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A number of sophisticated estimators of longitudinal effects have been proposed for estimating the intervention-specific mean outcome. However, there is a relative paucity of research comparing these methods directly to one another. In this study, we compare various approaches to estimating a causal effect in a longitudinal treatment setting using both simulated data and data measured from a human immunodeficiency virus cohort. Six distinct estimators are considered: (i) an iterated conditional expectation representation, (ii) an inverse propensity weighted method, (iii) an augmented inverse propensity weighted method, (iv) a double robust iterated conditional expectation estimator, (v) a modified version of the double robust iterated conditional expectation estimator, and (vi) a targeted minimum loss-based estimator. The details of each estimator and its implementation are presented along with nuisance parameter estimation details, which include potentially pooling the observed data across all subjects regardless of treatment history and using data adaptive machine learning algorithms. Simulations are constructed over six time points, with each time point steadily increasing in positivity violations. Estimation is carried out for both the simulations and applied example using each of the six estimators under both stratified and pooled approaches of nuisance parameter estimation. Simulation results show that double robust estimators remained without meaningful bias as long as at least one of the two nuisance parameters were estimated with a correctly specified model. Under full misspecification, the bias of the double robust estimators remained better than that of the inverse propensity estimator under misspecification, but worse than the iterated conditional expectation estimator. Weighted estimators tended to show better performance than the covariate estimators. As positivity violations increased, the mean squared error and bias of all estimators considered became worse, with covariate-based double robust estimators especially susceptible. Applied analyses showed similar estimates at most time points, with the important exception of the inverse propensity estimator which deviated markedly as positivity violations increased. Given its efficiency, ability to respect the parameter space, and observed performance, we recommend the pooled and weighted targeted minimum loss-based estimator.

Abstract Background Patient engagement is effective in promoting adherence to HIV care. In an effort to promote patient-centered care, we implemented an enhanced patient care (EPC) intervention that addresses a combination of system-level barriers including provider training, continuity of clinician-patient relationship, enhanced treatment dialogue and better clinic scheduling. We describe the initial implementation of the EPC intervention in a rural HIV clinic in Kenya, and the factors that facilitated its implementation. Methods The intervention occurred in one of the rural Academic Model Providing Healthcare (AMPATHplus) health facilities in Busia County in the western region of Kenya. Both qualitative and quantitative data were collected through training and meeting proceedings/minutes, a patient tracking tool, treatment dialogue and a peer confirmation tool. Qualitative data were coded and emerging themes on the implementation and adaptation of the intervention were developed. Descriptive analysis including percentages and means were performed on the quantitative data. Results Our analysis identified four key factors that facilitated the implementation of this intervention. (1) The smooth integration of the intervention as part of care that was facilitated by provider training, biweekly meetings between the research and clinical team and having an intervention that promotes the health facility agenda. (2) Commitment of stakeholders including providers and patients to the intervention. (3) The adaptability of the intervention to the existing context while still maintaining fidelity to the intervention. (4) Embedding the intervention in a facility with adequate infrastructure to support its implementation. Conclusions This analysis demonstrates the value of using mixed methods approaches to study the implementation of an intervention. Our findings emphasize how critical local support, local infrastructure, and effective communication are to adapting a new intervention in a clinical care program.

In conducting studies on an exposure of interest, a systematic roadmap should be applied for translating causal questions into statistical analyses and interpreting the results. In this paper we describe an application of one such roadmap applied to estimating the joint effect of both time to availability of a nurse-based triage system (low risk express care (LREC)) and individual enrollment in the program among HIV patients in East Africa. Our study population is comprised of 16,513 subjects found eligible for this task-shifting program within 15 clinics in Kenya between 2006 and 2009, with each clinic starting the LREC program between 2007 and 2008. After discretizing follow-up into 90-day time intervals, we targeted the population mean counterfactual outcome (i. e. counterfactual probability of either dying or being lost to follow up) at up to 450 days after initial LREC eligibility under three fixed treatment interventions. These were (i) under no program availability during the entire follow-up, (ii) under immediate program availability at initial eligibility, but non-enrollment during the entire follow-up, and (iii) under immediate program availability and enrollment at initial eligibility. We further estimated the controlled direct effect of immediate program availability compared to no program availability, under a hypothetical intervention to prevent individual enrollment in the program. Targeted minimum loss-based estimation was used to estimate the mean outcome, while Super Learning was implemented to estimate the required nuisance parameters. Analyses were conducted with the ltmle R package; analysis code is available at an online repository as an R package. Results showed that at 450 days, the probability of in-care survival for subjects with immediate availability and enrollment was 0.93 (95% CI: 0.91, 0.95) and 0.87 (95% CI: 0.86, 0.87) for subjects with immediate availability never enrolling. For subjects without LREC availability, it was 0.91 (95% CI: 0.90, 0.92). Immediate program availability without individual enrollment, compared to no program availability, was estimated to slightly albeit significantly decrease survival by 4% (95% CI 0.03,0.06, p

