF highly sensitive and speeds time-to-initiation of TB treatment among PLHIV in Botswana
“The sensitivity of the [Xpert MTB/Rif TB test] was very high when used for intensified case finding under programmatic conditions in Botswana,” according to Dr. Tefera Agizew, TB-HIV researcher for the Botswana-USA Partnership (BOTUSA), speaking at the 44th Union World Conference on Lung Health held from October 31 to November 4th in Paris.15
While South Africa’s well-funded transition from smear microscopy-based TB diagnosis to use of Xpert MTB/RIF as their first-line TB diagnostic has been highly publicised, there are limited reports from other countries in the region attempting to do the same — particularly from the perspective of addressing the case finding challenges among people living with HIV.
Dr Agizew’s presentation, during the first ever TB-HIV late breaker session at the Union meeting, described the results of an ongoing study that evaluated the impact of the switch to using the Xpert MTB/RIF for TB case finding among PLHIV. In particular the study looked at whether introduction of Xpert MTB/RIF decreased the time to initiation of TB treatment when used in ‘real world’ clinical settings in Botswana.
“The [Xpert diagnostic] algorithm reduced time to antituberculosis treatment initiation and rapidly diagnosed rifampicin resistance,” he said. But, he added, difficulty collecting sputum in this population “limits Xpert’s potential to maximize TB case finding, especially for patients with advanced HIV disease.”
Phased Xpert MTB/RIF implementation in Botswana
Botswana has an HIV prevalence of around 17% in the general population and 24% among people of the childbearing age. One of the very first countries to begin offering antiretroviral therapy through its public health programme — first primarily in specialised ART clinics, and now through decentralised HIV care and treatment.
Botswana also has a high rate of TB — and a very high HIV-TB co-infection rate (around 64% in 2011).
In June 2012, the Botswana Ministry of Health adopted the WHO guidelines for the GeneXpert MTB/RIF test and incorporated the test into their TB diagnostic algorithm. It was decided to implement Xpert MTB/RIF in phases and so a study was designed to assess Xpert performance under programme conditions to inform the country’s further scale-up. There were two major objectives in this study:
- To evaluate the sensitivity of the new Xpert-based TB diagnostic algorithm for new adult ART enrolees compared to the pre-Xpert smear-microscopy-based algorithm in diagnosing culture-positive TB disease;
- To evaluate the impact of the whole “Xpert package” on all-cause mortality during the first 6-months of ART, among adult patients.
“We introduced the Xpert diagnostic package which includes Xpert-based ICF algorithm, training of health facility personnel and Xpert device and testing services at point-of-care and other laboratory service sites. We used the stepped wedge design of the phased implementation of the Xpert diagnostic package,” said Dr Agizew.
[A stepped wedge randomised trial evaluates the sequential roll out of an intervention to individuals or clusters (sites) over more than one time period. All participants or sites should have the intervention in place by the end of the study, but the order in which participants or sites receive the intervention is determined at random.]
Thirteen GeneXpert devices were installed to provide diagnostic services to 22 purposefully selected health facilities (four were point-of-care and the remainder were placed in centralised laboratories). Dr Agizew noted that these sites cover about half of the population living with HIV in Botswana. There were three cohorts in the trial: a prospective pre-Xpert implementation cohort; a prospective, post-Xpert implementation cohort; and a retrospective cohort.
The phased-in implementation has taken place over a 9-month period. The sample size is 9614: 3300 pre-Xpert implementation, and 6314 patients post-Xpert implementation — but the study is still ongoing.
Results to date
Out of the 4331 patients evaluated so far, 1078 (25%) screened positive for one or more TB symptoms, 125 of whom were subsequently diagnosed with TB (3%). Of these, 82 have culture-confirmed TB, of which 58 were diagnosed after having implemented Xpert. 54 of the 58 received positive Xpert results, which yielded a sensitivity of 91% for Xpert in this setting. Rifampicin resistance was found in 4 patients (7.4 %).
Xpert has shortened the median time to antituberculosis treatment (drug sensitive). In the pre-Xpert algorithm for DS TB smear microscopy, the time to treatment was 9 days (IQR 2-28); and in the post-Xpert algorithm group, the time was 4 days (IQR 2-6). For MDR-TB post-Xpert, the median time to anti-TB treatment initiation was 20 days (IQR N/A).
However, a number of people have died in the study. In the prospective cohort, as of 20 September 2013 — there had been 91 deaths so far, 53 out of 1743 in the pre-Xpert cohort (3%) and 38/2588 (1.5%) in the post-Xpert cohort.
