Effect of pneumococcal conjugate vaccines on viral respiratory infections: a systematic literature review.

BACKGROUND: In addition to preventing pneumococcal disease, emerging evidence indicates that pneumococcal conjugate vaccines (PCVs) might indirectly reduce viral respiratory tract infections (RTI) by affecting pneumococcal-viral interactions. METHODS: We performed a systematic review of interventional and observational studies published during 2000-2022 on vaccine efficacy/adjusted effectiveness (VE) and overall effect of PCV7, PCV9, PCV10, or PCV13 against viral RTI. RESULTS: Sixteen of 1671 records identified were included. Thirteen publications described effects of PCVs against viral RTIs in children. VE against influenza ranged between 41-86% (n=4), except for the 2010-2011 influenza season. In a randomized controlled trial, PCV9 displayed efficacy against any viral RTI, human seasonal coronavirus, parainfluenza, and human metapneumovirus. Data in adults were limited (n=3). PCV13 VE ranged between 4-25% against viral lower RTI, 32-35% against COVID-19 outcomes, 24-51% against human seasonal coronavirus, and 13-36% against influenza A lower RTI, with some 95%CI spanning zero. No protection was found against adenovirus or rhinovirus in children or adults. CONCLUSIONS: PCVs were associated with protection against some viral RTI, with the strongest evidence for influenza in children. Limited evidence for adults was generally consistent with pediatric data. Restricting public health evaluations to confirmed pneumococcal outcomes may underestimate the full impact of PCVs.

Characterization of type-specific HPV prevalence in a population of persistent cutaneous warts in Flanders, Belgium.

Cutaneous warts are benign skin lesions caused by the human papillomavirus (HPV). Even though they are considered benign, they can have a considerable impact on the quality of life and cause serious illness in certain immunocompromised populations. Studies have shown that the efficacy of wart treatment is dependent on the causative HPV type. Therefore, in this article, we aim to determine the HPV genotype-specific prevalence in cutaneous warts of a Flemish population as part of the Omnivirol-Salycilic acid randomized controlled trial. Swab samples of cutaneous warts (n = 269) were collected during enrollment. The DNA extraction was performed on the automated NucliSENS® easyMAG® system (bioMérieux). The samples were analyzed with two separate in-house PCR assays capable of detecting the most prevalent cutaneous HPV types (i.e. wart-associated HPV qPCR) as well as the most relevant mucosal types (i.e. RIATOL qPCR assay). In total, the type-specific prevalence of 30 distinct HPV genotypes was determined. The beta-globin gene was used as a cellularity control and for viral load quantification. Data concerning wart persistence, previous treatment, wart type, and other relevant wart and patient characteristics was collected through a baseline questionnaire. The study population consisted mostly of persistent warts considering that 98% (n = 263) of the sampled skin lesions were older than six months and 92% (n = 247) had undergone previous treatment. The most prominent wart type was the mosaic verruca plantaris (42%, n = 113). The most prevalent HPV types were cutaneous HPV types 27 (73%, n = 195), 57 (63%, n = 169), and 2 (42%, n = 113). Only 2% (n = 6) of the lesions was HPV negative. The highest median viral loads were observed with HPV27 and 57 (i.e. 6.29E+04 and 7.47E+01 viral copies per cell respectively). The multivariate analysis found significant associations between wart persistence and certain wart types, the number of warts, and HPV genotypes. Based on these findings, persistent warts are more likely to: (1) be verruca vulgaris, verruca plantaris simple or mosaic, (2) to manifest as multiple warts, (3) and to be negative for HPV type 2 or 4. These characteristics can be useful in the clinical setting for future risk stratification when considering treatment triage and management. Trial registration: NCT05862441, 17/05/2023 (retrospectively registered).

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

The epidemiology of tuberculosis-associated hyperglycemia in individuals newly screened for type 2 diabetes mellitus: systematic review and meta-analysis.

