12 research outputs found
Resurgence of HIV infection among men who have sex with men in Switzerland : mathematical modelling study
No full textNew HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. METHODOLOGY/PRINCIPAL FINDINGS: The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995-1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. CONCLUSIONS/SIGNIFICANCE: The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions
New and improved methods for the diagnosis of susceptibility to tuberculosis drugs
No full textThesis (PhD)--Stellenbosch University, 2023.ENGLISH ABSTRACT: Drug-resistant tuberculosis (DR-TB) is a global threat. Diagnosing patients with DR-TB and
initiating them onto appropriate treatment, in the shortest possible time, is of utmost
importance. The optimisation of existing rapid molecular assays and the implementation of
drug susceptibility testing (DST) for new drugs to monitor patients on treatment is crucial in
curbing transmission.
Firstly (chapter 2), showed that Mycobacterium tuberculosis (Mtb) DNA recoverable from
used Xpert MTB/RIF (Xpert) cartridges ‒ cartridge extract (CE) – that would otherwise be
discarded, can be used for downstream second-line molecular DST. No additional DNA
extraction or sample purification was needed. We defined a threshold of Xpert semiquantitative
category “low” to ensure that no MTBDRsl assays are wasted on CE likely to give invalid
results. This alleviated the need for collection of a second sputum specimen, thereby reducing
diagnostic delays, and enabling patients to be placed on treatment sooner. This approach is
being developed into a cartridge extraction device and will be evaluated by TB programmes.
Secondly and thirdly (chapter 3 and 4), MTBDRplus and MTBDRsl focussed on WHOendorsed
rapid molecular assays that have reported suboptimal sensitivities and high
indeterminate rates especially in smear-negative specimens. We hypothesised that ramp rate
(speed of temperature change between PCR cycles) could impact assay performance. We
showed that correcting thermocycler ramp rate (manufacturer-recommended ramp rate
≤2.2°C/s) likely improved the yield of rapid diagnoses for first-and second-line DST, done with
MTBDRplus and MTBDRsl respectively, especially in paucibacillary specimens. Our survey
showed that suboptimal ramp rate is a common problem but is easily fixable. This manuscript
informed WHO course training material (https://openwho.org/courses/multi-drug-resistant-tb). Finally (chapter 5), bedaquiline (BDQ), a lifesaving TB drug, is undergoing rapid scale-up but
largely in the absence of DST. In a group of programmatic patients still culture-positive after
≥4 months of BDQ-based treatment, more than half had isolates that gained BDQ resistance
(mostly acquisition, some transmission). Several Rv0678 and pepQ variants were associated
with phenotypic resistance, many previously undescribed. Patients with baseline
fluoroquinolone-resistance, clofazimine exposure, and ≤4 effective drugs were more likely to
be BDQ-resistant.
This thesis has resulted in four first author manuscripts (three published, one submitted).
Additionally, two 2nd author manuscripts and seven manuscripts as a middle co-author. These
nine total are briefly discussed in chapter 6 and can be found in the appendices (and included
as ancillary publications). The candidate presented three times at international and twice at
national peer-reviewed conferences.
In summary, this work shows that second-line DR time-to-treatment initiation could be reduced
by doing second-line DST on CE from used cartridges. The number of smear-negative patients
in whom DST is possible will improve substantially after ramp rate correction for MTBDRplus
and MTBDRsl. Finally, we show the existence of a potentially infectious pool of BDQ resistant
strains created under programmatic conditions, as well as the challenges and risks associated
with starting patients with complex TB-treatment histories on a regimen containing a novel
drug without routinely available DST. Our findings also inform on how and in whom new TB
drugs are prioritised for use.AFRIKAANS OPSOMMING: Middelbestande-tuberkulose (DR-TB) is ‘n wêreldwye bedreiging en dit is belangrik om
pasiënte te diagnoseer en met toepaslike behandeling in die kortste moontlike tyd te begin.
Optimalisering van bestaande vinnige molekulêre toetse en implementering van nuwe
medisyne-vatbaarheidstoetse (DST) om pasiënte op behandeling te monitor, is belangrik om
die oordrag van DR-TB te beperk.
