Measuring additive interaction using odds ratios

Interaction measured on the additive scale has been argued to be better correlated with biologic interaction than when measured on the multiplicative scale. Measures of interaction on the additive scale have been developed using risk ratios. However, in studies that use odds ratios as the sole measure of effect, the calculation of these measures of additive interaction is usually performed by directly substituting odds ratios for risk ratios. Yet assessing additive interaction based on replacing risk ratios by odds ratios in formulas that were derived using the former may be erroneous. In this paper, we evaluate the extent to which three measures of additive interaction – the interaction contrast ratio (ICR), the attributable proportion due to interaction (AP), and the synergy index (S), estimated using odds ratios versus using risk ratios differ as the incidence of the outcome of interest increases in the source population and/or as the magnitude of interaction increases. Our analysis shows that the difference between the two depends on the measure of interaction used, the type of interaction present, and the baseline incidence of the outcome. Substituting odds ratios for risk ratios, when calculating measures of additive interaction, may result in misleading conclusions. Of the three measures, AP appears to be the most robust to this direct substitution. Formulas that use stratum specific odds and odds ratios to accurately calculate measures of additive interaction are presented

Should home-based HIV testing and counseling services be offered periodically in programs of ARV treatment as prevention? A case study in Likoma (Malawi).

To reduce HIV incidence, prevention programs centered on the use of antiretrovirals require scaling-up HIV testing and counseling (HTC). Home-based HTC services (HBHTC) increase HTC coverage, but HBHTC has only been evaluated during one-off campaigns. Two years after an initial HBHTC campaign ("round 1"), we conducted another HBHTC campaign ("round 2") in Likoma (Malawi). HBHTC participation increased during round 2 among women (from 74 to 83%, P < 0.01). New HBHTC clients were recruited, especially at ages 25 and older. Only 6.9% of women but 15.9% of men remained unreached by HBHTC after round 2. HIV prevalence during round 2 was low among clients who were HIV-negative during round 1 (0.7%), but high among women who received their first ever HIV test during round 2 (42.8%). The costs per newly diagnosed infection increased significantly during round 2. Periodically conducting HBHTC campaigns can further increase HTC, but supplementary interventions to enroll individuals not reached by HBHTC are needed

Malaria in pregnancy and drug therapies in Malawi

In this dissertation, I investigated the effect of timing and frequency of Plasmodium falciparum infection during pregnancy on the risk of low birth weight and maternal anemia. I also investigated the efficacy of sulfadoxine-pyrimethamine combined with azithromycin or artesunate compared with sulfadoxine-pyrimethamine monotherapy as treatment for uncomplicated Plasmodium falciparum infection in pregnant women. We conducted a prospective observational study recruiting 2,462 pregnant women in Malawi. Malaria was assessed during follow-up and delivery. Birth weight and hemoglobin concentration were measured at delivery. The prevalence of low birth weight increased with the number of malaria episodes: [1 episode (prevalence ratio [PR] =2.17; 95% C.I. 1.22-3.86), and 2 episodes (PR=3.68; 95% C.I. 1.81-7.47)]. The prevalence of anemia increased with the number of episodes of malaria: [1 episode (PR= 1.16; 95% C.I. 0.77-1.77) and 2 episodes (PR= 1.82 95% C.I. 1.04-3.19)]. The prevalence of low birth weight was higher with infection in the second trimester (PR=2.97; 95% CI 1.60-5.53) than in the third trimester (PR=1.42; 95% CI 0.63-3.22). The prevalence of maternal anemia was higher with infection in the third trimester (PR=1.44; 95% CI 0.90-2.29) than in the second trimester (PR=0.94; 95% CI 0.51-1.71). Timing and frequency of infection affect the risk of maternal anemia and low birth weight. We conducted a randomized open-label clinical trial, recruiting 141 pregnant women. They were randomly allocated to 3 treatment groups: sulfadoxine-pyrimethamine (SP; 3 tablets, 500mg sulfadoxine and 25mg pyrimethamine per tablet); SP plus azithromycin (1g/day x 2 days); or SP plus artesunate (400mg/day x 3 days). All treatment regimens were well tolerated. Two women vomited soon after ingesting azithromycin. Recrudescent episodes of malaria were less frequent with SP-azithromycin [Hazard Ratio 0.14 (95% confidence interval 0.02 to 0.78)] and SP-artesunate [Hazard Ratio 0.13 (95% confidence interval 0.03 to 0.53)] compared with SP monotherapy. There were more abortions in the SP-azithromycin group, and more stillbirths in the SP-artesunate groups, but they were probably unrelated to treatment. A larger study is needed to determine its safety and efficacy in preventing poor birth outcomes