“We have not yet confirmed the cause of the mortality at this point,” said Dr Agizew, “but of these 91 deaths, 58 of them – or 64 percent – were screened positive [for TB symptoms] at enrolment. But unfortunately only 36 percent managed to give us a sputum sample. And this is one of the big challenges of GeneXpert. So even if we implement it in a marvellous way, if we don’t get sputum then we’ll fail there.”
The median time of death, from enrolment, was 39.5 days IQR 18 – 89.5) and the CD4 was 81(IQR 44 – 167).
“This again is a group with very late presentation and advanced disease. Xpert was not helpful at all for this group,” said Dr Agizew.
Mechanical and operational challenges with implementation
Not everything went smoothly with the introduction of Xpert however. For instance, initially there were high error rates: an average of 8% of the tests — but as high as 15% at one site. Three per cent were invalid results (as high as 11% at some sites).
However, between the first and third quarter of the trial, there was a reduction of invalid results as well as errors. As has been noted in other sites, some of this may have been due to the cartridges in the early stage of the rollout. Botswana was using version 3 of the Xpert MTB/RIF cartridges but has now switched to version 4 — which seem to be more reliable.
Dr Agizew said that they also encountered many universal power supply (UPS) breakdowns. UPS is supposed to provide an uninterrupted power supply, but six of the thirteen UPS’s kept failing. Mostly Dr Agizew suspects that there were power outages or surges — the cause is still under investigation.
However, Dr Agizew attributed the errors “mainly due to the human factor, and also to some extent the use of version 3 of the cartridges.” There was a high turnover of the lab technicians at the sites — and more training was required to bring new technicians up to speed.
Lessons learned have informed scale-up to additional sites in 2013
Dr Agizew listed a number of the key operational lessons learnt in his setting:
1) Sputum Collection
“One of the big ones is the low sputum collection rate, and we were at 63%,” he said.
Recently, they’ve increased sputum collection to 74% and their goal is to increase it to more than 90% by taking the following steps: closer follow-up of the patient by study staff, patient coaching during sputum collection, having a poster/or job aide on sputum collection and sputum induction has been introduced now for routine program use.
“The sputum induction was part of our protocol but it was not part of the national TB guidelines, we put it in just in case and mostly we opted to put it for the children’s sake [children with TB have difficulty producing good sputum specimens]. But lately we’ve learnt that if we don’t use sputum induction, we’ll be missing maybe patients who deserve Xpert. And more than two quarters of patients who died could not produce sputum, so what’s the use of Xpert then if we don’t have any sputum?”
2) Failure to adhere to TB diagnostic algorithms:
Dr Agizew also noted that they found clinicians at the clinic were not adhering to the algorithm or felt uncomfortable ordering and reading chest x-rays for symptomatic patients who were smear negative or Xpert negative.
3) Inconsistent screening performed by clinic (non-study) staff:
The study did not train staff at the clinics to perform TB screening — it was assumed that they would follow the national guidelines as the national programme had trained them to do. “But they were not doing it,” said Dr Agizew.
4) Ongoing training and supervision are needed to counter the effects of substantial staff turnover/in rotation.
5) A good laboratory quality assurance plan is essential, with good supervision and also emphasising the use of the standard operating procedures.
6) There was also one laptop theft, and other misuse of the laptops in the setting, so the programme is switching over to desktops units (which people are less likely to try to take home).
Perhaps the most critical recommendation Dr Agizew offered was to follow Botswana’s example, and closely study the rollout of this (or any) new tool.
“We recommend countries to consider how to evaluate and to monitor early implementation of Xpert to inform the program scale-up,” said Dr Agizew.
Dr Agizew said programmes may also need to explore alternative reliable power supplies. The UPS they used didn’t work in Botswana and is very expensive to replace, he said. One option they are considering is to put in solar panels.
Another recommendation he stressed is that programmes need to emphasise and monitor adherence to laboratory standard operating procedures.
“We also recommend promoting high sputum collection rates, if possible by considering sputum induction for all symptomatic patients.. But most importantly, we need to identify rapid ways to diagnose TB in patients who fail to produce sputum,” he concluded.
Integrating methadone and TB-HIV treatment in sub-Saharan Africa
Preliminary results from the first programme to integrate directly observed therapy (DOT) TB treatment with methadone treatment for people who inject heroin in Africa show that it “is feasible and the patients found it quite acceptable despite stigma related to TB/HIV treatments,” said Dr Robert Bruce of Yale University, speaking during the TB-HIV Late Breaker Session.16
Dr Bruce was describing a preliminary report on a small open label study involving 51 participants, who were all willing to receive their TB and HIV medications from the window where methadone was being dispensed.