Eerstens (hoofstuk 2), Mycobacterium tuberculosis (Mtb)-DNA herwinbaar vanaf gebruikte
Xpert MTB/RIF (Xpert) toetse ‒ “cartridge extract” (CE) ‒ wat andersins weggegooi sou word,
kan gebruik word vir tweedelyn molekulêre-DST. Geen bykomende DNA-ekstraksie of
monstersuiwering was nodig nie. Ons het Xpert semikwantitatiewe kategorie "low" gedefinieer
om te verseker dat geen MTBDRsl-toetse op CE vermors word wat waarskynlik ongeldige
resultate sou gee nie. Dit het die behoefte verlig om 'n tweede sputummonster te neem, wat tot
gevolg diagnostiese vertragings kon verminder en pasiënte vinniger op behandeling kon plaas.
Hierdie benadering word ontwikkel tot 'n “cartridge device” en sal deur TB-programme
geëvalueer word.
Tweedens en derdens (hoofstuk 3 en 4), MTBDRplus en MTBDRsl (vinnige molekulêre
WHO-aanbeveelde toetse), het suboptimale sensitiwiteit en hoë onbepaalde koerse
gerapporteerde, veral in smeer-negatiewe monsters. Ons het hipotese dat die “ramp rate”
(spoed van temperatuurverandering tussen PCR-siklusse) toetsprestasie kan beïnvloed. Ons het
getoon dat die regstelling van “ramp rate” op die “thermocycler” (vervaardiger-aanbevole
“ramp rate” ≤2.2°C/s) waarskynlik die opbrengs van vinnige diagnose vir eerste- en tweedelyn
DST, gedoen met MTBDRplus en MTBDRsl, onderskeidelik, verbeter het, veral in
paucibacillêre monsters. Ons het 'n opname gedoen wat getoon het dat suboptimale “ramp rate” is 'n algemene probleem, maar is maklik om reg te stel. Die manuskrip het die WHOkursusopleidingsmateriaal
geingelig: https://openwho.org/courses/multi-drug-resistant-tb).
Laastens (hoofstuk 5), bedaquiline (BDQ), 'n lewensreddende TB-middel, is vinnig aan die
toeneem, maar grootliks in die afwesigheid van DST. In 'n groep van programmatiese pasiënte
wat steeds kultuur-positief is na ≥4 maande van 'n BDQ-gebaseerde behandeling, het meer as
die helfte “isolates” gehad wat BDQ-weerstand gekry (meestal verkryging, sommige oordrag).
Verskeie Rv0678 en pepQ variante was geassosieer met fenotipiese weerstand, baie voorheen
onbeskryf. Pasiënte met basislyn fluoroquinolone-weerstand, clofazimine blootstelling en ≤4
effektiewe middels was meer geneig om BDQ-weerstandig te wees.
Hierdie tesis het tot vier eerste-outeur manuskripte gelei (drie gepubliseer, een ingedien).
Daarbenewens twee 2de-outeur manuskripte en sewe manuskripte as middel mede-outeur.
Hierdie nege totaal word kortliks in hoofstuk 6 bespreek en kan in die bylaes gevind word (en
as bykomende publikasies ingesluit). Die kandidaat het aangebied by drie internasionale en
twee nasionale eweknie-geëvalueerde konferensies.
Samevattend toon hierdie werk dat tweedelyn-middelweerstand tyd-tot-behandeling-aanvang
verminder kan word deur tweedelyn-DST op CE van gebruikte toetse te doen. Die aantal
smeer-negatiewe pasiënte by wie DST moontlik is, sal aansienlik verbeter na “ramp rate”-
korreksie vir MTBDRplus en MTBDRsl. Laastens toon ons die bestaan van 'n potensieel
aansteeklike-poel van BDQ-weerstandige “isolates” wat onder programmatiese toestande
geskep is, sowel as die uitdagings en risiko's wat verband hou met die begin van pasiënte met
komplekse TB-behandelingsgeskiedenis op 'n regime wat 'n nuwe geneesmiddel bevat sonder
gereeld beskikbare DST. Ons bevindinge gee ook inligting oor hoe en by wie nuwe TB-middels
geprioritiseer word vir gebruik.Doctora
'Break the Chains 2015' community-based HIV prevention campaign for men who have sex with men in Switzerland: non-randomised evaluation and cost analysis.
No full textOBJECTIVES
To study the implementation, effects and costs of Break the Chains, a community-based HIV prevention campaign for men who have sex with men (MSM) in Switzerland, from March to May 2015, which aimed to reduce early HIV transmission by promoting the campaign message to adopt short-term risk reduction followed by HIV testing.
