Effect of the relationship between anaemia and systemic inflammation on the risk of incident tuberculosis and death in people with advanced HIV: a sub-analysis of the REMEMBER trial.

Background: Tuberculosis (TB) is an infectious morbidity that commonly occurs in people living with HIV (PWH) and increases the progression of HIV disease, as well as the risk of death. Simple markers of progression are much needed to identify those at highest risk for poor outcome. This study aimed to assess how baseline severity of anaemia and associated inflammatory profiles impact death and the incidence of TB in a cohort of PWH who received TB preventive therapy (TPT). Methods: This study is a secondary posthoc analysis of the AIDS Clinical Trials Group A5274 REMEMBER clinical trial (NCT0138008), an open-label randomised clinical trial of antiretroviral-naïve PWH with CD4 <50 cells/µL, performed from October 31, 2011 to June 9, 2014, from 18 outpatient research clinics in 10 low- and middle-income countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda) who initiated antiretroviral therapy and either isoniazid TPT or 4-drug empiric TB therapy. Plasma concentrations of several soluble inflammatory biomarkers were measured prior to the commencement of antiretroviral and anti-TB therapies, and participants were followed up for at least 48 weeks. Incident TB or death during this period were primary outcomes. We performed multidimensional analyses, logistic regression analyses, survival curves, and Bayesian network analyses to delineate associations between anaemia, laboratory parameters, and clinical outcomes. Findings: Of all 269 participants, 76.2% (n = 205) were anaemic, and 31.2% (n = 84) had severe anaemia. PWH with moderate/severe anaemia exhibited a pronounced systemic pro-inflammatory profile compared to those with mild or without anaemia, hallmarked by a substantial increase in IL-6 plasma concentrations. Moderate/severe anaemia was also associated with incident TB incidence (aOR: 3.59, 95% CI: 1.32-9.76, p = 0.012) and death (aOR: 3.63, 95% CI: 1.07-12.33, p = 0.039). Interpretation: Our findings suggest that PWH with moderate/severe anaemia display a distinct pro-inflammatory profile. The presence of moderate/severe anaemia pre-ART was independently associated with the development of TB and death. PWH with anaemia should be monitored closely to minimise the occurrence of unfavourable outcomes. Funding: National Institutes of Health.

Computer-Based Counseling Program (CARE+ Kenya) to Promote Prevention and HIV Health for People Living With HIV/AIDS: A Randomized Controlled Trial.

In countries experiencing the dual burden of HIV disease and health care worker shortages, information and communication technology tools offer the potential to help support HIV treatment adherence and secondary HIV transmission risk reduction for people living with HIV/AIDS. We conducted a randomized controlled trial (September 1, 2011-July 12, 2012) with follow-up through April 2013. Participants were recruited from two clinics affiliated with the Academic Model Providing Access to Healthcare program in western Kenya. A total of 236 participants were enrolled, randomly assigned to intervention (n = 118) or risk-assessment only control (n = 118) and followed up for 9 months. Both arms had > 0.5 log10 reduction in viral load over time (p = .0007), a clinically relevant finding. A computer-based counseling tool is feasible and acceptable in a high-volume East African HIV setting and provides evidence-based ART adherence and risk reduction support that may extend health workforce deficits.

Factors Associated with Late Engagement to HIV Care in Western Kenya: A Cross-Sectional Study.

BACKGROUND: Late presentation of patients contributes significantly to the high mortality reported in HIV -care and treatment programs in sub-Saharan Africa. METHODS: A cross-sectional study was conducted to assess factors associated with late engagement to HIV care at the Academic Model Providing Access to Healthcare in western Kenya. Late engagement was defined as baseline CD4 ≤100 cells/mm3. RESULTS: Of the 10 533 participants included in the analysis, 67% were female and mean age was 36.7 years. Overall, 23% of the participants presented late. Factors associated with late engagement included male gender (adjusted odds ratio [AOR]: 1.54, 95% confidence interval [CI]: 1.35-1.75), older age (AOR: 1.62, 95% CI: 1.02-2.56), and longer travel time to clinic (AOR: 1.18, 95% CI: 1.04-1.34). CONCLUSION: Nearly one-quarter of HIV-infected patients in our setting present with advanced immune suppression at initial encounter. Being male, older age, and living further away from clinic are associated with late engagement to care.

