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1.
Pharmacol Res Perspect ; 9(3): e00769, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33929078

RESUMEN

We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R- and S-PZQ in healthy male participants. This was toward evaluating the risk of drug-drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non-randomized, open-label, single-dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC-MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T1/2 , Cmin , and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ (p < .05), reducing the AUC by 4-fold (1213.15 vs. 281.35 h·ng/ml for R-PZQ and 5669 vs. 871.84 h·ng/ml for S-PZQ). Ritonavir had no significant effect on R-PZQ but increased the AUC 2-fold for S-PZQ (p < .05) (4154.79 vs. 7291.05 h·ng/ml). Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition, respectively.

2.
BMC Infect Dis ; 21(1): 5, 2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-33446115

RESUMEN

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/efectos adversos , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Oxazinas/administración & dosificación , Oxazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piridonas/administración & dosificación , Piridonas/efectos adversos , Adolescente , Peso Corporal , Niño , Preescolar , Estudios de Cohortes , Cálculo de Dosificación de Drogas , Europa (Continente)/epidemiología , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Humanos , Masculino , ARN Viral/genética , Sudáfrica/epidemiología , Tailandia/epidemiología , Resultado del Tratamiento , Uganda/epidemiología , Carga Viral/efectos de los fármacos , Organización Mundial de la Salud , Zimbabwe/epidemiología
3.
J Acquir Immune Defic Syndr ; 86(1): 98-103, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33306565

RESUMEN

BACKGROUND: WHO treatment guidelines recommend tenofovir plus lamivudine or emtricitabine as the nucleoside reverse transcriptase inhibitor backbone in first-line regimens for HIV-infected adults. Lamivudine alone is not recommended, because of the risk of hepatitis B virus (HBV) resistance. We studied HBV responses in a large cohort of co-infected patients in a resource-limited setting. SETTING: Clinical centers in Uganda and Zimbabwe. METHODS: DART was a randomized trial of monitoring practices in HIV-infected adults starting antiretroviral therapy. Baseline samples were tested retrospectively for HBV serological markers and HBV DNA. Longitudinal HBV DNA testing at 48 weeks and the last available sample before HBV-relevant modification of antiretroviral therapy was performed on patients with detectable HBV DNA at baseline. RESULTS: Two hundred twenty-four hepatitis B surface antigen-positive patients were followed for up to 4.8 years. Of the drugs with anti-HBV activity, 166 were prescribed lamivudine-tenofovir and 58 lamivudine alone. Ninety-eight percent (96/98) patients with baseline HBV DNA <6 log10 IU/mL achieved viral suppression at 48 weeks (HBV DNA <48 IU/mL), regardless of regimen, compared with 50%(26/52) for HBV DNA >6 log10 IU/mL. Of the 83 patients suppressed at 48 weeks and with follow-up data, only 7(8%) experienced viral rebound (range 200-3460 IU/mL). Of the 20 patients not suppressed at 48 weeks and with follow-up data, HBV DNA levels generally declined with lamivudine-tenofovir, but increased with lamivudine alone. Alanine transaminase flares were not observed in any patient who experienced viral rebound. CONCLUSIONS: The suppressive effect of lamivudine alone was highly durable (up to 5 years) in HIV-HBV co-infected patients with baseline HBV DNA <6 log10 IU/mL. It may be feasible to develop stratified approaches using lamivudine as the only drug with anti-HBV activity.

4.
AIDS ; 2020 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-33306556

RESUMEN

OBJECTIVES: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. DESIGN: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4<100 cells/µL starting antiretroviral therapy who were randomised to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). METHODS: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24-weeks, by baseline CrAg positivity. RESULTS: Excluding 24(1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781(7.5%) participants were CrAg-positive. By 24-weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of 9 standard-cotrimoxazole and 3 enhanced-prophylaxis cryptococcal deaths, 7 and 2 respectively were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives (hazard-ratio, HR = 0.36 (95% CI 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years) and CrAg-negatives (HR = 0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; pheterogeneity = 0.95); nor for all deaths, cryptococcal deaths or unknown deaths (pheterogeneity > 0.3). CONCLUSIONS: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at ART initiation where CrAg screening is unavailable/impractical.

