The Utility of ctDNA in Lung Cancer Clinical Research and Practice: A Systematic Review and Meta-Analysis of Clinical Studies.

This systematic review with embedded meta-analysis aimed to evaluate the clinical utility of circulating tumor DNA (ctDNA) in lung cancer. After screening and review of the Embase database search, 111 studies from 2015 to 2020 demonstrated ctDNA's value in prognostication/monitoring disease progression, mainly in patients with advanced/metastatic disease and non-small cell lung cancer. ctDNA positivity/detection at any time point was associated with shorter progression-free survival and overall survival, whereas ctDNA clearance/decrease during treatment was associated with a lower risk of progression and death. Validating these findings and addressing challenges regarding ctDNA testing integration into clinical practice will require further research.

Metastatic non-small-cell lung cancer without driver mutations: projections by therapy line in Western Europe, 2021-2026.

Aim: To estimate the incidence, prevalence and treated prevalence by line of therapy (LOT) for non-small-cell lung cancer (NSCLC) patients without driver mutations from 2021 to 2026. Materials & methods: Country-specific registry data for Western Europe were used to project incidence and prevalence of NSCLC; LOT information was obtained from CancerMPact® Treatment Architecture physician surveys. Results: Incidence, prevalence and treated prevalence across LOTs for NSCLC are projected to increase across five WE countries, including for stage IV patients without driver mutations (184,966 cases [2021] to 197,925 [2026]). Pembrolizumab monotherapy is utilized by ∼50% of NSCLC patients with programmed death-ligand 1 expression ≥50%. Conclusion: Improved treatment options for NSCLC patients without known driver mutations are important for combating the projected increase in prevalence.

Lung cancer is the leading cause of cancer-related death in Europe. This study estimated how the number of patients living with, and being treated for, lung cancer is projected to change between 2021 and 2026 in Western Europe by collecting past data on lung cancer in France, Germany, Italy, Spain and the UK, and analyzing the trends to create estimates for the future. The number of new cases of lung cancer is projected to increase each year from 2021 to 2026, and in line with this, the number of patients receiving treatment for their disease will increase. Improving treatment options for lung cancer will be an important step to combat the expected increase in cancer cases.

Identification of pregnancies and infants within a US commercial healthcare administrative claims database.

PURPOSE: Health care insurance claims databases are becoming a more common data source for studies of medication safety during pregnancy. While pregnancies have historically been identified in such databases by pregnancy outcomes, International Classification of Diseases, 10th revision Clinical Modification (ICD-10-CM) Z3A codes denoting weeks of gestation provide more granular information on pregnancies and pregnancy periods (i.e., start and end dates). The purpose of this study was to develop a process that uses Z3A codes to identify pregnancies, pregnancy periods, and links infants within a commercial health insurance claims database. METHODS: We identified pregnancies, gestation periods, pregnancy outcomes, and linked infants within the US-based Optum Research Database between 2015 and 2020 via a series of algorithms utilizing diagnosis and procedure codes on claims. The diagnosis and procedure codes included ICD-10-CM codes, Current Procedural Terminology (CPT) codes, and Healthcare Common Procedure Coding System (HCPCS) codes. RESULTS: We identified 1 030 874 pregnancies among 841 196 women of reproductive age. Of pregnancies with livebirth outcomes, 84% were successfully linked to infants. The prevalence of pregnancy outcomes (livebirth, stillbirth, ectopic, molar, and abortion) was similar to national estimates. CONCLUSIONS: This process provides an opportunity to study drug safety and care patterns during pregnancy and may be replicated in other claims databases containing ICD-10-CM, CPT, and HCPCS codes. Work is underway to validate and refine the various algorithms.

Evaluation of Medication-mediated Effects in Pharmacoepidemiology.

