Mobile Technology for Community Health in Ghana: Is Maternal Messaging and Provider Use of Technology Cost-Effective in Improving Maternal and Child Health Outcomes at Scale?

BACKGROUND: Mobile technologies are emerging as tools to enhance health service delivery systems and empower clients to improve maternal, newborn, and child health. Limited evidence exists on the value for money of mobile health (mHealth) programs in low- and middle-income countries. OBJECTIVE: This study aims to forecast the incremental cost-effectiveness of the Mobile Technology for Community Health (MOTECH) initiative at scale across 170 districts in Ghana. METHODS: MOTECH's "Client Data Application" allows frontline health workers to digitize service delivery information and track the care of patients. MOTECH's other main component, the "Mobile Midwife," sends automated educational voice messages to mobile phones of pregnant and postpartum women. We measured program costs and consequences of scaling up MOTECH over a 10-year analytic time horizon. Economic costs were estimated from informant interviews and financial records. Health effects were modeled using the Lives Saved Tool with data from an independent evaluation of changes in key services coverage observed in Gomoa West District. Incremental cost-effectiveness ratios were presented overall and for each year of implementation. Uncertainty analyses assessed the robustness of results to changes in key parameters. RESULTS: MOTECH was scaled in clusters over a 3-year period to reach 78.7% (170/216) of Ghana's districts. Sustaining the program would cost US $17,618 on average annually per district. Over 10 years, MOTECH could potentially save an estimated 59,906 lives at a total cost of US $32 million. The incremental cost per disability-adjusted life year averted ranged from US $174 in the first year to US $6.54 in the tenth year of implementation and US $20.94 (95% CI US $20.34-$21.55) over 10 years. Uncertainty analyses suggested that the incremental cost-effectiveness ratio was most sensitive to changes in health effects, followed by personnel time. Probabilistic sensitivity analyses suggested that MOTECH had a 100% probability of being cost-effective above a willingness-to-pay threshold of US $50. CONCLUSIONS: This is the first study to estimate the value for money of the supply- and demand-side of an mHealth initiative. The adoption of MOTECH to improve MNCH service delivery and uptake represents good value for money in Ghana and should be considered for expansion. Integration with other mHealth solutions, including e-Tracker, may provide opportunities to continue or combine beneficial components of MOTECH to achieve a greater impact on health.

Mobile Technology for Community Health in Ghana: what happens when technical functionality threatens the effectiveness of digital health programs?

BACKGROUND: Despite the growing use of technology in the health sector, little evidence is available on the technological performance of mobile health programs nor on the willingness of target users to utilize these technologies as intended (behavioral performance). In this case study of the Mobile Technology for Health (MOTECH) program in Ghana, we assess the platform's effectiveness in delivering messages, along with user response across sites in five districts from 2011 to 2014. METHODS: MOTECH is comprised of "Client Data Application" (CDA) which allows providers to digitize and track service delivery information for women and infants and "Mobile Midwife" (MM) which sends automated educational voice messages to the mobile phones of pregnant and postpartum women. Using a naturalist study design, we draw upon system generated data to evaluate message delivery, client engagement, and provider responsiveness to MOTECH over time and by level of facility. RESULTS: A total of 7,370 women were enrolled in MM during pregnancy and 14,867 women were enrolled postpa1rtum. While providers were able to register and upload patient-level health information using CDA, the majority of these uploads occurred in Community-based facilities versus Health Centers. For MM, 25% or less of expected messages were received by pregnant women, despite the majority (>77%) owning a private mobile phone. While over 80% of messages received by pregnant women were listened to, postpartum rates of listening declined over time. Only 25% of pregnant women received and listened to at least 1 first trimester message. By 6-12 months postpartum, less than 6% of enrolled women were exposed to at least one message. CONCLUSIONS: Caution should be exercised in assuming that digital health programs perform as intended. Evaluations should measure the technological, behavioral, health systems, and/or community factors which may lead to breaks in the impact pathway and influence findings on effectiveness. The MOTECH platform's technological limitations in 'pushing' out voice messages highlights the need for more timely use of data to mitigate delivery challenges and improve exposure to health information. Alternative message delivery channels (USSD or SMS) could improve the platform's ability to deliver messages but may not be appropriate for illiterate users. TRIAL REGISTRATION: Not applicable.

Induction therapy with protease-inhibitors modifies the effect of nevirapine resistance on virologic response to nevirapine-based HAART in children.