5.
PLoS One ; 15(10): e0240865, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33075094

RESUMEN

BACKGROUND: Since the scale-up of the HIV "Treat All" recommendation, evidence on its real-world effect on predictors of attrition (either death or lost to follow-up) is lacking. We conducted a retrospective study using Zimbabwe ART program data to assess the association between "Treat All" and, patient-mix, programmatic characteristics, retention and predictors of attrition. METHODS: We used patient-level data from the electronic patient monitoring system (ePMS) from the nine districts, which piloted the "Treat All" recommendation. We compared patient-mix, programme characteristics, retention and predictors of attrition (lost to follow-up, death or stopping ART) in two cohorts; before (April/May 2016) and after (January/February 2017) "Treat All". Retention was estimated using survival analysis. Predictors of attrition were determined using a multivariable Cox regression model. Interactions were used to assess the change in predictors of attrition before and after "Treat All". RESULTS: We analysed 3787 patients, 1738 (45.9%) and 2049 (54.1%) started ART before and after "Treat All", respectively. The proportion of men was higher after "Treat All" (39.4.% vs 36.2%, p = 0.044). Same-day ART initiation was more frequent after "Treat All" (43.2% vs 16.4%; p<0.001) than before. Retention on ART was higher before "Treat All" (p<0.001). Among non-pregnant women and men, the adjusted hazard ratio (aHR) of attrition after compared to before "Treat All" was 1.73 (95%CI: 1.30-2.31). The observed hazard of attrition for women being pregnant at ART initiation decreased by 17% (aHR: 1.73*0.48 = 0.83) after "Treat All". Being male (vs female; aHR: 1.45; 95%CI: 1.12-1.87) and WHO Stage IV (vs WHO Stage I-III; aHR: 2.89; 95%CI: 1.16-7.11) predicted attrition both before and after "Treat All" implementation. CONCLUSION: Attrition was higher after "Treat All"; being male, WHO Stage 4, and pregnancy predicted attrition in both before and after Treat All. However, pregnancy became a less strong risk factor for attrition after "Treat All" implementation.

6.
Lancet HIV ; 7(8): e533-e544, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32763217

RESUMEN

BACKGROUND: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. METHODS: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. FINDINGS: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir. INTERPRETATION: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Adolescente , Peso Corporal , Niño , Relación Dosis-Respuesta a Droga , Femenino , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas , Comprimidos , Uganda , Zimbabwe
7.
BMC Res Notes ; 13(1): 393, 2020 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-32847619

RESUMEN

OBJECTIVE: We conducted a descriptive cross-sectional study using survey and programme data to assess district-level performance along the HIV care cascade (HIV testing target achievement, linkage to ART and ART coverage) in order to formulate district-specific recommendations, taking into consideration prevalence and yield of testing. RESULTS: Data from 60 districts were analysed. Forty-eight districts (80.0%) surpassed 90% of their 2018 HIV testing targets. Linkage to ART was less than 90% in 40 districts (83.3%). Thirty districts (50.0%) had ART coverage above 90%. Of the 30 districts with suboptimal (< 90%) ART coverage, 18 districts had achieved high HIV testing target but with suboptimal linkage to ART, 6 had achieved high HIV testing targets and high linkage to ART, 4 had both suboptimal HIV testing target achievement and linkage to ART and 2 had suboptimal HIV testing target achievement and high linkage to ART. Priority should be given to districts with suboptimal ART coverage. Remediation strategies should be tailored to address the poorly performing stage of the cascade in each of the districts.

