26 research outputs found
Temporal trends of population viral suppression in the context of Universal Test and Treat: the ANRS 12249 TasP trial in rural South Africa
Introduction: The universal test-and-treat (UTT) strategy aims to maximize population viral suppression (PVS), that is, the proportion of all people living with HIV (PLHIV) on antiretroviral treatment (ART) and virally suppressed, with the goal of reducing HIV transmission at the population level. This article explores the extent to which temporal changes in PVS explain the observed lack of association between universal treatment and cumulative HIV incidence seen in the ANRS 12249 TasP trial conducted in rural South Africa.
Methods: The TasP cluster-randomized trial (2012 to 2016) implemented six-monthly repeat home-based HIV counselling and testing (RHBCT) and referral of PLHIV to local HIV clinics in 2 9 11 clusters opened sequentially. ART was initiated according to national guidelines in control clusters and regardless of CD4 count in intervention clusters. We measured residency status, HIV status, and HIV care status for each participant on a daily basis. PVS was computed per cluster among all resident PLHIV (â„16, including those not in care) at cluster opening and daily thereafter. We used a mixed linear model to explore time patterns in PVS, adjusting for sociodemographic changes at the cluster level.
Results: 8563 PLHIV were followed. During the course of the trial, PVS increased significantly in both arms (23.5% to 46.2% in intervention, +22.8, p < 0.001; 26.0% to 44.6% in control, +18.6, p < 0.001). That increase was similar in both arms (p = 0.514). In the final adjusted model, PVS increase was most associated with increased RHBCT and the implementation of local trial clinics (measured by time since cluster opening). Contextual changes (measured by calendar time) also contributed slightly. The effect of universal ART (trial arm) was positive but limited.
Conclusions: PVS was improved significantly but similarly in both trial arms, explaining partly the null effect observed in terms of cumulative HIV incidence between arms. The PVS gains due to changes in ART-initiation guidelines alone are relatively small compared to gains obtained by strategies to maximize testing and linkage to care. The achievement of the 90-90-90 targets will not be met if the operational and implementational challenges limiting access to care and treatment, often context-specific, are not properly addressed. Clinical trial number: NCT01509508 (clinicalTrials.gov)/DOH-27-0512-3974 (South African National Clinical Trials Register)
The relationship between the insecticide dichloro-diphenyl-trichloroethane and chloroquine in Plasmodium falciparum resistance
Thesis (MSc)--Stellenbosch University, 2012.ENGLISH ABSTRACT: Dichloro-diphenyl-trichloroethane (DDT) was extensively used in agriculture pest control and
is still used for indoor residual spraying to control malaria. The lipophylicity of DDT and its
breakdown product dichloro-diphenyl-dichloroethylene (DDE) dictates that they associate
with membranes, lipids and hydrophobic proteins in the biological environment. Their poor
degradable nature causes DDT and DDE to persist for decades in the environment and in
individuals who are or were in contact with the pesticide. In many countries the synchronised
resistance of the mosquito vector to insecticides and the malaria parasite towards antimalarial
drugs led to a drastic rise in malaria cases and to malaria epidemics. This study assesses the
influence of low level exposure of DDT and DDE on chloroquine (CQ) resistance of the dire
human malaria parasite, Plasmodium falciparum.
The in vitro activity of p,pâ-DDT and p,pâ-DDE towards blood stages of chloroquine sensitive
(CQS) P. falciparum D10 and chloroquine resistant (CQR) P. falciparum Dd2 was
determined using two complementary in vitro assays (Malstat and SYBR Green 1). The 50%
inhibition concentrations (IC50s) of p,pâ-DDT and p,pâ-DDE were found to be ±14 to 38 ÎŒM
(5-12 ÎŒg/mL) and highly similar towards CQS and CQR P. falciparum strains. This result
indicated that the proteins involved in CQ resistance have no effect on the activity of the
insecticide DDT and it breakdown product DDE.
In order to assess the influence of DDT and DDE on CQ activity, in vitro fixed ratio drug
combination assays were performed, as well as isobologram analysis. We found that CQ
works in synergy with p,pâ-DDT and p,pâ-DDE against CQS P. falciparum D10. However,
both p,pâ-DDT and p,pâ-DDE were antagonistic toward CQ activity in CQR P. falciparum
Dd2. This indicated that p,pâ-DDT and p,pâ-DDE do have an effect on CQ resistance or on
the action of CQ via a target other than hemozoin polymerization. The observation of
reciprocal synergism of p,pâ-DDT and p,pâ-DDE with CQ against CQS D10 and antagonism
against CQR Dd2 strain is highly significant and strongly indicates selection of CQ resistant
strains in the presence of p,pâ-DDT and p,pâ-DDE. People who have low levels of circulating
DDE and/or DDT could be at a high risk of contracting CQR malaria. However, medium term
(nine days) DDE exposure of CQS P. falciparum D10 did not induce resistance, as no
significant change in activity of CQ, p,pâ-DDT and p,pâ-DDE towards blood stages the CQS
strain was observed. This exposure was, however, shorter than expected for a malaria
infection and would be addressed in future studies.
