Genetic diversity and occult hepatitis B infection in Africa: A comprehensive review.

BACKGROUND: Occult hepatitis B infection (OBI) is a globally prevalent infection, with its frequency being influenced by the prevalence of hepatitis B virus (HBV) infection in a particular geographic region, including Africa. OBI can be transmitted through blood transfusions and organ transplants and has been linked to the development of hepatocellular carcinoma (HCC). The associated HBV genotype influences the infection. AIM: To highlight the genetic diversity and prevalence of OBI in Africa. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and involved a comprehensive search on PubMed, Google Scholar, Science Direct, and African Journals Online for published studies on the prevalence and genetic diversity of OBI in Africa. RESULTS: The synthesis included 83 articles, revealing that the prevalence of OBI varied between countries and population groups, with the highest prevalence being 90.9% in patients with hepatitis C virus infection and 38% in blood donors, indicating an increased risk of HBV transmission through blood transfusions. Cases of OBI reactivation have been reported following chemotherapy. Genotype D is the predominant, followed by genotypes A and E. CONCLUSION: This review highlights the prevalence of OBI in Africa, which varies across countries and population groups. The study also demonstrates that genotype D is the most prevalent.

Expansion of Neisseria meningitidis Serogroup C Clonal Complex 10217 during Meningitis Outbreak, Burkina Faso, 2019.

During January 28-May 5, 2019, a meningitis outbreak caused by Neisseria meningitidis serogroup C (NmC) occurred in Burkina Faso. Demographic and laboratory data for meningitis cases were collected through national case-based surveillance. Cerebrospinal fluid was collected and tested by culture and real-time PCR. Among 301 suspected cases reported in 6 districts, N. meningitidis was the primary pathogen detected; 103 cases were serogroup C and 13 were serogroup X. Whole-genome sequencing revealed that 18 cerebrospinal fluid specimens tested positive for NmC sequence type (ST) 10217 within clonal complex 10217, an ST responsible for large epidemics in Niger and Nigeria. Expansion of NmC ST10217 into Burkina Faso, continued NmC outbreaks in the meningitis belt of Africa since 2019, and ongoing circulation of N. meningitidis serogroup X in the region underscore the urgent need to use multivalent conjugate vaccines in regional mass vaccination campaigns to reduce further spread of those serogroups.

Killer cell immunoglobulin-like receptor alleles influence susceptibility to occult hepatitis B infection in West African population.

Occult hepatitis B infection (OBI) is a public health problem in Burkina Faso. OBI represents a risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). OBI could be due to mutant viruses undetectable by HBsAg assays or a strong suppression of viral replication and gene expression under the pression of the host immune system. To investigate the role of killer cell immunoglobulin-like receptor (KIR) gene polymorphisms in patients with OBI in Burkina Faso compared to healthy and chronic hepatitis B subjects. A total of 286 participants was recruited, including 42 cases of OBI, 110 cases of chronic hepatitis B and 134 HBV negative subjects. SSP-PCR was performed to search for the presence of KIR genes. The HBV viral load was determined by qPCR. The frequencies of the activator gene KIR2DS5 (P=0.045) and the pseudogene KIR2DP1 (P<0.001) in patients with OBI were higher than those in patients with chronic hepatitis B. These genes are associated with susceptibility of occult hepatitis B infection. The frequencies of the inhibitory KIR gene KIR2DL3 (P=0.01) of patients with occult hepatitis B were lower than those in chronic hepatitis B patients. This gene KIR2DL3 is associated with protection against occult hepatitis B infection. Also, the frequencies of the inhibitory KIR genes KIR2DL2 (P<0.001), KIR2DL3 (P<0.001) and activators KIR2DS2 (P<0.001) in chronic hepatitis B patients were higher compared to the frequencies of the KIR genes in healthy subjects. These genes KIR2DL3, KIR2DL5 (A, B), KIR3DL3, KIR3DS1, KIR2DL2 and KIR2DS2 are thought to be genes associated with the susceptibility to OBI. The KIR2DS5 and KIR2DP1 genes could be associated with susceptibility to OBI. As for the KIR gene KIR2DL3 could be associated with protection against occult hepatitis B infection.

