Achieving HIV Epidemic Control and Improving Maternal Healthcare Services with Community-Based HIV Service Delivery in Zambia: Mixed-Methods Assessment of the SMACHT Project.

Novel community-based approaches are needed to achieve and sustain HIV epidemic control in Zambia. Under the Stop Mother and Child HIV Transmission (SMACHT) project, the Community HIV Epidemic Control (CHEC) differentiated service delivery model used community health workers to support HIV testing, ART linkage, viral suppression, and prevention of mother-to-child transmission (MTCT). A multi-methods assessment included programmatic data analysis from April 2015 to September 2020, and qualitative interviews from February to March 2020. CHEC provided HIV testing services to 1,379,387 clients; 46,138 were newly identified as HIV-positive (3.3% yield), with 41,366 (90%) linked to ART. By 2020, 91% (60,694/66,841) of clients on ART were virally suppressed. Qualitatively, healthcare workers and clients benefitted from CHEC, with provision of confidential services, health facility decongestion, and increased HIV care uptake and retention. Community-based models can increase uptake of HIV testing and linkage to care, and help achieve epidemic control and elimination of MTCT.

Nanoskiving core-shell nanowires: a new fabrication method for nano-optics.

This paper describes the fabrication of functional optical devices by sectioning quantum-dot-in-nanowires systems with predefined lengths and orientations. This fabrication process requires only two steps, embedding the nanowires in epoxy and using an ultramicrotome to section them across their axis ("nanoskiving"). This work demonstrates the combination of the following four capabilities: (i) the control of the length of the nanowire sections at the nanometer scale; (ii) the ability to process the nanowires after cutting using wet etching; (iii) the possibility of modifying the geometry of the wire by varying the sectioning angle; and (iv) the generation of as many as 120 consecutive slabs bearing nanowires that have uniform size and approximately reproducible lateral patterns and that can subsequently be transferred to different substrates. The quantum dots inside the nanowires are functional and of a high optical quality after the sectioning process and exhibit photoluminescent emission with wavelengths in the range of 650-710 nm.

SARS-CoV-2 Infection of Young Infants during the Omicron Wave: A Case Series.

We describe the clinical course of 4 infants infected with severe acute respiratory syndrome coronavirus 2. All were admitted to our tertiary care neonatal intensive care unit during the Omicron variant wave in our region. All 4 infants, who were less than 3 months of age, including three born prematurely, presented with critical illness. However, their clinical presentation varied considerably. Of them, two infants presented with apnea, one with respiratory distress, and one with gastrointestinal manifestation. Our experience with these four infants provides evidence for a severe form of disease and varied clinical presentation in neonates and young infants speculated to be infected with Omicron variant.

Slow human immunodeficiency virus type 1 evolution in viral reservoirs in infants treated with effective antiretroviral therapy.

A longitudinal study of viral reservoirs in children initiating highly active antiretroviral therapy (HAART) in early infancy was undertaken to test the hypothesis that early effective treatment affects the persistence of replication-competent viral latency and the evolution of HIV-1 in resting CD4(+) T cells. An end point dilution culture assay was used to measure the frequencies of latently-infected resting CD4(+) T cells harboring replication-competent virus in early and late treated children. Gag, pol, and env also were sequenced and compared to pretreatment sequences. HIV-1-specific humoral and cellular immune responses were also assessed. Blood samples were obtained from 12 HIV-1-infected children who started HAART at a median of 1.9 months of age and who maintained suppression of HIV-1 replication for up to 5.5 years. Replication-competent HIV-1 was recovered from 10/12 (84%) subjects. Evolution in gag, pol, and env was restricted for years in early-treated children. HAART initiated from early infancy does not prevent the establishment of a reservoir of latent provirus, but does significantly limit the evolution of HIV-1 in viral reservoirs. The effect of early therapy on HIV-1 evolution may have implications for long-term pharmacologic control of HIV-1.

Production of the HIV-suppressive chemokines CCL3/MIP-1alpha and CCL22/MDC is associated with more effective antiretroviral therapy in HIV-infected children.