DESIGN
Non-randomised evaluation and cost analysis.
SETTING
Gay venues in 11 of 26 cantons in Switzerland and national online media campaign.
PARTICIPANTS
MSM in online surveys (precampaign n=834, postcampaign n=688) or attending HIV testing centres (n=885); campaign managers (n=9); and campaign staff (n=38) or further intermediaries (n=80) in an online survey.
PRIMARY AND SECONDARY OUTCOME MEASURES
The primary outcome measure was the proportion of MSM at risk of HIV acquisition or transmission who adhered to the campaign message. Secondary outcomes were postcampaign test uptake, knowledge about HIV primary infection and sense of belonging to the gay community.
RESULTS
Campaign staff estimated that they contacted 17 145 MSM in 11 cantons. Among 688 respondents to the postcampaign survey, 311 (45.2%) were categorised as MSM at risk. Of 402/688 (58.5%) MSM who had heard about Break the Chains 2015, MSM categorised as being at risk were less likely to report adherence to the campaign message than MSM not at risk (adjusted OR 0.24; 95% CI 0.14 to 0.42). Twenty per cent of MSM with a defined risk of HIV acquisition or transmission who adopted risk reduction declared having done so because of the campaign. Costs for one MSM at risk to adhere to the campaign message were estimated at USD purchasing power parity 36-55. The number of HIV tests in the month after the campaign was twice the monthly average.
CONCLUSION
Break the Chains increased HIV testing, implying that community-based campaigns are useful HIV prevention strategies for MSM. Additional interventions are needed to reach MSM at the highest risk of infection more effectively
Diagnostic accuracy of the FluoroType MTB and MTBDR VER 2.0 assays for the centralized high-throughput detection of Mycobacterium tuberculosis complex DNA and isoniazid and rifampicin resistance
No full textAbstract: Objectives: To evaluate the accuracy of two new molecular diagnostic tests for the detection of drug-resistant tuberculosis, the FluoroType MTB and MTBDR VER 2.0 assays, in combination with manual and automated DNA extraction methods. Methods: Sputa from 360 Xpert Ultra Mycobacterium tuberculosis complex (MTBC)-positive patients and 250 Xpert Ultra MTBC-negative patients were tested. GenoType MTBDRplus served as reference for MTBC and drug resistance detection. Sanger sequencing was used to resolve discrepancies. Results: FluoroType MTB VER 2.0 showed similar MTBC sensitivity compared with FluoroType MTBDR VER 2.0 (manual DNA extraction: 91.6% (294/321) versus 89.8% (291/324); p 0.4); automated DNA extraction: 92.1% (305/331) versus 87.7% (291/332); p 0.05)). FluoroType MTBDR VER2.0 showed comparable diagnostic accuracy to FluoroType MTBDR VER1.0 as previously reported for the detection of MTBC and rifampicin and isoniazid resistance. Conclusions: The FluoroType MTB and MTBDR VER 2.0 assays together with an automated DNA extraction and PCR set-up platform may improve laboratory operational efficiency for the diagnosis of MTBC and resistance to rifampicin and isoniazid and show promise for the implementation in a centralized molecular drug susceptibility testing model. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases
Xpert MTB/RIF ultra on contaminated liquid cultures for tuberculosis and rifampicin-resistance detection : a diagnostic accuracy evaluation
No full textDATA SHARING : Study data can be accessed on request from the corresponding author without restriction.BACKGROUND : Xpert MTB/RIF Ultra (Ultra) is a widely used rapid front-line tuberculosis and rifampicin-susceptibility testing. Mycobacterium Growth Indicator Tube (MGIT) 960 liquid culture is used as an adjunct but is vulnerable to contamination. We aimed to assess whether Ultra can be used on to-be-discarded contaminated cultures. METHODS : We stored contaminated MGIT960 tubes (growth-positive, acid-fast bacilli [AFB]-negative) originally inoculated at a high-volume laboratory in Cape Town, South Africa, to diagnose patients with presumptive pulmonary tuberculosis. Patients who had no positive tuberculosis results (smear, Ultra, or culture) at contamination detection and had another, later specimen submitted within 3 months of the contaminated specimen were selected. We evaluated the sensitivity and specificity of Ultra on contaminated growth from the first culture for tuberculosis (next-available non-contaminated culture result reference standard) and rifampicin resistance (vs MTBDRplus on a later isolate). We calculated potential time-to-diagnosis improvements and also evaluated the immunochromatographic MPT64 TBc assay. FINDINGS : Between June 1 and Aug 31, 2019, 36 684 specimens from 26 929 patients were processed for diagnostic culture. 