Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody.

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

Characterization of treatment resistance and viral kinetics in the setting of single- versus dual-active monoclonal antibodies against SARS-CoV-2.

BACKGROUND: Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for SARS-CoV-2 infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs. METHODS: Participants were non-hospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant. RESULTS: Study participants receiving single- and dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared to single-active mAb, treatment with dual-active mAbs led to faster viral load decline at study day 3 (p < 0.001) and day 7 (p < 0.01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than placebo (2.6% vs 0%, P < 0.001), and more frequently detected in the setting of single-active compared to dual-active mAb treatment (7.2% vs 1.1%, p < 0.01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death. CONCLUSION: Compared to single-active mAb therapy, dual-active mAbs led to similar clinical outcomes, but significantly faster viral load decline and a lower risk of emergent resistance.

Adverse Pregnancy Outcomes Among Women with Human Immunodeficiency Virus Taking Isoniazid Preventive Therapy During the First Trimester.

BACKGROUND: Isoniazid preventive therapy (IPT) is recommended for tuberculosis prevention yet data on the safety of first-trimester pregnancy exposure are limited. METHODS: Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight <2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count, and antiretroviral therapy (ART). RESULTS: In total, 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (adjusted relative risk [aRR] 1.98; 95% confidence interval [CI] 1.15, 3.41), but the effect was attenuated when adjusted for covariates at pregnancy outcome (aRR 1.47; 95% CI .84, 2.55); IPT was not associated with preterm delivery (relative risk [RR] 0.87; 95% CI .32-2.42) or low birth weight (RR 1.01; 95% CI .29, 3.56). CONCLUSIONS: First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome including ART use. Further study is needed to inform TB prevention guidelines.

Effectiveness of double-dose dolutegravir in people receiving rifampin-based tuberculosis treatment: an observational, cohort study of people with HIV from six countries.

BACKGROUND: Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50 mg dose of dolutegravir (TLD + 50) is required with rifampin-containing tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD + 50 in individuals with TB/HIV. METHODS: Prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. Primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment. FINDINGS: We enrolled 91 participants with TB/HIV: 75 (82%) ART-naïve participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naïve participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz/lamivudine/tenofovir. Median age was 37 years, 35% female, median CD4 count 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. Primary virologic outcome was assessed in 73 participants, of whom 69 (95%, 95% CI 89-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among four participants with HIV-1 RNA >1000 copies/mL. INTERPRETATION: In routine programmatic settings, concurrent rifampin-containing TB treatment and TLD + 50 was feasible, well-tolerated, and achieved high rates of viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.

Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection.

BACKGROUND: Although symptom and viral rebound have been reported after nirmatrelvir-ritonavir treatment, the trajectories of symptoms and viral load during the natural course of COVID-19 have not been well described. OBJECTIVE: To characterize symptom and viral rebound in untreated outpatients with mild to moderate COVID-19. DESIGN: Retrospective analysis of participants in a randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04518410). SETTING: Multicenter trial. PATIENTS: 563 participants receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) platform trial. MEASUREMENTS: Participants recorded the severity of 13 symptoms daily between days 0 and 28. Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28. Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log10 copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL to a viral load of 5.0 log10 copies/mL or higher. RESULTS: Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. Most symptom and viral rebound events were transient, because 89% of symptom rebound and 95% of viral rebound events occurred at only a single time point before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants. LIMITATION: A largely unvaccinated population infected with pre-Omicron variants was evaluated. CONCLUSION: Symptom or viral relapse in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Safety and Efficacy of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies Amubarvimab Plus Romlusevimab in Nonhospitalized Patients With COVID-19.

BACKGROUND: Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life. OBJECTIVE: To assess the safety and efficacy of amubarvimab plus romlusevimab. DESIGN: Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410). SETTING: Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines. PATIENTS: Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression. INTERVENTION: Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo. MEASUREMENTS: Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death. RESULTS: Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P < 0.001), with no severe infusion reactions or drug-related serious adverse events. LIMITATION: The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants. CONCLUSION: Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

ACTIV-2: A Platform Trial for the Evaluation of Novel Therapeutics for the Treatment of Early COVID-19 in Outpatients.

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410.

Pooling Different Placebos as a Control Group in a Randomized Platform Trial: Benefits and Challenges From Experience in the ACTIV-2 COVID-19 Trial.

Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled phase 2/3 ACTIV-2 trial, which studied 7 investigational agents with diverse routes of administration. For each agent, safety and efficacy outcomes were compared to a pooled placebo control group, which included participants who received a placebo for that agent or for other agents in concurrent evaluation. A 2-step randomization framework was implemented to facilitate this. Over the study duration, the pooled placebo design achieved a reduction in sample size of 6% versus a trial involving distinct placebo control groups for evaluating each agent. However, a 26% reduction was achieved during the period when multiple agents were in parallel phase 2 evaluation. We discuss some of the complexities implementing the pooled placebo design versus a design involving nonoverlapping control groups, with the aim of informing the design of future platform trials. Clinical Trials Registration. NCT04518410.

Validity and Characterization of Time to Symptom Resolution Outcome Measures in the ACTIV-2/A5401 Outpatient COVID-19 Treatment Trial.

BACKGROUND: Time to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation. METHODS: ACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre-COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo. RESULTS: The analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences. CONCLUSIONS: There was good internal consistency between TSR and COVID-19-specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms. CLINICAL TRIALS REGISTRATION: NCT04518410.

Phase 2 Safety and Antiviral Activity of SAB-185, a Novel Polyclonal Antibody Therapy for Nonhospitalized Adults With COVID-19.

BACKGROUND: SAB-185, a novel fully human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for nonhospitalized adults with mild-moderate coronavirus disease 2019 (COVID-19). METHODS: Participants received intravenous SAB-185 3840 units/kg (low-dose) or placebo, or 10 240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA < lower limit of quantification (LLOQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28. RESULTS: Two-hundred thirteen participants received low-dose SAB-185/placebo (n = 107/106) and 215 high-dose SAB-185/placebo (n = 110/105). The proportions with SARS-CoV-2 RNA < LLOQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB-185 versus placebo only, relative risk 1.23 (95% confidence interval, 1.01-1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo: differences in medians of -0.78 log10 copies/mL (P = .08) and -0.71 log10 copies/mL (P = .10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (P = .24) for low-dose SAB-185/placebo and 8/10 days (P = .50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo. CONCLUSIONS: SAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk nonhospitalized adults with COVID-19. Clinical Trials Registration. NCT04518410.

Association Between Anterior Nasal and Plasma SARS-CoV-2 RNA Levels and Hospitalization or Death in Nonhospitalized Adults With Mild-to-Moderate COVID-19.

BACKGROUND: There is little information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA as a predictor for clinical outcomes in outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19). METHODS: Anterior nasal (AN) and plasma SARS-CoV-2 RNA data from 2115 nonhospitalized adults who received monoclonal antibodies (mAbs) or placebo in the ACTIV-2/A5401 trial were analyzed for associations with hospitalization or death. RESULTS: One hundred two participants were hospitalized or died through 28 days of follow-up. Higher day 0 (pretreatment) AN RNA was associated with increasing risk of hospitalization/death (risk ratio [RR], 1.24 per log10 copies/mL [95% confidence interval {CI}, 1.04-1.49]) among placebo recipients, ranging from 3% to 16% for <2 to ≥6 log10 copies/mL. Although only 1% had quantifiable levels, there was a similar trend across day 0 plasma RNA categories. Higher day 3 AN RNA was associated with subsequent hospitalization/death among placebo recipients (RR, 1.42 per log10 copies/mL [95% CI, 1.00-2.03]), but not mAb recipients (RR, 1.02 per log10 copies/mL [95% CI, 0.68-1.56]). The proportion of treatment effect (reduction in hospitalizations/deaths after day 3 for mAb vs placebo) explained by day 3 AN RNA was 8%. CONCLUSIONS: SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting, but AN RNA levels may not be a reliable surrogate marker of mAb treatment effect in COVID-19 trials. Clinical Trials Registration. NCT04518410.

Variant-Specific Viral Kinetics in Acute COVID-19.

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post-peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410.

Immune Status and SARS-CoV-2 Viral Dynamics.

Immunocompromised individuals are disproportionately affected by severe coronavirus disease 2019, but immune compromise is heterogenous, and viral dynamics may vary by the degree of immunosuppression. In this study, we categorized ACTIV-2/A5401 participants based on the extent of immunocompromise into none, mild, moderate, and severe immunocompromise. Moderate/severe immunocompromise was associated with higher nasal viral load at enrollment (adjusted difference in means: 0.47 95% confidence interval, .12-.83 log10 copies/mL) and showed a trend toward higher cumulative nasal RNA levels and plasma viremia compared to nonimmunocompromised individuals. Immunosuppression leads to greater viral shedding and altered severe acute respiratory syndrome coronavirus 2 viral decay kinetics. Clinical Trials Registration. NCT04518410.