BACKGROUND: Certain CC chemokines including ligands for the HIV-1 coreceptor CCR5 are associated with suppression of HIV-1 infection. Whether the release of these chemokines from lymphocytes influences treatment outcome in children receiving antiretroviral therapy is not known. METHODS: A study of 175 HIV-infected children in Rio de Janeiro, Brazil was conducted to compare clinical measures and HIV-suppressive chemokine release. Clinical measures including %CD4 T cells, viral loads, and antiretroviral drug-resistant mutations were obtained. Chemokine release was measured in cultures of peripheral blood mononuclear cells collected from 135 children before or after receiving therapy. Chemokine levels were compared between subject groups stratified according to clinical measures and treatment regimen (1-2, 3-4, or no antiretrovirals) extant at the time of cell sample collection. RESULTS: Mean viral loads did not vary significantly between treatment groups although there were significant differences in %CD4 T cells. Virus from children taking 3-4 antiretrovirals had significantly more drug-resistant mutations than did virus from those receiving 1-2 drugs. Among antiretroviral-treated children, there was a significant direct relationship between %CD4 T cells and MIP-1alpha/CCL3 and macrophage-derived chemokine/CCL22 production. In addition, there was a significant inverse relationship between viral load and MIP-1alpha production in patients receiving 3-4 antiretrovirals. Greater recovery of %CD4 T cells after therapy was associated with higher MIP-1alpha and macrophage-derived chemokine production at baseline. CONCLUSIONS: The production of HIV-suppressive chemokines is associated with better outcome in children receiving antiretroviral regimens in settings where drug-resistant mutations are prevalent. Such information may provide insights for the design of treatment strategies for pediatric HIV infection under similar circumstances.

The Arc of Human Immunodeficiency Virus Capacity Development: Insights from a Decade of Partnership for Medical Education in Zambia.

AbstractZambia and other sub-Saharan nations suffer from a critical shortage of trained health-care professionals to combat the human immunodeficiency virus/acquired immunodeficiency syndrome crisis. The University of Maryland and the Zambian Ministry of Health have partnered over the past decade to develop health-care capacity among physicians, nurses, and community health workers. We describe novel interventions to train health-care workers at all levels and argue that our collaboration represents a successful model for such partnerships between western medical institutions and African governmental health agencies.

Genotypic resistance and HIV-1 subtype in Brazilian children on dual and triple combination therapy.

BACKGROUND: Antiretroviral therapy is provided by the Brazilian Ministry of Health to eligible HIV-infected individuals. Based on clinical and immunological classification, the Brazilian guidelines recommend dual or triple therapy for children. However, the development of drug-resistant strains or poor adherence to therapy could impact the efficacy of this approach. OBJECTIVES: We examined relationships between RNA levels, CD4+ T-cell counts, treatment history, and the prevalence of drug-resistant variants in a cohort of HIV-1-infected children in Rio de Janeiro, Brazil. STUDY DESIGN: Direct sequencing of reverse transcriptase and protease genes from plasma was performed. Virologic and CD4+ T-cell counts responses to therapy were assessed by changes in HIV-1 RNA levels and CD4+ T-cell counts from baseline. RESULTS: Thirty-seven patients were receiving dual therapy and 38 were on triple therapy at enrollment, segregated by antiretroviral history. Both groups had a higher increase in CD4+ T cell counts and a lower viral load in pre-treatment antiretroviral-naïve subjects. Notably, there was a direct correlation between the higher frequencies of drug-resistance mutations and cross-resistance with previous usage of antiretroviral (ARV) therapy in both groups. Non-B subtypes isolates were found in 21.3% of samples. A smaller increase in CD4+ T cell counts was found between non-B subtypes when compared to B-subtypes. CONCLUSIONS: These results suggest that less immunological recovery and a higher number of mutations related to drug resistance were associated with previous usage of ARV and consequent higher time under drug selective pressure in these HIV-infected Brazilian children. These facts suggest the preferential use of triple drug combination as first line regimen in children.

Effectiveness of efavirenz-based regimens in young HIV-infected children treated for tuberculosis: a treatment option for resource-limited settings.

