Judy Caldwell

Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa

Vitamin D deficiency is associated with susceptibility to tuberculosis (TB) in HIV-uninfected people in Europe, but it is not known whether such an association exists among HIV-infected people in subtropical Africa. We conducted a cross-sectional study to determine whether vitamin D deficiency was associated with susceptibility to active TB in HIV-uninfected (n = 196) and HIV-infected (n = 174) black Africans in Cape Town, South Africa. We also investigated whether there was evidence of seasonal variation in vitamin D status and TB notifications in this setting over an 8-y period. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) was present in 232 (62.7%) of 370 participants and was associated with active TB in both HIV-uninfected (odds ratio = 5.2, 95% confidence interval: 2.8–9.7; P < 0.001) and HIV-infected (odds ratio = 5.6, 95% confidence interval: 2.7–11.6; P < 0.001) people. Vitamin D status varied according to season: The mean serum 25(OH)D concentration was highest in January through March and lowest in July through September (56.8 vs. 30.7 nmol/L, respectively; P < 0.001). Reciprocal seasonal variation in TB notifications was observed: The mean number of TB notifications per quarter for Cape Town in 2003 to 2010 was lowest in April through June and highest in October through December (4,222 vs. 5,080; P < 0.001). Vitamin D deficiency is highly prevalent among black Africans in Cape Town and is associated with susceptibility to active TB both in the presence and absence of HIV infection. Reciprocal seasonal variation in serum 25(OH)D concentration and TB notifications suggests that seasonal variations in vitamin D status and TB incidence in this setting are causally related.

Burden of New and Recurrent Tuberculosis in a Major South African City Stratified by Age and HIV-Status

Aim To describe the burden of tuberculosis (TB) in Cape Town by calculating TB incidence rates stratified by age and HIV-status, assessing the contribution of retreatment disease and estimating the cumulative lifetime TB risk in HIV-negative individuals. Methods Details of TB cases were abstracted from the 2009 electronic TB register. Population denominators were estimated from census data and actuarial estimates of HIV prevalence, allowing calculation of age-specific and HIV-stratified TB notification rates. Results The 2009 mid-year population was 3,443,010 (3,241,508 HIV-negative and 201,502 HIV-positive individuals). There were 29,478 newly notified TB cases of which 56% were laboratory confirmed. HIV status was recorded for 87% of cases and of those with known HIV-status 49% were HIV-negative and 51% were positive. Discrete peaks in the incidence of non-HIV-associated TB occurred at three ages: 511/100,000 at 0–4 years of age, 553/100,000 at 20–24 years and 628/100,000 at 45–49 years with 1.5%, 19% and 45% being due to retreatment TB, respectively. Only 15.5% of recurrent cases had a history of TB treatment failure or default. The cumulative lifetime risks in the HIV-negative population of all new TB episodes and new smear-positive TB episodes were 24% and 12%, respectively; the lifetime risk of retreatment disease was 9%. The HIV-positive notification rate was 6,567/100,000 (HIV-associated TB rate ratio = 17). Although retreatment cases comprised 30% of the HIV-associated TB burden, 88% of these patients had no history of prior treatment failure or default. Conclusions The annual burden of TB in this city is huge. TB in the HIV-negative population contributed almost half of the overall disease burden and cumulative lifetime risks were similar to those reported in the pre-chemotherapy era. Retreatment TB contributed significantly to both HIV-associated and non-HIV-associated TB but infrequently followed prior inadequate treatment. This likely reflects ongoing TB transmission to both HIV-negative and positive individuals.

A comparison of multidrug-resistant tuberculosis treatment commencement times in MDRTBPlus line probe assay and Xpert® MTB/RIF-based algorithms in a routine operational setting in Cape Town.