Medical conditions such as epilepsy or infection with human immunodeficiency virus (HIV) are known to be associated with a spectrum of adverse health outcomes if not appropriately managed by efficacious treatment and care. Medications for such conditions can be potent, and their use might sometimes have unintended health consequences. Prominent examples have emerged in HIV perinatal research in which use of antiretroviral treatment during pregnancy to treat maternal HIV infection and prevent transmission of the virus to the fetus have been shown to be associated with adverse birth outcomes. Likewise, use of antiepileptic drugs during pregnancy to treat maternal epilepsy has been shown to increase the risk of birth defects. Pharmacoepidemiology studies routinely aim to quantify the extent to which, in such settings, an observed association between an underlying medical condition and certain health outcomes can be attributed to the natural progression of the disease, and the extent to which it might be mediated by medication used to slow disease progression. We describe a simple yet principled methodology to quantify medication-mediated effects to address these types of queries. While methods for causal mediation analysis abound, there also has been much criticism of these methods as relying on untestable and sometimes unrealistic assumptions. In contrast, here we show that when the disease-free control group is also medication-free, mediated effects of the type described above are nonparametrically identified under standard no-unobserved confounding conditions, thus establishing that such effects are in a sense immune to recent criticism leveled at causal mediation methodology.

A Simple Regression-based Approach to Account for Survival Bias in Birth Outcomes Research.

In perinatal epidemiology, birth outcomes such as small for gestational age (SGA) may not be observed for a pregnancy ending with a stillbirth. It is then said that SGA is truncated by stillbirth, which may give rise to survival bias when evaluating the effects on SGA of an exposure known also to influence the risk of a stillbirth. In this article, we consider the causal effects of maternal infection with human immunodeficiency virus (HIV) on the risk of SGA, in a sample of pregnant women in Botswana. We hypothesize that previously estimated effects of HIV on SGA may be understated because they fail to appropriately account for the over-representation of live births among HIV negative mothers, relative to HIV positive mothers. A simple yet novel regression-based approach is proposed to adjust effect estimates for survival bias for an outcome that is either continuous or binary. Under certain straightforward assumptions, the approach produces an estimate that may be interpreted as the survivor average causal effect of maternal HIV, which is, the average effect of maternal HIV on SGA among births that would be live irrespective of maternal HIV status. The approach is particularly appealing, because it recovers an exposure effect which is robust to survival bias, even if the association between the risk of SGA and that of a stillbirth cannot be completely explained by adjusting for observed shared risk factors. The approach also gives a formal statistical test of the null hypothesis of no survival bias in the regression framework.

Accuracy of ICD-9-CM coding to identify small for gestational age newborns.

PURPOSE: This study aimed to evaluate the accuracy of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code for small for gestational age (SGA) recorded in administrative healthcare records using birthweight and gestational age information recorded in electronic medical records. METHODS: We used billing and medical records from women aged 13-55 years who delivered at a tertiary care center in the USA between 2004 and 2011. Information on birthweight, gestational age at birth, and ICD-9-CM code for SGA, 656.5x, was abstracted from the database. Each infant's birthweight percentile for gestational age was calculated on the basis of published US references; infants below the 10th percentile were classified as SGA. The performance characteristics of SGA ICD-9-CM diagnosis code against SGA classification based on birthweight and gestational age were calculated, for all deliveries and by strata of demographic and delivery characteristics. RESULTS: We identified 51 292 singleton live birth deliveries. The prevalence of SGA infants calculated from birthweight and gestational age at birth was higher (13%) than the prevalence based on ICD-9-CM code (2%). Sensitivity of the SGA ICD-9-CM code was 14.2%, specificity was 99.7%, positive predictive value was 86.8%, and negative predictive value was 88.4%. Stratification by demographic and delivery characteristics yielded similar results. CONCLUSIONS: Identification of SGA infants using ICD-9-CM code, 656.5x, from administrative healthcare records has low sensitivity but high specificity; the accuracy did not differ across demographic and delivery characteristics. Thus, although this source of information would underestimate the prevalence of SGA, it could produce valid relative risk estimates.

Development and Validation of ICD-10-CM-based Algorithms for Date of Last Menstrual Period, Pregnancy Outcomes, and Infant Outcomes.