BACKGROUND: Antiretroviral treatment (ART) options for young children co-infected with HIV and tuberculosis are limited in resource-poor settings due to limited data on the use of efavirenz (EFV). Using available pharmacokinetic data, an EFV dosing schedule was developed for young co-infected children and implemented as the standard of care at Macha Hospital in Southern Province, Zambia. Treatment outcomes in children younger than 3 years of age or weighing less than 10 kg receiving either EFV-based ART plus anti-tuberculous treatment or nevirapine-based (NVP) ART were compared. METHODS: Treatment outcomes were measured in a cohort of HIV-infected children seeking care at Macha Hospital in rural Zambia from 2007 to 2010. Information on the diagnosis and treatment of tuberculosis was abstracted from medical records. RESULTS: Forty-five children treated for tuberculosis initiated an EFV-based regimen and 69 children initiated a NVP-based regimen, 7 of whom also were treated for tuberculosis. Children receiving both regimens were comparable in age, but children receiving EFV started ART with a lower CD4(+) T-cell percentage and weight-for-age z-score. Children receiving EFV experienced increases in both CD4(+) T-cell percentage and weight-for-age z-score during follow-up, such that levels were comparable to children receiving NVP after two years of ART. Cumulative survival after 12 months of ART did not differ between groups (NVP:87%;EFV:80%;p = 0.25). Eleven children experienced virologic failure during follow-up.The adjusted hazard ratio of virologic failure comparing EFV to NVP was 0.25 (95% CI:0.05,1.24) and 0.13 (95% CI:0.03,0.62) using thresholds of 5000 and 400 copies/mL, respectively.Five children receiving EFV were reported to have had convulsions after ART initiation compared to only one child receiving NVP (p = 0.04). CONCLUSIONS: Despite poorer health at ART initiation, children treated for tuberculosis and receiving EFV-based regimens showed significant improvements comparable to children receiving NVP-based regimens. EFV-based regimens should be considered for young HIV-infected children co-infected with tuberculosis in resource-limited settings.

Placental Cryptococcus neoformans infection without neonatal disease: case report and review of the literature.

We report placental cryptococcosis in a woman with multidrug resistant human immunodeficiency virus (HIV) infection. She received antifungal therapy for cryptococcal meningitis prior to delivery. Cesarean section was performed with delivery of a single full-term male infant. There was no evidence of HIV or cryptococcal infection in the infant. The placenta grossly showed multiple white nodules. Microscopically, numerous encapsulated budding yeasts, morphologically consistent with cryptococci, were identified in the intervillous space and, to a lesser extent, in the chorionic villi. Cryptococcal infections are not uncommon, but only 2 cases of placental cryptococcosis have been reported. Our case is the 1st account documenting cryptococcal organisms within the chorionic villi, and yet there was no evidence of infection in the infant. Mother-to-fetal transmission of cryptococcal infection is not well defined. We review the literature and discuss its possible mechanisms.

Growth hormone deficiency in HIV-infected children following successful treatment with highly active antiretroviral therapy.

Growth failure is common in children with untreated HIV, although growth hormone (GH) deficiency is rare. Treatment with highly active antiretroviral therapy usually results in resumption of normal growth. We report the cases of 2 children with growth failure despite stable full suppression of viremia who were found to be GH deficient.

Continued production of drug-sensitive human immunodeficiency virus type 1 in children on combination antiretroviral therapy who have undetectable viral loads.

Highly active antiretroviral therapy (HAART) can suppress plasma human immunodeficiency virus type 1 (HIV-1) levels to below the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in cellular reservoirs, and in adults, persistent low-level viremia is detected with more sensitive assays. The nature of this viremia is poorly understood, and it is unclear whether viremia persists in children on HAART, particularly those who start therapy shortly after birth. We therefore developed a reverse transcriptase PCR (RT-PCR) assay that allows genotyping of HIV-1 protease even when viremia is present at levels as low as 5 copies of HIV-1 RNA/ml. We demonstrated that viremia persists in children with plasma virus levels below the limit of detection of clinical assays. Viremia was detected even in children who began HAART in early infancy and maintained such strong suppression of viremia that HIV-1-specific antibody responses were absent or minimal. The low-level plasma virus lacked protease inhibitor resistance mutations despite the frequent use of nelfinavir, which has a low mutational barrier to resistance. Protease sequences resembled those of viruses in the latent reservoir in resting CD4(+) T cells. Thus, in most children on HAART with clinically undetectable viremia, there is continued virus production without evolution of resistance in the protease gene.