8.
Am Heart J ; 225: 69-77, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32474206

RESUMEN

BACKGROUND: Rheumatic heart disease (RHD) is a neglected disease affecting 33 million people, mainly in low and middle income countries. Yet very few large trials or registries have been conducted in this population. The INVICTUS program of research in RHD consists of a randomized-controlled trial (RCT) of 4500 patients comparing rivaroxaban with vitamin K antagonists (VKA) in patients with RHD and atrial fibrillation (AF), a registry of 17,000 patients to document the contemporary clinical course of patients with RHD, including a focused sub-study on pregnant women with RHD within the registry. This paper describes the rationale, design, organization and baseline characteristics of the RCT and a summary of the design of the registry and its sub-study. Patients with RHD and AF are considered to be at high risk of embolic strokes, and oral anticoagulation with VKAs is recommended for stroke prevention. But the quality of anticoagulation with VKA is poor in developing countries. A drug which does not require monitoring, and which is safe and effective for preventing stroke in patients with valvular AF, would fulfill a major unmet need. METHODS: The INVestIgation of rheumatiC AF Treatment Using VKAs, rivaroxaban or aspirin Studies (INVICTUS-VKA) trial is an international, multicentre, randomized, open-label, parallel group trial, testing whether rivaroxaban 20 mg given once daily is non-inferior (or superior) to VKA in patients with RHD, AF, and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo-contrast or thrombus, or a CHA2DS2VASc score ≥2). The primary efficacy outcome is a composite of stroke or systemic embolism and the primary safety outcome is the occurrence of major bleeding. The trial has enrolled 4565 patients from 138 sites in 23 countries from Africa, Asia and South America. The Registry plans to enroll an additional 17,000 patients with RHD and document their treatments, and their clinical course for at least 2 years. The pregnancy sub-study will document the clinical course of pregnant women with RHD. CONCLUSION: INVICTUS is the largest program of clinical research focused on a neglected cardiovascular disease and will provide new information on the clinical course of patients with RHD, and approaches to anticoagulation in those with concomitant AF.


Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Embolia/prevención & control , Inhibidores del Factor Xa/uso terapéutico , Cardiopatía Reumática/tratamiento farmacológico , Rivaroxabán/uso terapéutico , Accidente Cerebrovascular/prevención & control , Vitamina K/antagonistas & inhibidores , Adulto , Anciano , Fibrilación Atrial/complicaciones , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Embarazo , Complicaciones Cardiovasculares del Embarazo/tratamiento farmacológico , Cardiopatía Reumática/complicaciones , Rivaroxabán/efectos adversos
9.
Clin Infect Dis ; 71(16): 2180-2183, 2020 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-32392333

RESUMEN

The trajectory and impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in sub-Saharan Africa are unclear, but they are seemingly varied between different countries, with most reporting low numbers. We use the situation in Zimbabwe to build an argument that the epidemic is likely to be attenuated in some countries with similar socioeconomic and cultural structures. However, even an attenuated epidemic may overwhelm weak health systems, emphasizing the importance of prevention. These prevention strategies should be tailored to the unique social and cultural networks of individual countries, which may facilitate the spread of SARS-CoV-2. It is also equally important to maintain services for the major infectious diseases in the region, such as tuberculosis and malaria. A breakdown of treatment and prevention services for these conditions may even overshadow the projected morbidity and mortality from coronavirus disease 2019 (COVID-19).