INTRODUCTION AND OBJECTIVE: Validation studies of algorithms for pregnancy outcomes based on International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes are important for conducting drug safety research using administrative claims databases. To facilitate the conduct of pregnancy safety studies, this exploratory study aimed to develop and validate ICD-10-CM-based claims algorithms for date of last menstrual period (LMP) and pregnancy outcomes using medical records. METHODS: Using a mother-infant-linked claims database, the study included women with a pregnancy between 2016-2017 and their infants. Claims-based algorithms for LMP date utilized codes for gestational age (Z3A codes). The primary outcomes were major congenital malformations (MCMs) and spontaneous abortion; additional secondary outcomes were also evaluated. Each pregnancy outcome was identified using a claims-based simple algorithm, defined as presence of ≥ 1 claim for the outcome. Positive predictive values (PPV) and 95% confidence intervals (CI) were calculated. RESULTS: Overall, 586 medical records were sought and 365 (62.3%) were adjudicated, including 125 records each for MCMs and spontaneous abortion. Last menstrual period date was validated among maternal charts procured for pregnancy outcomes and fewer charts were adjudicated for the secondary outcomes. The median difference in days between LMP date based on Z3A codes and adjudicated LMP date was 4.0 (interquartile range: 2.0-10.0). The PPV of the simple algorithm for spontaneous abortion was 84.7% (95% CI 78.3, 91.2). The PPV for the MCM algorithm was < 70%. The algorithms for the secondary outcomes pre-eclampsia, premature delivery, and low birthweight performed well, with PPVs > 70%. CONCLUSIONS: The ICD-10-CM claims-based algorithm for spontaneous abortion performed well and may be used in pregnancy studies. Further algorithm refinement for MCMs is needed. The algorithms for LMP date and the secondary outcomes would benefit from additional validation in a larger sample.

Real-world treatment patterns and clinical outcomes after introduction of immune checkpoint inhibitors: Results from a retrospective chart review of patients with advanced/metastatic non-small cell lung cancer in the EU5.

BACKGROUND: Real-world evidence is increasingly used to guide treatment and regulatory decisions for non-small cell lung cancer (NSCLC). Real-world treatment patterns and clinical outcomes among patients with advanced/metastatic NSCLC in France, Germany, Italy, Spain, and the UK (EU5) were assessed. METHODS: This retrospective physician-completed patient chart review assessed treatment patterns (regimen, duration of treatment [DOT], time to discontinuation), and clinical outcomes (duration of response [DOR], progression-free survival [PFS], and overall survival [OS]) of patients with stage IIIB/C or IV NSCLC who received pembrolizumab-based first-line induction chemotherapy. RESULTS: Overall, 322 patients were included; at first-line maintenance (1LM), 92% had stage IV NSCLC, 68% had nonsquamous histology, and 89% had no central nervous system (CNS)/brain metastasis. The two most common 1LM regimens were pembrolizumab monotherapy (76% overall) and pembrolizumab + pemetrexed (21% overall). Docetaxel monotherapy was the most common second-line regimen in all countries except Germany (54% overall). For 1LM therapy, the overall median DOT and DOR were 5 and 10 months, respectively; PFS was 7 months and OS was 8 months. Germany had a longer duration of each outcome except for DOR which was longer in Spain. Clinical outcomes were generally poorer for patients with squamous histology and CNS/brain metastases. CONCLUSIONS: This study demonstrated differences in treatment patterns and clinical outcomes in NSCLC across the EU5 and patient subgroups. Improved survival was generally associated with response to first-line therapy, nonsquamous histology, and CNS/brain metastases absence. These real-world data provide valuable insights which may aid treatment decision-making and clinical trial design.

Adverse Birth Outcomes in Botswana Among Women With Vertically or Horizontally Acquired Human Immunodeficiency Virus.

