Journal Article > Meta-AnalysisFull Text
Lancet HIV. 2022 April 1; Volume S2352-3018 (Issue 22); 00002-9.; DOI:10.1016/S2352-3018(22)00002-9
Dhana A, Hamada Y, Kengne AP, Kerkhoff AD, Rangaka MX, et al.
Lancet HIV. 2022 April 1; Volume S2352-3018 (Issue 22); 00002-9.; DOI:10.1016/S2352-3018(22)00002-9
BACKGROUND
Since 2011, WHO has recommended that HIV-positive inpatients be routinely screened for tuberculosis with the WHO four-symptom screen (W4SS) and, if screened positive, receive a molecular WHO-recommended rapid diagnostic test (eg, Xpert MTB/RIF [Xpert] assay). To inform updated WHO tuberculosis screening guidelines, we conducted a systematic review and individual participant data meta-analysis to assess the performance of W4SS and alternative screening tests to guide Xpert testing and compare the diagnostic accuracy of the WHO Xpert algorithm (ie, W4SS followed by Xpert) with Xpert for all HIV-positive inpatients.
METHODS
We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011, to March 1, 2020, for studies of adult and adolescent HIV-positive inpatients enrolled regardless of tuberculosis signs and symptoms. The separate reference standards were culture and Xpert. Xpert was selected since it is most likely to be the confirmatory test used in practice. We assessed the proportion of inpatients eligible for Xpert testing using the WHO algorithm; assessed the accuracy of W4SS and alternative screening tests or strategies to guide diagnostic testing; and compared the accuracy of the WHO Xpert algorithm (W4SS followed by Xpert) with Xpert for all. We obtained pooled proportion estimates with a random-effects model, assessed diagnostic accuracy by fitting random-effects bivariate models, and assessed diagnostic yield descriptively. This systematic review has been registered on PROSPERO (CRD42020155895).
FINDINGS
Of 6162 potentially eligible publications, six were eligible and we obtained data for all of the six publications (n=3660 participants). The pooled proportion of inpatients eligible for an Xpert was 90% (95% CI 89-91; n=3658). Among screening tests to guide diagnostic testing, W4SS and C-reactive protein (≥5 mg/L) had highest sensitivities (≥96%) but low specificities (≤12%); cough (≥2 weeks), haemoglobin concentration (<8 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had higher specificities (61-90%) but suboptimal sensitivities (12-57%). The WHO Xpert algorithm (W4SS followed by Xpert) had a sensitivity of 76% (95% CI 67-84) and specificity of 93% (88-96; n=637). Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78% (95% CI 69-85) and specificity was 93% (87-96; n=639). In two cohorts that had sputum and non-sputum samples collected for culture or Xpert, diagnostic yield of sputum Xpert was 41-70% and 61-64% for urine Xpert.
INTERPRETATION
The W4SS and other potential screening tests to guide Xpert testing have suboptimal accuracy in HIV-positive inpatients. On the basis of these findings, WHO now strongly recommends molecular rapid diagnostic testing in all medical HIV-positive inpatients in settings where tuberculosis prevalence is higher than 10%.
Since 2011, WHO has recommended that HIV-positive inpatients be routinely screened for tuberculosis with the WHO four-symptom screen (W4SS) and, if screened positive, receive a molecular WHO-recommended rapid diagnostic test (eg, Xpert MTB/RIF [Xpert] assay). To inform updated WHO tuberculosis screening guidelines, we conducted a systematic review and individual participant data meta-analysis to assess the performance of W4SS and alternative screening tests to guide Xpert testing and compare the diagnostic accuracy of the WHO Xpert algorithm (ie, W4SS followed by Xpert) with Xpert for all HIV-positive inpatients.
METHODS
We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011, to March 1, 2020, for studies of adult and adolescent HIV-positive inpatients enrolled regardless of tuberculosis signs and symptoms. The separate reference standards were culture and Xpert. Xpert was selected since it is most likely to be the confirmatory test used in practice. We assessed the proportion of inpatients eligible for Xpert testing using the WHO algorithm; assessed the accuracy of W4SS and alternative screening tests or strategies to guide diagnostic testing; and compared the accuracy of the WHO Xpert algorithm (W4SS followed by Xpert) with Xpert for all. We obtained pooled proportion estimates with a random-effects model, assessed diagnostic accuracy by fitting random-effects bivariate models, and assessed diagnostic yield descriptively. This systematic review has been registered on PROSPERO (CRD42020155895).