BACKGROUND: Nevirapine resistance after failed prophylaxis to prevent mother-to-child human immunodeficiency virus (HIV) transmission can compromise subsequent nevirapine-based highly active antiretroviral therapy (HAART). METHODS: Nevirapine-exposed children who achieved virologic suppression with lopinavir/ritonavir-based induction HAART before switch to nevirapine-based HAART or who continued the lopinavir/ritonavir regimen were studied. Nevirapine-resistant HIV was quantified (≥ 1% frequency) in plasma before therapy and archived in peripheral blood mononuclear cells after induction HAART with ultradeep pyrosequencing. The primary endpoint was virologic failure (confirmed viremia ≥ 1000 copies/mL by 52 weeks) on nevirapine-based HAART, and Receiver operating characteristic analysis identified threshold levels of resistance associated with failure. RESULTS: Nevirapine resistance mutations were detected in plasma at a median frequency of 25.6% in 41 (33%) of 124 children starting HAART at median 9 months of age. After a median nine months of induction HAART, nevirapine-resistant HIV remained archived in cells in 59 (61%) of 96 children (median 13.6% of cells). The threshold frequency of nevirapine resistance in plasma most predictive of virologic failure on nevirapine-based HAART was 25%. Children maintaining resistance before therapy at or above this threshold frequency had a 3.5 fold higher risk of failure (95% confidence interval, 1.1-10.8) than children without detectable plasma resistance. In contrast, virologic failure was not independently associated with age, resistance in plasma below 25% frequencies, or archived in cells. CONCLUSIONS: Virologic suppression with lopinavir/ritonavir-based HAART in nevirapine-exposed children raises the threshold level of resistance at which reuse of nevirapine-based therapy is compromised. Standard genotyping may allow identification of children likely to benefit from an induction-switch approach.

Qualitative Assessment of the Feasibility, Usability, and Acceptability of a Mobile Client Data App for Community-Based Maternal, Neonatal, and Child Care in Rural Ghana.

Mobile phone applications may enhance the delivery of critical health services and the accuracy of health service data. Yet, the opinions and experiences of frontline health workers on using mobile apps to track pregnant and recently delivered women are underreported. This evaluation qualitatively assessed the feasibility, usability, and acceptability of a mobile Client Data App for maternal, neonatal, and child client data management by community health nurses (CHNs) in rural Ghana. The mobile app enabled CHNs to enter, summarize, and query client data. It also sent visit reminders for clients and provided a mechanism to report level of care to district officers. Fourteen interviews and two focus groups with CHNs, midwives, and district health officers were conducted, coded, and thematically analyzed. Results indicated that the app was easily integrated into care, improved CHN productivity, and was acceptable due to its capacity to facilitate client follow-up, data reporting, and decision-making. However, the feasibility and usability of the app were hindered by high client volumes, staff shortages, and software and device challenges. Successful integration of mobile client data apps for frontline health workers in rural and resource-poor settings requires real-time monitoring, program investments, and targeted changes in human resources.

Quantitative real-time RT-PCR as a method for monitoring T lymphocyte reactivity to full-length tyrosinase protein in vaccinated melanoma patients.

The major goal of therapeutic cancer vaccine trials is to mediate tumor regression. However, it is critically important to devise in vitro immunological assays that correlate with clinical outcome, for use as surrogate markers of vaccine efficacy. To date, clinical emphasis has been placed on peptide vaccines, but trends towards the use of more complex immunogens such as whole proteins require the development of efficient and sensitive methods for monitoring their immunological effects. In the context of a vaccination trial using full-length tyrosinase (Ty) to immunize patients with metastatic melanoma, a monitoring technique was developed in which autologous dendritic cells (DC) infected with a recombinant adenovirus encoding the Ty protein were used to assess the Ty-specific reactivity of fresh peripheral blood lymphocytes (PBL) collected from patients at different intervals during therapy. Quantitative real-time RT-PCR (qRT-PCR) was used to measure the production of cytokine mRNA by T cells following a 2.5-h incubation with Ty-expressing DC. Two out of ten patients studied demonstrated Ty protein-specific reactivity that increased during and after the period of vaccination. While one of these patients also reacted to an HLA-A1-compatible Ty peptide, the second did not recognize any of the known Ty epitopes, highlighting the importance of this technique for monitoring the effects of complex vaccines.

Productive HIV infection of resting CD4+ T cells: role of lymphoid tissue microenvironment and effect of immunomodulating agents.

The ability of resting CD4+ T cells to support HIV replication is relevant to understanding how the reservoir of HIV-1-infected resting CD4+ T cells is generated, maintained and, hopefully, how it might be reduced or eliminated. We have utilized a tonsillar histoculture system to demonstrate that HIV, particularly X4 strains, can productively infect phenotypically resting CD4+ T cells in vitro and that this event is largely dependent on the lymphoid tissue microenvironment. Highly purified CD4+ tonsillar T cells that lack expression of both cell surface and nuclear antigens characteristic of classic T cell activation produce X4 HIV-1 mRNA, p24, and infectious virus while maintaining a resting phenotype when cultured in a tonsillar tissue microenvironment; in contrast, comparable purified resting CD4+ tonsillar T cells that have been exposed to X4 HIV do not support HIV replication when cultured in the absence of a lymphoid tissue microenvironment. HIV production from phenotypically resting CD4+ T cells is dramatically inhibited by anti-proinflammatory cytokine agents or immunosuppressive cytokines, but is only modestly suppressed by an inhibitor of the cell cycle. The ability of resting CD4+ T cells to support HIV replication in the microenvironment of the lymphoid tissue has implications in the pathogenesis of HIV disease and may provide an additional avenue for therapeutic intervention.