BACKGROUND: There is scarce evidence that tuberculosis (TB) can cause diabetes in those not previously known to be diabetic. Whilst the World Health Organization (WHO) recommends screening for Diabetes Mellitus (DM) at the onset of TB treatment, nevertheless, it remains to be elucidated which patients with TB-associated hyperglycemia are at higher risk for developing DM and stand to benefit from a more regular follow-up. This review aims to firstly quantify the reduction of newly detected hyperglycemia burden in TB patients who are on treatment over time; secondly, determine the burden of TB-associated hyperglycemia after follow-up, and thirdly, synthesize literature on risk factors for unresolved TB-associated hyperglycemia in previously undiagnosed individuals. METHODS: We searched PUBMED, EMBASE, SCOPUS, and Global Health for articles on TB-associated hyperglycemia up to September 30th, 2019. Search terms included Tuberculosis and hyperglycemia/DM, and insulin resistance. We appraised studies, extracted data, and conducted a meta-analysis to assess the change of the burden of hyperglycemia in prospective studies. The review is registered in the PROSPERO database (CRD42019118173). RESULTS: Eleven studies were included in the meta-analysis yielding a total of 677 (27,3%) of patients with newly detected hyperglycemia at baseline. The mean quality score of eligible studies using the Newcastle-Ottawa Quality Assessment Scale was 7.1 out of 9 (range 6-9). The pooled unresolved new cases of hyperglycemia at the end of follow up was 50% (95% CI: 36-64%) and the total pooled burden of hyperglycemia at 3-6 months of follow up was 11% (95% CI: 7-16%), with both estimates displaying a high heterogeneity, which remained significant after performing a sub-analysis by DM diagnostic method and 3 months of follow up. As only 2 studies explored risk factors for unresolved hyperglycemia, no meta-analysis was performed on risk factors. CONCLUSION: Our meta-analysis showed that although in half of the patients with newly observed hyperglycemia at baseline, it remained unresolved at a follow-up of 3 to 6 months, the total burden of hyperglycemia is slightly above 10%, 3 months after initiating TB treatment. Studies are warranted to assess whether risk factors including HIV positivity, smoking, and extensive pulmonary TB disease put patients at higher risk for DM.

Prevalence of malaria parasitaemia in school-aged children and pregnant women in endemic settings of sub-Saharan Africa: A systematic review and meta-analysis.

Despite increased malaria control efforts, school-aged children (5-14 years) have higher a malaria prevalence compared to children under-five. In high-transmission settings, up to 70% of school-aged children harbour malaria parasitaemia and therefore contribute significantly to the reservoir for transmission. A systematic review was performed to explore the correlation between the malaria parasite carriage in pregnant women and school-aged children living in similar endemic settings of sub Saharan Africa to inform strategies to improve targeted malaria control. In order to obtain data on malaria prevalence in pregnant women and school-aged children living in the same endemic setting, we searched the Malaria in Pregnancy Library, PubMed, Cochrane library and Web of Science in December 2018. We fit a fixed effect model to obtain a pooled risk ratio (PRR) of malaria in school-aged children versus pregnant women and used Poisson regression to estimate risk ratios in school-aged children for every increase in prevalence in pregnant women. We used data from six (out of 1096) sources that included 10 data points. There was a strong linear relation between the prevalence of malaria infection in pregnant women and school-aged children (r = 0·93, p < 0·0001). School-aged children were nearly twice at risk to carry parasites compared to pregnant women (RR = 1.95, 95% CI: 1·69-2.25, p < 0.01). Poisson regression showed that a 1% increase in prevalence of malaria infection in pregnant women was significantly associated with increase in risk in school-aged children by 4%. Malaria infection prevalence in school-aged children is strongly correlated with the prevalence in pregnant women living in the same community, and may be considered as alternative indicators to track temporal and spatial trends in malaria transmission intensity. Chemoprevention strategies targeting school-aged children should be explored to reduce malaria burden and transmission in school-aged children and its potential impact on communities.

Performance of OncoE6TM Cervical Test in detecting cervical precancer lesions in HIV-positive women attending an HIV clinic in Bujumbura, Burundi: a cross-sectional study.