“The study has demonstrated treatment successes and low rates of mortality and treatment default — only three patients so far have defaulted. The treatment completion rates approach the WHO global standard but in a high risk and traditionally non-adherent population,” he said.
Drugs and HIV in Africa
Heroin has been coming into East Africa through Mombasa into Kenya as well as through Zanzibar into Tanzania for the last two decades.
In 2011 The United Nations Office on Drugs and Crime (UNODC) estimated in 2011 that there were 1,736,000 heroin users in Africa with approximately 533,000 residing in East-Africa. In 2005, an estimated 200,000 to 250,000 heroin users were in Dar es Salaam alone – most of whom were smoking heroin while approximately twenty to forty thousand people were injecting heroin.
According to Dr Bruce, these tend to be individuals (the majority are male) with a median age of 34 (between 25 to 49) who live on the street. Most of them have a history of incarceration.
The HIV prevalence in Tanzania is 5.6%, and in Dar es Salaam it is approximately 9.5%. However among residents from Dar es Salaam who inject heroin, an estimated 42% are living with HIV. And as has been observed in Eastern Europe, Russia and Asia, injecting drug use leads to HIV, and HIV-infected drug users are at a great elevated for tuberculosis.
The methadone Clinic at Muhimibili Hospital
One evidence-based method to reduce these risks is opioid substitution therapy in the form of methadone.
Methadone is a synthetic opioid which helps treat heroin dependence by controlling withdrawal symptoms. It is administered once daily in structured settings — and people who are seeking to reduce dependence on street heroin may be highly motivated to come to the clinic for their daily treatment.
Methadone has also demonstrated HIV-preventive effects since it can lead to a reduction of unsafe injecting practices that spread HIV among people who inject heroin.
So, in an effort to help address the epidemic of HIV among people who inject heroin, the first publically available methadone clinic in sub-Sahara Africa was established in Dar es Salaam at Muhimibili Hospital.
“It took a lot of effort to sell the country that methadone was not enslaving people to a medication that caused harm. But as individual patients, and as physicians began to see the added benefits of the treatment, it has become very in demand,” said Dr Bruce. “Most recently what has helped is that President Jakaya Kikwete had an individual that he was quite close to obtain methadone maintenance. It was very helpful to that person’s life and since then the president did a photo op at the methadone clinic and has been encouraging the ministry of health to expand evidence-based treatment for heroin addiction throughout the country.”
Addressing tuberculosis among people who use Drugs
There is also a high rate of tuberculosis in this key population in Tanzania. According to the WHO Global TB Report for 2013, the rate of TB in the general population in Tanzania is 177 per 100,000. But Dr Bruce’s group has looked at the rate of TB in the methadone population and found it to be around 4,000 per 100,000. Aside from the greater risk associated with a high HIV burden, people who inject drugs are also placed at higher risk of TB because they congregate during the day in intimate settings to use drugs, and many of them have previously been incarcerated. The risk of contracting Mycobacterium TB in many of the prisons in Africa is extremely high.
However, it can be difficult for people who inject heroin to adhere to TB (or HIV) treatment when they are threatened by withdrawal symptoms — finding the next hit of heroin to prevent withdrawal can become one’s overriding concern.
Enhancing adherence to TB medication through methadone provision
“The National TB programme has a very warranted concern about non-adherence in this TB population who are heroin injectors,” said Dr Bruce. “We wanted to use methadone, which is administered, once daily under observation, as an avenue to address adherence by integrating the TB treatment with the methadone maintenance.”
“Methadone is a very powerful incentive for adherence. When patients come to the clinic every day and take their methadone they feel normal, functional; they can go get a job and participate in life. If you don’t get your methadone you become quite ill. And so you’re very incentivised to attend the clinic,” Dr Bruce said, adding, “and the methadone is free,” (while heroin is not).
A pharmacist dispenses methadone through a dispensary window at the clinic, seven days a week. TB medications (or HIV medications for that matter) can be dispensed at the same time, and adherence directly observed.
For the purposes of this evaluation, a retrospective chart review was performed of all the people attending the methadone clinic at the Muhimibili National Hospital as of July 2013 — a total of 638 patients — looking for those who had received first-line anti-TB treatment with their methadone from the start of the clinic, which was February 2011. (The TB diagnoses had been made using standard microbiological and/or clinical criteria).
