Influences of 23 different equations used to calculate gene copies of SARS-CoV-2 during wastewater-based epidemiology.

Following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, the use of wastewater-based surveillance (WBS) has increased dramatically along with associated infrastructure globally. However, due to the global nature of its application, and various workflow adaptations (e.g., sample collection, water concentration, RNA extraction kits), numerous methods for back-calculation of gene copies per volume (gc/L) of sewage have also emerged. Many studies have considered the comparability of processing methods (e.g., water concentration, RNA extraction); however, for equations used to calculate gene copies in a wastewater sample and subsequent influences on monitoring viral trends in a community and its association with epidemiological data, less is known. Due to limited information on how many formulas exist for the calculation of SARS-CoV-2 gene copies in wastewater, we initially attempted to quantify how many equations existed in the referred literature. We identified 23 unique equations, which were subsequently applied to an existing wastewater dataset. We observed a range of gene copies based on use of different equations, along with variability of AUC curve values, and results from correlation and regression analyses. Though a number of individual laboratories appear to have independently converged on a similar formula for back-calculation of viral load in wastewater, and share similar relationships with epidemiological data, differential influences of various equations were observed for variation in PCR volumes, RNA extraction volumes, or PCR assay parameters. Such observations highlight challenges when performing comparisons among WBS studies when numerous methodologies and back-calculation methods exist. To facilitate reproducibility among studies, the different gc/L equations were packaged as an R Shiny app, which provides end users the ability to investigate variability within their datasets and support comparisons among studies.

Predicting Global Fund grant disbursements for procurement of artemisinin-based combination therapies.

BACKGROUND: An accurate forecast of global demand is essential to stabilize the market for artemisinin-based combination therapy (ACT) and to ensure access to high-quality, life-saving medications at the lowest sustainable prices by avoiding underproduction and excessive overproduction, each of which can have negative consequences for the availability of affordable drugs. A robust forecast requires an understanding of the resources available to support procurement of these relatively expensive antimalarials, in particular from the Global Fund, at present the single largest source of ACT funding. METHODS: Predictive regression models estimating the timing and rate of disbursements from the Global Fund to recipient countries for each malaria grant were derived using a repeated split-sample procedure intended to avoid over-fitting. Predictions were compared against actual disbursements in a group of validation grants, and forecasts of ACT procurement extrapolated from disbursement predictions were evaluated against actual procurement in two sub-Saharan countries. RESULTS: Quarterly forecasts were correlated highly with actual smoothed disbursement rates (r = 0.987, p < 0.0001). Additionally, predicted ACT procurement, extrapolated from forecasted disbursements, was correlated strongly with actual ACT procurement supported by two grants from the Global Fund's first (r = 0.945, p < 0.0001) and fourth (r = 0.938, p < 0.0001) funding rounds. CONCLUSION: This analysis derived predictive regression models that successfully forecasted disbursement patterning for individual Global Fund malaria grants. These results indicate the utility of this approach for demand forecasting of ACT and, potentially, for other commodities procured using funding from the Global Fund. Further validation using data from other countries in different regions and environments will be necessary to confirm its generalizability.

Can modeling of HIV treatment processes improve outcomes? Capitalizing on an operations research approach to the global pandemic.

BACKGROUND: Mathematical modeling has been applied to a range of policy-level decisions on resource allocation for HIV care and treatment. We describe the application of classic operations research (OR) techniques to address logistical and resource management challenges in HIV treatment scale-up activities in resource-limited countries. METHODS: We review and categorize several of the major logistical and operational problems encountered over the last decade in the global scale-up of HIV care and antiretroviral treatment for people with AIDS. While there are unique features of HIV care and treatment that pose significant challenges to effective modeling and service improvement, we identify several analogous OR-based solutions that have been developed in the service, industrial, and health sectors. RESULTS: HIV treatment scale-up includes many processes that are amenable to mathematical and simulation modeling, including forecasting future demand for services; locating and sizing facilities for maximal efficiency; and determining optimal staffing levels at clinical centers. Optimization of clinical and logistical processes through modeling may improve outcomes, but successful OR-based interventions will require contextualization of response strategies, including appreciation of both existing health care systems and limitations in local health workforces. CONCLUSION: The modeling techniques developed in the engineering field of operations research have wide potential application to the variety of logistical problems encountered in HIV treatment scale-up in resource-limited settings. Increasing the number of cross-disciplinary collaborations between engineering and public health will help speed the appropriate development and application of these tools.