FINDINGS
Of 6162 potentially eligible publications, six were eligible and we obtained data for all of the six publications (n=3660 participants). The pooled proportion of inpatients eligible for an Xpert was 90% (95% CI 89-91; n=3658). Among screening tests to guide diagnostic testing, W4SS and C-reactive protein (≥5 mg/L) had highest sensitivities (≥96%) but low specificities (≤12%); cough (≥2 weeks), haemoglobin concentration (<8 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had higher specificities (61-90%) but suboptimal sensitivities (12-57%). The WHO Xpert algorithm (W4SS followed by Xpert) had a sensitivity of 76% (95% CI 67-84) and specificity of 93% (88-96; n=637). Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78% (95% CI 69-85) and specificity was 93% (87-96; n=639). In two cohorts that had sputum and non-sputum samples collected for culture or Xpert, diagnostic yield of sputum Xpert was 41-70% and 61-64% for urine Xpert.
INTERPRETATION
The W4SS and other potential screening tests to guide Xpert testing have suboptimal accuracy in HIV-positive inpatients. On the basis of these findings, WHO now strongly recommends molecular rapid diagnostic testing in all medical HIV-positive inpatients in settings where tuberculosis prevalence is higher than 10%.
Journal Article > ResearchFull Text
Southern African Journal of HIV medicine. 2019 November 8; Volume 20 (Issue 1); 1030.; DOI:10.4102/sajhivmed.v20i1.1030
Govender NP, Meintjes GA, Mangena PM, Nel J, Potgieter S, et al.
Southern African Journal of HIV medicine. 2019 November 8; Volume 20 (Issue 1); 1030.; DOI:10.4102/sajhivmed.v20i1.1030
Journal Article > ResearchFull Text
PLOS Med. 2019 April 5; Volume 16 (Issue 4); DOI:10.1371/journal.pmed.1002776
Gupta-Wright A, Corbett EL, Wilson D, van Oosterhout JJ, Dheda K, et al.
PLOS Med. 2019 April 5; Volume 16 (Issue 4); DOI:10.1371/journal.pmed.1002776
The prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings. A cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30-43), 45.4% were female, median CD4 cell count at admission was 76 cells/μl (IQR 23-206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%-55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%-25.4%) in the low-risk group (p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4-15.2) in high-risk patients compared to low-risk patients (p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63-0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61-0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21-145). OR for mortality was 5.3 (95% CI 2.2-9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortality (e.g., tuberculosis drug resistance). This risk score is capable of identifying patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions, although further prospective validation studies are necessary. Given the scale of HIV/TB morbidity and mortality in African hospitals, better prognostic tools along with interventions could contribute towards global targets to reduce tuberculosis mortality.
Journal Article > LetterFull Text
Trop Med Int Health. 1999 March 1; Volume 4 (Issue 3); 236-238.; DOI:10.1046/j.1365-3156.1999.43384.x
Kumphitak A, Cawthorne P, Lakhonphol S, Kasi-Sedapan S, Sanaeha S, et al.
Trop Med Int Health. 1999 March 1; Volume 4 (Issue 3); 236-238.; DOI:10.1046/j.1365-3156.1999.43384.x
Journal Article > ResearchFull Text
Int J Infect Dis. 2020 June 1; Volume 95; 459-461.; DOI:10.1016/j.ijid.2020.02.057
Shroufi A, Govender NP, Meintjes GA, Black JM, Nel J, et al.
Int J Infect Dis. 2020 June 1; Volume 95; 459-461.; DOI:10.1016/j.ijid.2020.02.057
BACKGROUND
Cryptococcal Meningitis (CM) is estimated to cause 181,000 deaths annually; with the majority occurring in Sub Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure quality assured flucytosine remains unregistered and largely inaccessible throughout Africa.
METHODS
The recently established South African flucytosine clinical access programme is an attempt to address market failure which led to a lack of public-sector access to flucytosine for cryptococcal meningitis, by making the medicine freely available to tertiary hospitals in South Africa.
RESULTS
Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observation from this experience that may have wider relevance.
CONCLUSIONS
The South African Flucytosine Access Programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.
Cryptococcal Meningitis (CM) is estimated to cause 181,000 deaths annually; with the majority occurring in Sub Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure quality assured flucytosine remains unregistered and largely inaccessible throughout Africa.