OBJECTIVE: New rapid and low-cost molecular tests for cervical cancer screening, such as the OncoE6 Cervical Test, are emerging and could be alternatives for low-income and middle-income countries. To this end, we evaluated the clinical performance of the OncoE6 Cervical Test in detecting cervical intraepithelial neoplasia (CIN) among HIV-infected women in Bujumbura, Burundi. METHODS: From June to December 2017, a cross-sectional study was conducted in 680 HIV-positive women at the University Hospital. Women aged 25-65 years who declared having had vaginal intercourse were consecutively recruited, and cervical specimens for OncoE6, liquid-based cytology and human papillomavirus (HPV) genotyping were obtained and visual inspection with acetic acid performed. Thereafter, participants underwent a colposcopic examination. The sensitivity, specificity, and positive and negative predictive values of the different tests were calculated with reference to 'colposcopic-histological' diagnoses, and areas under the receiver operating curves of OncoE6 and cytology tests were compared. RESULTS: The prevalence of CIN was 4.9%, and OncoE6 positivity was 3.1%. OncoE6 sensitivity varied from poor to low with increasing disease severity (42.1%, 95% CI 19.9% to 64.3% at CIN2+ threshold; and 58.3%, 95% CI 30.4% to 86.2% at CIN3+ threshold). OncoE6 had the highest specificity compared with all other tests used together. The performance of the OncoE6 test was significantly lower compared with cytology at atypical squamous cell of undetermined significance (ASCUS+) cut-off (AUC=0.68 vs 0.85, p=0.03) and low-grade squamous intraepithelial lesion (LSIL+) cut-off (AUC=0.68 vs 0.83, p=0.04) for CIN2+ diagnoses. However, the performance of the OncoE6 test was similar to that of cytology at high-grade squamous intraepithelial lesion (HSIL+) cut-off (AUC=0.68 vs 0.76; p=0.30) for CIN2+ diagnoses and was also similar to that of cytology at all cut-offs (ASCUS+, LSIL+ and HSIL+) for CIN3+ diagnoses (p1=0.76, p2=0.95 and p3=0.50, respectively). CONCLUSION: The current OncoE6 test proved to be a point-of-care test. However, given its poor performance for CIN2+ diagnoses, we do not recommend it for primary screening. We recommend to enrich it with more oncogenic HPV types, which may improve the performance of the test akin to that of cytology.

Effects of malaria/helminthic coinfections on cervical cancer progression among sub Saharan African women on highly active antiretroviral therapy: A scoping review.

In Africa, the HIV prevalence in rural areas has begun to reach levels estimated within urban settings, where women are also more at risk for both malaria and intestinal parasitic infections. The objective of this review is to assess whether concomitant infections with malaria and/or helminthic diseases have an impact on cervical disease progression in women on HAART. This scoping review was conducted in August 2018. To conduct this scoping review, we searched the relevant studies in electronic databases such as PUBMED, Global Health, EMBASE, CINAHL and SCOPUS published in the year between 1960 and 2018 using the following search terms HAART AND malaria OR Helminth and Female OR women. Eight studies qualified for this review. The literature underscores the need for women on HAART with multiple co-infections to use adjuncts to retain immune recovery and undetectable HIV viral load, to reduce risk of cervical disease progression. A trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection was observed in one study. Given the public health impact of synergistic interactions between malaria and helminthic infections in HIV/HPV co-infected women on HAART, it is urgent that these interactions are elucidated.

Relationship between Highly Active Antiretroviral Therapy (HAART) and human papillomavirus type 16 (HPV 16) infection among women in Sub-Saharan Africa and public health implications: A systematic review.

Invasive cervical cancer is the most prevalent cancer among women in Sub-Saharan Africa. In 2013, the World Health Organization (WHO) emitted recommendations to start Highly Active Antiretroviral Therapy (HAART) regardless of CD4 count. Although HAART has been shown to reduce the prevalence of high-risk human papillomavirus (HR-HPV) genotypes, it is unclear whether it confers a protective effect specifically for HPV 16. This review summarizes the existing evidence regarding the effect of HAART on HPV 16 infection, as this genotype may not be influenced by immunity level and explores its implications for Sub Saharan Africa. A comprehensive literature review was undertaken and quality assessment was carried out on the selected papers. Four cohort studies and three cross-sectional studies were identified for which the overall quality score assessment ranged from weak/moderate (Score of 1.8) to strong (Score of 3). The evidence yielded by our review was conflicting. Thus, the high heterogeneity between study populations and results did not allow us to draw any firm conclusions as to whether HAART has an impact on HPV 16 acquisition/prevalence. As only three studies were conducted in Africa, there are insufficient grounds for solid comparison between geographic regions. In light of inadequate data, HPV unvaccinated women on HAART should still receive more frequent follow-up.

Correction to: Multiple HPV infections in female sex workers in Western Kenya: implications for prophylactic vaccines within this sub population.

[This corrects the article DOI: 10.1186/s13027-016-0114-5.].

Determining the HPV vaccine schedule for a HIV-infected population in sub Saharan Africa, a commentary.

