OpenUCT :: Browsing by Author "Lawn, Stephen D"

Browsing by Author "Lawn, Stephen D"

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Open Access
Antiretroviral therapy for prevention of tuberculosis in adults with HIV: a systematic review and meta-analysis
(Public Library of Science, 2012) Suthar, Amitabh B; Lawn, Stephen D; Del Amo, Julia; Getahun, Haileyesus; Dye, Christopher; Sculier, Delphine; Sterling, Timothy R; Chaisson, Richard E; Williams, Brian G; Harries, Anthony D
In a systematic review and meta-analysis, Amitabh Suthar and colleagues investigate the association between antiretroviral therapy and the reduction in the incidence of tuberculosis in adults with HIV infection.
Open Access
Antiretroviral treatment cohort analysis using time-updated CD4 counts: assessment of bias with different analytic methods
(Public Library of Science, 2011) Kranzer, Katharina; Lewis, James J; White, Richard G; Glynn, Judith R; Lawn, Stephen D; Middelkoop, Keren; Bekker, Linda-Gail; Wood, Robin
BACKGROUND: Survival analysis using time-updated CD4+ counts during antiretroviral therapy is frequently employed to determine risk of clinical events. The time-point when the CD4+ count is assumed to change potentially biases effect estimates but methods used to estimate this are infrequently reported. METHODS: This study examined the effect of three different estimation methods: assuming i) a constant CD4+ count from date of measurement until the date of next measurement, ii) a constant CD4+ count from the midpoint of the preceding interval until the midpoint of the subsequent interval and iii) a linear interpolation between consecutive CD4+ measurements to provide additional midpoint measurements. Person-time, tuberculosis rates and hazard ratios by CD4+ stratum were compared using all available CD4+ counts (measurement frequency 1-3 months) and 6 monthly measurements from a clinical cohort. Simulated data were used to compare the extent of bias introduced by these methods. RESULTS: The midpoint method gave the closest fit to person-time spent with low CD4+ counts and for hazard ratios for outcomes both in the clinical dataset and the simulated data. CONCLUSION: The midpoint method presents a simple option to reduce bias in time-updated CD4+ analysis, particularly at low CD4 cell counts and rapidly increasing counts after ART initiation.
Open Access
Are the effects of isoniaid preventive therapy and highly active antiretroviral therapy additive in preventing HIV-associated tuberculosis
(2009) Wood, Robin; Lawn, Stephen D; Bekker, Linda-Gail
Golub et al. [1] recently reported a retrospective analysis of rates of incident tuberculosis (TB) in a large observational cohort of 2778 patients accessing HIV care in rural and urban South Africa. The TB incidence rate was highest [7.1/100 person-years; 95% confidence interval (CI)¼ 6.2–8.2] during the period of care when patients did not receive isoniazid preventive therapy (IPT) or highly active antiretroviral therapy (HAART). The rates were lower during person-time that accrued throughout follow-up after initiation of IPT (5.2/100 person-years; 95% CI¼ 3.4–7.8) and throughout follow-up on HAART alone (4.6/100 person-years, 95% CI¼ 3.4– 6.2). The rate was lower still (1.1/100 person-years 95% CI¼ 0.2–7.6) during person-time accrued during sequential IPT and HAART (IPTþ HAART). The authors concluded that TB risk was significantly reduced by IPT in HAART-treated adults. It was further concluded that 'the dramatic reduction in TB risk' demonstrated in this study together with supportive data from a similarly analysed study from Brazil [2] indicates that widespread use 1444 AIDS 2009, Vol 23 No 11 Fig. 1. T2-weighted flair image demonstrating enhancing lesion in the right precentral gyrus. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. of IPT should be implemented in conjunction with the roll-out of HAART.
