With this issue, we are launching a monthly column focused on advancing the integration of HIV and TB services, exploring the challenges and practical solutions to the implementation of TB/HIV collaborative activities, and the improving the diagnosis and treatment of the more difficult to manage forms of TB that are common in people with HIV, including smear negative, extrapulmonary and drug resistant TB.
The focus of this issue of HATIP, and of the column this month is South Africa with recent news from the South African AIDS Conference. Several TB news stories from the conference are included below.
In addition, there were a number of interesting posters and other TB highlights at the meeting:
Improving the diagnosis of smear-negative TB
One of our stories addresses the work of HATIP advisory panellist, Dr Doug Wilson of Edendale Hospital who has found that screening for high levels of C-reactive protein (CRP) can help identify active TB cases in smear-negative individuals with suspected pulmonary tuberculosis.
At present, smear microscopy fails to detect TB in a large proportion of people with HIV. Although the WHO has published an algorithm to speed the diagnosis of smear negative TB, potentially effective TB treatment is still delayed for three to five days, at least while clinicians wait to see whether the TB suspect responds to a trial course of antibiotics. In practice, this sometimes takes longer, because the antibiotics can improve the health of someone with TB, but only transiently. As Dr Wilson pointed out in his talk, a low cost point of care diagnostic that quickly recognises active TB would greatly improve the confidence to simply treat for TB.
A poster presentation from Gous et al suggested another possible option — sputum PCR. Last year, several countries announced the intention to roll out the use of PCR for drug sensitivity testing — as drug resistant PCR needs to be diagnosed as quickly as possible. South Africa is scaling up capacity to perform these tests countrywide — and the goal is to have every TB patient quickly screened for drug resistance. However, the tests have not really been optimised for smear-negative specimens.
However, the researchers from Johannesburg found that the PCR tests performed virtually as well as culture — in much less time. Three different TB PCR formats were evaluated, and their results compared to that of culture, microscopy and clinical case definitions. The Roche Lightcycler Mycobacterium Detection Kit detected 16 out of 17 culture positive specimens (6 were smear negative), and correctly diagnosed 17 other specimens as negative (94% sensitivity and 100% specificity). Two other assays, the Hain GenoType MDRplus and MTB ACE Detection assays were in complete agreement with culture — plus they detected two cases of drug-resistant TB.
“Preliminary findings show sputum PCR may facilitate the diagnosis of smear-negative TB in HIV-positive patients and can be readily implemented in routine diagnostic workflow,” wrote Gous et al.
That is, if health officials can get healthcare workers to send in specimens to the laboratory, and then improve management of results delivery. But another poster from Lancaster et al, on diagnosis of TB in HIV-infected patients, provided another clear reason to make sure that the drug sensitivity assays are rolled out and utilised — HIV-infected people were more likely to have drug resistant TB.
The study evaluated baseline indicators for HIV infection is specimens collected during South Africa’s last drug-resistant TB survey in 2001 to 2002. A number of the indicators, such as the higher risk of being smear- negative, or having a “scanty” culture result, come as no surprise. But people with HIV showed a trend toward a higher risk of rifampicin resistance (odds ratio 1.33, 95% confidence interval (CI) 0.97-1.82, p = 0.076) and a significantly higher risk of ethambutol resistance (odds ratio 2.16 (95% CI 1.13-4.103, p= 0.020).
“Drug resistance testing against all first-line drugs for HIV-positive cases at baseline will have benefit,” wrote the poster’s authors.
Improving the diagnosis of extrapulmonary TB
WHO’s diagnostic guidelines also contain criteria for the diagnosis of some forms of extrapulmonary TB. However, they say little about abdominal TB, which is common in people with HIV. Dr Tom Heller and other colleagues at Hlabisa District Hospital and the Africa Centre for Health and Population studies presented two posters assessing whether ultrasound, which they said would be the most commonly available imaging modality in rural district hospital settings. Diagnostic criteria included: abdominal lymph node enlargement (>1.5) and visceral involvement in the form of focal splenic lesions. Ascites were also noted, but were not considered diagnostic if found on their own (as they may be related to cirrhosis or congestive heart failure, etc).