ObjectivesTenofovir disoproxil fumarate (TDF) has been associated with renal insufficiency. Co-administration with boosted protease inhibitors, which increases its exposure, may further increase the risk of renal insufficiency.MethodsWe compared the incidence of renal events among women taking TDF co-administered with lopinavir/ritonavir (LPV/r) versus those co-administering TDF with nevirapine (NVP). Renal events were defined as a confirmed drop in creatinine clearance associated with a serum creatinine grade 2 or higher, or that leading to treatment modification.ResultsOverall, 741 HIV-infected women were enrolled into the study. Of these, 24 (3.2%) had reportable renal events (18 in LPV/r arm, six in NVP arm). In multivariate analysis, renal events were significantly associated with the LPV/r arm [odds ratio (OR) 3.12, 95% confidence interval (CI) 1.21, 8.05; P = 0.019], baseline HIV-1 RNA (OR 2.65, 95% CI 1.23, 5.69 per 1 log10 copies/ml higher; P = 0.013) and baseline creatinine clearance (OR 0.83, 95% CI 0.70-0.98 per 10 ml/min higher; P = 0.030). In multivariate analysis evaluating renal events requiring treatment modification, only baseline HIV-1 RNA and creatinine clearance were significantly associated (OR 4.41, 95% CI 1.65, 11.78 per 1 log10 copies/ml higher; P = 0.003 and OR 0.80, 95% CI 0.64, 0.99 per 10 ml/min higher; P = 0.040, respectively).ConclusionThe rates of renal events were relatively low in the two treatment arms. However, patients taking TDF co-administered with LPV/r had significantly more renal events compared to those co-administered with NVP. Furthermore, higher baseline HIV RNA and lower creatinine clearance were associated with the development of renal insufficiency requiring treatment modification.

Differentiated care delivery aims to simplify care of people living with HIV, reflect their preferences, reduce burdens on the healthcare system, maintain care quality and preserve resources. However, assessing program effectiveness using observational data is difficult due to confounding by indication and randomized trials may be infeasible. Also, benefits can reach patients directly, through enrollment in the program, and indirectly, by increasing quality of and accessibility to care. Low-risk express care (LREC), the program under evaluation, is a nurse-centered model which assigns patients stable on ART to a nurse every two months and a clinician every third visit, reducing annual clinician visits by two thirds. Study population is comprised of 16,832 subjects from 15 clinics in Kenya. We focus on patient retention in care based on whether the LREC program is available at a clinic and whether the patient is enrolled in LREC. We use G-estimation to assess the effect on retention of two "strategies": (i) program availability but no enrollment; (ii) enrollment at an available program; versus no program availability. Compared to no availability, LREC results in a non-significant increase in patient retention, among patients not enrolled in the program (indirect effect), while enrollment in LREC is associated with a significant extension of the time retained in care (direct effect). G-estimation provides an analytical framework useful to the assessment of similar programs using observational data. [ABSTRACT FROM AUTHOR]

HIV protease inhibitors (PIs) show antimalarial activity in vitro and in animals. Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine-rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial (A5208; ClinicalTrials.gov: NCT00089505). Participants were randomized to treatment with PI-containing vs. PI-sparing ART, and were followed prospectively for ≥48 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population.

Introduction: the increasing number of people receiving antiretroviral therapy (ART) in sub-Saharan Africa has stressed already overburdened health systems. A care model utilizing communitybased peer-groups (ART Co-ops) facilitated by community health workers (CHW) was implemented (2016-2018) to address these challenges. In 2018, a post-intervention study assessed perceptions of the intervention. Methods: forty participants were engaged in focus group discussions consisting of ART Co-op clients, study staff, and health care providers from Kitale HIV clinic. Data were analyzed thematically for content on the intervention, challenges, and recommendations for improvement. Results: all participants liked the intervention. However, some reported traveling long distances to attend ART Coop meetings and experiencing stigma with ART Coops participation. The ART Co-op inclusion criteria were considered appropriate; however, additional outreach to deliberately include spouses living with HIV, the disabled, the poor, and HIV pregnant women was recommended. Participants liked CHWdirected quarterly group meetings which included ART distribution, adherence review, and illness identification. The inability of the CHW to provide full clinical care, inconvenient meeting venues, poor timekeeping, and non-attendance behaviors were noted as issues. Participants indicated that program continuation, regular CHW training, rotating meetings at group members' homes, training ART Co-ops leaders to assume CHW tasks, use of pill diaries to check adherence, nutritional support, and economically empowering members through income generation projects would be beneficial. Conclusion: the intervention was viewed positively by both clinic staff and clients. They identified specific challenges and generated actionable key considerations to improve access and acceptability of the community-based model of care. [ABSTRACT FROM AUTHOR]