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Are the effects of isoniaid preventive therapy and highly active antiretroviral therapy additive in preventing HIV-associated tuberculosis
(2009) Wood, Robin; Lawn, Stephen D; Bekker, Linda-Gail
Golub et al. [1] recently reported a retrospective analysis of rates of incident tuberculosis (TB) in a large observational cohort of 2778 patients accessing HIV care in rural and urban South Africa. The TB incidence rate was highest [7.1/100 person-years; 95% confidence interval (CI)¼ 6.2–8.2] during the period of care when patients did not receive isoniazid preventive therapy (IPT) or highly active antiretroviral therapy (HAART). The rates were lower during person-time that accrued throughout follow-up after initiation of IPT (5.2/100 person-years; 95% CI¼ 3.4–7.8) and throughout follow-up on HAART alone (4.6/100 person-years, 95% CI¼ 3.4– 6.2). The rate was lower still (1.1/100 person-years 95% CI¼ 0.2–7.6) during person-time accrued during sequential IPT and HAART (IPTþ HAART). The authors concluded that TB risk was significantly reduced by IPT in HAART-treated adults. It was further concluded that ‘the dramatic reduction in TB risk’ demonstrated in this study together with supportive data from a similarly analysed study from Brazil [2] indicates that widespread use 1444 AIDS 2009, Vol 23 No 11 Fig. 1. T2-weighted flair image demonstrating enhancing lesion in the right precentral gyrus. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. of IPT should be implemented in conjunction with the roll-out of HAART.
Open Access
Blood neutrophil counts in HIV-infected patients with pulmonary tuberculosis: association with sputum mycobacterial load
(Public Library of Science, 2013) Kerkhoff, Andrew D; Wood, Robin; Lowe, David M; Vogt, Monica; Lawn, Stephen D
BACKGROUND: Increasing evidence suggests that neutrophils play a role in the host response to Mycobacterium tuberculosis . We determined whether neutrophil counts in peripheral blood are associated with tuberculosis (TB) and with mycobacterial load in sputum in HIV-infected patients. METHODOLOGY/PRINCIPAL FINDINGS: Adults enrolling in an antiretroviral treatment (ART) clinic in a Cape Town township were screened for TB regardless of symptoms. Paired sputum samples were examined using liquid culture, fluorescence microscopy, and the Xpert MTB/RIF assay. Absolute neutrophil counts (ANC) were measured in blood samples. Of 602 HIV-infected patients screened, 523 produced one or more sputum samples and had complete results available for analysis. Among these 523 patients, the median CD4 count was 169×10 9 /L (IQR, 96-232) and median ANC was 2.6×10 9 /L (IQR, 1.9-3.6). Culture-positive pulmonary tuberculosis was diagnosed in 89 patients. Patients with TB had a median ANC of 3.4×10 9 /L (IQR, 2.4-5.1) compared to 2.5×10 9 /L (IQR, 1.8-3.4) among those who were culture negative (p<0.0001). In multivariable analyses, having pulmonary TB was associated with an adjusted risk ratio (aRR) of 2.6 (95%CI, 1.5-4.5) for having an ANC level that exceeded the median value (ANC ≥2.6×10 9 /L; p = 0.0006) and an aRR of 6.8 (95%CI, 2.3-20.4) for having neutrophilia defined by a neutrophil count exceeding the upper limit of the normal range (ANC >7.5×10 9 /L; p = 0.0005). Patients were then classified into four mutually exclusive groups with increasing sputum mycobacterial load as defined by the results of culture, Xpert MTB/RIF and sputum smear microscopy. Multivariable analyses demonstrated that increasing sputum mycobacterial load was positively associated with blood ANC ≥2.6×10 9 /L and with neutrophilia. Conclusions/Significance Increased blood neutrophil counts were independently associated with pulmonary TB and sputum mycobacterial burden in this HIV-infected patient group. This observation supports the growing body of literature regarding the potential role for neutrophils in the host response to TB.
Open Access
Burden of new and recurrent tuberculosis in a major South African city stratified by age and HIV-status
(Public Library of Science, 2011) Wood, Robin; Lawn, Stephen D; Caldwell, Judy; Kaplan, Richard; Middelkoop, Keren; Bekker, Linda-Gail
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.