BACKGROUND: Women with vertically acquired HIV (VHIV) may have a greater risk of adverse birth outcomes than women with horizontally acquired HIV (HHIV). METHODS: The Tsepamo study performed birth outcomes surveillance at 8 government delivery sites in Botswana from July 2014 through March 2019. Pregnant women diagnosed with HIV before their 11th birthday received VHIV status, and other women had HHIV. Small for gestational age (SGA), preterm delivery (PTD), stillbirth, and neonatal death were compared using χ2 and Fisher's exact tests. Log-binomial regression models determined risk ratios (RRs). RESULTS: VHIV women (n = 402) aged 15-27 years were identified over 4 years of surveillance and compared with HHIV women (n = 8465) of the same age. VHIV women were more likely to use nevirapine (NVP)-based antiretroviral treatment (ART) in pregnancy and to have SGA and very SGA infants, but less likely to have very PTD infants. In unadjusted analyses, VHIV women had a higher risk of any adverse birth outcome combined (RR = 1.21, 95% confidence interval [CI], 1.08-1.36). After adjusting for potential confounders, particularly use of NVP-based regimens, the risk of adverse birth outcomes among VHIV and HHIV women was similar. CONCLUSIONS: NVP-based ART is a primary and modifiable risk factor for adverse birth outcomes. Updating ART regimens could improve birth outcomes for women with HIV.

Cardiovascular Risk in Users of Mirabegron Compared with Users of Antimuscarinic Treatments for Overactive Bladder: Findings from a Non-Interventional, Multinational, Cohort Study.

INTRODUCTION: During clinical trials, mirabegron, a ß3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder. OBJECTIVE: The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use. METHODS: We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012-December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated. RESULTS: Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73-0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76-0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings. CONCLUSIONS: This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics.

During clinical trials, mirabegron, which is a treatment for overactive bladder, was associated with small increases in heart rate and blood pressure. This study was conducted to compare the frequency of cardiac events following the use of mirabegron or antimuscarinics, a group of treatments also used to treat overactive bladder. We obtained the data for this study from four countries: Denmark, Sweden, the UK and the USA. We identified people who were new users of mirabegron or antimuscarinics from 2012 to 2018 using prescription or dispensing records. Occurrences of major cardiac events, heart attack, stroke, death due to cardiac events and death from any cause were evaluated. Overall, we identified 152,026 times when mirabegron or antimuscarinics were each used as new treatments. Most of the people in the study were women (63.1%) and at least 65 years old (72.6%). There were no notable differences between the treatment groups with regard to how often major cardiac events, heart attack or stroke occurred. Further, death due to cardiac events and death from any cause were no higher with mirabegron compared with antimuscarinics. We obtained similar results when the data were assessed for patients who were at high risk for cardiac events or split by age (less than 65 years or at least 65 years) or a history of overactive bladder medication use. In conclusion, this large study involving data from several countries found no higher risk of major cardiac events, heart attack, stroke or death among people prescribed mirabegron compared with antimuscarinics.

A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder.

OBJECTIVE: This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designed to compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinic medications. METHODS: Cohorts of mirabegron initiators during 2012-2018 were propensity-score matched to antimuscarinic medication initiators within real-world data sources (Danish National Registers, Swedish National Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incident cancer cases were identified during follow-up from direct linkage to cancer registers or validated through medical record review or through physician questionnaires. Comparisons of sex-specific composite cancer outcomes (cancer of the lung/bronchus, colon/rectum, melanoma of skin, urinary bladder, non-Hodgkin lymphoma, kidney/renal pelvis, pancreas, prostate in men and breast and uterus in women) were made overall and for person-time in the first year and after the first year following start of treatment, for all ages and for the subgroup ≥65 years. RESULTS: Among the 80,637 mirabegron initiators matched to 169,885 antimuscarinic medication initiators, 68% were at least 65 years of age and 66% were women. Over 5000 incident cancer cases were observed overall. Incidence rates were higher for men than women for composite and individual cancer outcomes. The pooled fixed effects hazard ratios for composite cancer outcomes (all ages) were 1.05 (95% confidence interval [CI]: 0.98-1.14) for women and 1.06 (95% CI: 0.98-1.14) for men. Results were similar in persons ≥65 years. CONCLUSIONS: The results suggest no association between mirabegron use and risk of cancer, compared with antimuscarinic medications, in either men or women. Registration: EU PAS Register Number: EUPAS16088.

Effects of HIV type 1 infection on hematopoiesis in Botswana.