Long COVID After Bamlanivimab Treatment.

BACKGROUND: Prospective evaluations of long COVID in outpatients with coronavirus disease 2019 (COVID-19) are lacking. We aimed to determine the frequency and predictors of long COVID after treatment with the monoclonal antibody bamlanivimab in ACTIV-2/A5401. METHODS: Data were analyzed from participants who received bamlanivimab 700 mg in ACTIV-2 from October 2020 to February 2021. Long COVID was defined as the presence of self-assessed COVID symptoms at week 24. Self-assessed return to pre-COVID health was also examined. Associations were assessed by regression models. RESULTS: Among 506 participants, median age was 51 years. Half were female, 5% Black/African American, and 36% Hispanic/Latino. At 24 weeks, 18% reported long COVID and 15% had not returned to pre-COVID health. Smoking (adjusted risk ratio [aRR], 2.41 [95% confidence interval {CI}, 1.34- 4.32]), female sex (aRR, 1.91 [95% CI, 1.28-2.85]), non-Hispanic ethnicity (aRR, 1.92 [95% CI, 1.19-3.13]), and presence of symptoms 22-28 days posttreatment (aRR, 2.70 [95% CI, 1.63-4.46]) were associated with long COVID, but nasal severe acute respiratory syndrome coronavirus 2 RNA was not. CONCLUSIONS: Long COVID occurred despite early, effective monoclonal antibody therapy and was associated with smoking, female sex, and non-Hispanic ethnicity, but not viral burden. The strong association between symptoms 22-28 days after treatment and long COVID suggests that processes of long COVID start early and may need early intervention. CLINICAL TRIALS REGISTRATION: NCT04518410.

Statistical Challenges When Analyzing SARS-CoV-2 RNA Measurements Below the Assay Limit of Quantification in COVID-19 Clinical Trials.

Most clinical trials evaluating coronavirus disease 2019 (COVID-19) therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels from baseline were commonly assessed using analysis of covariance (ANCOVA) or mixed models for repeated measures (MMRM) with single imputation for results below assay lower limits of quantification (LLoQ). Analyzing changes in viral RNA levels with singly imputed values can lead to biased estimates of treatment effects. In this article, using an illustrative example from the ACTIV-2 trial, we highlight potential pitfalls of imputation when using ANCOVA or MMRM methods, and illustrate how these methods can be used when considering values

Nasal and Plasma Severe Acute Respiratory Syndrome Coronavirus 2 RNA Levels Are Associated With Timing of Symptom Resolution in the ACTIV-2 Trial of Nonhospitalized Adults With Coronavirus Disease 2019.

Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement. Clinical Trials Registration. https://clinicaltrials.gov/ct2/show/NCT04518410.

One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate Coronavirus Disease 2019: A Randomized Controlled Phase 2 Trial.

BACKGROUND: Camostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults. METHODS: We conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. RESULTS: Of 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (P = .99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA

1-Year Incidence of Tuberculosis Infection and Disease Among Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis.

BACKGROUND: Tuberculosis infection (TBI) and TB disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant TB exposure. We sought to characterize TBI and TBD incidence at 1 year in HHCs and to evaluate TB preventive treatment (TPT) use in high-risk groups. METHODS: We previously conducted a cross-sectional study of HHCs with rifampin-/multidrug-resistant TB in 8 high-burden countries and reassessed TBI (interferon-gamma release assay, HHCs aged ≥5 years) and TBD (HHCs all ages) at 1 year. Incidence was estimated across age and risk groups (<5 years; ≥5 years, diagnosed with human immunodeficiency virus [HIV]; ≥5 years, not diagnosed with HIV/unknown, baseline TBI-positive) by logistic or log-binomial regression fitted using generalized estimating equations. RESULTS: Of 1016 HHCs, 850 (83.7%) from 247 households were assessed (median, 51.4 weeks). Among 242 HHCs, 52 tested interferon-gamma release assay-positive, yielding a 1-year 21.6% (95% confidence interval [CI], 16.7-27.4) TBI cumulative incidence. Sixteen of 742 HHCs developed confirmed (n = 5), probable (n = 3), or possible (n = 8) TBD, yielding a 2.3% (95% CI, 1.4-3.8) 1-year cumulative incidence (1.1%; 95% CI, .5-2.2 for confirmed/probable TBD). TBD relative risk was 11.5-fold (95% CI, 1.7-78.7), 10.4-fold (95% CI, 2.4-45.6), and 2.9-fold (95% CI, .5-17.8) higher in age <5 years, diagnosed with HIV, and baseline TBI high-risk groups, respectively, vs the not high-risk group (P = .0015). By 1 year, 4% (21 of 553) of high-risk HHCs had received TPT. CONCLUSIONS: TBI and TBD incidence continued through 1 year in rifampin-/multidrug-resistant TB HHCs. Low TPT coverage emphasizes the need for evidence-based prevention and scale-up, particularly among high-risk groups.