Background Xpert MTB/RIF was introduced as a screening test for all presumptive tuberculosis cases in primary health services in Cape Town, South Africa. Study Aim To compare multidrug-resistant tuberculosis (MDR-TB) treatment commencement times in MDRTBPlus Line Probe Assay and Xpert MTB/RIF-based algorithms in a routine operational setting. Methods The study was undertaken in 10 of 29 high tuberculosis burden primary health facilities, selected through stratified random sampling. An observational study was undertaken as facilities transitioned to the Xpert MTB/RIF-based algorithm. MDR-TB diagnostic data were collected from electronic laboratory records and treatment data from clinical records and registers. Kaplan Meier time-to-event analysis was used to compare treatment commencement time, laboratory turnaround time and action delay between algorithms. A facility-level paired analysis was done: the median time-to-event was estimated per facility in each algorithm and mean differences between algorithms compared using a paired t-test. Cox proportional hazards regression was used to assess the effect of patient-level variables on treatment commencement time. The difference between algorithms was compared using the hazard ratio. Results The median treatment commencement time in the Xpert MTB/RIF-based algorithm was 17 days (95% CI 13 to 22 days), with a median laboratory turnaround time (to result available in the laboratory) of <1 day (95% CI<1 to 1 day). There was a decrease of 25 days (95% CI 17 to 32 days, p<0.001) in median MDR-TB treatment commencement time in the Xpert MTB/RIF-based algorithm. We found no significant effect on treatment commencement times for the patient-level variables assessed. Conclusion MDR-TB treatment commencement time was significantly reduced in the Xpert MTB/RIF-based algorithm. Changes in the health system may have contributed. However, an unacceptable level of delay remains. Health system and patient factors contributing to delay need to be evaluated and addressed to optimise test benefits.

Provider-initiated HIV testing increases access of patients with HIV-associated tuberculosis to antiretroviral treatment

BACKGROUND Timely initiation of antiretroviral treatment (ART) is a critical component of the case management of patients with HIV-associated tuberculosis (TB) and advanced immunodeficiency. We sought to determine the impact of the introduction of provider-initiated HIV-testing in TB clinics in 2005 on subsequent referrals of patients with HIV-associated TB at a community-based ART service in Cape Town. METHODS Retrospective analysis of an ART cohort database (2002 - 2008) stratified by calendar periods. RESULTS Between 2002 and 2008, 3 770 ART-naive adults enrolled in the ART service. Overall, 27.4% of these patients had been referred from TB clinics with a diagnosis of HIV-associated TB. This proportion increased from 16.0% of referrals in the period 2002 - 2005 prior to the introduction of provider-initiated HIV testing, to 34.7% in 2007 - 2008 (p<0.001). The median duration of TB treatment completed prior to referral decreased from 3 months to 1 month (p<0.001) and patients enrolled with higher median CD4 cell counts (71 cells/microl v. 95 cells/microl; p<0.001). Moreover, the proportion with recurrent TB epiSodes decreased from 8.6% to 3.2% (p<0.001). CONCLUSIONS Introduction of provider-initiated HIV testing by the TB control programme was temporally associated with a major increase in referrals of patients with HIV-associated TB to this ART service, a progressive decline in referral delay, improvements in baseline CD4 cell counts, and fewer recurrent TB episodes. Such trends are likely to be associated with improved survival, and these data strongly support this HIV-testing strategy.

Impact of human immunodeficiency virus and CD4 count on tuberculosis diagnosis: analysis of city-wide data from Cape Town, South Africa.