Open Access
Corneal endothelial cells provide evidence of accelerated cellular senescence associated with HIV infection: a case-control study
(Public Library of Science, 2013) Pathai, Sophia; Lawn, Stephen D; Shiels, Paul G; Weiss, Helen A; Cook, Colin; Wood, Robin; Gilbert, Clare E
BACKGROUND: Cellular senescence may be a key factor in HIV-related premature biological aging. We assessed features of the corneal endothelium that are known to be associated with biological aging, and cellular senescence markers in HIV-infected adults. METHODS: Case-control study of 242 HIV-infected adults and 249 matched controls. Using specular microscopy, the corneal endothelium was assessed for features of aging (low endothelial cell density [ECD], high variation in cell size, and low hexagonality index). Data were analysed by multivariable regression. CDKN2A expression (a cell senescence mediator) was measured in peripheral blood leukocytes and 8-hydroxy-2′-deoxyguanosine (8-OHDG; an oxidative DNA damage marker) levels were measured in plasma. RESULTS: The median age of both groups was 40 years. Among HIV-infected adults, 88% were receiving antiretroviral therapy (ART); their median CD4 count was 468 cells/µL. HIV infection was associated with increased odds of variation in cell size (OR = 1.67; 95% CI: 1.00-2.78, p = 0.04). Among HIV-infected participants, low ECD was independently associated with current CD4 count <200 cells/µL (OR = 2.77; 95%CI: 1.12-6.81, p = 0.03). In participants on ART with undetectable viral load, CDKN2A expression and 8-OHDG levels were higher in those with accelerated aging, as reflected by lower ECD. CONCLUSIONS: The corneal endothelium shows features consistent with HIV-related accelerated senescence, especially among those with poor immune recovery.
Open Access
Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa
(Public Library of Science, 2013) Jarvis, Joseph N; Harrison, Thomas S; Lawn, Stephen D; Meintjes, Graeme; Wood, Robin; Cleary, Susan
Objectives Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM. Design Cost-effectiveness analysis. METHODS: Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts <100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART. RESULTS: The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence ≥0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US$158 versus US$51per person year; incremental cost effectiveness ratio(ICER) US$889,267 per life year gained). Both CRAG screening strategies are less costly and more clinically effective than current practice. Primary prophylaxis is more effective than current practice, but relatively cost-ineffective (ICER US$20,495). CONCLUSIONS: CRAG screening would be a cost-effective strategy to prevent CM-related mortality among patients initiating ART in South Africa. These findings provide further justification for programmatic implementation of CRAG screening.
Open Access
Feasibility, yield, and cost of active tuberculosis case finding linked to a mobile HIV service in Cape Town, South Africa: a cross-sectional study
(Public Library of Science, 2012) Kranzer, Katharina; Lawn, Stephen D; Meyer-Rath, Gesine; Vassall, Anna; Raditlhalo, Eudoxia; Govindasamy, Darshini; Van Schaik, Nienke; Wood, Robin; Bekker, Linda-Gail
Katharina Kranzer and colleagues investigate the operational characteristics of an active tuberculosis case-finding service linked to a mobile HIV testing unit that operates in underserviced areas in Cape Town, South Africa.
Open Access
High prevalence of self-reported undiagnosed HIV despite high coverage of HIV testing: a cross-sectional population based sero-survey in South Africa
(Public Library of Science, 2011) Kranzer, Katharina; van Schaik, Nienke; Karmue, Unice; Middelkoop, Keren; Sebastian, Elaine; Lawn, Stephen D; Wood, Robin; Bekker, Linda-Gail
Objectives: To measure HIV prevalence and uptake of HIV counseling and testing (HCT) in a peri-urban South African community. To assess predictors for previous HIV testing and the association between the yield of previously undiagnosed HIV and time of last negative HIV test. METHODS: A random sample of 10% of the adult population (≥15 years) were invited to attend a mobile HCT service. Study procedures included a questionnaire, HIV testing and CD4 counts. Predictors for previous testing were determined using a binominal model. RESULTS: 1,144 (88.0%) of 1,300 randomly selected individuals participated in the study. 71.0% (68.3-73.6) had previously had an HIV test and 37.5% (34.6-40.5) had tested in the past 12 months. Men, migrants and older (>35 years) and younger (<20 years) individuals were less likely to have had a previous HIV test. Overall HIV prevalence was 22.7 (20.3-25.3) with peak prevalence of 41.8% (35.8-47.8) in women aged 25.1-35 years and 37.5% (26.7-48.3) in men aged 25.1-45 years. Prevalence of previously undiagnosed HIV was 10.3% (8.5-12.1) overall and 4.5% (2.3-6.6), 8.0% (CI 3.9-12.0) and 20.0% (13.2-26.8) in individuals who had their most recent HIV test within 1, 1-2 and more than 2 years prior to the survey. CONCLUSION: The high burden of undiagnosed HIV in individuals who had recently tested underscores the importance of frequent repeat testing at least annually. The high prevalence of previously undiagnosed HIV in individuals reporting a negative test in the 12 months preceding the survey indicates a very high incidence. Innovative prevention strategies are needed.
