Placental Malaria and Mother-to-Child Transmission of Human Immunodeficiency Virus-1 in Rural Rwanda

We conducted a nested case-control study of placental malaria (PM) and mother-to-child transmission (MTCT) of human immunodeficiency virus-1 (HIV-1) within a prospective cohort of 627 mother-infant pairs followed from October 1989 until April 1994 in rural Rwanda. Sixty stored placentas were examined for PM and other placental pathology, comparing 20 HIV-infected mother-infant (perinatal transmitter) pairs, 20 HIV-uninfected pairs, and 20 HIV-infected mothers who did not transmit to their infant perinatally. Of 60 placentas examined, 45% showed evidence of PM. Placental malaria was associated with increased risk of MTCT of HIV-1 (adjusted odds ratio [aOR] = 6.3; 95% confidence interval [CI] = 1.4–29.1), especially among primigravidae (aOR = 12.0; 95% CI = 1.0–150; P < 0.05). Before antiretroviral therapy or prophylaxis, PM was associated with early infant HIV infection among rural Rwandan women living in a hyper-endemic malaria region. Primigravidae, among whom malaria tends to be most severe, may be at higher risk

Combining Phylogenetic and Network Approaches to Identify HIV-1 Transmission Links in San Mateo County, California

The HIV epidemic in San Mateo County is sustained by multiple overlapping risk groups and is an important hub for HIV transmission in northern California. Limited access to care has led historically to delayed clinical presentation, higher rates of opportunistic infections, and an increased prevalence of antiretroviral drug resistance. The virologic and clinical consequences of treatment within these multiple ethnic and behavioral groups are poorly understood, highlighting the need for efficient surveillance strategies that are able to elucidate transmission networks and drug resistance patterns. We obtained sequence data from a group of 316 HIV-positive individuals in the San Mateo AIDS Program over a 14-year period and integrated epidemiologic, phylogenetic, and network approaches to characterize transmission clusters, risk factors and drug resistance. Drug resistance mutations were identified using the Stanford HIV Drug Resistance Database. A maximum likelihood tree was inferred in RAxML and subjected to clustering analysis in Cluster Picker. Network analysis using pairwise genetic distances was performed in HIV-TRACE. Participants were primarily male (60%), white Hispanics and non-Hispanics (32%) and African American (20.6%). The most frequent behavior risk factor was male-male sex (33.5%), followed by heterosexual (23.4%) and injection drug use (9.5%). Nearly all sequences were subtype B (96%) with subtypes A, C, and CRF01_AE also observed. Sequences from 65% of participants had at least one drug resistance mutation. Clustered transmissions included a higher number of women when compared to non-clustered individuals and were more likely to include heterosexual or people who inject drugs (PWID). Detailed analysis of the largest network (N = 47) suggested that PWID played a central role in overall transmission of HIV-1 as well as bridging men who have sex with men (MSM) transmission with heterosexual/PWID among primarily African American men. Combined phylogenetic and network analysis of HIV sequence data identified several overlapping risk factors in the epidemic, including MSM, heterosexual and PWID transmission with a disproportionate impact on African Americans and a high prevalence of drug resistance

Molecular Epidemiology of Human Immunodeficiency Virus Type 1 (HIV-1) in Southern Africa and Northern California

Human immunodeficiency virus type 1 (HIV-1) exhibits extraordinary genetic diversity that is driven by high rates of mutation and recombination, coupled with elevated rates of viral turnover and the persistent nature of infection. Through these mechanisms, HIV-1 group M, the group largely responsible for the global pandemic, diversified into nine distinct subtypes and additional circulating recombinant forms. Subtype C HIV-1, which accounts for approximately 50% of the estimated 37 million individuals living with HIV/AIDS worldwide, predominates the epidemics in southern Africa and South / Southeast Asia. In contrast, subtype B HIV-1, predominant in the United States and Europe, comprises 12% of the global HIV-1 prevalence.Current US and, increasingly, international guidelines recommend that HIV genotypic sequencing be performed for newly-identified HIV-positive patients, in order to identify genetic mutations that may confer drug resistance and pose a barrier to effective antiretroviral therapy (ART). This practice has resulted in the generation of enormous amounts of genotypic data often linked with clinical, demographic, and geospatial information. Analyses of these large datasets, utilizing sophisticated statistical and computational methods, has enabled identification of important and previously unrecognized trends in epidemiologic and vertical transmission, persistence of HIV within and among distinct risk groups, and the accumulation and propagation of ART resistance. Results of these analyses, in turn, advance treatment and care for persons living with HIV.This thesis takes advantage of large, de-identified and anonymized datasets of HIV-1 genotypic and demographic information available through clinical testing and treatment programs in two distinct and epidemiologically important regions in the global HIV pandemic, northern California and southern Africa. Employing innovative and computationally intensive tools which combine experience from molecular biology, evolutionary biology and biostatistics, in-depth analyses were undertaken to explore and define risk factors, underlying epidemiologic features and clinical characteristics relevant to transmission and ART resistance. The final chapter provides a comprehensive literature review of the relevance of molecular epidemiologic principles and innovative biology to the complex and continued phenomenon of mother-to-child transmission of HIV, as a case study exemplifying the need for continued molecular studies grounded in solid epidemiologic principles. The findings presented here are ultimately intended to help guide domestic and global efforts to scale up ART treatment while considering well-known and lesser-known factors that may influence eventual clinical and epidemiologic outcomes

