Trends and Determinants of Antiretroviral Therapy Patient Monitoring Practices in Kenya and Uganda

Introduction

Patients receiving antiretroviral therapy (ART) require routine monitoring to track response to treatment and assess for treatment failure. This study aims to identify gaps in monitoring practices in Kenya and Uganda.

Methods

We conducted a systematic retrospective chart review of adults who initiated ART between 2007 and 2012. We assessed the availability of baseline measurements (CD4 count, weight, and WHO stage) and ongoing CD4 and weight monitoring according to national guidelines in place at the time. Mixed-effects logistic regression models were used to analyze facility and patient factors associated with meeting monitoring guidelines.

Results

From 2007 to 2012, at least 88% of patients per year in Uganda had a recorded weight at initiation, while in Kenya there was a notable increase from 69% to 90%. Patients with a documented baseline CD4 count increased from 69% to about 80% in both countries. In 2012, 83% and 86% of established patients received the recommended quarterly weight monitoring in Kenya and Uganda, respectively, while semiannual CD4 monitoring was less common (49% in Kenya and 38% in Uganda). Initiating at a more advanced WHO stage was associated with a lower odds of baseline CD4 testing. On-site CD4 analysis capacity was associated with increased odds of CD4 testing at baseline and in the future.

Discussion

Substantial gaps were noted in ongoing CD4 monitoring of patients on ART. Although guidelines have since changed, limited laboratory capacity is likely to remain a significant issue in monitoring patients on ART, with important implications for ensuring quality care.     

Text Messaging to Improve Attendance at Post-Operative Clinic Visits after Adult Male Circumcision for HIV Prevention: A Randomized Controlled Trial

Background

Following male circumcision for HIV prevention, a high proportion of men fail to return for their scheduled seven-day post-operative visit. We evaluated the effect of short message service (SMS) text messages on attendance at this important visit.

Methodology

We enrolled 1200 participants >18 years old in a two-arm, parallel, randomized controlled trial at 12 sites in Nyanza province, Kenya. Participants received daily SMS text messages for seven days (n = 600) or usual care (n = 600). The primary outcome was attendance at the scheduled seven-day post-operative visit. The primary analysis was by intention-to-treat.

Principal Findings

Of participants receiving SMS, 387/592 (65.4%) returned, compared to 356/596 (59.7%) in the control group (relative risk [RR] = 1.09, 95% confidence interval [CI] 1.00–1.20; p = 0.04). Men who paid more than US$1.25 to travel to clinic were at higher risk for failure to return compared to those who spent ≤US$1.25 (adjusted relative risk [aRR] 1.35, 95% CI 1.15–1.58; p<0.001). Men with secondary or higher education had a lower risk of failure to return compared to those with primary or less education (aRR 0.87, 95% CI 0.74–1.01; p = 0.07).

Conclusions

Text messaging resulted in a modest improvement in attendance at the 7-day post-operative clinic visit following adult male circumcision. Factors associated with failure to return were mainly structural, and included transportation costs and low educational level.

Trial Registration

ClinicalTrials.gov NCT01186575     

Overexpression of rice thaumatin-like protein (Ostlp) gene in transgenic cassava results in enhanced tolerance to Colletotrichum gloeosporioides f. sp. manihotis

Cassava (Manihot esculenta Crantz) is the most important staple food for more than 300?million people in Africa, and anthracnose disease caused by Colletotrichum gloeosporioides f. sp. manihotis is the most destructive fungal disease affecting cassava production in sub-Saharan Africa. The main objective of this study was to improve anthracnose resistance in cassava through genetic engineering. Transgenic cassava plants harbouring rice thaumatin-like protein (Ostlp) gene, driven by the constitutive CaMV35S promoter, were generated using Agrobacterium-mediated transformation of friable embryogenic calli (FEC) of cultivar TMS 60444. Molecular analysis confirmed the presence, integration, copy number of the transgene all the independent transgenic events. Semi-quantitative RT-PCR confirmed high expression levels of Ostlp in six transgenic lines tested. The antifungal activity of the transgene against Colletotrichum gloeosporioides pathogen was evaluated using the leaves and stem cuttings bioassay. The results demonstrated significantly delayed disease development and reduced size of necrotic lesions in leaves and stem cuttings of all transgenic lines compared to the leaves and stem cuttingss of non-transgenic control plants. Therefore, constitutive overexpression of rice thaumatin-like protein in transgenic cassava confers enhanced tolerance to the fungal pathogen C. gloeosporioides f. sp. manihotis. These results can therefore serve as an initial step towards genetic engineering of farmer-preffered cassava cultivars for resistance to anthracnose disease.     