10.
BMC Infect Dis ; 20(1): 383, 2020 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-32471350

RESUMEN

BACKGROUND: HIV affects the central nervous system resulting in HIV associated neurocognitive impairment (NCI) in approximately 50% of people living with HIV. It typically affects memory, learning, working memory, fine motor skills, speed of information processing, verbal fluency and executive functioning cognitive domains. NCI can affect adherence to antiretroviral therapy (ART), employability, driving ability and activities of daily living. NCI is not routinely screened for in Zimbabwe, and the burden is not known in this setting. The objectives of this study were: 1) To determine NCI prevalence using a comprehensive neuropsychological battery at two primary health care clinics in Harare; 2) To assess the pattern of cognitive impairment across cognitive domains using a gold standard neuropsychological (NP) battery in HIV-positive patients compared to HIV-negative controls. METHODS: Inclusion criteria: 18 years or older; minimum 7 years education; no neurological or psychiatric disorders. HIV-positive participants were on ART for ≥3 months; HIV-negative participants had a confirmed HIV negative status in the past month. A comprehensive NP battery, functional assessments, demographic and medical history questionnaires were administered. The NP battery consisted of tests assessing memory, learning, working memory, fine motor skills, speed of information processing, verbal fluency and executive functioning. RESULTS: Two-hundred-and-thirty-one participants were recruited. Of those, 155 were HIV-positive (Female = 70%, Age M = 37.8; SD 11.2) and 76 HIV-negative (Female = 63%, Age M = 31.2; SD 9.9). HIV-positive participants were on ART for an average of 6 years. NCI was present in 49.7% HIV positive participants. Compared to HIV-negative participants, the HIV-positive group had significantly poorer scores in 5 out of 7 cognitive domains. A good level of education is negatively correlated with NCI. CONCLUSIONS: NCI prevalence in HIV-positive population Zimbabwe is consistent with global estimates. NCI persists in adults who are on ART. Routine assessment of NCI in adults attending primary care clinics using this adapted battery is therefore important so that they are identified early and are provided the necessary interventions.


Asunto(s)
Antirretrovirales/uso terapéutico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH , Atención Primaria de Salud , Actividades Cotidianas , Adolescente , Adulto , Antirretrovirales/efectos adversos , Función Ejecutiva , Femenino , Infecciones por VIH/virología , Humanos , Aprendizaje , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Prevalencia , Encuestas y Cuestionarios , Adulto Joven , Zimbabwe/epidemiología
11.
PLoS One ; 15(1): e0222309, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31910445

RESUMEN

BACKGROUND: The last evaluation to assess outcomes for patients receiving antiretroviral therapy (ART) through the Zimbabwe public sector was conducted in 2011, covering the 2007-2010 cohorts. The reported retention at 6, 12, 24 and 36 months were 90.7%, 78.1%, 68.8% and 64.4%, respectively. We report findings of a follow-up evaluation for the 2012-2015 cohorts to assess the implementation and impact of recommendations from this prior evaluation. METHODS: A nationwide retrospective study was conducted in 2016. Multi-stage proportional sampling was used to select health facilities and study participants records. The data extracted from patient manual records included demographic, baseline clinical characteristics and patient outcomes (active on treatment, died, transferred out, stopped ART and lost to follow-up (LTFU)) at 6, 12, 24 and 36 months. The data were analysed using Stata/IC 14.2. Retention was estimated using survival analysis. The predictors associated with attrition were determined using a multivariate Cox regression model. RESULTS: A total of 3,810 participants were recruited in the study. The median age in years was 35 (IQR: 28-42). Overall, retention increased to 92.4% (p-value = 0.060), 86.5% (p-value<0.001), 79.2% (p-value<0.001) and 74.4% (p-value<0.001) at 6, 12, 24 and 36 months respectively. LTFU accounted for 98% of attrition. Being an adolescent or a young adult (15-24 years) (vs adult;1.41; 95% CI:1.14-1.74), children (<15years) (vs adults; aHR 0.64; 95% CI:0.46-0.91), receiving care at primary health care facility (vs central and provincial facility; aHR 1.23; 95% CI:1.01-1.49), having initiated ART between 2014-2015 (vs 2012-2013; aHR1.45; 95%CI:1.24-1.69), having WHO Stage IV (vs Stage I-III; aHR2.06; 95%CI:1.51-2.81) and impaired functional status (vs normal status; aHR1.25; 95%CI:1.04-1.49) predicted attrition. CONCLUSION: The overall retention was higher in comparison to the previous 2007-2010 evaluation. Further studies to understand why attrition was found to be higher at primary health care facilities are warranted. Implementation of strategies for managing patients with advanced HIV disease, differentiated care for adolescents and young adults and tracking of LTFU clients should be prioritised to further improve retention.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Adolescente , Adulto , Fármacos Anti-VIH/efectos adversos , Antirretrovirales/efectos adversos , Niño , Preescolar , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Humanos , Lactante , Recién Nacido , Masculino , Cumplimiento de la Medicación/psicología , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Adulto Joven , Zimbabwe/epidemiología
12.
Clin Infect Dis ; 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31922537