Efficacy and clinical effectiveness of influenza vaccines in HIV-infected individuals: a meta-analysis

Abstract Background Though influenza vaccines are the cornerstone of medical interventions aimed at protecting individuals against epidemic influenza, their effectiveness in HIV infected individuals is not certain. With the recent detection of influenza strains in countries with high HIV prevalence rates, we aimed at evaluating the current evidence on the efficacy and clinical effectiveness of influenza vaccines in HIV-infected individuals. Methods We used electronic databases to identify studies assessing efficacy or effectiveness of influenza vaccines in HIV patients. We included studies that compared the incidence of culture- or serologically-confirmed influenza or clinical influenza-like illness in vaccinated to unvaccinated HIV infected individuals. Characteristics of study participants were independently abstracted and the risk difference (RD), the number needed to vaccinate to prevent one case of influenza (NNV) and the vaccine effectiveness (VE) computed. Results We identified six studies that assessed the incidence of influenza in vaccinated HIV-infected subjects. Four of these studies compared the incidence in vaccinated versus unvaccinated subjects. These involved a total of 646 HIV-infected subjects. In all the 4 studies, the incidence of influenza was lower in the vaccinated compared to unvaccinated subjects with RD ranging from -0.48 (95% CI: -0.63, -0.34) to -0.15 (95% CI: -0.25, 0.05); between 3 and 7 people would need to be vaccinated to prevent one case of influenza. Vaccine effectiveness ranged from 27% to 78%. A random effects model was used to obtain a summary RD of -0.27 (95%CI: -0.42, -0.11). There was no evidence of publication bias. Conclusion Current evidence, though limited, suggests that influenza vaccines are moderately effective in reducing the incidence of influenza in HIV-infected individuals. With the threat of a global influenza pandemic, there is an urgent need to evaluate the effectiveness of influenza vaccines in trials with a larger number of representative HIV-infected persons

Prevalence and Risk Factors for Trachoma in Central and Southern Malawi

BACKGROUND: Trachoma, one of the neglected tropical diseases is suspected to be endemic in Malawi. OBJECTIVES: To determine the prevalence of trachoma and associated risk factors in central and southern Malawi. METHODOLOGY/PRINCIPAL FINDINGS: A population based survey conducted in randomly selected clusters in Chikwawa district (population 438,895), southern Malawi and Mchinji district (population 456,558), central Malawi. Children aged 1-9 years and adults aged 15 and above were assessed for clinical signs of trachoma. In total, 1010 households in Chikwawa and 1016 households in Mchinji districts were enumerated within 108 clusters (54 clusters in each district). A total of 6,792 persons were examined for ocular signs of trachoma. The prevalence of trachomatous inflammation, follicular (TF) among children aged 1-9 years was 13.6% (CI 11.6-15.6) in Chikwawa and 21.7% (CI 19.5-23.9) in Mchinji districts respectively. The prevalence of trachoma trichiasis (TT) in women and men aged 15 years and above was 0.6% (CI 0.2-0.9) in Chikwawa and 0.3% (CI 0.04-0.6) in Mchinji respectively. The presence of a dirty face was significantly associated with trachoma follicular (TF) in both Chikwawa and Mchinji districts (P10%), and warrants the trachoma SAFE control strategy to be undertaken in Chikwawa and Mchinji districts

Provider and user acceptability of intermittent screening and treatment for the control of malaria in pregnancy in Malawi.