Birds in the matrix: the role of agriculture in avian conservation in the Taita Hills,Kenya

Agricultural conversion of tropical forests is a major driver of biodiversity loss. Slowing rates of deforestation is a conservation priority, but it is also useful to consider how species diversity is retained across the agricultural matrix. Here, we assess how bird diversity varies in relation to land use in the Taita Hills, Kenya. We used point counts to survey birds along a land‐use gradient that included primary forest, secondary vegetation, agroforest, timber plantation and cropland. We found that the agricultural matrix supports an abundant and diverse bird community with high levels of species turnover, but that forest specialists are confined predominantly to primary forest, with the matrix dominated by forest visitors. Ordination analyses showed that representation of forest specialists decreases with distance from primary forest. With the exception of forest generalists, bird abundance and diversity are lowest in timber plantations. Contrary to expectation, we found feeding guilds at similar abundances in all land‐use types. We conclude that whilst the agricultural matrix, and agroforest in particular, makes a strong contribution to observed bird diversity at the landscape scale, intact primary forest is essential for maintaining this diversity, especially amongst species of conservation concern.     

Risk Factors for Inadequate TB Case Finding in Rural Western Kenya: A Comparison of Actively and Passively Identified TB Patients

Background

The findings of a prevalence survey conducted in western Kenya, in a population with 14.9% HIV prevalence suggested inadequate case finding. We found a high burden of infectious and largely undiagnosed pulmonary tuberculosis (PTB), that a quarter of the prevalent cases had not yet sought care, and a low case detection rate.

Objective and methods

We aimed to identify factors associated with inadequate case finding among adults with PTB in this population by comparing characteristics of 194 PTB patients diagnosed in a health facility after self-report, i.e., through passive case detection, with 88 patients identified through active case detection during the prevalence survey. We examined associations between method of case detection and patient characteristics, including HIV-status, socio-demographic variables and disease severity in univariable and multivariable logistic regression analyses.

Findings

HIV-infection was associated with faster passive case detection in univariable analysis (crude OR 3.5, 95% confidence interval (CI) 2.0–5.9), but in multivariable logistic regression this was largely explained by the presence of cough, illness and clinically diagnosed smear-negative TB (adjusted OR (aOR) HIV 1.8, 95% CI 0.85–3.7). Among the HIV-uninfected passive case detection was less successful in older patients aOR 0.76, 95%CI 0.60–0.97 per 10 years increase), and women (aOR 0.27, 95%CI 0.10–0.73). Reported current or past alcohol use reduced passive case detection in both groups (0.42, 95% CI 0.23–0.79). Among smear-positive patients median durations of cough were 4.0 and 6.9 months in HIV-infected and uninfected patients, respectively.

Conclusion

HIV-uninfected patients with infectious TB who were older, female, relatively less ill, or had a cough of a shorter duration were less likely found through passive case detection. In addition to intensified case finding in HIV-infected persons, increasing the suspicion of TB among HIV-uninfected women and the elderly are needed to improve TB case detection in Kenya.     

Developing Content for a mHealth Intervention to Promote Postpartum Retention in Prevention of Mother-To-Child HIV Transmission Programs and Early Infant Diagnosis of HIV: A Qualitative Study

Background

Maternal attendance at postnatal clinic visits and timely diagnosis of infant HIV infection are important steps for prevention of mother-to-child transmission (PMTCT) of HIV. We aimed to use theory-informed methods to develop text messages targeted at facilitating these steps.