METHODS
The recently established South African flucytosine clinical access programme is an attempt to address market failure which led to a lack of public-sector access to flucytosine for cryptococcal meningitis, by making the medicine freely available to tertiary hospitals in South Africa.
RESULTS
Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observation from this experience that may have wider relevance.
CONCLUSIONS
The South African Flucytosine Access Programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.
Journal Article > CommentaryFull Text
Lancet Infect Dis. 2018 October 18; Volume 19 (Issue 4); DOI:10.1016/S1473-3099(18)30493-6
Loyse A, Burry J, Cohn J, Ford NP, Chiller T, et al.
Lancet Infect Dis. 2018 October 18; Volume 19 (Issue 4); DOI:10.1016/S1473-3099(18)30493-6
In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.
Journal Article > CommentaryFull Text
Lancet. 1999 November 27; Volume 354; 1893-1895.
Wilson D, Cawthorne P, Ford NP, Aongsonwang S
Lancet. 1999 November 27; Volume 354; 1893-1895.
Journal Article > ResearchFull Text
AIDS. 2007 July 1; Volume 21 (Issue Suppl 4); DOI:10.1097/01.aids.0000279703.78685.a6
Ford NP, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K
AIDS. 2007 July 1; Volume 21 (Issue Suppl 4); DOI:10.1097/01.aids.0000279703.78685.a6
ANTIRETROVIRAL ROLLOUT IN BRAZIL AND THAILAND: Brazil and Thailand are among few developing countries to achieve universal access to antiretroviral therapy. Three factors were critical to this success: legislation for free access to treatment; public sector capacity to manufacture medicines; and strong civil society action to support government initiatives to improve access. LOCAL PRODUCTION OF AFFORDABLE, NON-PATENTED DRUGS: Many older antiretroviral drugs are not patented in either country and affordable generic versions are manufactured by local pharmaceutical institutes. EFFORTS TO ENSURE ACCESS TO EXPENSIVE, PATENTED DRUGS: Developing countries were not required to grant patents on medicines until 2005, but under US government threats of trade sanctions, Thailand and Brazil began doing so at least ten years prior to this date. Brazil has used price negotiations with multi-national pharmaceutical companies to lower the price of newer patented antiretrovirals. However, the prices obtained by this approach remain unaffordable. Thailand recently employed compulsory licensing for two antiretrovirals, obtaining substantial price reductions, both for generic and brand products. Following Thailand's example, Brazil has issued its first compulsory license. LESSONS LEARNED: Middle-income countries are unable to pay the high prices of multinational pharmaceutical companies. By relying on negotiations with companies, Brazil pays up to four times more for some drugs compared with prices available internationally. Compulsory licensing has brought treatment with newer antiretrovirals within reach in Thailand, but has resulted in pressure from industry and the US government. An informed and engaged civil society is essential to support governments in putting health before trade.
Journal Article > ResearchFull Text
Int J STD AIDS. 2005 June 1
Ponnet M, Frederix K, Petdachai W, Wilson D, Eksaengsri A, et al.
Int J STD AIDS. 2005 June 1
Scaling up of antiretroviral treatment (ART) for children in countries like Thailand will require decentralization and management by non-specialist doctors. We describe (a) the formulation of a standardized drug dosage table to facilitate antiretroviral drug (ARV) prescriptions for children, (b) the acceptability of such a table among doctors and (c) the safety and efficacy of drug doses in the table. Acceptability was assessed using a questionnaire. Safety and efficacy were assessed on the basis of incidence of adverse effects and virological response to treatment, respectively. Of all doctors (n=18), 17 (94%) found that the table was practical to use, avoided miscalculations and made them more confident with prescriptions. Of 49 children prescribed ARVs, less than 5% had adverse side-effects. All ARV-naïve children achieved undetectable viral loads within six months of ART. In our setting, a standardized drug dosage table provided a simple and reliable tool that facilitated ARV prescriptions for children.
Journal Article > ResearchFull Text
Nature. 2015 December 1; Volume 528 (Issue 7580); S68-S76.; DOI:10.1038/nature16046
Phillips AN, Shroufi A, Vojnov L, Cohn J, Roberts TR, et al.
Nature. 2015 December 1; Volume 528 (Issue 7580); S68-S76.; DOI:10.1038/nature16046
There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.