BACKGROUND: Malaria in pregnancy is a major cause of adverse maternal and fetal outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) is one of the control strategies promoted by WHO. In response to mounting resistance to SP, intermittent screening and treatment (ISTp) has been proposed as an alternative. The objective of this study was to explore the acceptability of ISTp for health workers and pregnant women. METHODS: Semi-structured interviews of ten health workers and five focus group discussions of 38 women enrolled in an ongoing trial comparing IPTp-SP and ISTp with dihydroartemisinin-piperaquine (DP) were conducted at two antenatal clinics in rural Malawi. All transcripts were coded and themes were identified using a content analysis approach. RESULTS: Amongst health workers, there were contrasting opinions on the preference of blood sampling methods, and the influence of method on reliability of diagnosis. The perceived greater effectiveness of DP compared to SP was appreciated, however concerns of user compliance with the full dose of DP in non-trial settings were raised. Despite the discomfort of repeated finger pricks, pregnant women were generally accepting of ISTp, particularly the chance for regular blood tests to check for infections and the perceived greater effectiveness with fewer side effects of DP compared to SP. CONCLUSION: In the trial context, pregnant women tended to prefer ISTp-DP over IPTp-SP. Health workers were also accepting of ISTp-DP as an alternative to IPTp-SP in light of increasing SP resistance. However, reliability of stock, adherence to malaria test results and user adherence to the full course of DP may present barriers to successful routine implementation. Effective communication with health workers and between health workers, pregnant women and their communities will be essential for the acceptability of focused antenatal care, including the best malaria control measures available

Potential impact of infant feeding recommendations on mortality and HIV-infection in children born to HIV-infected mothers in Africa: a simulation

Abstract Background Although breast-feeding accounts for 15–20% of mother-to-child transmission (MTCT) of HIV, it is not prohibited in some developing countries because of the higher mortality associated with not breast-feeding. We assessed the potential impact, on HIV infection and infant mortality, of a recommendation for shorter durations of exclusive breast-feeding (EBF) and poor compliance to these recommendations. Methods We developed a deterministic mathematical model using primarily parameters from published studies conducted in Uganda or Kenya and took into account non-compliance resulting in mixed-feeding practices. Outcomes included the number of children HIV-infected and/or dead (cumulative mortality) at 2 years following each of 6 scenarios of infant-feeding recommendations in children born to HIV-infected women: Exclusive replacement-feeding (ERF) with 100% compliance, EBF for 6 months with 100% compliance, EBF for 4 months with 100% compliance, ERF with 70% compliance, EBF for 6 months with 85% compliance, EBF for 4 months with 85% compliance Results In the base model, reducing the duration of EBF from 6 to 4 months reduced HIV infection by 11.8% while increasing mortality by 0.4%. Mixed-feeding in 15% of the infants increased HIV infection and mortality respectively by 2.1% and 0.5% when EBF for 6 months was recommended; and by 1.7% and 0.3% when EBF for 4 months was recommended. In sensitivity analysis, recommending EBF resulted in the least cumulative mortality when the a) mortality in replacement-fed infants was greater than 50 per 1000 person-years, b) rate of infection in exclusively breast-fed infants was less than 2 per 1000 breast-fed infants per week, c) rate of progression from HIV to AIDS was less than 15 per 1000 infected infants per week, or d) mortality due to HIV/AIDS was less than 200 per 1000 infants with HIV/AIDS per year. Conclusion Recommending shorter durations of breast-feeding in infants born to HIV-infected women in these settings may substantially reduce infant HIV infection but not mortality. When EBF for shorter durations is recommended, lower mortality could be achieved by a simultaneous reduction in the rate of progression from HIV to AIDS and or HIV/AIDS mortality, achievable by the use of HAART in infants

Buccal, intranasal or intravenous lorazepam for the treatment of acute convulsions in children in Malawi: An open randomized trial

