Monitoring HIV disease progression among antiretroviral therapy patients in Zimbabwe from 2004 to 2017: spatial and multistate model approaches
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Date
2020
Authors
Zingoni, Zvifadzo Matsena
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Abstract
Globally, remarkable progress has been made on the treatment of HIV-infected people using
antiretroviral therapy (ART), particularly in sub-Saharan Africa (SSA). SSA region is
disproportionately affected by the pandemic as it accounts for more than 50% of people living
with HIV (PLWHIV). With the global efforts to achieve zero HIV incidences by 2030, the 90-
90-90 UNAIDS targets were launched, whereby 90% of the PLWHIV should know their status,
90% of those diagnosed should be initiated on ART, and 90% of those on ART should achieve
viral suppression(1). In Zimbabwe, strides have been made towards achieving these targets;
however, limitations exist. Statistical modelling approaches like multistate models framework
and geostatistical models can be used to determine how well ART patients are adhering to ART
by estimating the ART attrition rate due to loss to follow-up (LTFU), immune deterioration
patterns using CD4 cell counts and viral rebound trajectories. Geo-spatial modelling techniques
can also be used to determine the spatial patterns of ART drop-out at the health facility and
district levels and identify hot spots for ART drop-out to guide policy.
Study objectives
The main focus of this study was to answer the following questions crucial in HIV disease
progression and monitoring: 1) what are the LTFU patterns after ART decentralization?; 2) what
are the immune-deterioration patterns among ART patients?; 3) what are the underlying factors
associated with poor viral suppression rates?; 4) what are the viral suppression among ART
patients?; 5) which regions are heavily affected by poor ART outcomes (drop-outs, viral rebound
or immune–deterioration) in Zimbabwe?; 6) and which statistical tools can be most appropriate
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to answer these epidemiological questions using routinely collected individual-level data and
partially observed aggregated data?
The specific objectives of this study were:
1. To demonstrate the use of Kolmogorov’s forward equations in estimating transition
probabilities if data is partially observed using Bayesian estimation approach as an
application in the multistate models' review.
2. To describe the spatio-temporal patterns of ART drop-out at the health facility and
district levels and identify cold spots and hot spots for ART drop-out
3. To determine the time to occurrence of LTFU with mortality as a competing event over
13 years follow-up period across health facility levels and other associated factors
4. To describe the HIV disease progression, and immune recovery patterns based on CD4
cell counts among adult patients on ART in Zimbabwe accounting for decentralization of
ART services to all levels of care
5. To determine spatial heterogeneity of viral suppression and viral rebound trajectories
among patient on ART in Zimbabwe adjusting for individual frailty, non-linear and
spatial effects using Bayesian estimation
6. To jointly model viral load (VL) and CD4 cell counts prognostic markers in a multistate
model framework and identify the shared geographical patterns of low CD4 cell counts
and viral rebound patterns
Methods
This study was a secondary data analysis of routinely collected individual-level data of HIV infected patients who initiated ART between 2004 and 2017. The data was compiled through the
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electronic patient management system (ePMS) under the Zimbabwe national ART programme.
The final study sample had 390,771 participants from 538 health facilities aged 15 years and
above. The study endpoints were mortality if a patient was reported to have died, loss to LTFU
defined as a failure of a patient to report for drug refill for at least 90 days from last appointment
date or if the patient missed the next scheduled visit date and never showed up again; withdrawal
and drop-outs. CD4 cell counts and VL prognostic markers were used to define the finite states
of the HIV disease progression models. Semi-parametric time-homogeneous Multistate Markov
model was used in the CD4 cell counts model: State 1(CD4≥500cells/uL), State
2(350cells/uL≤CD4<500cells/uL), State 3(200cells/uL≤CD4 <350cells/uL), State
4(CD4<200cells/uL) and the absorbing state death (State 5). The geoadditive Bayesian
regression multistate model was fitted in the VL model. The geoadditive Bayesian regression
multistate model accounted for the nonlinear effects of continuous variables, fixed effects and
spatial variation. In this model, we assumed that individuals from state 1 (VL<50copies/uL) with
an undetectable viral load may die (state 3) via state 2 (VL≥50copies/uL) which indicates a viral
load rebound or detectable viral load, or directly from state 1 (VL<50copies/uL). Again
individuals may move back to state 1(VL<50copies/uL) once they are in state 2
(VL≥50copies/uL) after ART which shows a reversible transition. Time-varying log-baseline
effects of the transition intensities and nonlinear effects of continuous covariates were estimated
as smoothed functions of time using penalized splines (P-splines). Non-parametric effects of
fixed covariates and frailty effects to account for individual variability were also considered.