BACKGROUND: Epidemiological studies have established human papillomavirus (HPV) infection as the central cause of invasive cervical cancer (ICC) and its precursor lesions. HIV is associated with a higher prevalence and persistence of a broader range of high-risk HPV genotypes, which in turn results in a higher risk of cervical disease. Recent WHO HPV vaccination schedule recommendations, along with the roll out of HAART at an earlier CD4 count within the female HIV-infected population, may have programmatic implications for sub Saharan Africa. This communication identifies research areas, which will need to be addressed for determining a HPV vaccine schedule for this population in sub Saharan Africa. A review of WHO latest recommendations and the evidence concerning one-dose HPV vaccine schedules was undertaken. CONCLUSION: For females ≥15 years at the time of first dose and immunocompromised and/or HIV-infected, a 3-dose schedule (0, 1-2, 6 months) is recommended for all three vaccines. There is some evidence that there is similar protection against HPV 16 and 18 infection from a single vaccination than from two or three doses, however there is no cross protection conferred to other genotypes. There is a need for periodic prevalence studies to determine the vaccination coverage of bivalent, quadrivalent and nonavalent vaccine targeted oncogenic HPV genotypes in women with CIN 3 or ICC at national level. In light of the increasing number of sub Saharan HIV-infected girls initiating HAART at a CD4 count above 350 mm3, there are a number of clinical, virological and public health research gaps to address before a tailored vaccine schedule can be established for this population.

Uptake of three doses of HPV vaccine by primary school girls in Eldoret, Kenya; a prospective cohort study in a malaria endemic setting.

BACKGROUND: All women are potentially at risk of developing cervical cancer at some point in their life, yet it is avoidable cause of death among women in Sub- Saharan Africa with a world incidence of 530,000 every year. It is the 4th commonest cancer affecting women worldwide with over 260,000 deaths reported in 2012. Low resource settings account for over 75% of the global cervical cancer burden. Uptake of HPV vaccination is limited in the developing world. WHO recommended that 2 doses of HPV vaccine could be given to young girls, based on studies in developed countries. However in Africa high rates of infections like malaria and worms can affect immune responses to vaccines, therefore three doses may still be necessary. The aim of this study was to identify barriers and facilitators associated with uptake of HPV vaccine. METHODS: A cross-sectional survey was conducted at Eldoret, Kenya involving 3000 girls aged 9 to 14 years from 40 schools. Parents/guardians gave consent through a questionnaire. RESULTS: Of all 3083 the school girls 93.8% had received childhood vaccines and 63.8% had a second HPV dose, and 39.1% had a third dose. Administration of second dose and HPV knowledge were both strong predictors of completion of the third dose. Distance to the hospital was a statistically significant risk factor for non-completion (P: 0.01). CONCLUSIONS: Distance to vaccination centers requires a more innovative vaccine-delivery strategy and education of parents/guardians on cervical screening to increase attainment of the HPV vaccination.

Human papilloma virus correlates of high grade cervical dysplasia in HIV-infected women in Mombasa, Kenya: a cross-sectional analysis.

BACKGROUND: Women living with HIV are at increased risk to be co-infected with HPV, persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR HPV viral load, which make them more at risk for cervical cancer. Despite their inherent vulnerability, there is a scarcity of data on potential high risk (pHR) and HR HPV genotypes in HIV- infected women with cervical dysplasia and HPV-type specific viral load in this population in Sub Saharan Africa. The aim of this analysis of HIV-infected women was to explore the virological correlates of high-grade cervical dysplasia (CIN 2+) in HIV-infected women, thereby profiling HPV genotypes. METHOD: This analysis assesses baseline data obtained from a cohort study of 74 HIV-infected women with abnormal cytology attending a Comprehensive Care Centre for patients with HIV infection in Mombasa, Kenya. Quantitative real-time PCR was used for HPV typing and viral load. RESULTS: CIN 2 was observed in 16% (12/74) of women, CIN 3 in 23% (17/74), and, invasive cervical carcinoma (ICC) in 1% (1/74) of women. In women with CIN 3+, HPV 16 (44%), HPV 56 (33%), HPV 33 and 53 (HPV 53 (28%) were the most prevalent genotypes. HPV 53 was observed as a stand-alone HPV in one woman with ICC. A multivariate logistic regression adjusting for age, CD4 count and HPV co-infections suggested the presence of HPV 31 as a predictor of CIN 2+ (adjusted odds ratio [aOR]:4.9; p = 0.05; 95% (Confidence Interval) [CI]:1.03-22.5). Women with CIN2+ had a significantly higher viral log mean of HPV 16, (11.2 copies/ 10,000 cells; 95% CI: 9.0-13.4) than with CIN 1. CONCLUSION: The high prevalence of HPV 53 in CIN 3 and as a stand-alone genotype in the patient with invasive cervical cancer warrants that its clinical significance be further revisited among HIV-infected women. HPV 31, along with elevated means of HPV 16 viral load were predictors of CIN 2 + .