Accuracy and Acceptability of Oral Fluid HIV Self-Testing in a General Adult Population in Kenya.

We evaluated performance, accuracy, and acceptability parameters of unsupervised oral fluid (OF) HIV self-testing (HIVST) in a general population in western Kenya. In a prospective validation design, we enrolled 240 adults to perform rapid OF HIVST and compared results to staff administered OF and rapid fingerstick tests. All reactive, discrepant, and a proportion of negative results were confirmed with lab ELISA. Twenty participants were video-recorded conducting self-testing. All participants completed a staff administered survey before and after HIVST to assess attitudes towards OF HIVST acceptability. HIV prevalence was 14.6 %. Thirty-six of the 239 HIVSTs were invalid (15.1 %; 95 % CI 11.1-20.1 %), with males twice as likely to have invalid results as females. HIVST sensitivity was 89.7 % (95 % CI 73-98 %) and specificity was 98 % (95 % CI 89-99 %). Although sensitivity was somewhat lower than expected, there is clear interest in, and high acceptability (94 %) of OF HIV self-testing.

Health facility barriers to HIV linkage and retention in Western Kenya.

BACKGROUND: HIV linkage and retention rates in sub-Saharan Africa remain low. The objective of this study was to explore perceived health facility barriers to linkage and retention in an HIV care program in western Kenya. METHODS: This qualitative study was conducted July 2012-August 2013. A total of 150 participants including; 59 patients diagnosed with HIV, TB, or hypertension; 16 caregivers; 10 community leaders; and 65 healthcare workers, were purposively sampled from three Academic Model Providing Access to Healthcare (AMPATH) sites. We conducted 16 in-depth interviews and 17 focus group discussions (FGDs) in either, English, Swahili, Kalenjin, Teso, or Luo. All data were audio recorded, transcribed, translated to English, and a content analysis performed. Demographic data was only available for those who participated in the FGDs. RESULTS: The mean age of participants in the FGDs was 36 years (SD = 9.24). The majority (87%) were married, (62.7%) had secondary education level and above, and (77.6%) had a source of income. Salient barriers identified reflected on patients' satisfaction with HIV care. Barriers unique to linkage were reported as quality of post-test counseling and coordination between HIV testing and care. Those unique to retention were frequency of clinic appointments, different appointments for mother and child, lack of HIV care for institutionalized populations including students and prisoners, lack of food support, and inconsistent linkage data. Barriers common to both linkage and retention included access to health facilities, stigma associated with health facilities, service efficiency, poor provider-patient interactions, and lack of patient incentives. CONCLUSION: Our findings revealed that there were similarities and differences between perceived barriers to linkage and retention. The cited barriers reflected on the need for a more patient-centered approach to HIV care. Addressing health facility barriers may ultimately be more efficient and effective than addressing patient related barriers.

"I understood but some parts were confusing and hard to grasp": Patients' perception of informed consent forms and clinical trials in Eldoret, Kenya.

BACKGROUND: A signed informed consent (IC) form proves voluntary participation in a study. Yet the development of accessible and understandable IC forms comes with its own set of challenges, particularly when conducting international research. PURPOSE: This study explores understanding by participants in an Eldoret-based clinical trial of IC and its implications as well as whether they will volunteer for future trials. MATERIALS AND METHODS: In mid-2010, in-depth interviews with trial participants were recorded in audio format. Content analysis provides a description of trial participants' experiences and thoughts. RESULTS: All participants were informed about the trial and its voluntariness and they consented. However, some were too ill to scrutinize trial details. Thus, they relied on their health care provider's advice, or on their guardians. In general, participants understood their role and were happy to volunteer or invite others to participate in future trials. They also emphasised the importance of an open on-going dialogue in order for participants to be able to ask questions. CONCLUSION: Clinical trial participants in Eldoret seem to understand their role, but rely on providers and guardians when consenting. They are very willing to participate in future trials. Evaluation of research participants' opinions may improve trial protocols, increase comprehension and guard against manipulation of study participants. In addition, this research focus should guide development of consent forms and process that facilitates a truly IC.

"These are good problems to have ": establishing a collaborative research partnership in East Africa.