180 consecutive patients were screened by ultrasound — and 30 showed signs of abdominal TB. The most common sonographic finding was enlarged lymph nodes were, seen in 97% of the subjects. 73% had ascites and 50% had focal splenic lesions. Clinical symptoms included weight loss in 87%, abdominal pain in 73%, diarrhoea in 60% and abdominal distension in 33%. The patients had very advanced HIV disease, with a median CD4 count of 78 and either underweight or severely underweight. The authors noted that the weight loss decreased the likelihood of fat and air interfering with the ultrasound. Also worth noting — 23 of these 30 also had chest x-ray evidence compatible with TB, 21% with a miliary pattern.
Follow-up was available for 25 of the patients after a mean of 17 weeks on TB treatment. Six had died within the first two weeks of initiating treatment, but the remainder continued on treatment with clinical improvements. All but one had also initiated antiretroviral therapy.
Dr Heller’s second poster stressed that while ultrasound showed utility, “trained ultrasonagraphers are scarce in the rural environment.” So they developed a short training course ‘Focused assessment with sonography for HIV/TB’ (FASH), and trained 4 clinicians without prior experience in ultrasonography or radiology (one who had very limited access to the scanner dropped out). After gaining some experience, most of the clinicians eventually achieved a high level of confidence using the technique. In an assessment of 62 patients, use of sonography added a diagnosis in 28, and excluded a diagnosis that was previously expected in 30. In 32 therapy was changed on the basis of the sonographic results.
Challenges and solutions to TB/HIV service integration
Dr Heller’s colleagues also presented their experience at integrating TB and HIV services in these same rural settings. One key element, they found was optimising the physical proximity of the services. They actually placed the TB and ART teams directly next to each other in a shared park home at one peripheral clinic. They also set up a streamlined referral system to a central ‘cough’ clinic” to expedite TB diagnosis. Also, “training activities for the nurses and counsellors in both programmes as well as strategies to monitor and feed back the performance are important to ensure sustained commitment of the staff,” Wallrauch et al wrote. Although HIV testing in South Africa is voluntary, the Hlabisa district achieved 88% uptake of testing in its 16 clinics— and had CD4 cell count measurements available for 81% of those testing positive.
The difficulty getting this sort of uptake of collaborative services countrywide was the subject of a health system survey by researchers at the University of the Western Cape and the TB/HIV Care Association (Uwimana). One of the chief problems cited by the survey was the lack of a coordinating body above the TB and HIV programmes. Generally, the HIV/AIDS, Sexually transmitted infections and TB (HAST) unit is perceived of as the framework for the coordination of collaborative activities, but the HAST manager has the same rank as the TB and HIV/AIDS programme managers, which leads to power and role conflicts.
Another problem noted was that programme managers lack an understanding of what “integration” means, which leads to uncooperative attitudes. (This survey and similar presentations will be addressed in greater detail in a future issue)
Addressing issues such as poor understanding of the concept of integration and collaborative services will take better communication and education efforts targeting programme managers, clinicians, nurses and other healthcare professionals. Conferences offer one venue where these messages can be delivered, but the competition for conference-goer’s attention can be fierce.
The Aurum Institute may have found a way around this, when it held a symposium on the Three I’s (isoniazid preventive therapy, TB infection control, and intensified case finding). The room was packed — they had to turn about 250 people away. They held small money lotteries, distributed ice cream and even had entertainment. It seems they are putting the lessons learned from providing incentives that CREATE studies have been using to enrol and engage clinical trial participants to getting the doctors and nurses in at these conferences as well.
Improving the management of drug-resistant TB
There were several presentations that could help address some of the therapeutic nihilism surrounding the treatment of drug resistant (DR) TB, especially extensively drug resistant TB (XDR-TB). In one poster, researchers from the MRC presented findings suggesting that replacing ethambutol with terizidone (similar to cycloserine but much less toxic) could result in a faster culture conversion rate in HIV-positive MDR-TB cases (Odendaal).
Previous research had noted better clinical responses among MDR-TB patients who are resistant to ethambutol than those who were susceptible to the drug. The chief difference between these patients was that rather than being put on an ethambutol-containing regimen, those with ethambutol resistance had been put on regimens containing either cycloserine or the closely related (but much less toxic) terizidone. So they performed an analysis of 1189 subjects on regimens containing the three different drugs (note only 89 were on terizidone). The hazard ratio for time to culture conversion was 1.80 (90% CI 1.06-3.05, p=0.067) in people with HIV and MDR-TB. Oddly, culture conversion took longer in the HIV-negative subjects.