Human papilloma virus infection in HIV-infected women in Belgium: implications for prophylactic vaccines within this subpopulation.

Although high-risk (HR) human papilloma virus (HPV) infection is the primary causative factor for cervical squamous intraepithelial lesions and invasive cervical cancer, the epidemiology of potentially HR (pHR) and low-risk HPV still remains to be elucidated in HIV-infected women. In addition, the synergistic potential of the multiplicity of HPV infections harboured renders it difficult to model the impact of vaccines. This cross-sectional analysis of HIV-infected women explores the epidemiology of abnormal cytology, thereby profiling and pairing pHR/HR HPV genotypes. This cross-sectional analysis reports the findings of 593 HIV-infected women, who underwent a cytological examination and HPV genotyping. A logistic regression model was fitted to adjust for age and coinfection with pHR/HR HPV genotypes. In the 143 women with abnormal cytology, a multiple pHR/HR HPV genotype prevalence of 64.1% [95% confidence interval (CI): 44.6-57.6%] was observed. A combined prevalence of HPV 16 and HPV 18 of 29.6% (95% CI: 22.2-37.8%) was found. HPV 6 and HPV 66 were found in two cases of low-grade squamous intraepithelial lesions as stand-alone genotypes and HPV 53 in a high-grade squamous intraepithelial lesion case. Pairing involving HPV 31 with HPV 16 and HPV 58 was found in high-grade squamous intraepithelial lesion cases. Significant associations were observed between abnormal cytology, multiple HPV, HPV 39 and HPV 53 [adjusted odds ratio (aOR): 2.02; P=0.01; 95% CI: 1.2-3.5; aOR: 3.8; P=0.01; 95% CI: 1.4-10.7; and aOR: 0.5; P=0.03; 95% CI: 0.2-0.9, respectively]. Coinfection with pHR/HR HPV genotypes HPV 39 and 53 was significantly associated with abnormal cytology. Research into the imputed role of HPV 31 in pairings, low-risk and pHR HPV genotypes in HIV-infected women is warranted.

Public health approach to prevent cervical cancer in HIV-infected women in Kenya: Issues to consider in the design of prevention programs.

Women living with HIV in Africa are at increased risk to be co-infected with Human Papilloma Virus (HPV), persistent high risk (HR) HPV infection and bacterial vaginosis (BV), which compounds HPV persistence, thereby increasing the risk for cervical dysplasia. New guidance from WHO in 2014 advocating for a "screen and treat" approach in resource poor settings is becoming a more widely recommended screening tool for cervical cancer prevention programs in such contexts. This review article summarizes the risk factors to be considered when designing a primary and secondary cervical prevention program in a post-vaccination era for HIV-infected women in Kenya. This review article is based on our prior research on the epidemiology of pHR/HR-HPV genotypes in HIV-infected women and CIN 2 + in Kenya and other sub-Saharan contexts. In order to contextualize the findings, a literature search was carried out in March 2017 by means of four electronic databases: PUBMED, EMBASE, SCOPUS, and PROQUEST. Risk factors for potential (pHR)/HR HPV acquisition, including CD4 count, HAART initiation, Female Sex Worker status (FSW) and BV need to be considered. Furthermore, there may be risk factors for abnormal cytology, including FSW status, multiple potential (p)HR/HR HPV genotypes, which may require that HIV-infected women be subjected to screening at more frequent intervals than the three year recommended by the WHO. The quadruple synergistic interaction between HIV, HPV and BV and its related cervicitis may need to be reflected within a larger prevention framework at the community level. The opportunities brought forth by the roll out of HAART could lead to task shifting of HIV-HPV-BV care to nurses, which may increase access in poorly-served areas.

Associations between highly active antiretroviral therapy and the presence of HPV, premalignant and malignant cervical lesions in sub-Saharan Africa, a systematic review: current evidence and directions for future research.