Concordance between allele-specific PCR and ultra-deep pyrosequencing for the detection of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations.

Recent advances in genotyping technologies have allowed for detection of HIV-1 drug resistance mutations present at low levels. The presence and percentage of Y181C and K103N drug-resistant variants in the blood of 105 subtype C HIV-infected infants who failed single-dose nevirapine prophylaxis for HIV transmission were compared using two highly sensitive genotyping methods, allele-specific PCR (AS-PCR) and ultra-deep pyrosequencing. Significant correlations in detection between both methods were found for both Y181C (correlation coefficients of 0.94 [95% CI 0.91-0.96]) and K103N (0.89 [95% CI 0.84-0.92]) mutations. The majority of discordant specimens (3/5 Y181C and 8/11 K103N) had wild-type variants when population sequencing was used, but mutant variants were detectable at very low levels (≤5%) with either assay. This difference is most likely due to stochastic variations in the appearance of mutant variants. Overall, both AS-PCR and ultra-deep pyrosequencing methods have proven to be sensitive and accurate, and may confidently be used where feasible.

Slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission.

Nevirapine resistance mutations arise commonly following single or extended-dose nevirapine (ED-NVP) prophylaxis to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV), but decay within 6-12 months of single-dose exposure. Use of ED-NVP prophylaxis in infants is expected to rise, but data on decay of nevirapine resistance mutations in infants in whom ED-NVP failed remain limited. We assessed, in Ethiopian infants participating in the Six-Week Extended Nevirapine (SWEN) Trial, the prevalence and persistence of nevirapine resistance mutations at 6 and 12 months following single-dose or up to 6 weeks of ED-NVP, and correlated their presence with the timing of infection and the type of resistance mutations. Standard population genotyping followed by high-throughput cloning were done on dried blood spot samples collected during the trial. More infants who received ED-NVP had nevirapine resistance detected by standard population genotyping (high frequencies) at age 6 months compared with those who received single-dose nevirapine (SD-NVP) (58% of 24 vs. 26% of 19, respectively; p = 0.06). Moreover, 56% of ED-NVP-exposed infants with nevirapine resistance at age 6 months still had nevirapine resistance mutations present at high frequencies at age 1 year. Infants infected before 6 weeks of age who received either SD- or ED-NVP were more likely to have Y181C or K103N; these mutations were also more likely to persist at high frequencies through 1 year of age. HIV-infected infants in whom ED-NVP prophylaxis fails are likely to experience delayed clearance of nevirapine-resistant virus in the first year of life, which in turn places them at risk for early selection of multidrug-resistant HIV after initial therapy with nonnucleoside reverse transcriptase inhibitor-based regimens.

Nevirapine resistance and breast-milk HIV transmission: effects of single and extended-dose nevirapine prophylaxis in subtype C HIV-infected infants.

BACKGROUND: Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the "six-week extended-dose nevirapine" (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life. METHODS/FINDINGS: Standard population sequencing and cloning for viral subpopulations present at > or =5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission. CONCLUSIONS/SIGNIFICANCE: Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00061321.

Tumor-specific CD8+ T lymphocytes derived from the peripheral blood of prostate cancer patients by in vitro stimulation with autologous tumor cell lines.

To identify tumor-associated antigens as putative targets for developing immunotherapies against prostate cancer, we investigated the ability of T cells derived from the peripheral blood lymphocytes of prostate cancer patients to recognize autologous tumor cells. The technical challenge of growing in vitro carcinoma cell lines from small prostate cancer samples was previously addressed by immortalization of early epithelial cell cultures with the HPV16 transforming proteins E6 and E7 and by genetic characterization of the carcinoma and normal prostate cell lines. In our study, peripheral blood lymphocytes were stimulated in vitro using autologous IFNgamma-treated prostate carcinoma cells transduced with the B7.1 molecule as a source of T-cell costimulation. Tumor-specific CD8+ T lymphocytes were obtained from 3 of 6 prostate cancer patients tested and included T cells restricted by classical and nonclassical HLA molecules. In 1 case, we demonstrated that the prostate cancer-reactive T cells were TCRalpha/beta+ and recognized autologous tumor cells but not autologous normal cells in the context of HLA-B or -C molecules. These results validate the approach of in vitro stimulation of peripheral blood lymphocytes from prostate cancer patients with autologous tumor cell lines to isolate prostate cancer-specific T cells and demonstrate the existence of a functionally diverse immune response against prostate cancer.