51 patients who met these criteria were identified, 40 men, 11 women — which reflects the general demographics of the methadone clinic.
Of those 51, thirty have finished TB treatment, and thirteen (25%) are still on continuing on treatment.
Only three of the fifty-one patients default from treatment, and five have died, all of whom had HIV and were on HIV therapy.
“As you can imagine, patients attending the methadone clinic as heroin injectors are often coming in late in their disease,” said Dr Bruce. “In fact, the first patient died in the clinic before being able to be started on any treatment, patient no. 7, died of overwhelming TB infection.”
Thirty-eight of the fifty-one were HIV co-infected and thirty-two of these were on HIV therapy.
“We would all like to see one hundred per cent of co-infected patients with HIV therapy, but it is not a small task for us to convince the HIV department at the hospital to treat drug users,” he said. “We also had to vouch for the adherence of the HIV component as well, providing in some cases HIV, TB and methadone treatment simultaneously from the methadone-dispensing window.”
Dr Bruce’s work highlights that heroin injecting is not just an issue in Eastern Europe and Asia but is an emerging issue in sub-Saharan Africa. In fact, there’s a very large population of heroin users in Africa who have high rates of HIV and TB — a population that receives too little attention in sub-Saharan Africa.
Furthermore, while the study is small, and needs to be confirmed in a larger number of patients and at other sites, it does suggest that an integrated methadone and TB-HIV treatment programme is feasible in an urban African setting — and achieves results similar to global standard for TB treatment.
“Prior to this programme, this population remained largely untreated. The general parlance in the environment was that these individuals were untreatable due to their heroin addiction,” said Dr Bruce. “This work highlights the importance of methadone as an essential component of TB treatment success among heroin injectors and stresses the need to expand access to methadone treatment.”
Next steps and future research
The challenge of meeting the need should not be underestimated — as Dr Bruce noted, there are an estimated 200,000 people who use heroin in Dar es Salaam alone.
Future work in this area includes epidemiological research on the extent, severity and consequences for HIV and TB co-infection control among heroin users throughout the community and throughout Africa. Ongoing pharmacokinetic research is needed for TB/HIV interactions as well as methadone interactions. For instance, streptomycin, efavirenz and nevirapine all induce the metabolism of methadone.
According to Dr Bruce, this was a significant issue for the programme. “We budgeted for an average of 100 mg a day of methadone and in some cases patients run 200 mg a day due to induction from either nevirapine, azithromycin or nevirapine/efavirenz-based regimens. So we were giving people more methadone.”
Dr Bruce added that “additional operational and implementation science research is needed to expand this interventional strategy to other settings.”
One, not so far away, is Zanzibar, which is a conservative Muslim autonomous region of Tanzania that has been harder to sell on harm reduction. For instance, programmes working with people who inject drugs in Zanzibar have not been able to offer syringe exchange services.
“From an HIV prevention perspective the cheapest most effective thing to do is large-scale syringe exchange, for injection drug users,” said Dr Bruce. “But syringe exchange is fraught with multiple problems due to funding limitations and the misbelief that the exchange of syringes promotes drug use – and I will stress, ‘the misbelief’ — there is not evidence that shows that syringe exchange promotes drug use, it prevents HIV and saves lives. A lot of countries don’t like to do it, and Zanzibar is one of those places.”
Similarly, efforts have been underway since 2008 to roll out methadone in Zanzibar — it was supposed to start there before the programme in Dar es Salaam, but progress has been very slow.
“Part of it is that Zanzibar is a very Muslim part of Tanzania and so has different beliefs on being maintained on medication – we’ve been working closely with colleagues in Muslim countries who have methadone maintenance notably Malaysia, Iran to try and encourage our Zanzibar colleagues on the acceptability of methadone maintenance therapy in the population. But I think we’ll have methadone in Zanzibar maybe by this year or next year.
The audience of the presentation suggested a couple of other ideas for research in this setting. One was to study the use of this for isoniazid preventive therapy in people living with HIV on methadone maintenance therapy. Another issue, raised by doctor from the Ukraine was that TB is sometimes diagnosed late in people on methadone — because opioids can suppress cough — and so requires extra care.
Dr Bruce agreed and noted that he had listened closely to a presentation by Dr Stephen Lawn, which focused on the diagnosis of TB using urine as a specimen — “because in methadone clinics, we collect a lot of urine,” he said.
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