Lastly, adjusted transition intensities, hazard ratios (HR) and regression coefficients were
estimated from the joint modelling of CD4 cell counts and VL. Joint mapping of HIV disease
progression conditions was done using the Bayesian intrinsic Multivariate Conditional
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Autoregressive (MCAR) prior model. The Kolmogorov-Chapman forward equations were also
used to estimate transition rates on a partially observed aggregated data.
Results:
From a total of 390,771 participants enrolled in 538 health care facilities, the proportions of
mortality, becoming LTFU and attrition were 4.7% (n=18,328), 22.7% (n=88,744) and 31.2%
(n=121,875), respectively. LTFU rate was 5.75(95% confidence interval (CI): 5.71-5.78) per 100
person-years. Those who had CD4 cell counts below 200cells/uL had a mortality rate of 5.7 per
100 person-years (4,541 deaths). Adjustment for the competing event independently increased
LTFU rate ratio in provincial and referral (adjusted sub-hazard ratios (AsHR) 1.24; 95%CI: 1.20-
1.28) and district and mission (AsHR 1.47; 95%CI: 1.45-1.45) hospitals; higher-level health
facilities were associated with an increased risk of ART drop-out (RR=1.46; 95%CI: 1.43-1.48
(secondary level facilities) and RR=1.41; 95%CI: 1.43-1.45 (tertiary level facilities); higher
levels of care had an increased risk of high rate ratios of LTFU and mortality while primary
health care (PHC) facilities had an increased risk of poor immune recovery.
Adolescence and young adults (15-24 years) group had an increase rate ratio of becoming LTFU.
The effects of patients' age on mortality increased with age while the effects of age on LTFU
increased with age for the 15-20 years age group and decreased after that; patients aged 20-60
years had a high risk of attrition, and patients aged 45+ years were more likely to immune
deteriorate. Male patients had a higher risk of becoming LTFU; 32% increased risk of death; and
a higher risk of immune deterioration. The longer the individuals were on ART, the less likely
they were to drop-out (district level: RR=0.7552; 95%CI: 0.69-0.83); health facility level:
RR=0.8194; 95%CI: 0.81-0.83).
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There existed a strong shared geographical pattern of 66% spatial correlation between the
relative risks of VL rebound and low CD4 cell counts from the joint mapping model. High
relative risks of VL
50copies/uL and CD4 cell counts
350cells/uL after ART initiation was
observed in Matabeleland North and Mashonaland East provinces. The geoadditive Bayesian
model showed that mortality rates decreased with increase in the time since ART initiation and
viral rebound transition was significantly prevalent among patients living on the long-distance
truck route region (Matabeleland North province) which borders with Botswana and Zambia.
The southern and northern parts of Zimbabwe show a high risk of ART drop-out based on the
structured effects.
Conclusions:
ART drop-outs or "leakages" within the ART treatment cascade persist after the decentralization
of ART services. Interventions which immediately link HIV patients to care and strengthen
patients’ retention are a priority to achieve viral suppression among ART patients. Though ART
uptake has increased after ART decentralisation, poor immune recovery and viral suppression
are high in PHC; hence, there is need to upgrade PHC infrastructure and strengthen their VL
monitoring capacity for better outcomes. The observed poor immune recovery and viral rebound
among subpopulation groups confirm the low viral suppression estimates. The poor viral
suppression among males could be due to them being a blind spot in HIV response. Interventions
which reach out to men in their "male spaces" and target their risk masculinity norms are
encouraged to boost their HIV services uptake. The poor immune recovery among adolescents
requires the launching of the social deprivation programmes to break food insecurity pathways
and financial support, and the paediatric to adult transition programme to mitigate treatment
lapses. Moreover, targeted interventions to highly burdened regions to improve patients'
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retention coupled with strategies which will enhance ART adherence are core in the global HIV
control campaign.
The main strength of this study was the statistical rigour which involves extending the Bayesian
multistate model with the spatial covariate accounting for individual frailty terms and joint
modelling of VL and CD4 cell counts. HIV decision-making programmes, model inferences
based on BE perspective are the preferred as they provide coherent estimates despite model
fitting challenges associated with Bayes models. However, future studies should consider
assessing the time-varying effects of covariates; determine underlying latent covariates
associated with ART outcomes, but the issues on the generalizability of research finding remain
a priority to epidemiologists. Strategies which strengthen data quality of routinely collected
programme data are a priority in this era of evidence-based decision making, for valid and
precise findings.
Description
A thesis submitted in fulfilment of the requirements for the degree of
Doctor of Philosophy to the Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Johannesburg, 2020