In the context of a long-term institutional 'twinning' partnership initiated by Indiana and Moi Universities more than 22 years ago, a vibrant program of research has arisen and grown in size and stature. The history of the AMPATH (Academic Model Providing Access to Healthcare) Research Program is described, with its distinctive attention to Kenyan-North American equity, mutual benefit, policies that support research best practices, peer review within research working groups/cores, contributions to clinical care, use of healthcare informatics, development of research infrastructure and commitment to research workforce capacity. In the development and management of research within our partnership, we describe a number of significant challenges we have encountered that require ongoing attention, many of which are "good problems" occasioned by the program's success and growth. Finally, we assess the special value a partnership program like ours has created and end by affirming the importance of organizational diversity, solidarity of purpose, and resilience in the 'research enterprise.'

Active tuberculosis is associated with worse clinical outcomes in HIV-infected African patients on antiretroviral therapy.

OBJECTIVE: This cohort study utilized data from a large HIV treatment program in western Kenya to describe the impact of active tuberculosis (TB) on clinical outcomes among African patients on antiretroviral therapy (ART). DESIGN: We included all patients initiating ART between March 2004 and November 2007. Clinical (signs and symptoms), radiological (chest radiographs) and laboratory (mycobacterial smears, culture and tissue histology) criteria were used to record the diagnosis of TB disease in the program's electronic medical record system. METHODS: We assessed the impact of TB disease on mortality, loss to follow-up (LTFU) and incident AIDS-defining events (ADEs) through Cox models and CD4 cell and weight response to ART by non-linear mixed models. RESULTS: We studied 21,242 patients initiating ART-5,186 (24%) with TB; 62% female; median age 37 years. There were proportionately more men in the active TB (46%) than in the non-TB (35%) group. Adjusting for baseline HIV-disease severity, TB patients were more likely to die (hazard ratio--HR = 1.32, 95% CI 1.18-1.47) or have incident ADEs (HR = 1.31, 95% CI: 1.19-1.45). They had lower median CD4 cell counts (77 versus 109), weight (52.5 versus 55.0 kg) and higher ADE risk at baseline (CD4-adjusted odds ratio = 1.55, 95% CI: 1.31-1.85). ART adherence was similarly good in both groups. Adjusting for gender and baseline CD4 cell count, TB patients experienced virtually identical rise in CD4 counts after ART initiation as those without. However, the overall CD4 count at one year was lower among patients with TB (251 versus 269 cells/µl). CONCLUSIONS: Clinically detected TB disease is associated with greater mortality and morbidity despite salutary response to ART. Data suggest that identifying HIV patients co-infected with TB earlier in the HIV-disease trajectory may not fully address TB-related morbidity and mortality.

Differences between self-reported and electronically monitored adherence among patients receiving antiretroviral therapy in a resource-limited setting.

BACKGROUND: Measurement of adherence to antiretroviral therapy (ART) by patient self-report is common in resource-limited settings but widely believed to overstate actual adherence. The extent to which these measures overstate adherence has not been examined among a large patient population. METHODS: HIV-infected adult patients in Kenya who initiated ART within the past 3 months were followed for 6 months. Adherence was measured by participants' self-reports of doses missed in the past 7 days during monthly clinic visits and by continuous Medication Event Monitoring System (MEMS) in participants' pill bottles. Seven-day self-reported adherence was compared to 7-day MEMS adherence, 30-day MEMS adherence, and adherence more than 90% during each of the first 6 months. RESULTS: Self-reported and MEMS adherence measures were linked for 669 participants. Mean 7-day self-reported adherence was 98.7% and mean 7-day MEMS adherence was 86.0%, a difference of 12.7% (P < 0.01). The difference between the two adherence measures increased over time due to a decline in 7-day MEMS adherence. However, patients with lower MEMS adherence were in fact more likely to self-report missed doses and the difference between self-reported and MEMS adherence was similar for each number of self-reported missed doses. When analysis was limited to patients who reported rarely or never removing multiple doses at the same time, mean difference was 10.5% (P < 0.01). CONCLUSION: There is a sizable and significant difference between self-reported and MEMS adherence. However, a strong relationship between the measures suggests that self-reported adherence is informative for clinical monitoring and program evaluation.

Human immunodeficiency virus and leprosy coinfection: challenges in resource-limited setups.