Open Access
Increasing transfers-out from an antiretroviral treatment service in South Africa: patient characteristics and rates of virological non-suppression
(Public Library of Science, 2013) Nglazi, Mweete D; Kaplan, Richard; Orrell, Catherine; Myer, Landon; Wood, Robin; Bekker, Linda-Gail; Lawn, Stephen D
Objectives: To determine the proportion, characteristics and outcomes of patients who transfer-out from an antiretroviral therapy (ART) service in a South African township. METHODS: This retrospective cohort study included all patients aged ≥15 years who enrolled between September 2002 and December 2009. Follow-up data were censored in December 2010. Kaplan-Meier survival analysis was used to describe time to transfer-out and cox proportional hazard analysis was used to determine associated risk factors. RESULTS: 4511 patients (4003 ART-naïve and 508 non-naïve at baseline) received ART during the study period. Overall, 597 (13.2%) transferred out. The probability of transferring out by one year of ART steadily increased from 1.4% in 2002/2004 cohort to 8.9% for the 2009 cohort. Independent risk factors for transfer-out were more recent calendar year of enrolment, younger age (≤25 years) and being ART non-naïve at baseline (i.e., having previously transferred into this clinic from another facility). The proportions of patients transferred out who had a CD4 cell count <200 cells/µL and/or a viral load ≥1000 copies/mL were 19% and 20%, respectively. CONCLUSIONS: With scale-up of ART over time, an increasing proportion of patients are transferring between ART services and information systems are needed to track patients. Approximately one-fifth of these have viral loads >1000 copies/mL around the time of transfer, suggesting the need for careful adherence counseling and assessment of medication supplies among those planning transfer.
Open Access
Indoor social networks in a South African township: potential contribution of location to tuberculosis transmission
(Public Library of Science, 2012) Wood, Robin; Racow, Kimberly; Bekker, Linda-Gail; Morrow, Carl; Middelkoop, Keren; Mark, Daniella; Lawn, Stephen D
BACKGROUND: We hypothesized that in South Africa, with a generalized tuberculosis (TB) epidemic, TB infection is predominantly acquired indoors and transmission potential is determined by the number and duration of social contacts made in locations that are conducive to TB transmission. We therefore quantified time spent and contacts met in indoor locations and public transport by residents of a South African township with a very high TB burden. METHODS: A diary-based community social mixing survey was performed in 2010. Randomly selected participants (n = 571) prospectively recorded numbers of contacts and time spent in specified locations over 24-hour periods. To better characterize age-related social networks, participants were stratified into ten 5-year age strata and locations were classified into 11 types. RESULTS: Five location types (own-household, other-households, transport, crèche/school, and work) contributed 97.2% of total indoor time and 80.4% of total indoor contacts. Median time spent indoors was 19.1 hours/day (IQR:14.3-22.7), which was consistent across age strata. Median daily contacts increased from 16 (IQR:9-40) in 0-4 year-olds to 40 (IQR:18-60) in 15-19 year-olds and declined to 18 (IQR:10-41) in ≥45 year-olds. Mean daily own-household contacts was 8.8 (95%CI:8.2-9.4), which decreased with increasing age. Mean crèche/school contacts increased from 6.2/day (95%CI:2.7-9.7) in 0-4 year-olds to 28.1/day (95%CI:8.1-48.1) in 15-19 year-olds. Mean transport contacts increased from 4.9/day (95%CI:1.6-8.2) in 0-4 year-olds to 25.5/day (95%CI:12.1-38.9) in 25-29 year-olds. CONCLUSIONS: A limited number of location types contributed the majority of indoor social contacts in this community. Increasing numbers of social contacts occurred throughout childhood, adolescence, and young adulthood, predominantly in school and public transport. This rapid increase in non-home socialization parallels the increasing TB infection rates during childhood and young adulthood reported in this community. Further studies of the environmental conditions in schools and public transport, as potentially important locations for ongoing TB infection, are indicated.