RESUMEN

BACKGROUND: Phylogenetic analysis can be used to assess HIV transmission in populations. We inferred the direction of HIV transmission using whole-genome HIV sequences from couples with known linked infection and known transmission direction. METHODS: Complete next generation sequencing (NGS) data were obtained for 105 unique index-partner sample pairs from 32 couples enrolled in the HIV Prevention Trials Network (HPTN) 052 trial (up to two samples/person). Index samples were obtained up to 5.5 years before partner infection; partner samples were obtained near the time of seroconversion. The bioinformatics method, phyloscanner, was used to infer transmission direction. Analyses were performed using samples from individual sample pairs, samples from all couples (one sample/person; group analysis) and all available samples (multi-sample group analysis). Analysis was also performed using NGS data from defined regions of the HIV genome (gag, pol, env). RESULTS: Using whole-genome NGS data, transmission direction was inferred correctly (index to partner) for 98/105 (93.3%) of the individual sample pairs, 99/105 (94.3%) sample pairs using group analysis, and 31 (96.9%) of the 32 couples using multi-sample group analysis. There were no cases where the incorrect transmission direction (partner to index) was inferred. The accuracy of the method was higher with greater time between index and partner sample collection. Pol region sequences performed better than env or gag sequences for inferring transmission direction. CONCLUSIONS: We demonstrate the potential of a phylogenetic method to infer the direction of HIV transmission between two individuals using whole-genome and pol NGS data.

13.
Clin Infect Dis ; 71(1): 158-165, 2020 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-31630166

RESUMEN

BACKGROUND: Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)-naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. METHODS: PLWH with a CD4+ count <300 cells/mm3 underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once.Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. RESULTS: Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. CONCLUSIONS: Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

15.
PLoS One ; 14(11): e0225199, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31725787

RESUMEN

A retrospective analysis of the randomized controlled DART (Development of AntiRetroviral Therapy in Africa; ISRCTN13968779) trial in HIV-1-positive adults initiating antiretroviral therapy with co-formulated zidovudine/lamivudine plus either tenofovir, abacavir, or nevirapine was conducted to evaluate the safety of initiating standard lamivudine dosing in patients with impaired creatinine clearance (CLcr). Safety data collected through 96 weeks were analyzed after stratification by baseline CLcr (estimated using Cockcroft-Gault) of 30-49 mL/min (n = 168) versus ≥50 mL/min (n = 3,132) and treatment regimen. The Grade 3-4 adverse events (AEs) and serious AEs (for hematological, hepatic and gastrointestinal events), maximal toxicities for liver enzymes, serum creatinine and bilirubin and maximum treatment-emergent hematology toxicities were comparable for groups with baseline CLcr 30-49 versus CLcr≥50 mL/min. No new risks or trends were identified from this dataset. Substantial and similar increases in the mean creatinine clearance (>25 mL/min) were observed from baseline though Week 96 among participants who entered the trial with CLcr 30-49 mL/min, while no increase or smaller median changes in creatinine clearance (<7 mL/min) were observed for participants who entered the trial with CLcr ≥50 mL/min. Substantial increases (> 150 cells/ mm3) in mean CD4+ cells counts from baseline to Week 96 were also observed for participants who entered the trial with CLcr 30-49 mL/min and those with baseline CLcr ≥50 mL/min. Though these results are descriptive, they suggest that HIV-positive patients with CLcr of 30-49 mL/min would have similar AE risks in comparison to patients with CLcr ≥50 mL/min when initiating antiretroviral therapy delivering doses of 300 mg of lamivudine daily through 96 weeks of treatment. Overall improvements in CLcr were observed for patients with baseline CLcr 30-49 mL/min.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Creatinina/metabolismo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Lamivudine/administración & dosificación , Lamivudine/efectos adversos , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad
16.
Clin Neuropsychol ; 33(sup1): 1-26, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31043112