Forecast of demand for antiretroviral drugs in low and middle-income countries: 2007-2008.

BACKGROUND: Middle and low-income countries have scaled up HIV treatment in the past 5 years. To maintain this effort, information regarding the amounts and types of drugs is needed. Shortages or overstock of active pharmaceutical ingredients make the scale-up efforts more difficult and costly. To inform global planning and implementation, we estimate the volume of current and future demand for active pharmaceutical ingredients for first and second-line antiretroviral drugs. METHODS: Using regression analysis and documented assumptions, we estimated the number of individuals receiving antiretroviral drugs to 2008. The volume of active pharmaceutical ingredients was calculated using two methods: a normative approach modelling implementation of country-specific guidelines, and an empirical model projecting current trends in drug use estimated by a survey of country HIV programmes. RESULTS: The number of patients treated was estimated to reach 3.38 million by the end of 2008, of which 94.6% would be on first-line and 5.4% on second-line treatment. The largest estimated absolute demand volumes for 2008 were for nevirapine, lamivudine, and zidovudine using either approach; the largest proportional increases in 2007-2008, were observed for emtricitabine, tenofovir, indinavir, and nelfinavir. The gap between normative and empirical estimates was greatest (most positive) for tenofovir, zidovudine, didanosine, and smallest (most negative) for saquinavir and nelfinavir. CONCLUSION: A comparison of the results from the normative and empirical demand quantities suggests that more tenofovir, zidovudine and didanosine would be required if national treatment guidelines were fully implemented, whereas the countries seem to be using more saquinavir and nelfinavir than would be required by their current guidelines.

Anemia is an independent predictor of mortality and immunologic progression of disease among women with HIV in Tanzania.

OBJECTIVES: To examine the association of anemia with mortality and disease progression among a cohort of women with HIV in Dar es Salaam, Tanzania. METHODS: Time to all-cause death, AIDS-related death, and a 50% decrease in CD4 cell count among 1078 HIV-positive pregnant women enrolled in a clinical trial of vitamin supplementation from 1995-2003. RESULTS: Adjusted models showed that anemia was associated with an increased risk of all-cause mortality (relative hazard [RH]: 2.06, 95% CI: 1.52 to 2.79 for moderate anemia and RH: 3.19, 95% CI: 2.23 to 4.56 for severe anemia) and AIDS-related mortality (RH: 2.21, 95% CI: 1.53 to 3.19 for moderate anemia and RH: 3.47, 95% CI: 2.25 to 5.33 for severe anemia), independent of CD4 cell count, World Health Organization clinical stage, age, pregnancy, vitamin supplementation, and body mass index. Anemia was also associated with a more rapid decline in CD4 counts, measured as time to a 50% drop in CD4 cell count from baseline. Erythrocyte characteristics suggestive of iron deficiency were also associated with all-cause and AIDS-related death and a 50% decline in CD4 cell count. CONCLUSIONS: Anemia is an independent predictor of mortality and disease progression in this cohort. Screening for anemia, coupled with prevention and treatment efforts, should be included in HIV care initiatives, particularly those that target women.

Wasting during pregnancy increases the risk of mother-to-child HIV-1 transmission.

OBJECTIVES: To examine whether wasting during pregnancy, as measured by weight loss and low weight gain, is associated with increased mother-to-child transmission (MTCT) of HIV-1. METHODS: This was a cohort study in Dar es Salaam, Tanzania, among 957 HIV-1-infected pregnant women. Weight was measured at the first prenatal visit and every month thereafter until delivery. Weight loss was defined as a weekly rate of weight gain 0 and /=167 g/wk, weight loss during pregnancy was related to higher risk of intrauterine MTCT (adjusted relative risk [RR] = 2.32, 95% CI = 1.23-4.36, P = 0.009), HIV positive at birth or fetal death (RR = 2.13, 95% CI = 1.40-3.24, P = 0.0004), and HIV positive at birth or early neonatal death (RR = 1.96, 95% CI = 1.26-3.07, P = 0.003). The rate of weight gain during the 3rd trimester was inversely related to the risk of intrapartum/early breast-feeding transmission (adjusted P value, test for trend = 0.05). CONCLUSIONS: Weight loss during pregnancy increases the risk of early MTCT. Identifying causes of wasting during pregnancy may provide clues for new strategies to prevent MTCT.

Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort.

OBJECTIVES: To describe the patterns and correlates of discontinuation of the initial highly active antiretroviral therapy (HAART) regimen in an urban, outpatient cohort of antiretroviral-naive patients. DESIGN: Retrospective cohort of 345 randomly selected antiretroviral-naive patients who initiated HAART on 6 selected regimens between January 1997 and May 2001 in New Orleans, LA. METHODS: An investigator reviewed medical records to collect information on concurrent medications, symptoms/diagnoses, staging indicators, and reasons for HAART discontinuation. Proportional hazards regression methods were used to identify predictors of discontinuation. RESULTS: After a median follow-up of 8.1 months, 61% of patients changed or discontinued their initial HAART regimen; 24% did so because of an adverse event. The events most commonly cited as the cause for discontinuation were nausea, vomiting, and diarrhea. A detectable viral load was associated with discontinuation at any time, while reporting nausea/vomiting or dizziness at the previous visit were associated with discontinuation during the first 3 months on HAART. Nausea/vomiting and not having AIDS at the time of HAART initiation were associated with discontinuation due to an adverse event at any time, while a high viral load, and dizziness or anorexia/weight loss at the previous visit were associated with discontinuation due to an adverse event in the first 3 months on HAART. CONCLUSIONS: Gastrointestinal adverse events of HAART are the most frequently cited reason for discontinuation of HAART. An effort should be made to educate patients about these events and to encourage continued adherence. Additionally, appropriate prophylaxes for these events are warranted.

Prevalence and correlates of HIV serostatus disclosure.

BACKGROUND AND OBJECTIVE: A study of HIV-positive individuals in New Orleans, Louisiana, found that the majority of patients disclosed to their main partners and family members, but less than one fourth disclosed to any casual sex partner. Older age and lower CD4 cell counts were associated with disclosure. GOAL: The goal was to describe patterns of HIV serostatus disclosure among a diverse sample of patients at an HIV outpatient clinic in New Orleans, Louisiana. STUDY DESIGN: A convenience sample of HIV-seropositive patients provided information about disclosure of seropositivity, demographics, date of HIV diagnosis, CD4 cell count, mode of HIV acquisition, and sexual activity since HIV diagnosis. RESULTS: The 269 persons disclosed their HIV status to people in the following categories: main sex partner (74.2%), casual sex partner (24.8%), immediate family member (69.8%), other relative (27.0%), or friend (26.4%). Adolescents were less likely than adults to disclose to a main partner, immediate family member, or a friend. Immunosuppressed persons were more likely than nonimmunosuppressed persons to disclose to a main partner, immediate family member, or another relative. CONCLUSION: Many HIV-infected individuals delay disclosure until their disease has progressed. Interventions such as partner notification and skill-building to facilitate appropriate HIV disclosure are needed.

Older partners not associated with recurrence among female teenagers infected with Chlamydia trachomatis.

BACKGROUND: Chlamydia trachomatis-infected female teenagers with older partners may be less likely to discuss the infection with their partner(s) and to use condoms and therefore may be more likely to get reinfected. GOAL: To determine if C trachomatis-infected female teenagers with older partners were more likely to be reinfected than those with same-aged partners. STUDY DESIGN: Females aged 14 years to 18 years who had uncomplicated chlamydial infection, were nonpregnant, attended clinics in five United States cities from June 1995 to May 1997, completed treatment, and resumed sexual activity were observed at 1 and 4 months for interim history and retesting. RESULTS: Of 225 women studied, 73.3% were black, 34.5% had at least one partner who was 3 or more years older during follow-up, 51.6% reported using a condom at the last sex act with all partners, 13.8% had a recurrent infection, and 47.4% reported they were certain that all of their baseline partners were treated. Partner age was not associated with condom use, certainty of partners' taking medication, or recurrent infections after adjustment for visit. CONCLUSIONS: Older partners, accounting for approximately one third of all partners, did not increase the risk of reinfection. Given the high risk for recurrence, follow-up testing and enhanced efforts to ensure partner treatment are appropriate for all young women with chlamydial infections.