OBJECTIVES: In sub-Saharan Africa, substantial international funding along with evidence-based clinical practice have resulted in an unparalleled scale-up of access to antiretroviral treatment at a higher CD4 count. The role and timing of highly active antiretroviral therapy (HAART) in mediating cervical disease remains unclear. The aim of this article is to systematically review all evidence pertaining to Africa and identify research gaps regarding the epidemiological association between HAART use and the presence of premalignant/malignant cervical lesions. METHOD: Five databases were searched until January 2017 to retrieve relevant literature from sub-Saharan Africa. Publications were included if they addressed prevalence, incidence or clearance of human papillomavirus (HPV) infection in women undergoing HAART as well as cytological or histological neoplastic abnormalities. RESULTS: 22 studies were included, of which seven were prospective studies. Women receiving HAART are less likely to develop squamous intraepithelial lesions (SILs). There is evidence that duration of HAART along with the CD4 count may reduce the prevalence of high-risk HPV (HR-HPV), suggesting that without HAART, severe immunosuppression increases the risk of becoming or remaining infected with HR-HPV. Furthermore, according to existent literature, the CD4 count, rather than HAART coverage or its duration, plays a central role in the prevalence of cervical intraepithelial neoplasia (CIN) 2 and CIN 3. CONCLUSION: Our findings suggest a positive impact of HAART duration, in conjunction and interaction with CD4 count, on reducing the prevalence of HR-HPV. The greatest treatment effect might be seen among women starting at the lowest CD4 count, which may have a more instrumental role in cervical oncogenesis than either HAART use or the treatment duration on the prevalence of CIN 2 and CIN 3. There is still insufficient evidence to show a clear association between HAART coverage and the incidence of invasive cervical cancer. Enhanced surveillance on the impact of HAART treatment is crucial.

Multiple HPV infections in female sex workers in Western Kenya: implications for prophylactic vaccines within this sub population.

BACKGROUND: Whilst the imputed role of High Risk (HR) HPV infection in the development of cervical lesions and cancer has been established, the high number of HPV genotypes that Female Sex workers (FSW) harbour warrants that the synergistic effects of potential HR (pHR) and HR HPV genotypes be elucidated to assess the potential impact of prophylactic vaccines. This population in Kenya also harbours a number of other vaginal infections and STIs, including bacterial vaginosis (BV), trichomonas vaginalis (TV) and candida spp. The aims of this cross-sectional analysis in Kenya are to explore the epidemiology of abnormal cytology and the pairing of pHR/HPV genotypes in HIV-negative and HIV-infected FSW. METHODS: A cross-sectional study design of 616 FSW from Western Kenya aged between 18 and 61 years during 2009-2015 using a peer recruitment sampling strategy. RESULTS: Of the 599 FSW who underwent cytological examination, 87 had abnormal cytology (14.5%; 95% CI: 12.0-17.6%). A combined prevalence of HPV16 and 18 (29.6%; 95% CI: 22.2-37.8%) was observed in abnormal cytology. HPV 53 and 51 were the most observed pairing in FSW with abnormal cytology. Significant adjusted associations were found between abnormal cytology and TV (aOR: 30; 95% CI: 14.1-62.9), multiple HR HPV (aOR: 3.7; 95% CI: 1.9-7.3), HPV 51 (aOR 3.7; 95% CI 1.6-8.6) and HPV 52 (aOR 6.1; 95% CI: 2.8-13.3). CONCLUSION: HPV 51 and 52 were independently associated with abnormal cervical cytology in both HIV negative/positive FSW. The strong association between TV and cervical dysplasia and the high percentage of FSW harbouring more than one STI underscore the need for enhanced STI management within the framework of cervical cancer prevention.

Associations Between Vaginal Infections and Potential High-risk and High-risk Human Papillomavirus Genotypes in Female Sex Workers in Western Kenya.