RESUMEN

Objective: People living with HIV (PLWH) are at risk for HIV-Associated Neurocognitive Disorders (HAND)/Neurocognitive Impairment (NCI). HIV prevalence in Sub-Saharan Africa (SSA) is high, but neuropsychological screening and testing for NCI among HIV-infected individuals is not done frequently. This systematic review aims to establish how NCI among HIV-infected individuals is being assessed in SSA, if and how the tests are adapted, if norms exist and identify personnel who administer them.Method: We searched PubMed, Medline, EBSCO, PsycINFO, and Web of Science. Two reviewers screened the articles for inclusion and risk of bias. We included studies from SSA with a comprehensive neuropsychological assessment battery.Results: We retrieved 212 articles and 23 articles met inclusion criteria. The most commonly used tests were the Color Trails Test 1, Color Trails Test 2, and the WAIS III Digit Symbol Test. Some tests were translated into French (Cameroon), Luganda (Uganda), Chichewa (Malawi), isiXhosa (South Africa), and Afrikaans (South Africa). Some verbal learning tests were adapted to reflect culturally appropriate language. Test administrators were either non-specialized personnel supervised by clinical neuropsychologists or clinical psychologists.Conclusion: Overall, the tests used are similar to the tests being used globally to assess NCI among HIV-infected individuals and there is a general consistency across countries. However, there is generally a lack of norms for the tests and the process of adaptation is not always well described. Future research should establish whether these tests measure neuropsychological constructs as successfully as they do in western populations where the tests were developed.


Asunto(s)
Infecciones por VIH/complicaciones , Trastornos Neurocognitivos/etiología , Pruebas Neuropsicológicas/normas , Femenino , Infecciones por VIH/psicología , Humanos , Masculino , Sudáfrica
17.
Int J Mycobacteriol ; 8(1): 83-88, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30860184

RESUMEN

Background: Multidrug-resistant tuberculosis (MDR-TB) is a public health concern globally. MDR-TB is defined as resistance to rifampicin (RIF) and isoniazid (INH), the two-major anti-TB first-line TB treatment drugs. Rapid identification of MDR-TB can contribute significantly to the control of TB. The GenoType® MTBDRplus Ver 2.0 assay is a molecular assay used to detect genetic mutations that result in RIF and INH resistance. The aim of this study was to validate the performance of the GenoType® MTBDRplus Ver 2.0 assay for the detection of INH and RIF resistance. Methods: Fifty-five stored Mycobacterium tuberculosis isolates were tested using both the mycobacterial growth indicator tube (MGIT), antimicrobial susceptibility testing (AST), and the GenoType® MTBDRplus Ver 2.0 assay. The MGIT AST was done according to the BBL MGIT AST SIRE system with RIF and INH final critical concentrations of 1.0 µg/ml and 0.1 µg/ml, respectively. The GenoType® MTBDRplus assay (Hain Lifescience, Germany) was performed following the manufacturer's instructions. Results: The GenoType® MTBDRplus Ver 2.0 assay had a sensitivity, specificity, positive predictive value, and negative predictive value of 100% for INH and RIF resistance. The intra-assay precision for the assay was 100%. Conclusion: The GenoType® MTBDRplus Ver 2.0 assay's sensitivity and specificity show that the assay is highly accurate for the detection of RIF and INH resistance and thus can be used as an alternate platform due to its shorter results turnaround time.