Iron status among HIV-infected adults during the first year of antiretroviral therapy in Tanzania.

BACKGROUND: The influence of inflammation on iron status among people living with HIV (PLWHIV) has not been well explored. We evaluated the trajectory of iron status among PLWHIV during the first year of highly active antiretroviral therapy (HAART), compared alternative approaches for inflammation correction, and assessed the associations of iron status with HIV-1 viral load and anthropometric outcomes. METHODS: We conducted a secondary analysis of data from a randomized trial among 400 adults initiating HAART in Tanzania. Ferritin and C-reactive protein (CRP) were measured at baseline, 1, 6 or 12 months. Ferritin was considered in four ways: unadjusted, and adjusted for inflammation using higher cut-off (HC), Thurnham-corrected (TC) and regression-corrected (RC) approaches. For unadjusted, TC and RC ferritin, iron deficiency (ID) was defined using ferritin < 15 µg/L and elevated iron status was defined using ferritin > 150 µg/L among females and > 200 µg/L among males. For HC ferritin, elevated iron status was defined based on serum ferritin > 500 µg/L, while ID was defined using ferritin < 70 µg/L in the presence of inflammation and < 15 µg/L in the absence of inflammation. Regression models evaluated the trajectory of ferritin concentration across categories of baseline characteristics, and assessed the association of iron status with viral and anthropometric outcomes. RESULTS: The prevalence of iron deficiency at HAART initiation was 9% for unadjusted, 17% for HC, 12% for TC and 22% for RC ferritin. The prevalence of elevated iron status was 42% for unadjusted, 18% for HC, 31% for TC, and 15% for RC ferritin. The prevalence of iron deficiency for all three methods increased during the first year of HAART, while the prevalence of elevated iron status decreased. Baseline elevated iron status defined using HC ferritin was associated with a greater risk of HIV-1 viral load > 1000 copies/mL [relative risk (RR) = 4.29, 95% CI: 1.38-13.3] and incidence of being underweight [body mass index (BMI) < 18.5 kg/m2 , hazard ratio (HR) = 3.65, 95% confidence interval (CI): 1.38-9.67]. Neither baseline-elevated iron status defined using TC or RC ferritin nor baseline iron deficiency defined using any of the three methods was associated with HIV-1 viral load or anthropometric outcomes. CONCLUSIONS: Whether and how inflammation correction is done influences findings of studies of iron status among PLWHIV.

The effect of iron supplementation on maternal iron deficiency anemia does not differ by baseline anemia type among Tanzanian pregnant women without severe iron deficiency anemia.

PURPOSE: Whether anemia type modifies the risk of pregnancy and newborn outcomes and the effectiveness of iron supplementation is unclear. We examined the association of iron deficiency anemia (IDA) and non-iron deficiency anemia (NIDA) on the risks of these outcomes and the extent to which anemia type modifies the impact of prenatal iron supplementation. METHODS: This was a secondary analysis of a placebo-controlled trial of iron supplementation among 1450 HIV-negative women in Tanzania. Eligibility criteria included gestational age < 27 weeks, hemoglobin > 85 g/L, and ferritin > 12 µg/L. Individuals were categorized as non-anemia, IDA or NIDA using hemoglobin, ferritin and CRP. Analyses were conducted using regression models and likelihood ratio tests. RESULTS: Compared to the non-anemia group, delivery hemoglobin was lower by 15 g/L (95% CI 10.9, 19.3) in the baseline IDA group, and 7.3 g/L (95% CI 3.1, 11.5) in the baseline NIDA group. The RRs of anemia severity, iron deficiency, placental malaria, stillbirths, perinatal mortality, birthweight, and preterm birth were not different among women in the baseline NIDA group (vs. non-anemia) compared to the baseline IDA group (vs. non-anemia). The difference in the mean delivery hemoglobin for iron supplementation and placebo arms was 8 g/L (95% CI 6, 11) in the non-anemia group, 7 g/L (95% CI 2, 13) in the NIDA group, and 16 g/L (95% CI 10, 22) in the IDA group. CONCLUSION: Iron supplementation is effective even among pregnant women with NIDA. TRIAL REGISTRATION: NCT01119612 (May 7, 2010).