PURPOSE: Infection with and persistence of high-risk human papillomavirus (HR HPV) are the strongest risk factors for cervical cancer. Little is known about the prevalence and role of concurrent sexually transmitted infections (STIs) found in HPV-infected female sex workers (FSW) in Africa. This study purports to test our a priori hypotheses that STIs are associated with genotypes pertaining to the α-group species 9. The objectives were to determine the prevalence of bacterial vaginosis (BV), Trichomonas vaginalis, and Candida spp in FSW, the association between these STIs and the prevalence of any potential HR and HR HPV genotypes in FSWs. METHODS: A cross-sectional study design of 616 FSW from Western Kenya aged between 18 and 61 years during 2009-2015 using a peer recruitment sampling strategy. Inclusion criteria for the study entailed female sex and >18 years of age and having engaged in transactional sex in exchange for money, goods, services, or drugs in the last 3 months. Women were excluded if they were pregnant, <18 years of age, had a history of cervical dysplasia or cancer, had current abnormal bleeding, or had a hysterectomy. FINDINGS: Of the FSW, 33.3% had HIV and 57.7% harbored a potential HR and HR HPV genotype. The 2 most prevalent potential HR and HR genotypes were HPV 16 (16.10%) and HPV 59 (12.20%). BV was the most common infection (48.3%), followed by Trichomonas vaginalis (31.4%) and Candida spp (19.9%). A multivariate regression revealed significant associations with both α-group 9 and 6; BV and HPV 58 (adjusted odds ratio [aOR] = 2.3; 95% CI, 1.0-5.2; P = 0.05), Trichomonas vaginalis and HPV 31 and HPV 35 (aOR = 2.0; 95% CI, 1.0-3.8; P = 0.04 and aOR = 1.8; 95% CI, 1.0-3.3, P = 0.05 respectively); and between Candida spp and HPV 53 (aOR = 2.0; 95% CI, 1.1-4.0; P = 0.03) and 16 (aOR = 1.9; 95% CI, 1.1-3.3; P = 0.03). IMPLICATIONS: Snowball sampling may have inadvertently excluded FSW less likely to benefit from a social network. Significant associations between BV and HPV 58 and between Candida spp and HPV 16 and 53 suggest the need for sexually transmitted disease management within a cervical cancer prevention program. The probable synergistic effects of the vaginal microbiota should be elucidated, especially within this vulnerable population. Given the potential for FSW to transmit STIs, robust epidemiologic sampling methods are urgently required that account for the heterogeneity of the FSW population.

Epidemiology of HPV Genotypes among HIV Positive Women in Kenya: A Systematic Review and Meta-Analysis.

BACKGROUND: There is a scarcity of data on the distribution of human papillomavirus (HPV) genotypes in the HIV positive population and in invasive cervical cancer (ICC) in Kenya. This may be different from genotypes found in abnormal cytology. Yet, with the advent of preventive HPV vaccines that target HPV 16 and 18, and the nonavalent vaccine targeting 90% of all ICC cases, such HPV genotype distribution data are indispensable for predicting the impact of vaccination and HPV screening on prevention. Even with a successful vaccination program, vaccinated women will still require screening to detect those who will develop ICC from other High risk (HR) HPV genotypes not prevented by current vaccines. The aim of this review is to report on the prevalence of pHR/HR HPV types and multiple pHR/HR HPV genotypes in Kenya among HIV positive women with normal, abnormal cytology and ICC. METHODS: PUBMED, EMBASE, SCOPUS, and PROQUEST were searched for articles on HPV infection up to August 2nd 2016. Search terms were HIV, HPV, Cervical Cancer, Incidence or Prevalence, and Kenya. RESULTS: The 13 studies included yielded a total of 2116 HIV-infected women, of which 89 had ICC. The overall prevalence of pHR/HR HPV genotypes among HIV-infected women was 64% (95%CI: 50%-77%). There was a borderline significant difference in the prevalence of pHR/HR HPV genotypes between Female Sex workers (FSW) compared to non-FSW in women with both normal and abnormal cytology. Multiple pHR/HR HPV genotypes were highly prominent in both normal cytology/HSIL and ICC. The most prevalent HR HPV genotypes in women with abnormal cytology were HPV 16 with 26%, (95%CI: 23.0%-30.0%) followed by HPV 35 and 52, with 21% (95%CI: 18%-25%) and 18% (95%CI: 15%-21%), respectively. In women with ICC, the most prevalent HPV genotypes were HPV 16 (37%; 95%CI: 28%-47%) and HPV 18 (24%; 95%CI: 16%-33%). CONCLUSION: HPV 16/18 gains prominence as the severity of cervical disease increases, with HPV 16/18 accounting for 61% (95%CI: 50.0%-70.0%) of all ICC cases. A secondary prevention program will be necessary as this population harbors multiple pHR/HR HPV co-infections, which may not be covered by current vaccines. A triage based on FSW as an indicator may be warranted.