IntroductionAcute convulsions in children are a common emergency worldwide. Benzodiazepines are the recommended first line treatment. Intravenous lorazepam is inexpensive, long acting and the first line drug in resource-rich settings. However, comparable efficacy by other routes of administration is unknown. We wished to compare the efficacy of lorazepam by the buccal, intranasal or intravenous route in the treatment of acute seizures in Malawian children.MethodsA prospective, open-label, randomised, non-inferiority trial was performed in children aged 2months to 14years presenting to the Queen Elizabeth Central Hospital in Blantyre, Malawi with acute seizures lasting longer than 5min. Children were randomly assigned to receive lorazepam, 0.1mg/kg, by the buccal, intranasal or intravenous route. The primary endpoint was seizure cessation within 10min of drug administration.ResultsThere were 761 seizures analysed, with 252 patients in the buccal, 245 in the intranasal and 264 in the intravenous groups. Intravenous lorazepam stopped seizures within 10min in 83%, intranasal lorazepam in 57% (RR 2.46, CI 1.82–3.34), and the buccal route in 46% (RR 3.14, CI 2.35–4.20; p=0.001) of children. There were no significant cardio-respiratory events and no difference in mortality or neurological deficits. The study was halted after an interim analysis showed that the primary endpoint had exceeded the protocol-stopping rule.ConclusionsIntravenous lorazepam effectively treats most childhood seizures in this setting. Intranasal and buccal routes are less effective but may be useful in pre-hospital care or when intravenous access cannot be obtained. Further studies comparing intranasal lorazepam to other benzodiazepines, or alternative doses by a non-intravenous route are warranted

The effect of timing and frequency of Plasmodium falciparum infection during pregnancy on the risk of low birth weight and maternal anemia

Plasmodium falciparum infection during pregnancy causes maternal anemia and low birth weight (LBW), but the effect of frequency and timing of infection on the severity of these adverse effects is unknown. We conducted a cohort study recruiting 2462 pregnant women in Malawi. Microscopy was used to diagnose malaria at enrollment, follow-up and delivery. Birth weight and maternal hemoglobin were measured at delivery. The association between timing and frequency of infection and LBW and maternal anemia was analyzed using a binomial regression model. Compared with uninfected women, (i) the risk of LBW increased with the number of malaria episodes [one episode: prevalence ratio (PR) 1.62 (95% CI 1.07–2.46); two episodes: PR 2.41 (95% CI 1.39–4.18)]; (ii) the risk for maternal anemia increased with the number of malaria episodes [one episode: PR 1.15 (95% CI 0.86–1.54); two episodes: PR 1.82 (95% CI 1.28–2.62)]; and (iii) the risk of LBW was higher with infection in the second (PR 1.71; 95% CI 1.06–2.74) than third trimester or at delivery (PR 1.55; 95% CI 0.88–2.75). The timing and frequency of P. falciparum infection during pregnancy affected the risk of LBW but only frequency of infection had an effect on the risk of maternal anemia. Identification of gestational periods when malaria causes most adverse outcomes will facilitate effective targeting of interventions

Real-world outcomes associated with poly(ADP-ribose) polymerase inhibitor monotherapy maintenance in patients with primary advanced ovarian cancer

OBJECTIVE: This study used real-world population data to assess the trends of first-line (1L) poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment uptake and outcomes in patients with primary advanced ovarian cancer (AOC). METHODS: Patients diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemotherapy were selected from a real-world database. Descriptive analyses were performed to evaluate patient demographics, clinicopathological characteristics, and 1L treatment patterns. Time to next treatment or death was used as a proxy for real-world progression-free survival (rwPFS). Kaplan-Meier methods and Cox models were used for statistical analyses. RESULTS: Of 705 patients who completed 1L chemotherapy, 166 received PARPi monotherapy and 539 underwent active surveillance (AS). Median follow-up was 10.9 months for PARPi monotherapy and 20.6 months for AS. PARPi monotherapy use increased from 6% in 2017 to 53% in 2021. Overall, patients receiving PARPi monotherapy had longer rwPFS than those who underwent AS (not reached vs 9.53 mo) respectively. rwPFS was also longer in patients who received PARPi monotherapy compared with AS in patients with BRCA- mutated disease (not reached vs 11.4 mo), BRCA- wild-type disease (13.5 vs 9.1 mo), homologous recombination-deficient tumors (not reached vs 10.2 mo), and homologous recombination-proficient or unknown status tumors (13.5 vs 9.3 mo). CONCLUSIONS: Our real-world analysis suggested that 47% of patients with primary AOC did not receive PARPi maintenance in the year 2021. PARPi use was associated with significantly improved outcomes compared with AS