Open Access
Linkage to HIV care and antiretroviral therapy in Cape Town, South Africa
(Public Library of Science, 2010) Kranzer, Katharina; Zeinecker, Jennifer; Ginsberg, Philip; Orrell, Catherine; Kalawe, Nosindiso N; Lawn, Stephen D; Bekker, Linda-Gail; Wood, Robin
BACKGROUND: Antiretroviral therapy (ART) has been scaled-up rapidly in Africa. Programme reports typically focus on loss to follow-up and mortality among patients receiving ART. However, little is known about linkage and retention in care of individuals prior to starting ART. METHODOLOGY: Data on adult residents from a periurban community in Cape Town were collected at a primary care clinic and hospital. HIV testing registers, CD4 count results provided by the National Health Laboratory System and ART registers were linked. A random sample (n = 885) was drawn from adults testing HIV positive through antenatal care, sexual transmitted disease and voluntary testing and counseling services between January 2004 and March 2009. All adults (n = 103) testing HIV positive through TB services during the same time period were also included in the study. Linkage to HIV care was defined as attending for a CD4 count measurement within 6 months of HIV diagnosis. Linkage to ART care was defined as initiating ART within 6 months of HIV diagnosis in individuals with a CD4 count ≤200 cells/µl taken within 6 months of HIV diagnosis. FINDINGS: Only 62.6% of individuals attended for a CD4 count measurement within 6 months of testing HIV positive. Individuals testing through sexually transmitted infection services had the best (84.1%) and individuals testing on their own initiative (53.5%) the worst linkage to HIV care. One third of individuals with timely CD4 counts were eligible for ART and 66.7% of those were successfully linked to ART care. Linkage to ART care was highest among antenatal care clients. Among individuals not yet eligible for ART only 46.3% had a repeat CD4 count. Linkage to HIV care improved in patients tested in more recent calendar period. CONCLUSION: Linkage to HIV and ART care was low in this poor peri-urban community despite free services available within close proximity. More efforts are needed to link VCT scale-up to subsequent care.
Open Access
Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review
(BioMed Central, 2013-12-02) Lawn, Stephen D; Meintjes, Graeme; McIlleron, Helen; Harries, Anthony D; Wood, Robin
The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB.
Open Access
Predicting the long-term impact of antiretroviral therapy scale-up on population incidence of tuberculosis
(Public Library of Science, 2013) Dodd, Peter J; Knight, Gwenan M; Lawn, Stephen D; Corbett, Elizabeth L; White, Richard G
Objective To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa. METHODS: We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage. RESULTS: All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year. CONCLUSIONS: Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART.
Open Access
Prevalent and incident tuberculosis are independent risk factors for mortality among patients accessing antiretroviral therapy in South Africa
(Public Library of Science, 2013) Gupta, Ankur; Wood, Robin; Kaplan, Richard; Bekker, Linda-Gail; Lawn, Stephen D
BACKGROUND: Patients with prevalent or incident tuberculosis (TB) in antiretroviral treatment (ART) programmes in sub-Saharan Africa have high mortality risk. However, published data are contradictory as to whether TB is a risk factor for mortality that is independent of CD4 cell counts and other patient characteristics. Methods/FINDINGS: This observational ART cohort study was based in Cape Town, South Africa. Deaths from all causes were ascertained among patients receiving ART for up to 8 years. TB diagnoses and 4-monthly CD4 cell counts were recorded. Mortality rates were calculated and Poisson regression models were used to calculate incidence rate ratios (IRR) and identify risk factors for mortality. Of 1544 patients starting ART, 464 patients had prevalent TB at baseline and 424 developed incident TB during a median of 5.0 years follow-up. Most TB diagnoses (73.6%) were culture-confirmed. A total of 208 (13.5%) patients died during ART and mortality rates were 8.84 deaths/100 person-years during the first year of ART and decreased to 1.14 deaths/100 person-years after 5 years. In multivariate analyses adjusted for baseline and time-updated risk factors, both prevalent and incident TB were independent risk factors for mortality (IRR 1.7 [95% CI, 1.2-2.3] and 2.7 [95% CI, 1.9-3.8], respectively). Adjusted mortality risks were higher in the first 6 months of ART for those with prevalent TB at baseline (IRR 2.33; 95% CI, 1.5-3.5) and within the 6 months following diagnoses of incident TB (IRR 3.8; 95% CI, 2.6-5.7). CONCLUSIONS: Prevalent TB at baseline and incident TB during ART were strongly associated with increased mortality risk. This effect was time-dependent, suggesting that TB and mortality are likely to be causally related and that TB is not simply an epiphenomenon among highly immunocompromised patients. Strategies to rapidly diagnose, treat and prevent TB prior to and during ART urgently need to be implemented.