Methods

We conducted five focus group discussions with health workers and women attending antenatal, postnatal, and PMTCT clinics to explore aspects of women''s engagement in postnatal HIV care and infant testing. Discussion topics were informed by constructs of the Health Belief Model (HBM) and prior empirical research. Qualitative data were coded and analyzed according to the construct of the HBM to which they related. Themes were extracted and used to draft intervention messages. We carried out two stages of further messaging development: messages were presented in a follow-up focus group in order to develop optimal phrasing in local languages. We then further refined the messages, pretested them in individual cognitive interviews with selected health workers, and finalized the messages for the intervention.

Results

Findings indicated that brief, personalized, caring, polite, encouraging, and educational text messages would facilitate women bringing their children to clinic after delivery, suggesting that text messages may serve as an important “cue to action.” Participants emphasized that messages should not mention HIV due to fear of HIV testing and disclosure. Participants also noted that text messages could capitalize on women''s motivation to attend clinic for childhood immunizations.

Conclusions

Applying a multi-stage content development approach to crafting text messages – informed by behavioral theory – resulted in message content that was consistent across different focus groups. This approach could help answer “why” and “how” text messaging may be a useful tool to support maternal and child health. We are evaluating the effect of these messages on improving postpartum PMTCT retention and infant HIV testing in a randomized trial.     

Efficient and robust approaches for analysis of sequential multiple assignment randomized trials: Illustration using the ADAPT-R trial

Personalized intervention strategies, in particular those that modify treatment based on a participant's own response, are a core component of precision medicine approaches. Sequential multiple assignment randomized trials (SMARTs) are growing in popularity and are specifically designed to facilitate the evaluation of sequential adaptive strategies, in particular those embedded within the SMART. Advances in efficient estimation approaches that are able to incorporate machine learning while retaining valid inference can allow for more precise estimates of the effectiveness of these embedded regimes. However, to the best of our knowledge, such approaches have not yet been applied as the primary analysis in SMART trials. In this paper, we present a robust and efficient approach using targeted maximum likelihood estimation (TMLE) for estimating and contrasting expected outcomes under the dynamic regimes embedded in a SMART, together with generating simultaneous confidence intervals for the resulting estimates. We contrast this method with two alternatives (G-computation and inverse probability weighting estimators). The precision gains and robust inference achievable through the use of TMLE to evaluate the effects of embedded regimes are illustrated using both outcome-blind simulations and a real-data analysis from the Adaptive Strategies for Preventing and Treating Lapses of Retention in Human Immunodeficiency Virus (HIV) Care (ADAPT-R) trial (NCT02338739), a SMART with a primary aim of identifying strategies to improve retention in HIV care among people living with HIV in sub-Saharan Africa.     

Social justice now for an equitable tomorrow: Reflections from the Consortium of Universities for Global Health Conference 2022

PLOS Medicine editors Beryne Odeny and Callam Davidson report from the Consortium of Universities for Global Health conference.