Asunto(s)
Antibióticos Antituberculosos/farmacología , Farmacorresistencia Bacteriana Múltiple , Técnicas de Genotipaje/métodos , Isoniazida/farmacología , Mycobacterium tuberculosis/genética , Rifampin/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Mycobacterium tuberculosis/efectos de los fármacos , Sensibilidad y Especificidad
18.
N Engl J Med ; 380(11): 1001-1011, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30865794

RESUMEN

BACKGROUND: Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates. METHODS: We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25. RESULTS: A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001). CONCLUSIONS: A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/prevención & control , Antituberculosos/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Isoniazida/administración & dosificación , Tuberculosis Latente/tratamiento farmacológico , Rifampin/análogos & derivados , Tuberculosis/prevención & control , Adulto , Antituberculosos/efectos adversos , Recuento de Linfocito CD4 , Esquema de Medicación , Quimioterapia Combinada , Femenino , Infecciones por VIH/complicaciones , Humanos , Isoniazida/efectos adversos , Tuberculosis Latente/complicaciones , Masculino , Cumplimiento de la Medicación , Rifampin/administración & dosificación , Rifampin/efectos adversos
19.
AAS Open Res ; 2: 1, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-32382699

RESUMEN

Biobanks and human genomics applications are key for understanding health, disease and heredity in Africa and globally. Growing interest in these technologies calls for strengthening relevant legal, ethical and policy systems to address knowledge disparities and ensure protection of society, while supporting advancement of science. In Zimbabwe there is limited understanding of ethical, legal, and societal issues (ELSI) for biobanking and genomics. The Genomics Inheritance Law Ethics and Society (GILES) initiative was established in 2015 to explore the current status and gaps in the ethical and legal frameworks, knowledge among various stakeholders, and to establish capacity for addressing ELSI of biobanking and genomics as applied in biomedical and population research, and healthcare. A multi-methods approach was applied including document reviews, focus group discussions and in-depth interviews among health and research professionals, and community members in six provinces comprising urban, peri-urban and rural areas. Emerging findings indicates a need for updating guidelines and policies for addressing ELSI in biobanking and genomics research in Zimbabwe. Emerging terminologies such as biobanking and genomics lack clarity suggesting a need for increased awareness and educational tools for health professionals, research scientists and community members. Common concerns relating to consent processes, sample and data use and sharing, particularly where there is trans-national flow of biospecimens and data, call for nationally tailored ELSI frameworks aligned to regional and international initiatives. This paper describes the strategy undertaken for the development and implementation of the GILES project and discusses the importance of such an initiative for characterisation of ELSI of human biobanking and genomics in Zimbabwe and Africa. Conducting this explorative study among a wide range of stakeholders over a countrywide geographical regions, established one of the most comprehensive studies for ELSI of human biobanking and genomics in Africa.

20.
J Public Health Afr ; 10(2): 1081, 2019 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-32257079

RESUMEN

Low-and-middle-income countries (LMICs) have high disease burdens, necessitating increased research. However, LMIC research output constitutes only 2% of global total. To increase output, researchers must be capacitated. The University of Zimbabwe (UZ) and the University at Buffalo (UB), developed and implemented the AIDS International Research Training Program (AITRP), in 2008, that focused on graduate scholars. The subsequent HIV Research Training Program (HRTP), begun in 2016, and piloted post-doctoral training to enhance research productivity at UZ. This report discusses the collaboration. As of 2016, prospective candidates applied by submitting letters of intent, research proposals, curriculum vitae and biographical sketches. The scholars research training included hypothesis and project development, completion of grant applications, research project budgets, research presentations to diverse audiences and the application of advanced statistics to research data. The first cohort of five postdoctoral scholars were trained at UZ and UB, between 2016 and 2019. Through the formalized postdoctoral training approach, scholars identified areas of focus. In 2017, one of the scholars obtained a National Institutes of Health (NIH) Emerging Global Leader Award and is now a highly-rated researcher based in South Africa. A second scholar made NIH D43 and K43 grant applications, while the remaining three are academicians and early researchers at UZ. Although research output in Africa and many LMICs is low, it can be built through cooperation similar to the UZ-UB HRTP. This manuscript reports on an effort aimed at building individual and institutional research capacity in Zimbabwe. This can serve as a model for building other similar training programs.

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