Malawi

Effect of self-administration versus provider-administered injection of subcutaneous depot medroxyprogesterone acetate on continuation rates in Malawi: a randomised controlled trial

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Background

Injectable contraceptives are popular in sub-Saharan Africa but have high discontinuation rates due partly to the need for provider-administered re-injection. We compared continuation rates of women who self-injected subcutaneous depot medroxyprogesterone acetate (DMPA-SC) and women who received DMPA-SC from a health-care provider, including community health workers (CHWs).

Methods

We did an open-label randomised controlled trial based at six Ministry of Health clinics in rural Mangochi District, Malawi. Health-care providers recruited adult women who presented at the six clinics or to CHWs in rural communities in the clinic catchment areas. Participants received DMPA-SC and were randomised (1:1) to receive provider-administered injections or training in how to self-inject DMPA-SC. Randomisation was done via a computer-generated block randomisation schedule with block sizes of four, six, and eight and stratified by study site, generated by an independent statistician. Self-injectors administered the first injection under observation and were sent home with three doses, written instructions, and a calendar. The provider-administered group received a DMPA-SC injection and a calendar, and were asked to return for subsequent injections. Data collectors contacted participants after the 14-week re-injection window at 3, 6, and 9 months to collect continuation data. At 12 months after enrolment or early discontinuation, women had their final interview, which included pregnancy testing. The primary outcome was discontinuation of DMPA-SC, as assessed in the intention-to-treat population. We used Kaplan-Meier methods to estimate the probabilities of continuation and a log-rank test to compare groups. Safety was assessed in the as-treated population, which consisted only of participants who successfully received at least one DMPA-SC injection after randomisation. This trial is registered with ClinicalTrials.gov, number NCT02293694.

Findings

This study lasted from Sept 17, 2015, to Feb 21, 2017. 731 women underwent randomisation, with 364 assigned to the self-administered group and 367 to the provider-administered group. One woman in the self-injection group withdrew at month 0. Treatment was discontinued by 99 women in the self-administered group and 199 women in the provider-administered group. The 12 month continuation rate was 73% in the self-injection group and 45% in the provider-administered group, giving an incidence rate ratio of 0·40 (95% CI 0·31–0·51; p<0·0001). Adverse events deemed to potentially be treatment-related were reported by ten women (20 events) in the self-administered group and 17 women (28 events) in the provider-administered group. Five serious adverse events were reported during the trial by four women; two events related to DMPA-SC (menorrhagia and anaemia requiring hospital admission) were reported by the same woman in the provider-administered group and resolved without sequelae. The other serious adverse events, including one death, were deemed to be unrelated to DMPA-SC.

Interpretation

Women who self-injected DMPA-SC had significantly higher rates of continuation than those receiving provider-injected DMPA-SC. Community-based provision of injectable contraception for self-injection in low-resource settings seems to be safe and feasible. Self-administration of DMPA-SC should be made widely available.

Source:http://www.thelancet.com

Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study.

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Abstract

Background

A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test.

Methods and Findings

Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture ofMycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491).

In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87–100]; specificity 90%, 95% CI [80–97]) and TB from OD (sensitivity 93%, 95% CI [83–100]; specificity 88%, 95% CI [74–97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85–100]; specificity 94%, 95% CI [84–100]) and OD patients (sensitivity 100%, 95% CI [100–100]; specificity 96%, 95% CI [93–100]).

Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group.

Conclusions

In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions.

Discussion

We have identified a host blood transcriptomic signature that distinguishes TB from a wide range of OD prevalent in HIV-infected and -uninfected African patients. We found that patients with TB can be distinguished from LTBI with only 27 transcripts and from OD with 44 transcripts. Our findings appear robust as the results are reproducible in both HIV-infected and -uninfected cohorts, in different geographic locations, and in an independent TB patient dataset. The high sensitivity and specificity of the signatures in distinguishing TB from OD, even in the HIV-infected patients that have differing levels of T cell depletion and a wide spectrum of opportunistic infections as well as HIV-related complications, suggests that the signatures are promising biomarkers of TB. The relatively small number of transcripts in our signatures may increase the potential for using transcriptional profiling as a clinical diagnostic tool from a single peripheral blood sample (i.e., using a multiplex assay [35],[36]).