“Healthy People, Healthy Planet & Social Justice,” was the theme of the second virtual Consortium of Universities for Global Health (CUGH) 2022 conference, held from March 28 to April 1, 2022. In the face of escalating global health and security challenges, this bold theme and the associated agenda (https://cugh.confex.com/cugh/2022/meetingapp.cgi) were welcomed with great anticipation by thousands of stakeholders from 135 countries across the globe. As adeptly put by Dr. Peter A Singer, Special Advisor to the Director General of WHO, the fundamental question at the heart of social justice is simple: “Do we value every human life equally?”. In answering this question, we must acknowledge that what we now consider to be the discipline of global health is in fact anchored by deep and tortuous colonialist roots that continue to bear the fruits of injustice to this day. Over the course of the conference, speakers conceptualized a human rights framework for rethinking global health. This perspective piece presents a curated synopsis of the main CUGH conference and preceding satellite sessions.The conference commenced with a call from Thuli N. Madonsela, Former Public Protector of South Africa, to uphold the sacrosanct respect for human life given the interconnectedness of humanity’s existence on our shared planet. Her insights on social justice as interpreted within the framework of Ubuntu philosophy brought a breath of fresh air to the debate on neo-colonialism. Thuli’s keynote concluded with an optimistic outlook: “Investing in justice today is like throwing a javelin into the future, one that will become the guardrail for sustainable development.”Globalization has brought tremendous advances in industry, commerce and trade, and eye-watering financial gains for some in both high income countries (HICs) and low- and middle-income countries (LMICs). Alongside these gains, global openness has contributed to the swift spread of the most formidable maladies of the present day, not least of which are the dual epidemics of COVID-19 and non-communicable diseases (NCDs), climate change and global warming, global corruption, conflict and wars, and ensuing humanitarian crises [1,2]. Pervasive health inequities which compound the toll of these calamities are a stark reminder of how global health has failed the most vulnerable. The COVID-19 pandemic continues to be the litmus test against which our truest values are tested. “If we can’t handle COVID-19, what does it mean about our approach to tackling climate change?”–this was a germane question from a speaker reflecting on inequitable vaccine distribution [3,4].Comparable to other health sectors awash with global funding, the global COVID-19 vaccine delivery effort has created fertile ground for corruption, due to a toxic combination of high commodity demand, unprecedented resource allocation, and perennially weak health systems with fragmented supply chains [5,6]. It has been shown that corruption can fuel vaccine hesitancy by creating suspicion and mistrust in science and government. This has been witnessed in some countries in Asia, despite commendable levels of vaccine coverage. In contrast, the long-standing National Immunization Program in Brazil created a culture of vaccination and helped minimize hesitancy (despite the influence of the country’s present leadership) [7]. Other factors beyond vaccine-specific factors include contextual, individual, and group influences that can inform hesitancy; these additional factors can be exploited to undergird vaccine efforts–barbers delivering vaccines, and outreach efforts by Buddhist monks, for example.Beyond the COVID-19 pandemic is the rise of Commercial Determinants of Health (CDoH). CDoH refer to approaches used by corporate sectors to promote products that are detrimental to health [8]. These products include processed foods and drinks, alcohol, and tobacco–factors that are fueling the rising burden of NCDs–more so in LMICs and among the socially disadvantaged in HICs, who bear the largest brunt of related mortality [9]. Unrestrained access to and use of harmful products such as heavy metals and asbestos, pose a threat to poor and vulnerable communities in proximity to mines and industries. These injustices are propagated by powerful corporates that stealthily evade restrictive public health policies to protect their profit margins [10]. A downstream impact of the surge of NCDs in LMICs, is the intense suffering among those dying from terminal illnesses due to