BACKGROUND The impact of human immunodeficiency virus (HIV) infection and CD4 count on the diagnosis of tuberculosis (TB) at population level is incompletely defined. OBJECTIVE To determine how HIV infection and CD4 count affect disease site, sputum smear status and overall rate of laboratory confirmation (sputum smear microscopy or culture) of TB cases under routine programme conditions. DESIGN Retrospective analysis of the 2009 electronic TB register for Cape Town, South Africa. RESULTS Of 29,478 TB cases notified in 2009, HIV status was known for 25,744 (87.3%) cases, of whom 13,237 (51.4%) were HIV-positive. Of these, 61.2% had CD4 cell counts of <200 cells/μl and 82.7% had counts of <350 cells/μl. Laboratory confirmation of TB (by smear or culture) was obtained less frequently in HIV-infected than non-HIV-infected adult cases (53.9% vs. 74.3%, P< 0.001). HIV infection was associated with a higher proportion of sputum smear-negative and extra-pulmonary TB and lower grades of sputum smear positivity even among those with CD4 counts of ≥ 500 cells/μl. However, the relationship between the proportion of smear-positive cases and CD4 count was non-linear. CONCLUSION Much TB is not laboratory-confirmed in this setting despite good laboratory services. HIV-associated TB is more difficult to diagnose even at high CD4 cell counts of >500 cells/μl, suggesting early impact after HIV seroconversion.

Scaling up integration: development and results of a participatory assessment of HIV/TB services, South Africa

BackgroundIn South Africa the need to integrate HIV, TB and STI programmes has been recognised at a policy and organisation level; the challenge is now one of translating policies into relevant actions and monitoring implementation to ensure that the anticipated benefits of integration are achieved. In this research, set in public primary care services in Cape Town, South Africa, we set out to determine how middle level managers could be empowered to monitor the implementation of an effective, integrated HIV/TB/STI service.MethodsA team of managers and researchers designed an evaluation tool to measure implementation of key components of an integrated HIV/TB/STI package with a focus on integration. They used a comprehensive health systems framework based on conditions for programme effectiveness and then identified and collected tracer indicators. The tool was extensively piloted in two rounds involving 49 clinics in 2003 and 2004 to identify data necessary for effective facility-level management. A subsequent evaluation of 16 clinics (2 per health sub district, 12% of all public primary care facilities) was done in February 2006.Results16 clinics were reviewed and 635 records sampled. Client access to HIV/TB/STI programmes was limited in that 50% of facilities routinely deferred clients. Whilst the physical infrastructure and staff were available, there was problem with capacity in that there was insufficient staff training (for example, only 40% of clinical staff trained in HIV care). Weaknesses were identified in quality of care (for example, only 57% of HIV clients were staged in accordance with protocols) and continuity of care (for example, only 24% of VCT clients diagnosed with HIV were followed up for medical assessment). Facility and programme managers felt that the evaluation tool generated information that was useful to manage the programmes at facility and district level. On the basis of the results facility managers drew up action plans to address three areas of weakness within their own facility.ConclusionsThis use of the tool which is designed to empower programme and facility managers demonstrates how engaging middle managers is crucial in translating policies into relevant actions.

Community health care workers in South Africa are at increased risk for tuberculosis.

2have indicated that HCWs have an increased risk of TB disease compared with the general population. The risk for TB disease is even higher among HCWs co-infected with HIV. Studies from South Africa found an HIV prevalence among HCWs of 15.7% in 4 provinces in 2002 3 and of 11.5% in 2 hospitals in Gauteng in 2005. 4 Many sub-Saharan African countries face a severe shortage of qualified HCWs as a result of the dual HIV/TB epidemic, which has triggered task shifting to a range of lay community health care workers (CHWs) – for example, home-based care workers, lay counsellors and adherence supporters, for both TB and highly active antiretroviral therapy (HAART). CHWs may experience a considerable occupational TB risk; however, their risk of TB disease and HIV prevalence has never been documented. The TB/HIV Care Association is a non-governmental organisation that employs CHWs to provide adherence support to both TB patients and patients taking HAART. The Desmond Tutu HIV Foundation partnered with the TB/HIV Care Association to provide HIV and TB testing to their CHWs, and subsequently determined the prevalence of diagnosed and undiagnosed TB and HIV among them. Methods

GeneXpert MTB/RIF Version G4 for Identification of Rifampin-Resistant Tuberculosis in a Programmatic Setting

ABSTRACT A recent Cochrane review estimated GeneXpert MTB/RIF specificity for rifampin resistance as 98% (95% confidence interval [CI], 97 to 99), based on results from earlier test versions. The measured positive predictive value of the new generation test from programmatic implementation in Cape Town, South Africa, was 99.5% (95% CI, 98.5 to 100), confirming excellent specificity.