Background In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. Methods and findings In a 2x2x2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76-1.28], p = 0.91); in serious (aHR = 0.99 [0.81-1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71-1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63-1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76-1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. Conclusions Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. Trial registration ClinicalTrials.gov NCT01825031. Trial registration International Standard Randomised Controlled Trials Number ISRCTN 43622374., Author(s): Cissy Kityo 1, Alexander J. Szubert 2, Abraham Siika 3, Robert Heyderman 4,5, Mutsa Bwakura-Dangarembizi 6, Abbas Lugemwa 7, Shalton Mwaringa 8, Anna Griffiths 2, Immaculate Nkanya 1, Sheila [...]

Background: In resource‐poor settings, mortality is at its highest during the first 3 months after combination antiretroviral treatment (cART) initiation. A clear predictor of mortality during this period is having a low CD4 count at the time of treatment initiation. The objective of this study was to evaluate the effect on survival and clinic retention of a nurse‐based rapid assessment clinic for high‐risk individuals initiating cART in a resource‐constrained setting. Methods: The USAID‐AMPATH Partnership has enrolled more than 140,000 patients at 25 clinics throughout western Kenya. High Risk Express Care (HREC) provides weekly or bi‐weekly rapid contacts with nurses for individuals initiating cART with CD4 counts of ≤100 cells/mm[sup.3]. All HIV‐infected individuals aged 14 years or older initiating cART with CD4 counts of ≤100 cells/mm[sup.3] were eligible for enrolment into HREC and for analysis. Adjusted hazard ratios (AHRs) control for potential confounding using propensity score methods. Results: Between March 2007 and March 2009, 4,958 patients initiated cART with CD4 counts of ≤100 cells/mm[sup.3]. After adjusting for age, sex, CD4 count, use of cotrimoxazole, treatment for tuberculosis, travel time to clinic and type of clinic, individuals in HREC had reduced mortality (AHR: 0.59; 95% confidence interval: 0.45‐0.77), and reduced loss to follow up (AHR: 0.62; 95% CI: 0.55‐0.70) compared with individuals in routine care. Overall, patients in HREC were much more likely to be alive and in care after a median of nearly 11 months of follow up (AHR: 0.62; 95% CI: 0.57‐0.67). Conclusions: Frequent monitoring by dedicated nurses in the early months of cART can significantly reduce mortality and loss to follow up among high‐risk patients initiating treatment in resource‐constrained settings., Background Combination antiretroviral treatment (cART) has proven itself to be an effective therapeutic mechanism for suppressing viral replication and enabling reconstitution of the immune system, thus allowing patients to recover [...]