Open Access
Prognostic value of a quantitative analysis of lipoarabinomannan in urine from patients with HIV-associated tuberculosis
(Public Library of Science, 2014) Kerkhoff, Andrew D; Wood, Robin; Vogt, Monica; Lawn, Stephen D
BACKGROUND: Detection of the mycobacterial cell wall antigen lipoarabinomannan (LAM) in urine can be used to diagnose HIV-associated tuberculosis (TB) using a qualitative (positive/negative) read-out. However, it is not known whether the quantity of LAM present in urine provides additional prognostic information. Methods/FINDINGS: Consecutively recruited adult outpatients initiating antiretroviral therapy (ART) in South Africa were investigated for TB regardless of clinical symptoms using sputum smear microscopy and liquid culture (reference standard). Urine samples were tested using the Clearview TB-ELISA for LAM and the Xpert MTB/RIF assay. The ELISA optical densities (OD) were used as a quantitative assessment of urine LAM. Among 514 patients with complete sputum and urine LAM OD results, culture-confirmed TB was diagnosed in 84 patients. Twenty-three (27.3%) were LAM-positive with a median LAM OD of 0.68 (IQR 0.16-2.43; range, 0.10-3.29) and 61 (72.6%) were LAM negative (LAM OD <0.1 above background). Higher LAM ODs were associated with a range of prognostic indices, including lower CD4 cell counts, lower haemoglobin levels, higher blood neutrophil counts and higher mycobacterial load as assessed using both sputum and urine samples. The median LAM OD among patients who died was more than 6.8-fold higher than that of patients who remained alive at 3 months (P<0.001). The small number of deaths, however, precluded adequate assessment of mortality risk stratified according to urine LAM OD. CONCLUSIONS: In patients with HIV-associated TB, concentrations of LAM in urine were strongly associated with a range of poor prognostic characteristics known to be associated with mortality risk. Urine LAM assays with a semi-quantitative (negative vs. low-positive vs. high-positive) read-out may have improved clinical utility over assays with a simple binary result.
Open Access
Rapid microbiological screening for tuberculosis in HIV-positive patients on the first day of acute hospital admission by systematic testing of urine samples using Xpert MTB/RIF: a prospective cohort in South Africa
(2015-08-14) Lawn, Stephen D; Kerkhoff, Andrew D; Burton, Rosie; Schutz, Charlotte; van Wyk, Gavin; Vogt, Monica; Pahlana, Pearl; Nicol, Mark P; Meintjes, Graeme
Abstract Background Autopsy studies of HIV/AIDS-related hospital deaths in sub-Saharan Africa reveal frequent failure of pre-mortem diagnosis of tuberculosis (TB), which is found in 34–64 % of adult cadavers. We determined the overall prevalence and predictors of TB among consecutive unselected HIV-positive adults requiring acute hospital admission and the comparative diagnostic yield obtained by screening urine and sputum samples obtained on day 1 of admission with Xpert MTB/RIF (Xpert). Methods To determine overall TB prevalence accurately, comprehensive clinical sampling (sputum, urine, blood plus other relevant samples) was done and TB was defined by detection of Mycobacterium tuberculosis in any sample using Xpert and/or mycobacterial liquid culture. To evaluate a rapid screening strategy, we compared the diagnostic yield of Xpert testing sputum samples and urine samples obtained with assistance from a respiratory study nurse in the first 24 h of admission. Results Unselected HIV-positive acute adult new medical admissions (n = 427) who were not receiving TB treatment were enrolled irrespective of clinical presentation or symptom profile. From 2,391 cultures and Xpert tests done (mean, 5.6 tests/patient) on 1,745 samples (mean, 4.1 samples/patient), TB was diagnosed in 139 patients (median CD4 cell count, 80 cells/μL). TB prevalence was very high (32.6 %; 95 % CI, 28.1–37.2 %; 139/427). However, patient symptoms and risk factors were poorly predictive for TB. Overall, ≥1 non-respiratory sample(s) tested positive in 115/139 (83 %) of all TB cases, including positive blood cultures in 41/139 (29.5 %) of TB cases. In the first 24 h of admission, sputum (spot and/or induced samples) and urine were obtainable from 37.0 % and 99.5 % of patients, respectively (P <0.001). From these, the proportions of total TB cases (n = 139) that were diagnosed by Xpert testing sputum, urine or both sputum and urine combined within the first 24 h were 39/139 (28.1 %), 89/139 (64.0 %) and 108/139 (77.7 %) cases, respectively (P <0.001). Conclusions The very high prevalence of active TB and its non-specific presentation strongly suggest the need for routine microbiological screening for TB in all HIV-positive medical admissions in high-burden settings. The incremental diagnostic yield from Xpert testing urine was very high and this strategy might be used to rapidly screen new admissions, especially if sputum is difficult to obtain.