the unethical lack of access to palliative care. There is a dearth of palliative resources, including trained health providers, particularly in low resource contexts such as fragile and conflict settings, and among ethnically diverse groups in HICs [11].The COVID-19 and NCDs conundrums are accompanied by another global health woe–namely the paternalist nature of HIC support for LMICs. Paternalistic support presents in the form of tied aid and technical support which have been used to determine the seat of power, with regard to who holds the money, who generates knowledge, who practices, who publishes, and, ultimately, who thrives in the global health ecosystem. This is demonstrated by institutionalized power asymmetries across funding, academic research, and global health priority setting, which disproportionately favor researchers from HICs at the expense of those from LMICs. To date, less priority has been accorded to health issues of concern, beyond infectious diseases, in the poorest parts of the world such as cancer among other NCDs. Conditionality and increased vertical funding have been shown to limit LMICs’ autonomy to finance their primary health challenges and are linked to reduced government health expenditure with commensurate increases in out-of-pocket/ household expenditure. The health sector is known to be highly corrupt as well as it is well-resourced (accounting of 10% of overall GDP spending) [12]. The lethal mixture of politics, power, and corruption in LMICs is a brewing pot for injustice as it perpetuates a vicious cycle of poverty and disease among the most vulnerable.Tackling corruption at international and national levels requires multisectoral attention to wider issues of global security, giving people a voice and providing the backing of legal frameworks, to demand accountability and transparency without fear of retaliation. Empowering global health stakeholders and civil societies to engage corporate and political sectors in planetary and global health discourse is an essential tool for fostering health equity, environmental justice, and social justice in business paradigms [2,8]. In this way, leaders can be enlightened and held accountable for performance of equity-based indicators e.g., proportion of specific global goods going to LMICs. Within the global health fraternity, decolonizing global health through inclusive partnerships is necessary to remove longstanding hierarchies in decisional spaces, and shift the balance of power so that more indigenous community actors can define their problems and find relevant solutions [13]. Inspirational stories of the national COVID-19 taskforce in Uganda demonstrate how active communities can promote vaccine uptake [14]. Scaling up community-led integrated health care efforts can extend beyond the pandemic and may even accelerate realization of the UN Sustainable Development Goals. Sustainable funding streams, training, and capacity development to create a robust workforce and enabling environments to host research in LMICs should be at the center of the global health agenda. Other considerations would include leveraging integrated digital and information systems that foster inclusion of marginalized populations in program planning and service delivery, and in so doing uphold equity and inclusion in health system strengthening globally.Decolonizing global health and upholding social justice will be crucial to containing the impending NCD tsunami, pandemics beyond COVID-19, and climate change. However, throwing off the pernicious colonial legacy presents one of the biggest challenges in global health. No one is exempt from the experience of neo-colonialism regardless of location; thus, all hands are needed on deck to disrupt and resist its existence. Dr. Madhukar Pai of McGill University in Montreal, Canada, and colleagues emphasized that allyship is invaluable to this end–it seeks to identify what the most privileged can do to elevate the voices of those suffocating under the weight of injustice [15]. Beyond speaking up against inequities, meaningful allyship needs disruptive change, sometimes as far as ceding positions of power. The global health community is at a crossroads, a defining moment since its existence, and needs to decide which way to proceed–whether to remain passive to entrenched notions of polarization or to embrace a disruptive paradigm shift that defends social justice and secures sustainable development for all. The question remains–are we ready to shift?     