2402 (7%) cultures from 2186 patients were contaminated. 1068 (49%) of 2186 patients had no other specimen submitted. After 319 exclusions, there were 799 people with at least one repeat specimen submitted; of these, we included in our study 246 patients (31%) with a culture-positive repeat specimen and 429 patients (54%) with a culture-negative repeat specimen. 124 patients (16%) with a culture-contaminated repeat specimen were excluded. When Ultra was done on the initial contaminated growth, sensitivity was 89% (95% CI 84–94) for tuberculosis and 95% (75–100) for rifampicin-resistance detection, and specificity was 95% (90–98) for tuberculosis and 98% (93–100) for rifampicin-resistance detection. If our approach were used the day after contamination detection, the time to tuberculosis detection would improve by a median of 23 days (IQR 13–45) and provide a result in many patients who had none. MPT64 TBc had a sensitivity of 5% (95% CI 0–25). INTERPRETATION : Ultra on AFB-negative growth from contaminated MGIT960 tubes had high sensitivity and specificity, approximating WHO criteria for sputum test target product performance and exceeding drug susceptibility testing. Our approach could mitigate negative effects of culture contamination, especially when repeat specimens are not submitted.The European & Developing Countries Clinical Trials Partnership, National Institutes of Health.www.thelancet.com/microbeam2024Medical MicrobiologySDG-03:Good heatlh and well-bein
Estimated rates (per year) of viral suppression and viral rebound and fraction experiencing rebound in SHCS participants (n = 1729).
No full text<p>Estimated rates (per year) of viral suppression and viral rebound and fraction experiencing rebound in SHCS participants (n = 1729).</p
Model structure.
No full text<p>Flow diagram of the mathematical model for HIV transmission amongst men who have sex with men (MSM) in Switzerland (adapted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044819#pone.0044819-Bezemer2" target="_blank">[20]</a>). The model describes progression through different stages of untreated and treated HIV infection. Arrows represent the flow between compartments at rates denoted by Greek letters. Parameter values are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044819#pone.0044819.s001" target="_blank">Table S1</a>.</p
Model estimates for unknown parameters.
No full text<p>A) percentage of infected patients remaining undiagnosed (solid line, dashed lines show 95% confidence interval) and percentage of new infections transmitted by those remaining undiagnosed (dotted line, dashed lines show 95% confidence interval); B) net transmission rate relative to the period 1980–1983 (dotted line, dashed lines show 95% confidence interval); C) average time from HIV infection to diagnosis in years (dotted line, dashed lines show 95% confidence interval); D) reproduction number (dotted line, dashed lines show 95% confidence interval). Grey lines show results of multivariate sensitivity analyses.</p
Model fits and estimates.
No full text<p>Model fits to reported HIV and AIDS cases. Panel A) annual HIV diagnoses separated into infections acquired in Switzerland (black filled squares, dashed line) and abroad (black filled circles, solid line); B) annual number of new AIDS cases (black filled circles, solid line) and concurrent HIV and AIDS diagnoses (squares, black dashed line). Model estimates: C) annual number of new infections in Switzerland, D) number of men who have sex in Switzerland living with HIV. Continuous lines show model fit; dashed lines in panels C and D are 95% confidence intervals. Solid shapes show reported data; black shapes are data points used for fitting, grey shapes are not used for fitting. Grey lines show results of multivariate sensitivity analyses.</p
Hypothetical scenarios for the potential development of the HIV epidemic in Switzerland.
No full text<p>Annual HIV incidence: A) without intervention and under various ‘Mission Possible’ scenarios with 10%, 50%, or 100% of MSM having safe sex for 3 months each year starting in 2011, followed by an HIV test; B) without intervention, under a ‘test and treat’ strategy (assuming that the average time between infection and diagnosis is reduced to 1 year and treatment is started immediately), or assuming that the net transmission rate falls to the levels attained in 1984–1994 or 1995–1999.</p
