Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial.

BACKGROUND: In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. METHODS AND FINDINGS: In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82-1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76-1.28], p = 0.91); in serious (aHR = 0.99 [0.81-1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71-1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63-1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76-1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. CONCLUSIONS: Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT01825031. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number ISRCTN 43622374.

Surveillance of respiratory viruses in the outpatient setting in rural coastal Kenya: baseline epidemiological observations.

Background: Endemic and seasonally recurring respiratory viruses are a major cause of disease and death globally. The burden is particularly severe in developing countries. Improved understanding of the source of infection, pathways of spread and persistence in communities would be of benefit in devising intervention strategies. Methods: We report epidemiological data obtained through surveillance of respiratory viruses at nine outpatient health facilities within the Kilifi Health and Demographic Surveillance System, Kilifi County, coastal Kenya, between January and December 2016. Nasopharyngeal swabs were collected from individuals of all ages presenting with acute respiratory infection (ARI) symptoms (up to 15 swabs per week per facility) and screened for 15 respiratory viruses using real-time PCR. Paediatric inpatient surveillance at Kilifi County Hospital for respiratory viruses provided comparative data. Results: Over the year, 5,647 participants were sampled, of which 3,029 (53.7%) were aged <5 years. At least one target respiratory virus was detected in 2,380 (42.2%) of the samples; the most common being rhinovirus 18.6% (1,050), influenza virus 6.9% (390), coronavirus 6.8% (387), parainfluenza virus 6.6% (371), respiratory syncytial virus (RSV) 3.9% (219) and adenovirus 2.7% (155). Virus detections were higher among <5-year-olds compared to older children and adults (50.3% vs 32.7%, respectively; χ 2(1) =177.3, P=0.0001). Frequency of viruses did not differ significantly by facility (χ 2(8) =13.38, P=0.072). However, prevalence was significantly higher among inpatients than outpatients in <5-year-olds for RSV (22.1% vs 6.0%; χ 2(1) = 159.4, P=0.0001), and adenovirus (12.4% vs 4.4%, χ 2(1) =56.6, P=0.0001). Conclusions: Respiratory virus infections are common amongst ARI outpatients in this coastal Kenya setting, particularly in young children. Rhinovirus predominance warrants further studies on the health and socio-economic implications. RSV and adenovirus were more commonly associated with severe disease. Further analysis will explore epidemiological transmission patterns with the addition of virus sequence data.

Cytomegalovirus viraemia is associated with poor growth and T-cell activation with an increased burden in HIV-exposed uninfected infants.

OBJECTIVE: Factors associated with poor health in HIV-exposed-uninfected (HEU) infants are poorly defined. We describe the prevalence and correlates of cytomegalovirus (CMV) viraemia in HEU and HIV-unexposed-uninfected (HUU) infants, and quantify associations with anthropometric, haematological, and immunological outcomes. DESIGN: Cross-sectional, including HEU and HUU infants from rural coastal Kenya. METHODS: Infants aged 2-8 months were studied. The primary outcome was CMV viraemia and viral load, determined by quantitative PCR. Correlates were tested by logistic and linear regression; coefficients were used to describe associations between CMV viraemia and clinical/immunological parameters. RESULTS: In total, 42 of 65 (64.6%) infants had CMV viraemia [median viral load, 3.0 (interquartile ranges: 2.7-3.5) log10 IU/ml]. Compared to community controls, HEU infants had six-fold increased odds of being viraemic (adjusted odds ratio 5.95 [95% confidence interval: 1.82-19.36], P = 0.003). Age, but not HEU/HUU status, was a strong correlate of CMV viral load (coefficient = -0.15, P = 0.009). CMV viral load associated negatively with weight-for-age (WAZ) Z-score (coefficient =  -1.06, P = 0.008) and head circumference-for-age Z-score (coefficient =  -1.47, P = 0.012) and positively with CD8 T-cell coexpression of CD38/human leucocyte antigen DR (coefficient = 15.05, P = 0.003). CONCLUSION: The odds of having CMV viraemia was six-fold greater in HEU than HUU infants when adjusted for age. CMV viral load was associated with adverse growth and heightened CD8 T-cell immune activation. Longitudinal assessments of the clinical effects of primary CMV infection and associated immunomodulation in early life in HEU and HUU populations are warranted.