Cancer Special Issue: Early detection and minimal residual disease

Beryne Odeny discusses PLOS Medicine’s Special Issue on early cancer detection and minimal residual disease.

PLOS Medicine’s editorial team, together with guest editors, Chris Abbosh, Sarah-Jane Dawson and Charles Swanton, are delighted to disseminate several high-quality translational research and clinical studies on advances in early cancer detection. In 2020 alone, there were upward of 19 million new cancer cases and 10 million cancer deaths, worldwide [1]. Cancer kills more people than HIV/AIDS, tuberculosis and malaria combined and should be a top health priority, regardless of region or country [2]. Early detection of cancer and identification of minimal residual disease (MRD), post-treatment, are key to timely treatment and cure. This issue features robust studies that bring cutting edge, and potentially scalable, innovations that have the potential to inform research, policy, and clinical cancer management.Three studies in this issue center on innovations for detection of MRD. Yaqi Wang and colleagues found that combining circulating tumor DNA (ctDNA) and Magnetic Resonance Imaging (MRI) improved prediction of response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC) before surgery [3]. This combined model also improved stratification of patients at high risk of recurrence, and clearly has important clinical implications for management of LARC as it could potentially inform guidelines on patient selection for non-operative management and targeted treatment strategies for those with highly recurrent diseases. Jeanne Tie and colleagues confirmed the prognostic utility of post-surgery and post-chemotherapy ctDNA in determining the risk of relapse among patients with colorectal cancer with liver metastases (CRCLM) [4]. They demonstrated the function of serial ctDNA measurement as an early marker of treatment of efficacy. This is a noteworthy advance that requires further study around optimized integration of ctDNA analyses in adjuvant chemotherapy for resectable CRCLM. Pradeep S. Chauhan and colleagues applied next-generation sequencing (NGS) for urine tumor DNA (utDNA) detection to assess MRD in patients with muscle-invasive bladder cancer who received neoadjuvant chemotherapy [5]. They found that MRD detection prior to radical cystectomy correlated with pathologic response and may be used to identify candidates for bladder sparing treatment. Urine tumor DNA also offers the ability to determine tumor mutational burden and can therefore facilitate personalized immunotherapy.Two studies in this issue focused on early cancer detection. Jeffrey J. Szymanski and colleagues investigated the use of plasma cell-free DNA (cfDNA) ultra-low-pass whole genome sequencing (ULP-WSG) to distinguish the malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion–plexiform neurofibroma–in patients with Neurofibromatosis type1(NF1) [6]. This provides a strong evidence base for use of plasma cfDNA in liquid biopsy to distinguish early between benign and malignant tumors of this hereditary cancer. This is proof of concept that cfDNA can be leveraged as a biomarker for monitoring treatment response in patients with MPNST. Brian D Nicholson and colleagues demonstrated that risk scores based on combinations of risk factors and routine blood tests can be used to stratify patients with unexpected weight loss based on their risk of cancer [7]. They found that these combined risk scores showed superior clinical utility–compared to the symptoms-only model–to discriminate between patients with and without cancer. In this, they clearly demonstrate innovation in the use of routine clinical tools at scale. This type of model could potentially be scaled-up in under-resourced settings.With growing global interest in cancer diagnostics and treatment, these robust assays and tools are a welcome addition to the early cancer detection armamentarium, prior to and post-treatment. Further innovation around low-cost technologies and tools for early detection that can be rapidly tested and scaled up will further galvanize, the universal commitment to defeat cancer in both high and low resource settings.     

Uptake of WHO Recommendations for First-Line Antiretroviral Therapy in Kenya,Uganda, and Zambia

Introduction

Antiretroviral therapy (ART) guidelines were significantly changed by the World Health Organization in 2010. It is largely unknown to what extent these guidelines were adopted into clinical practice.

Methods

This was a retrospective observational analysis of first-line ART regimens in a sample of health facilities providing ART in Kenya, Uganda, and Zambia between 2007-2008 and 2011-2012. Data were analyzed for changes in regimen over time and assessed for key patient- and facility-level determinants of tenofovir (TDF) utilization in Kenya and Uganda using a mixed effects model.

Results

Data were obtained from 29,507 patients from 146 facilities. The overall percentage of patients initiated on TDF-based therapy increased between 2007-2008 and 2011-2012 from 3% to 37% in Kenya, 2% to 34% in Uganda, and 64% to 87% in Zambia. A simultaneous decrease in stavudine (d4T) utilization was also noted, but its use was not eliminated, and there remained significant variation in facility prescribing patterns. For patients initiating ART in 2011-2012, we found increased odds of TDF use with more advanced disease at initiation in both Kenya (odds ratio [OR]: 2.78; 95% confidence interval [CI]: 1.73-4.48) and Uganda (OR: 2.15; 95% CI: 1.46-3.17). Having a CD4 test performed at initiation was also a significant predictor in Uganda (OR: 1.43; 95% CI: 1.16-1.76). No facility-level determinants of TDF utilization were seen in Kenya, but private facilities (OR: 2.86; 95% CI: 1.45-5.66) and those employing a doctor (OR: 2.86; 95% CI: 1.48-5.51) were more likely to initiate patients on TDF in Uganda.

Discussion

d4T-based ART has largely been phased out over the study period. However, significant in-country and cross-country variation exists. Among the most recently initiated patients, those with more advanced disease at initiation were most likely to start TDF-based treatment. No facility-level determinants were consistent across countries to explain the observed facility-level variation.