Mycobacteria leprae(leprosy) and HIV coinfection are rare in Kenya. This is likely related to the low prevalence (1 per 10,000 of population) of leprosy. Because leprosy is no longer a public health challenge there is generally a low index of suspicion amongst clinicians for its diagnosis. Management of a HIV-1-leprosy-coinfected individual in a resource-constrained setting is challenging. Some of these challenges include difficulties in establishing a diagnosis of leprosy; the high pill burden of cotreatment with both antileprosy and antiretroviral drugs (ARVs); medications' side effects; drug interactions; scarcity of drug choices for both diseases. This challenge is more profound when managing a patient who requires second-line antiretroviral therapy (ART). We present an adult male patient coinfected with HIV and leprosy, who failed first-line antiretroviral therapy (ART) and required second-line treatment. Due to limited choices in antileprosy drugs available, the patient received monthly rifampicin and daily lopinavir-/ritonavir-based antileprosy and ART regimens, respectively. Six months into his cotreatment, he seemed to have adequate virological control. This case report highlights the challenges of managing such a patient.

Approaches to Effectively Documenting Prior Single Dose Nevirapine Exposure among Women in Africa

Background: Single dose nevirapine (sdNVP) is widely used in resource-limited settings for the prevention of mother to child transmission of HIV; but can result in NVP resistance that negatively impacts the subsequent efficacy of maternal antiretroviral therapy (ART). It is important to determine prior sdNVP exposure status to help guide treatment decisions; but systematic data on approaches to documenting previous sdNVP ingestion are lacking. Aim: With the growing body of evidence of the effects of sdNVP exposure on subsequent choices of ART; we aim to highlight some of the practical challenges that exist in documenting prior sdNVP exposure or lack thereof. Materials and Methods: ACTG A5208 Optimized Combination Therapy after Nevirapine Exposure (OCTANE) is a randomized treatment trial of protease inhibitor vs. NVP-based ART that enrolled 745 HIV-infected women in 7 African countries. Documentation of previous exposure to sdNVP (or lack thereof) was collected prospectively and intensively; as were locally-available sources of such data. Results: All 243 women who were exposed to sdNVP recalled having taken sdNVP; written documentation of sdNVP exposure was found for 73 and an additional 20 identified having ingested a NVP tablet when the tablet was shown to them. Among 502 women not exposed to sdNVP; only 10 (2) had written documentation of lack of sdNVP exposure. NVP resistance was detected in 33 (13.8) of sdNVP-exposed and 1 of non-exposed women. Conclusion: Maternal self-report of prior sdNVP exposure was corroborated by supporting evidence in the majority of women participating in the trial

Impact of integrated family planning and HIV care services on contraceptive use and pregnancy outcomes: a retrospective cohort study.

OBJECTIVE: To determine the impact of routine care (RC) and integrated family planning (IFP) and HIV care service on family planning (FP) uptake and pregnancy outcomes. DESIGN: Retrospective cohort study conducted between October 10, 2005, and February 28, 2009. SETTING: United States Agency for International Development-Academic Model Providing Access To Healthcare (USAID-AMPATH) in western Kenya. SUBJECTS: Records of adult HIV-infected women. INTERVENTION: Integration of FP into one of the care teams. PRIMARY OUTCOMES MEASURES: Incidence of FP methods and pregnancy. RESULTS: Four thousand thirty-one women (1453 IFP; 2578 RC) were eligible. Among the IFP group, there was a 16.7% increase (P < 0.001) [95% confidence interval (CI): 13.2% to 20.2%] in incidence of condom use, 12.9% increase (P < 0.001) (95% CI: 9.4% to 16.4%) in incidence of FP use including condoms, 3.8% reduction (P < 0.001) (95% CI: 1.9% to 5.6%) in incidence of FP use excluding condoms, and 0.1% increase (P = 0.9) (95% CI: -1.9% to 2.1%) in incidence of pregnancies. The attributable risk of the incidence rate per 100 person-years of IFP and RC for new condom use was 16.4 (95% CI: 11.9 to 21.0), new FP use including condoms was 13.5 (95% CI: 8.7 to 18.3), new FP use excluding condoms was -3.0 (95% CI: -4.6 to -1.4) and new cases of pregnancies was 1.2 (95% CI: -0.6 to 3.0). CONCLUSIONS: Integrating FP services into HIV care significantly increased the use of modern FP methods but no impact on pregnancy incidence. HIV programs need to consider integrating FP into their program structure.