HIV-Exposed Uninfected Infants Show Robust Memory B-Cell Responses in Spite of a Delayed Accumulation of Memory B Cells: an Observational Study in the First 2 Years of Life.

Improved HIV care has led to an increase in the number of HIV-exposed uninfected (HEU) infants born to HIV-infected women. Although they are uninfected, these infants experience increased morbidity and mortality. One explanation may be that their developing immune system is altered by HIV exposure, predisposing them to increased postnatal infections. We explored the impact of HIV exposure on the B-cell compartment by determining the B-cell subset distribution, the frequency of common vaccine antigen-specific memory B cells (MBCs), and the levels of antibodies to the respective antigens in HEU and HIV-unexposed uninfected (HUU) infants born to uninfected mothers, using flow cytometry, a B-cell enzyme-linked immunosorbent spot assay, and an enzyme-linked immunosorbent assay, respectively, during the first 2 years of life. For the majority of the B-cell subsets, there were no differences between HEU and HUU infants. However, HIV exposure was associated with a lower proportion of B cells in general and MBCs in particular, largely due to a lower proportion of unswitched memory B cells. This reduction was maintained even after correcting for age. These phenotypic differences in the MBC compartment did not affect the ability of HEU infants to generate recall responses to previously encountered antigens or reduce the antigen-specific antibody levels at 18 months of life. Although HIV exposure was associated with a transient reduction in the proportion of MBCs, we found that the ability of HEU infants to mount robust MBC and serological responses was unaffected.

Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants.

Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted.

Outcomes of prevention of mother to child transmission of the human immunodeficiency virus-1 in rural Kenya--a cohort study.

BACKGROUND: Success in prevention of mother-to-child transmission (PMTCT) raises the prospect of eliminating pediatric HIV infection. To achieve global elimination, however, strategies are needed to strengthen PMTCT interventions. This study aimed to determine PMTCT outcomes and identify challenges facing its successful implementation in a rural setting in Kenya. METHODS: A retrospective cohort design was used. Routine demographic and clinical data for infants and mothers enrolling for PMTCT care at a rural hospital in Kenya were analysed. Cox and logistic regression were used to determine factors associated with retention and vertical transmission respectively. RESULTS: Between 2006 and 2012, 1338 infants were enrolled and followed up for PMTCT care with earlier age of enrollment and improved retention observed over time. Mother to child transmission of HIV declined from 19.4 % in 2006 to 8.9 % in 2012 (non-parametric test for trend p = 0.024). From 2009 to 2012, enrolling for care after 6 months of age, adjusted Odds Ratio [aOR]: 23.3 [95 % confidence interval (CI): 8.3-65.4], presence of malnutrition ([aOR]: 2.3 [95 % CI: 1.1-5.2]) and lack of maternal use of highly active antiretroviral therapy (HAART) (aOR: 6.5 [95 % CI: 1.4-29.4]) was associated with increased risk of HIV infection. Infant's older age at enrollment, malnutrition and maternal HAART status, were also associated with drop out from care. Infants who were not actively followed up were more likely to drop out from care (adjusted Hazard Ratio: 6.6 [95 % CI: 2.9-14.6]). DISCUSSION: We report a temporal increase in the proportion of infants enrolling for PMTCT care before 3 months of age, improved retention in PMTCT and a significant reduction in the proportion of infants enrolled who became HIV-infected, emphasizing the benefits of PMTCT. CONCLUSION: A simple set of risk factors at enrollment can identify mother-infant pairs most at risk of infection or drop out for targeted intervention.