Molecular Epidemiology of Human Immunodeficiency Virus Type 1 (HIV-1) in Southern Africa and Northern California

Human immunodeficiency virus type 1 (HIV-1) exhibits extraordinary genetic diversity that is driven by high rates of mutation and recombination, coupled with elevated rates of viral turnover and the persistent nature of infection. Through these mechanisms, HIV-1 group M, the group largely responsible for the global pandemic, diversified into nine distinct subtypes and additional circulating recombinant forms. Subtype C HIV-1, which accounts for approximately 50% of the estimated 37 million individuals living with HIV/AIDS worldwide, predominates the epidemics in southern Africa and South / Southeast Asia. In contrast, subtype B HIV-1, predominant in the United States and Europe, comprises 12% of the global HIV-1 prevalence.Current US and, increasingly, international guidelines recommend that HIV genotypic sequencing be performed for newly-identified HIV-positive patients, in order to identify genetic mutations that may confer drug resistance and pose a barrier to effective antiretroviral therapy (ART). This practice has resulted in the generation of enormous amounts of genotypic data often linked with clinical, demographic, and geospatial information. Analyses of these large datasets, utilizing sophisticated statistical and computational methods, has enabled identification of important and previously unrecognized trends in epidemiologic and vertical transmission, persistence of HIV within and among distinct risk groups, and the accumulation and propagation of ART resistance. Results of these analyses, in turn, advance treatment and care for persons living with HIV.This thesis takes advantage of large, de-identified and anonymized datasets of HIV-1 genotypic and demographic information available through clinical testing and treatment programs in two distinct and epidemiologically important regions in the global HIV pandemic, northern California and southern Africa. Employing innovative and computationally intensive tools which combine experience from molecular biology, evolutionary biology and biostatistics, in-depth analyses were undertaken to explore and define risk factors, underlying epidemiologic features and clinical characteristics relevant to transmission and ART resistance. The final chapter provides a comprehensive literature review of the relevance of molecular epidemiologic principles and innovative biology to the complex and continued phenomenon of mother-to-child transmission of HIV, as a case study exemplifying the need for continued molecular studies grounded in solid epidemiologic principles. The findings presented here are ultimately intended to help guide domestic and global efforts to scale up ART treatment while considering well-known and lesser-known factors that may influence eventual clinical and epidemiologic outcomes

Next Generation Sequencing of Microbial Cell-Free DNA for Rapid Noninvasive Diagnosis of Infectious Diseases in Immunocompromised Hosts

Cell-free DNA (cfDNA) sequencing has emerged as a novel laboratory method for rapid and noninvasive diagnosis in prenatal screening, organ transplant rejection, and tumor detection. We describe a series of immunocompromised patients in which cfDNA sequencing was applied to infectious disease diagnosis. Ten adult patients receiving chemotherapy or status post transplantation followed at the Sylvester Comprehensive Cancer Center with febrile illness or documented infection were enrolled between July 31 and October 2, 2018. As part of the clinical evaluation, 5ml of blood was sent for the Karius® Test (Redwood City, CA) which uses next generation sequencing (NGS) of microbial cfDNA in plasma to identify over 1,000 pathogens including bacteria, DNA viruses and fungi. The characteristics of the patients studied are presented in Table 1. The median age was 56 years (range, 20-65) with 60% males. Except for a kidney transplant recipient, all other patients had underlying hematological disease and/or had received a hematopoietic cell transplant. All patients were receiving antimicrobials at the time of plasma sample collection. Three patients had neutropenia (absolute neutrophil count < 500/µL) at the time of febrile illness. The kidney transplant recipient had Aspergillus fumigatus deep-seated abdominal abscess and Aspergillus cfDNA levels, although detected in plasma, were below threshold required for a positive test result. However, among hematological patients in whom a microbiological diagnosis was established (n=5), cfDNA NGS testing correlated with other methods in all cases (100% sensitivity). This included patients with proven/probable invasive aspergillosis, Pneumocystis jirovecii pneumonia (PJP), Stenotrophomonas maltophila bacteremia, and CMV or adenovirus viremia. Among four hematological patients with negative standard laboratory testing, NGS testing identified causes of bacterial sepsis in two, and both experienced good clinical response to antibiotic therapy with resolution of fever and hypotension. These data support the clinical utility of NGS-based detection of microbial cfDNA in peripheral blood for rapid noninvasive diagnosis of infections in immunocompromised hosts. Larger studies are needed to validate these findings