Clinical observations suggest that HIV-1 infection causes higher anemia rates in patients in southern Africa than in those in the United States. To explore this difference we performed a cross-sectional exploratory study on the effect of HIV-1 infection on hematopoiesis in Botswana by examining hematological presentation, HIV disease state, hematopoietic progenitor cell number, and circulating viral levels in HIV-infected patients and HIV-uninfected controls. We found significant associations between CD34(+) and CD4(+) cell counts in HIV-positive patients. Significant relationships were also seen between the CD34(+) CD4(+) cell population and hemoglobin levels, as well as colony-forming ability. These associations, however, were not seen in uninfected controls. Circulating viral p24 levels were found to correlate significantly with CD34(+) cell count, CD34(+) CD4(+) cell count, and colony-forming ability. These results demonstrate a direct association between HIV-1 infection in southern Africa and hematopoietic progenitor cell health.

Antiretroviral Therapy Use During Pregnancy and the Risk of Small for Gestational Age Birth in a Medicaid Population.

BACKGROUND: Several studies have assessed the association between antiretroviral (ARV) therapy use during pregnancy and small for gestational age (SGA), but the evidence remains incompletely elucidated. METHODS: We linked data from Tennessee Medicaid files and vital records to evaluate pregnancies among human immunodeficiency virus (HIV)-infected women who delivered between 1994 and 2009. Maternal HIV status was defined based on diagnosis codes, ARV prescriptions and laboratory codes for CD4 count or HIV RNA assays. ARV use was identified from pharmacy claims. Risk of SGA (defined as birth weight below the 10th percentile for gestational age) and preterm birth was evaluated using logistic regression models. RESULTS: Four hundred and seventy-seven HIV-infected pregnant women contributing 604 singleton pregnancies were identified; 156 (26%) delivered SGA infants. ARV use during pregnancy was not associated with SGA [adjusted odds ratio: 0.93; 95% confidence interval (CI): 0.56-1.56] or preterm birth (adjusted odds ratio: 0.74; 95% CI: 0.42-1.32). Exposure to a protease inhibitor during the first trimester was associated with a lower risk of SGA (odds ratio: 0.54; 95% CI: 0.29-1.01) compared with non-exposure to a protease inhibitor throughout pregnancy. CONCLUSIONS: We observed no evidence of an association between ARV exposure during pregnancy and SGA delivery in this Medicaid cohort of HIV-infected women.

Trends in antiretroviral drug use during pregnancy among HIV-infected women on medicaid: 2000-2007.

Optimal use of antiretroviral drugs by pregnant women living with human immunodeficiency virus (HIV) is crucial to treat maternal HIV infection and prevent perinatal transmission of the virus effectively. Our goal was to describe national trends of antiretroviral (ARV) use during pregnancy among HIV-infected women living in the U.S. and enrolled in Medicaid. We used the 2000-2007 Medicaid Analytic eXtract (MAX) files to identify our study cohort. ARV use was defined as the dispensing of at least one ARV drug prescription during pregnancy based on Medicaid pharmacy claims. The prevalence of HIV was calculated, and temporal trends of ARV use during pregnancy were compared to the U.S. perinatal treatment guidelines. Predictors of ARV use during pregnancy were assessed using logistic regression models. From 1,106,757 pregnancies (955,251 women), 3083 (2856 women, 0.28%) were identified as HIV positive. We found striking regional variations in the prevalence of HIV and ARV prescription dispensing among pregnant women. The states with the highest HIV prevalence were Washington DC (5.8%), Maryland (0.90%), and New York (0.89%); all other states had a prevalence below 0.5%. A substantial fraction of women did not have any ARV dispensing throughout pregnancy (637 of 3083 (21%) pregnancies), and women with limited health care utilization were the least likely to have ARV dispensings. This finding calls for further research to better characterize HIV-positive women who are enrolled in Medicaid prior to pregnancy and yet have no ARV prescriptions so that appropriate interventions can be implemented.

First trimester exposure to antiretroviral therapy and risk of birth defects.