From our results on the interaction of CQ with p,pâ-DDT and p,pâ-DDE, it was important to
assess the residual DDT and DDE variable and how much of residual p,pâ-DDT and/or p,pâ-
DDE would enter into or remain in the different compartments (the RPMI media, erythrocytes
and infected erythrocytes) over time. In combination with liquid-liquid extraction, we
developed a sensitive GC-MS analyses method and a novel HPLC-UV analysis method for
measuring DDT and DDE levels in malaria culturing blood and media. Whilst the HPLC-UV
method was relatively cheaper, faster, and effective in determining high DDT and DDE
concentrations, the optimised GC-MS method proved to be effective in detecting levels as
low as 78 pg/mL (ppt) DDE and 7.8 ng/mL (ppb) DDT in biological media. Using both the
HPLC and GC-MS methods we observed that malaria parasites influence distribution of the
compounds between the erythrocytic and media fractions. P. falciparum D10 infection at
±10% parasitemia lead to must faster equilibration (less than 8 hours) between compartments.
Equimolar distribution of p,pâ-DDE was observed, but the parasites lead to trapping of the
largest fraction of p,pâ-DDT in the erythrocyte compartment. These results indicate that a
substantial amount would reach the intra-erythrocytic parasite and could influence the
parasite directly, possibly leading to either synergistic or antagonistic drug interactions.
This study is the first to illustrate the âgood and badâ of the insecticide DDT in terms of CQ
resistance and sensitivity toward the human malaria parasite P. falciparum. These results will
hopefully have an important influence on how future policies on malaria control and
treatment particularly in endemic areas will be addressed and could also have an impact on
the anti-malarial drug discovery approach.AFRIKAANSE OPSOMMING: Dichlorodifenieltrichloroetaan (DDT) is op groot skaal in landbouplaagbeheer gebruik en
word nog steeds gebruik vir binnenshuise oppervlakbespuiting om malaria te beheer. Die
lipofilisiteit van DDT en sy afbraakproduk dichlorodifenieldichloroetileen (DDE) dikteer dat
hulle met membrane, lipiede en hidrofobiese proteĂŻene in die biologiese omgewing
assosieer. Stadige afbraak veroorsaak dat DDT en DDE vir dekades in die omgewing
agterbly, asook in individue wat in kontak is, of was met die insekdoder. In baie lande het
gesinkroniseerde weerstand van die muskietvektor teenoor insekdoders en die malariaparasiet
teenoor antimalariamiddels gelei tot 'n drastiese styging in malariagevalle en tot malariaepidemies.
In hierdie studie word die invloed van lae vlak blootstelling van DDT en DDE op
chlorokien (CQ) weerstand van die mens malariaparasiet, Plasmodium falciparum,
geëvalueer.
Die in vitro aktiwiteit van p,p'-DDT en p,p'-DDE teenoor die bloedstadia van chlorokiensensitiewe
(CQS) P. falciparum D10 en chlorokien-weerstandbiedende (CQW) P. falciparum
Dd2 is bepaal deur gebruik te maak van twee komplementĂȘre in vitro toetse (Malstat en
SYBR Groen toetse). Die 50% inhibisie konsentrasies (IC50s) van p,p'-DDT en p,p'-DDE is
bepaal as ±14 to 38 ΌM (5-12 Όg/mL) en was hoogs vergelykbaar tussen CQS en CQW P.
falciparum stamme. Hierdie resultaat het aangedui dat die proteĂŻene betrokke by CQ
weerstand geen effek op die aktiwiteit van die insekdoder DDT en die afbraakproduk DDE
het nie.