The major challenge for diagnosis of TB in Africa is how to distinguish this disease from the range of other conditions that show similar symptoms in countries where TB and HIV are co-endemic. Previous TB biomarker studies have focused on distinguishing patients with TB from healthy controls, or from LTBI [21],[22],[24], or have used other disease controls that may not represent the “real world” disease spectra from which TB should be clinically differentiated [19],[25]. Furthermore, these TB biomarker studies have also excluded HIV co-infected patients who are the group that most need new diagnostics. Our study design should ensure that our signatures are applicable in TB/HIV endemic countries as we recruited patients with TB concurrently with patients with a range of conditions that present with similar clinical features to TB, as well as recruiting both HIV-infected and -uninfected individuals.

We have identified separate signatures for distinguishing TB/OD and TB/LTBI, which only overlap in three transcripts. In practice the clinical applications of these signatures might be distinct as the TB/LTBI signature would be of value in contact screening, where the concern is distinguishing active disease from previous exposure in minimally symptomatic individuals. The TB/OD signature would be of most value in evaluating symptomatic patients presenting to medical services with symptoms of TB. We have also explored whether a single signature might be used to distinguish TB from both LTBI and OD. The combined signature showed lower performance to the separate TB/LTBI and TB/OD signatures. Further exploration of the operational performance of a combined signature or separate signatures is needed to establish the best strategy.

Although our signatures and DRS distinguished the majority of patients with TB from those with LTBI or OD, a proportion of patients were not correctly classified. There is increasing recognition that TB and LTBI may represent a dynamically evolving continuum, particularly in HIV-infected patients and thus failure to culture M.TB is not absolute proof that TB is not present. Some false assignment by our current “gold standard” is to be expected as noted by post mortem studies at which undiagnosed TB is confirmed [14],[15]. All patients in the OD group presented with symptoms for which TB was included in the differential diagnosis, and it is possible that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to each diagnostic group. Some improvement in sensitivity and specificity of our DRS may also be achieved by weighting the signal from the most discriminatory transcripts, and this could be explored in subsequent refinements of the method.

A major concern in using transcriptional signatures as a clinical diagnostic tool in resource poor settings is the complexity, as well as cost, of the current methodologies. Our results have shown that transcriptional signatures can be used to distinguish TB from OD in an African setting. We explored the feasibility of a simplified method for disease categorization that may facilitate development of a diagnostic test based on our signatures. Our DRS provides a new approach that enables the use of multi-transcript signatures for individual disease risk assignment without the requirement for complex analysis. Our method could be used to develop a simple test in which the transcripts comprising the diagnostic signature (separated into those that are either up- or down-regulated in TB relative to controls) are each measured using a suitable detection system [35], and the combined signature used to identify each patient’s risk of TB. For example, a simple test using the TB/OD signature probes that show increased transcript expression in TB relative to OD could be located in a single well or tube, and those probes that show reduced transcript expression in TB located in a second well or tube. Binding of RNA from a patient’s blood to these probes could be detected as a combined signal from each tube using one of the aforementioned detection systems. To allow normalization, expression of up- or down-regulated transcripts in an individual patient could be compared with that of housekeeping genes, which do not show variation between healthy and disease states. There are methods for rapid detection of multi-transcript signatures including lateral flow reverse transcription (RT)-PCR based systems, nano-pore technology [37], nano-particle enzyme linked detection [38],[39], and detection using nano-wires and electrical impedance [40]. Some of these may be suitable for direct analysis of multiple transcript signatures in blood and at a relatively low cost.

While this study provides a proof of principle that relatively small numbers of RNA transcripts can be used to discriminate active TB from latent TB infection and OD in Africa, limitations remain that need to be addressed in order to translate these results into a clinical test. One such limitation is that our study has not assessed performance of our DRS in patients treated for TB solely on the basis of clinical suspicion, without any microbiological confirmation. Amongst these “probable/possible” patients with TB, there is no gold standard to evaluate any new biomarker. Exclusion of probable/possible patients with TB may have produced better estimates of sensitivity and specificity than would be achieved in a prospective “all comers” study including the entire cohort of patients in whom TB is included in the differential diagnosis. Thus, further evaluation using a prospective population based study in which the decision whether and when to initiate TB treatment is evaluated against the new biomarker is required. Future studies will also be required to refine the use of these biomarkers in a clinical decision process either as an initial screening tool, or in conjunction with more detailed culture based diagnostics.