Integration of TB and ART services fails to improve TB treatment outcomes: Comparison of ART/TB primary healthcare services in Cape Town, South Africa

BACKGROUND The combined tuberculosis (TB) and HIV epidemics in South Africa (SA) have created enormous operational challenges for a health service that has traditionally run vertical programmes for TB treatment and antiretroviral therapy (ART) in separate facilities. This is particularly problematic for TB/HIV co-infected patients who need to access both services. OBJECTIVE To determine whether integrated TB facilities had better TB treatment outcomes than single-service facilities in Cape Town, SA. METHODS TB treatment outcomes were determined for newly registered, adult TB patients (aged > or = 18 years) at 13 integrated ART/TB primary healthcare (PHC) facilities and four single-service PHC facilities from 1 January 2009 to 30 June 2010. A chi2 test adjusted for a cluster sample design was used to compare outcomes by type of facility. RESULTS Of 13,542 newly registered patients, 10,030 received TB treatment in integrated facilities and 3,512 in single-service facilities. There was no difference in baseline characteristics between the two groups with HIV status determined for 9,351 (93.2%) and 3,227 (91.9%) patients, of whom 6 649 (66.3%) and 2,213 (63%) were HIV-positive in integrated facilities and single-service facilities, respectively. The median CD4+ count of HIV-positive patients was 152 cells/microl (interquartile range (IQR) 71-277) for integrated facilities and 148 cells/microl (IQR 67-260) for single-service facilities. There was no statistical difference in the TB treatment outcome profile between integrated and single-service facilities for all TB patients (p = 0.56) or for the sub-set of HIV-positive TB patients (p = 0.58) CONCLUSION: This study did not demonstrate improved TB treatment outcomes in integrated PHC facilities and showed that the provision of ART in the same facility as TB services was not associated with lower TB death and default rates.

Impact of ART on TB case fatality stratified by CD4 count for HIV-positive TB patients in Cape Town, South Africa (2009-2011).

Objective:To identify determinants of tuberculosis (TB) case fatality including the impact of antiretroviral therapy (ART) at different CD4 thresholds for HIV-positive adult and adolescent TB patients. Methods:Through a retrospective analysis of the electronic TB database, we identified the HIV status of newly registered patients aged ≥15 years. Multivariable Cox proportional hazard models were used to determine the risk factors for TB case fatality in these patients. Results:In 2009, 2010, and 2011, 25,841, 26,104, and 25,554 newly registered adult TB patients were treated in primary health care clinics in Cape Town, of whom 49.7%, 50.4%, and 50.9% were HIV positive. ART uptake increased over 3 years from 43% to 64.9%, and case fatality of the HIV-positive patients decreased from 7.0% to 5.8% (P < 0.001). Female gender, increasing age, retreatment TB, low CD4 counts, and extrapulmonary TB were associated with increased case fatality, whereas patients on ART had a substantial decrease in case fatality. The difference in case fatality between patients on ART and not on ART was most pronounced at low CD4 counts with the positive influence of ART noted up to a CD4 count threshold of 350 cells per cubic millimeter (P < 0.001). Despite improvements in ART uptake, in 2011, 21% of the patients with CD4 counts <350 cells per cubic millimeter did not start ART during TB treatment. Conclusion:This study showed a relatively poor uptake of ART among severely immune-compromised TB patients. Patients with CD4 counts <350 cells per cubic millimeter were shown to clearly benefit from ART during TB treatment, and ART initiation should be prioritized for this category of patients.