BACKGROUND: Use of antiretroviral (ARV) drugs during pregnancy has been associated with an increased risk of birth defects, but the evidence remains inconclusive. METHODS: We identified infants born to human immunodeficiency virus (HIV)-infected mothers between 1994 and 2009 using Tennessee Medicaid data linked to vital records. Maternal HIV status was based on diagnosis codes, prescriptions for ARVs and HIV-related laboratory testing. ARV exposure was identified from pharmacy claims. Birth defects diagnoses during the first year of life were identified from maternal and infant claims and vital records and were confirmed through medical record review. Multivariate logistic regression models were used to evaluate associations between first trimester ARV dispensing and birth defects. RESULTS: Of 806 infants included in the study, 32 (4.0%) had at least 1 major birth defect, most (44%) in the cardiac system. There was no increased risk for infants exposed in the first trimester to ARVs compared with unexposed infants (odds ratio = 1.07; 95% confidence interval: 0.50-2.31). Of the 20 infants exposed to efavirenz, none had a birth defect (0%; 95% confidence interval: 0.0-13.2). CONCLUSIONS: There was no significant association between first trimester ARV dispensing and the risk of birth defects in this Medicaid cohort of HIV-positive women.

Psychosocial factors affecting medication adherence among HIV-1 infected adults receiving combination antiretroviral therapy (cART) in Botswana.

As increasing numbers of persons are placed on potentially life-saving combination antiretroviral therapy (cART) in sub-Saharan Africa, it is imperative to identify the psychosocial and social factors that may influence antiretroviral (ARV) medication adherence. Using an 87 question survey, the following data were collected from patients on cART in Botswana: demographics, performance (Karnofsky) score, perceived stigma and level of HIV disclosure, attitudes and beliefs concerning HIV/AIDS, substance and/or drug use, depression, and pharmacy and healthcare provider-related factors. Overall adherence rates were determined by patient self-report, institutional adherence, and a culturally modified Morisky scale. Three hundred adult patients were recruited between April and May 2005. The overall cART adherence rate was 81.3% based on 4 day and 1 month patient recall and on clinic attendance for ARV medication refills during the previous 3 months. Adults receiving cART for 1-6 months were the least adherent (77%) followed by those receiving cART for greater than 12 months (79%). Alcohol use, depression, and nondisclosure of positive HIV status to their partner were predictive of poor adherence rates (p value <0.02). A significant proportion (81.3%) of cART-treated adults were adherent to their prescribed treatment, with rates superior to those reported in resource-rich settings. Adherence rates were poorest among those just starting cART, most likely due to the presence of ARV-related toxicity. Adherence was lower among those who have been treated for longer periods of time (greater than 1 year), suggesting complacency, which may become a significant problem, especially among these long-term cART-treated patients who return to improved physical and mental functioning and may be less motivated to adhere to their ARV medications. Healthcare providers should encourage HIV disclosure to "at-risk" partners and provide ongoing counseling and education to help patients recognize and overcome HIV-associated stigma, alcohol abuse, and depression.

Associations of chemokine receptor polymorphisms With HIV-1 mother-to-child transmission in sub-Saharan Africa: possible modulation of genetic effects by antiretrovirals.

BACKGROUND: HIV-1 mother-to-child transmission (MTCT) remains an important route of infection in sub-Saharan Africa. METHODS: Genetic variants in CCR5 promoter, CCR2, CX3CR1, and Stromal cell-derived factor-1 (SDF-1) genes were determined in 980 infants from sub-Saharan Africa using real-time polymerase chain reaction to determine association with MTCT. RESULTS: In antiretroviral-naive mother-infant pairs (n = 637), CCR5 promoter polymorphisms at positions 59029: A allele vs. G/G [odds ratio (OR): 1.61, 95% confidence interval (CI): 1.04 to 2.48; P = 0.032] and 59356: T allele vs. C/C (OR: 0.63, 95% CI: 0.41 to 0.96; P = 0.033) and CCR2-180: G allele vs. A/A (OR: 3.32, 95% CI: 1.13 to 9.73; P = 0.029) were associated with risk of MTCT. Treatment of HIV-1-infected mothers and infants with single-dose nevirapine or perinatal zidovudine altered but did not eliminate the association of genetic variants with MTCT. CONCLUSIONS: CCR5 promoter, CCR2, and CX3CR1 polymorphisms were associated with risk of MTCT likely through their role as an HIV-1 coreceptor or by modulating the early immune response. Host genetics may continue to alter MTCT when short-course interventions that only partially suppress virus are used. These findings will need to be confirmed in validation cohorts with a large number of infected infants.