From a clinical perspective a simple transcriptome-based test that reliably diagnoses or excludes TB in the majority of patients undergoing investigation for suspected TB, using a single blood sample, would be of great value, allowing scarce hospital resources to be focused on the small proportion of patients where the result was indeterminate. The challenge for the academic research community and for industry is to develop innovative methods to translate multi-transcript signatures into simple, cheap tests for TB suitable for use in African health facilities.

SOURCE: PLOS

Novartis collaboration aims to eliminate rheumatic heart disease (RHD) in Zambia, Africa.

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  • novartisRHD has been eliminated in most developed nations, but sub-Saharan Africa studies show at least 2-3% of school-age children suffer from this often fatal disease.

  • Collaboration between Novartis physicians, Zambian healthcare providers, cardiologists from Massachusetts General Hospital (MGH) and the Pan-African Cardiology Society will promote RHD prevention by treating children with streptococcal infections and silent RHD
  • The collaboration will screen 3,000 Zambian children by echocardiography and provide monthly penicillin injections to children with silent RHD to prevent recurrent strep throat and associated cardiac damage

Novartis today announced that it has launched an effort to eliminate rheumatic heart disease in Zambia in collaboration with the Lusaka University Teaching Hospital (UTH), the Ministry of Health in Zambia, the Pan-African Cardiology Society and Massachusetts General Hospital (MGH).

RHD is a complication of untreated streptococcal infections in which the valves of the heart are scarred and eventually degenerate, leading to heart failure. Eliminated by antibiotic treatment in most developed nations, in the developing world an estimated 15 million children suffer from this debilitating and often fatal disease[1].

“The toll of heart failure in young children with RHD in Zambia is immense, for the patient, their families, and the nation,” said Mark C. Fishman, Cardiologist and President of the Novartis Institutes for BioMedical Research (NIBR). “It is entirely preventable. For the past several years Novartis has been working with colleagues in Lusaka to help understand and treat asthma in young children. We are expanding the collaboration to raise awareness, educate, and provide antibiotic therapy to prevent RHD.”

To measure RHD prevalence and identify those in need of secondary prophylaxis, teams of health care professionals from Lusaka UTH, the MGH, and Novartis will use portable echocardiography machines to evaluate 3,000 children, ages 9-10, in Lusaka-area public schools. Echocardiography screening is estimated to detect more than 10 times as many cases as clinical screening[1].

Images from the echocardiography screens will be analyzed in Zambia and at the MGH using a cloud-based electronic registry developed by Dimagi Inc, a Cambridge, MA-based company that designs open-source electronic healthcare systems for low resource environments.

Children identified as having RHD will be treated with monthly penicillin injections (termed “secondary prophylaxis”) to prevent recurrent streptococcal infections and additional valve damage.
Primary prevention, the treatment of children with streptococcal infection to prevent RHD, is key to elimination of the disease. To this end, all children diagnosed with strep throat will be treated with injectable penicillin in the community-based study sites. Prevalence of RHD and adherence to secondary prophylaxis will be determined via the mobile electronic registry.

“We have assembled an experienced team from MGH who are excited to bring the mobile heart imaging technology to Zambia,” stated Michael H. Picard, MD, Director of Echocardiography at the Massachusetts General Hospital and a Past President of the American Society of Echocardiography. “We are creating a model for country-wide screening through schools that will not only raise awareness of the magnitude of this disease but also offer a simple method to identify those who will benefit from a very simple and safe treatment. The MGH Cardiology Division and its Cardiac Ultrasound Laboratory are delighted to be a partner in this initiative.”

The Pan-African Cardiology Society will assist with the development of the study protocol and ethics approval. Based on the experience of the initial Lusaka-based effort, Novartis plans to support the rollout of the RHD training and treatment effort to Provinces across Zambia, with the ultimate goal of eliminating RHD in Zambia.

“Rheumatic heart disease is the most common acquired heart ailment in Zambian children, but statistics are spotty and the disease is certainly diagnosed late when damage to the heart valves has already reached advanced stage,” said John Musuku, Principal Investigator and UTH pediatrician. “Our hope is that the collaboration with Novartis will lay the foundation to detect the disease early so preventative measures are instituted.  This is an effort to eradicate the disease across Zambia in our life time.”

 

Source: Novartis