Om die invloed van DDT en DDE op CQ aktiwiteit te evalueer, is die aktiwiteit van
kombinasies van die verbindings in vaste verhoudings getoets, tesame met isobologram
ontleding. Ons het gevind dat CQ sinergisties saam met p, p'-DDT en p, p'-DDE teen CQS P.
falciparum D10 werk. Daarteenoor het beide p, p'-DDT en p, p'-DDE antagonistiese werking
getoon teenoor CQ aktiwiteit met CQW P. falciparum Dd2 as teiken. Dit het aangedui dat
p,p'-DDT en p, p'-DDE wel 'n invloed op CQ weerstand het of ân aktiwiteit van CQ, anders as
hemozoin polimerisasie, beĂŻnvloed. Die waarneming van resiproke sinergisme en
antagonisme van p, p'-DDT en p, p'-DDE in kombinasie met CQ teenoor die CQS D10 en
CQW DD2 stamme respektiewelik, is hoogs betekenisvol en dui op seleksie van CQweerstandige
stamme in die teenwoordigheid van p, p'- DDT en p, p'-DDE. Mense wat lae
vlakke van sirkulerende DDE/DDT het, het dus 'n hoër risiko om CQW malaria te kry.
Verder is gevind dat medium termyn (nege dae) DDE blootstelling van CQS P. falciparum
D10 nie weerstand nie veroorsaak nie, want geen beduidende verandering in die aktiwiteit
van CQ, p,p'-DDT en p,p'-DDE teenoor die bloed stadiums van die CQS stam is waargeneem
nie. Hierdie blootstelling is egter korter as in 'n malaria-infeksie en sal verder bestudeer word
in toekomstige studies.
Vanuit die interaksie resultate van CQ met p, p'-DDT en p, p'-DDE was dit belangrik om die
residuele DDT en DDE veranderlike te evalueer, asook die distribusie van p,p'-DDT en p,p'-
DDE tussen die verskillende kompartemente (die kultuurmedium, eritrosiete en geĂŻnfekteerde
rooibloedselle) oor verloop van tyd. In kombinasie met vloeistof-vloeistof ekstraksie, het ons
'n sensitiewe GC-MS en nuwe HPLC-UV analisemetode ontwikkel vir die meet van DDT en
DDE-vlakke in bloed (normale en geĂŻnfekteerde eritrosiete) en die kultuurmedium. Terwyl
die HPLC-UV metode relatief goedkoper, vinniger en effektief in die bepaling van hoë DDT
en DDE-konsentrasies is, was die geoptimaliseerde GC-MS metode doeltreffend in die
opsporing van vlakke so laag as 78 pg/mL (dpt) DDE en 7.8 ng/mL (dpb) DDT in biologiese
media. Met behulp van beide die HPLC-UV en GC-MS metodes is waargeneem dat die
malariaparasiet die ekwilibrasie van die verbindings tussen die eritrosiet- en media
kompartemente beïnvloed. P. falciparum D10 infeksie met ± 10% parasitemia lei tot vinniger
ekwilibrasie (minder as 8 uur) tussen die kompartemente. EkwimolĂȘre verspreiding van p,p'-
DDE is waargeneem, maar die parasiete het die grooste fraksie van p,p'-DDT in die eritrosiet
kompartement vasgevang. Hierdie resultate wys dat 'n aansienlike fraksie die intraeritrositiese
parasiet kan bereik en sodoende die parasiet direk kan beĂŻnvloed en moontlik kan
lei tot sinergistiese of antagonistiese middel interaksies.
Hierdie studie is die eerste om die "goed en sleg" van die insekdoder DDT in terme van CQ
weerstand en sensitiwiteit teenoor die menslike malariaparasiet P. falciparum te
illustreer. Hierdie resultate sal hopelik 'n belangrike invloed hĂȘ op die toekomstige beleid oor
die beheer van malaria en behandeling, veral in endemiese gebiede, en mag ook 'n impak hĂȘ
op die antimalariamiddel navorsing
MOESM2 of Prevalence of antimicrobial drug resistant bacteria carried by in- and outpatients attending a secondary care hospital in Zambia
Additional file 2: Figure S1. Species identification of the resistant Enterobacteriaceae and their distribution among in- and outpatients. The figure specifies the species the resistant Enterobacteriaceae belong to and how these are distributed between the in- and outpatient group
The impact of age on incremental elastic modulus and incremental compliance of pig hepatic portal vein for liver xenotransplantation
MOESM1 of Prevalence of antimicrobial drug resistant bacteria carried by in- and outpatients attending a secondary care hospital in Zambia
Additional file 1: Table S1. Patient characteristics. The table contains information on patient average age, gender, antibiotic use and length of stay in hospital
The impact of universal test and treat on HIV incidence in a rural South African population: ANRS 12249 TasP trial, 2012-2016