Influence of gender on loss to follow-up in a large HIV treatment programme in western Kenya.

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 and 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.

The structure and outcomes of a HIV postexposure prophylaxis program in a high HIV prevalence setup in western Kenya.

BACKGROUND: In 2001, HIV postexposure prophylaxis (PEP) was initiated in western Kenya. METHODS: Design, implementation, and evolution of the PEP program are described. Patient data were analyzed for reasons, time to initiation, and PEP outcome. RESULTS: Occupational PEP was initiated first followed by nonoccupational PEP (nPEP). Antiretroviral regimens were based upon national PEP guidelines, affordability and availability, and prevailing HIV prevalence. Emerging side effects data and cost improvements influenced regimen changes. Between November 2001 and December 2006, 446 patients sought PEP. Occupational exposure: 91 patients: 51 males; 72 accepted HIV testing; 48 of 52 source patients were HIV infected; median exposure-PEP time 3 hours (range: 0.3-96 hours). Of 72 HIV-negative patients receiving PEP, 3 discontinued, 69 completed, and 23 performed post-PEP HIV RNA polymerase chain reaction (all negative). Eleven follow-up HIV enzyme-linked immunosorbent assay tests have all turned negative. Nonoccupational exposure: 355 patients; 285 females; 90 children; 300 accepted HIV testing; median exposure-nPEP time 19 hours (range: 1-672 hours). Of 296 HIV-negative patients on nPEP, 1 died, 15 discontinued, 104 are on record having completed PEP, and 129 returned for 6-week HIV RNA polymerase chain reaction (1 patient tested positive). Eighty-seven follow-up HIV enzyme-linked immunosorbent assay tests have all turned negative. CONCLUSIONS: It is feasible to provide PEP and nPEP in resource-constrained settings.

The AMPATH medical record system: creating, implementing, and sustaining an electronic medical record system to support HIV/AIDS care in western Kenya.

Providing high-quality HIV/AIDS care requires high-quality, accessible data on individual patients and visits. These data can also drive strategic decision-making by health systems, national programs, and funding agencies. One major obstacle to HIV/AIDS care in developing countries is lack of electronic medical record systems (EMRs) to collect, manage, and report clinical data. In 2001, we implemented a simple primary care EMR at a rural health centre in western Kenya. This EMR evolved into a comprehensive, scalable system serving 19 urban and rural health centres. To date, the AMPATH Medical Record System contains 10 million observations from 400,000 visit records on 45,000 patients. Critical components include paper encounter forms for adults and children, technicians entering/managing data, and modules for patient registration, scheduling, encounters, clinical observations, setting user privileges, and a concept dictionary. Key outputs include patient summaries, care reminders, and reports for program management, operating ancillary services (e.g., tracing patients who fail to return for appointments), strategic planning (e.g., hiring health care providers and staff), reports to national AIDS programs and funding agencies, and research.

An electronic medical record system for ambulatory care of HIV-infected patients in Kenya.

Administering and monitoring therapy is crucial to the battle against HIV/AIDS in sub-Saharan Africa. Electronic medical records (EMRs) can aid in documenting care, monitoring drug adherence and response to therapy, and providing data for quality improvement and research. Faculty at Moi University in Kenya and Indiana and University in the USA opened adult and pediatric HIV clinics in a national referral hospital, a district hospital, and six rural health centers in western Kenya using a newly developed EMR to support comprehensive outpatient HIV/AIDS care. Demographic, clinical, and HIV risk data, diagnostic test results, and treatment information are recorded on paper encounter forms and hand-entered into a central database that prints summary flowsheets and reminders for appropriate testing and treatment. There are separate modules for monitoring the Antenatal Clinic and Pharmacy. The EMR was designed with input from clinicians who understand the local community and constraints of providing care in resource poor settings. To date, the EMR contains more than 30,000 visit records for more than 4000 patients, almost half taking antiretroviral drugs. We describe the development and structure of this EMR and plans for future development that include wireless connections, tablet computers, and migration to a Web-based platform.