And a late breaker presentation from Dr Karen Shean and colleagues at the University of Cape Town reported better than expected survival in people with HIV and XDR-TB. The researchers reviewed case record for 224 patients with XDR-TB on treatment in the Western Cape, Eastern Cape and Gauteng Provinces. 43% were HIV infected and 83.3% were smear negative at diagnosis. The 12-month survival in HIV-positive and HIV-negative subjects was 52% and 75% respectively. Survival time and time to conversion did not differ by HIV status (log rank test p=0.08 and 0.55 respectively. These findings up the ante on the early detection of XDR-TB, because early treatment can save lives.
But the best news came at the very end of the conference, when the South African Minister of Health, Barbara Hogan, just back from a high-level meeting in Beijing on drug resistant TB was clearly quite energised about tackling TB/HIV and drug resistant TB issues. There were a number of high points in her speech include her mention of the need to address the cross-border dumping of patients with drug-resistant TB and her goal for South Africa to lead the way to developing more effective regional responses to TB/HIV. She also opened the door to moving more towards the community-based care of drug-resistant TB."
“At the ministerial MDR-TB meeting, I requested the agencies there to offer technical assistance in determining how best to ensure that hospital based treatment and isolation are not a permanent means of treating DR TB,” she said. “It is arguably unaffordable and it presents a whole range of other ethical and human rights issues that require further thought. The encouraging outcomes of the two pilot community based DR-TB programmes in the Western Cape and KZN tell us that we need to ask how and to what extent we can replicate them in a manner that protects the human rights of the patient, healthcare worker and the community.... I am hopeful that a policy recommendation will be consolidated within the next 4-6 weeks by officials in the National Department of Health for consideration."
As votes are being counted in the South African election, it is our sincere hope is that Minister Hogan will remain in her position in the next administration to fulfil these promises, or that at the very least, her successor will carry this vision forward.
TB/HIV Research meeting in Cape Town, South Africa, July 18-19
The TB/HIV Working group of the Stop TB Partnership and WHO, in conjunction with other partners such as the International AIDS Society and CREATE, will host an international meeting in order to enhance networking and scientific interest for priority HIV/TB research issues.
The meeting will bring notable researchers and leaders in the areas of TB prevention, childhood TB/HIV, TB treatment and diagnosis, and the interaction between HIV and drug resistant TB.
It is also intended to create a forum to exchange ongoing research activities, including data among researchers. The meeting will also inform the revision of the WHO HIV/TB research priorities.
The meeting will be held in the Desmond Tutu HIV Centre, University of Cape Town on July 18- 19, 2009, prior to the opening of the 5th International Conference on HIV Pathogenesis, Treatment and Prevention Conference.
Deadline for registration: Registration should be submitted no later than June 15, 2009 by emailing Ms Rosalie Edma at edmar@who.int ; mention “HIV/TB research meeting” in the subject line.
References
Gous N et al. Diagnosing pulmonary TB in HIV+ persons: preliminary results from a comparison of conventional laboratory diagnostics, 3 commercial sputum TB PCR formats and a clinical case definition. 4th South African AIDS Conference, Durban, abstract 236, 2009.
Lancaster J, Van der Walt M, Odendaal, R. Baseline indicators for the diagnosis of TB in HIV infected patients. 4th South African AIDS Conference, Durban, abstract 189, 2009.
Heller T et al Abdominal tuberculosis: Sonographic diagnosis and treatment response in HIV-positive adults. 4th South African AIDS Conference, Durban, abstract 278, 2009.
Heller T et al. Focused Assessment with sonography for HIV/TB (FASH): Evaluation of a ultrasound course in a rural African setting with high HIV prevalence. 4th South African AIDS Conference, Durban, abstract 279, 2009.
Wallrauch C et al. Practical TB/HIV integration: experience from Hlabisa subdistrict in northern KwaZulu Natal. 4th South African AIDS Conference, Durban, abstract 271, 2009.
Uwimana J et al. Barriers for implementation of TB/HIV collaborative activities including PMTCT in a rural dstrict of KwaZulu Natal. 4th South African AIDS Conference, Durban, abstract 398, 2009.
Odendaal R, Lancaster J, Van der Walt, M. The effect of terizidone-based standard treatment on culture-conversions for HIV coinfected MDR-TB patients in South Africa. 4th South African AIDS Conference, Durban, abstract 172, 2009.
Shean K et al. Extensively drug resistant TB (XDR-TB) in high HIV prevalence areas of South Africa. 4th South African AIDS Conference, Durban, abstract LB23, 2009.