Objective To determine the incidence of loss to follow-up in a treatment programme for people living with human immunodeficiency virus (HIV) infection in Kenya and to investigate how loss to follow-up is affected by gender. Methods Between November 2001 and November 2007, 50 275 HIV-positive individuals aged > 14 years (69% female; median age: 36.2 years) were enrolled in the study. An individual was lost to follow-up when absent from the HIV treatment clinic for > 3 months if on combination antiretroviral therapy (cART) or for > 6 months if not. The incidence of loss to follow-up was calculated using Kaplan-Meier methods anal factors associated with loss to follow-up were identified by logistic and Cox multivariate regression analysis. Findings Overall, 8% of individuals attended no follow-up visits, and 54% of them were lost to follow-up. The overall incidence of loss to follow-up was 25.1 per. 100 person-years. Among the 92% who attended at least one follow-up visit, the incidence of loss to follow-up before and after starting CART was 27.2 and 14.0 per 100 person- years, respectively. Baseline factors associated with loss to follow-up included younger age, a long travel time to the clinic, patient disclosure of positive HIV status, high CD4+ lymphocyte count, advanced-stage HIV disease, and rural clinic location. Men were at an increased risk overall and before and after starting cART. Conclusion The risk of being lost to follow-up was high, particularly before starting cART. Men were more likely to become lost to follow-up, even after adjusting for baseline sociodemographic and clinical characteristics. Interventions designed for men and women separately could improve retention. Objectif Determiner l'incidence de perte de suivi dans un programme de traitement pour les personnes vivant avec l'infection par le virus de l'immunodeficience humaine (VIH) au Kenya, et investiguer comment la perte de suivi est influencee par le sexe. Methodes Entre novembre 2001 et novembre 2007, 50 275 individus seropositifs d'age [is greater than or equal to] 14 ans (69% de sexe feminin; age median: 36,2 ans) ont participe a l'etude. Le suivi a ete perdu lorsque les individus ont ete absents de la clinique de traitement du VIH pendant > 3 mois lorsqu'ils etaient sous combinaison therapeutique antiretrovirale (TARV), et pendant > 6 mois dans le cas contraire. L'incidence de perte du suivi a ete calculee au moyen des methodes Kaplan-Meier, et les facteurs associes a la perte du suivi ont ete identifies par la regression logistique et l'analyse multivariable par regression du modele de Cox. Resultats Globalement, 8% des individus ne se sont jamais presentes a unevisite de suivi, et 54% d'entre eux ont perdu le suivi. L'incidence totale de perte du suivi etait de 25,1 par 100 personnes-annees. Parmi les 92% qui ont assiste a une visite de suivi au moins, l'incidence de perte du suivi avant et apres le debut du TARV a ete de 27,2 et 14,0 par 100 personnes-annees, respectivement. Parmi les facteurs de la ligne de base associes a la perte du suivi, ont ete constates le jeune age, la longueur du temps de trajet pour se rendre a la clinique, la revelation de l'etat VIH positif du patient, un nombre eleve de lymphocytes CD4+, un stade avance de la maladie a VIH et la ruralite de la clinique. Les hommes ont presente un risque plus eleve en general et ce, avant et apres le debut du TARV. Conclusion Le risque de perte du suivi a ete eleve, particulierement avant le debut du TARV. Les hommes ont ete plus enclins a perdre le suivi, meme apres ajustement pour base sociodemographique et caracteristiques cliniques. Des interventions concues separement pour les hommes et les femmes pourraient ameliorer la retention. Objetivo Determinar la incidencia de bajas en el seguimiento de un programa terapeutico de personas portadoras del virus de la inmunodeficiencia humana (VIH) en Kenya, e investigar si el sexo de dichas personas influye en las bajas en el seguimiento. Metodos Entre noviembre de 2001 y noviembre de 2007 se inscribieron en el estudio 50 275 personas VIH-positivas de mas de 14 anos de edad (69% mujeres; edad media: 36,2 anos). Se considero Una baja en el seguimiento cuando la persona se ausento de la clinica de tratamiento del VIH durante mas de tres meses si estaba en tratamiento antirretroviral combinado (TARC) o, en el caso contrario, durante mas de seis meses. La incidencia de bajas en el seguimiento se ha calculado utilizando los metodos de Kaplan-Meier, y los factores asociados con las bajas en el seguimiento se han identificado mediante un analisis de regresion logistica y de regresion multifactorial de Cox. Resultados En terminos generales, el 8% de las personas no acudieron a las visitas de seguimiento, de las que el 54% se consideraron como bajas en el seguimiento. La incidencia total de bajas en el seguimiento fue de 25,1 por 100 anos-persona. Dei 92% que acudio al menos a una visita de seguimiento, la incidencia de baja en el seguimiento, antes y despues de comenzar el TARC fue de 27,2 y 14,0 por 100 anos persona, respectivamente. Los factores iniciales asociados a la baja en el seguimiento incluyeron: la juventud, la lejania de la clinica, la revelacion dei paciente de su estado de VIH-positivo, el recuento linfocitico CD4+ elevado, enfermedades debidas al VIH en fase avanzada y la ubicacion de la clinica rural. El riesgo general en hombres fue elevado, antes y despues de iniciar el TARC. Conclusion El riesgo de baja en el seguimiento dei paciente fue elevado, sobre todo antes de iniciar el TARC. Hubo una tendencia de mas bajas en el seguimiento entre los hombres, aun despues dei ajuste de las caracteristicas sociodemograficas y clinicas iniciales. Las intervenciones especificas e individuales para hombres y mujeres podrian mejorar la permanencia en el programa., Introduction Approximately 33 million people worldwide are living with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), and the majority are in sub-Saharan Africa. (1) The use of [...]