Open Access
Rates of switching antiretroviral drugs in a primary care service in South Africa before and after introduction of tenofovir
(Public Library of Science, 2013) Njuguna, Christine; Orrell, Catherine; Kaplan, Richard; Bekker, Linda-Gail; Wood, Robin; Lawn, Stephen D
Introduction Antiretroviral changes (single drug substitutions and regimen switches) limit treatment options and introduce challenges such as increased cost, monitoring and adherence difficulties. Patterns of drug substitutions and regimen switches from stavudine (d4T) and zidovudine (AZT) regimens have been well described but data on tenofovir (TDF) are more limited. This study describes the patterns and risk factors for drug changes of these antiretroviral drugs in adults. Method This retrospective cohort study included HIV positive, antiretroviral treatment (ART) naïve adults aged ≥18 years who started ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor. Follow-up was censored at first drug change and analysis focused on NRTI changes only. RESULTS: Between September 2002 and April 2011, 5095 adults initiated ART in Gugulethu. This comprised 948 subjects on TDF, 3438 on d4T and 709 subjects on AZT. Virological suppression rates at 1 year, regimen switching due to virological failure and overall losses to the programme were similar across the three groups. TDF had the lowest incidence rate of drug substitutions (2.6 per 100 P/Ys) compared to 17.9 for d4T and 8.5 per 100 P/Ys for AZT. Adverse drug reactions (ADRs) accounted for the majority of drug substitutions of d4T. Multivariate analysis showed that increasing age, female sex and d4T exposure were associated with increased hazard of drug substitution due to ADRs. Conversely, TDF exposure was associated with a substantially lower risk of substitution (adjusted hazards ratio 0.38; 95% CI 0.20-0.72). CONCLUSION: Regimen switches and virological suppression were similar for patients exposed to TDF, d4T and AZT, suggesting all regimens were equally effective. However, TDF was better tolerated with a substantially lower rate of drug substitutions due to ADRs.
Open Access
Retinal arterioles narrow with increasing duration of anti-retroviral therapy in HIV infection: a novel estimator of vascular risk in HIV?
(Public Library of Science, 2012) Pathai, Sophia; Weiss, Helen A; Lawn, Stephen D; Peto, Tunde; D'Costa, Leris M; Cook, Colin; Wong, Tien Y; Gilbert, Clare E
Objectives HIV infection is associated with an increased risk of age-related morbidity mediated by immune dysfunction, atherosclerosis and inflammation. Changes in retinal vessel calibre may reflect cumulative structural damage arising from these mechanisms. The relationship of retinal vessel calibre with clinical and demographic characteristics was investigated in a population of HIV-infected individuals in South Africa. METHODS: Case-control study of 491 adults ≥30 years, composed of 242 HIV-infected adults and 249 age- and gender-matched HIV-negative controls. Retinal vessel calibre was measured using computer-assisted techniques to determine mean arteriolar and venular diameters of each eye. RESULTS: The median age was 40 years (IQR: 35-48 years). Among HIV-infected adults, 87.1% were receiving highly active antiretroviral therapy (HAART) (median duration, 58 months), their median CD4 count was 468 cells/µL, and 84.3% had undetectable plasma viral load. Unadjusted mean retinal arteriolar diameters were 163.67±17.69 µm in cases and 161.34±17.38 µm in controls (p = 0.15). Unadjusted mean venular diameters were 267.77±18.21 µm in cases and 270.81±18.98 µm in controls (p = 0.07). Age modified the effect of retinal arteriolar and venular diameters in relation to HIV status, with a tendency towards narrower retinal diameters in HIV cases but not in controls. Among cases, retinal arteriolar diameters narrowed with increasing duration of HAART, independently of age (167.83 µm <3 years of HAART vs. 158.89 µm >6 years, p-trend = 0.02), and with a HIV viral load >10,000 copies/mL while on HAART (p = 0.05). HIV-related venular changes were not detected. CONCLUSIONS: Narrowing of retinal arteriolar diameters is associated with HAART duration and viral load, and may reflect heightened inflammatory and pro-atherogenic states of the systemic vasculature. Measurement of retinal vascular calibre could be an innovative non-invasive method of estimating vascular risk in HIV-infected individuals.