Background: The population impact of universal test and treat (UTT) on HIV transmission has not yet been evaluated.Methods: A cluster-randomized trial was implemented in 2x11 rural communities in KwaZulu-Natal, South Africa. All residents â„16 years were offered rapid HIV testing and provided dried blood spots (DBS) during 6-monthly home-based survey rounds. HIV-positive participants were referred to cluster-based trial clinics to receive ART regardless of CD4 count (intervention arm) or according to national guidelines (control arm). Standard of care ART was also available in the Department of Health clinics. HIV incidence was estimated on repeat DBS using cluster-adjusted Poisson regression.Results: Between 03/2012 and 04/2016, 13,239 and 14,916 individuals (63% women, median age 30 years) were registered in the intervention and control arms. Contact frequency per round among registered individuals ranged from 64% to 83%, HIV ascertainment from 74% to 85%. Baseline HIV prevalence was 29.4%(95%CI 28.8-30.0), with 7,578 individuals identified as HIV-positive. 1,513(36%) of 4,172 HIV-positive individuals not previously in care linked to trial clinics within 6 months of referral. ART initiation in trial clinics at 3 months was 90.9%(576/634) and 52.3%(332/635) in the intervention and control arms; viral suppression (< 400 copies/mL) 12 months after ART initiation was 94.9%(300/316) and 94.2%(194/206), respectively. Overall ART coverage at entry was 31% and 36% in the intervention and control arms, reaching 41% in both arms by closing date. Repeat DBS tests were available for 13,693 individuals HIV-negative at baseline, yielding 461 seroconversions in 20,833 person-years (PY). HIV incidence was 2.16 per 100 PY (1.88-2.45) in the intervention arm and 2.26 (1.98-2.54) in the control arm (adjusted relative risk: 0.95 [0.82-1.10]). Severe adverse events rates were 3.4%(45/1,323) and 3.5%(57/1,604) in the intervention and control arms. Follow-up will be completed by 06/2016.Conclusions: Our trial shows high acceptance of home-based HIV testing and high levels of viral suppression among individuals on ART. However overall linkage to care remains poor. No reduction in HIV incidence was demonstrated. Several factors are being investigated, including determinants of poor linkage, change in national ART guidelines, migration and geography of sexual networks
The impact of universal test and treat on HIV incidence in a rural South African population: ANRS 12249 TasP trial, 2012-2016
Background: The population impact of universal test and treat (UTT) on HIV transmission has not yet been evaluated.Methods: A cluster-randomized trial was implemented in 2x11 rural communities in KwaZulu-Natal, South Africa. All residents â„16 years were offered rapid HIV testing and provided dried blood spots (DBS) during 6-monthly home-based survey rounds. HIV-positive participants were referred to cluster-based trial clinics to receive ART regardless of CD4 count (intervention arm) or according to national guidelines (control arm). Standard of care ART was also available in the Department of Health clinics. HIV incidence was estimated on repeat DBS using cluster-adjusted Poisson regression.Results: Between 03/2012 and 04/2016, 13,239 and 14,916 individuals (63% women, median age 30 years) were registered in the intervention and control arms. Contact frequency per round among registered individuals ranged from 64% to 83%, HIV ascertainment from 74% to 85%. Baseline HIV prevalence was 29.4%(95%CI 28.8-30.0), with 7,578 individuals identified as HIV-positive. 1,513(36%) of 4,172 HIV-positive individuals not previously in care linked to trial clinics within 6 months of referral. ART initiation in trial clinics at 3 months was 90.9%(576/634) and 52.3%(332/635) in the intervention and control arms; viral suppression (< 400 copies/mL) 12 months after ART initiation was 94.9%(300/316) and 94.2%(194/206), respectively. Overall ART coverage at entry was 31% and 36% in the intervention and control arms, reaching 41% in both arms by closing date. Repeat DBS tests were available for 13,693 individuals HIV-negative at baseline, yielding 461 seroconversions in 20,833 person-years (PY). HIV incidence was 2.16 per 100 PY (1.88-2.45) in the intervention arm and 2.26 (1.98-2.54) in the control arm (adjusted relative risk: 0.95 [0.82-1.10]). Severe adverse events rates were 3.4%(45/1,323) and 3.5%(57/1,604) in the intervention and control arms. Follow-up will be completed by 06/2016.Conclusions: Our trial shows high acceptance of home-based HIV testing and high levels of viral suppression among individuals on ART. However overall linkage to care remains poor. No reduction in HIV incidence was demonstrated. Several factors are being investigated, including determinants of poor linkage, change in national ART guidelines, migration and geography of sexual networks