Distribution and Incidence of Blood-Borne Infection among Blood Donors from Regional Transfusion Centers in Burkina Faso: A Comprehensive Study.

There is a high prevalence of blood-borne infections in West Africa. This study sought to determine the seroprevalence of blood-borne infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and syphilis, in blood donors in Burkina Faso. Blood donors were recruited from 2009 to 2013 in four major cities in Burkina Faso of urban area (Ouagadougou) and rural area (Bobo Dioulasso, Fada N'Gourma, and Ouahigouya). Serology tests including hepatitis B surface antigen, anti-HCV, anti-HIV, and rapid plasma reagin test were used for screening and were confirmed with ELISA. Disease prevalence was calculated among first-time donors. Incidence and residual risk were calculated from repeat donors. There were 166,681 donors; 43,084 had ≥ 2 donations. The overall seroprevalence of HBV, HCV, HIV, and syphilis were 13.4%, 6.9%, 2.1%, and 2.4%, respectively. The incidence rates (IRs) of HBV, HCV, HIV, and syphilis infection were 2,433, 3,056, 1,121, and 1,287 per 100,000 person-years. There was lower seroprevalence of HBV and HCV in urban area than in rural area (12.9% versus 14.0%, P < 0.001; and 5.9% versus 8.0%, P < 0.001), and no difference in HIV (2.1% versus 2.1%, P = 0.25). The IRs of new HBV, HCV, HIV, and syphilis were 2.43, 3.06, 1.12, and 1.29 per 100,000 person-years, respectively. The residual risk was one per 268 donations for HBV, one per 181 donations for HCV, and one per 1,480 donations for HIV, respectively. In conclusion, this comprehensive study from four blood donation sites in Burkina Faso showed high HBV and HCV seroprevalence and incidence with high residual risk from blood donation.

Characteristics of Patients With Chronic Hepatitis B Virus Infection With Genotype E Predominance in Burkina Faso.

Hepatitis B virus (HBV) genotype E (HBV-E) accounts for the majority of chronic hepatitis B (CHB) infections in West Africa. We aimed to determine factors associated with HBV-E-induced hepatocellular carcinoma (HCC) in West Africa. Data on patients from Burkina Faso who were hepatitis B surface antigen positive (HBsAg+) and had CHB were analyzed. HBV viral load and hepatitis B e antigen (HBeAg) status were measured in 3,885 individuals with CHB without HCC (CHB HCC-) and 59 individuals with CHB with HCC (CHB HCC+). HBV genotyping was performed for 364 subjects with CHB HCC- and 41 subjects with CHB HCC+. Overall, 2.5% of the CHB HCC- group was HBeAg+ compared with 0% of the CHB HCC+ group. Of the 364 patients who were CHB HCC- with available genotyping, the frequencies of HBV genotypes E and C/E were 70.3% and 12.9%, respectively. Age (odds ratio [OR] for older age, 1.08; 95% confidence interval [CI], 1.06-1.10 per 1-year increase in age), male sex (OR, 2.03; 95% CI, 1.11-3.69), and HBV viremia (OR, 1.48; 95% CI, 1.31-1.67 per 1 log10 IU/mL) were each associated with HCC diagnosis. Patients with genotype E had a lower HBeAg prevalence (6.3% vs. 14.9%), lower HBV viral load, and higher prevalence of cirrhosis (14.5% vs. 4.8%) than patients with genotype C/E. Conclusion: HBV-E is the most common circulating strain (70.3%) in West African patients. HCC was associated with older age, male sex, and high HBV viral load. It is expected that these results will further inform guidance on clinical management of HBV infection in West Africa.

Molecular insights into meningococcal carriage isolates from Burkina Faso 7 years after introduction of a serogroup A meningococcal conjugate vaccine.

In 2010, Burkina Faso completed the first nationwide mass-vaccination campaign of a meningococcal A conjugate vaccine, drastically reducing the incidence of disease caused by serogroup A meningococci. Since then, other strains, such as those belonging to serogroups W, X and C, have continued to cause outbreaks within the region. A carriage study was conducted in 2016 and 2017 in the country to characterize the meningococcal strains circulating among healthy individuals following the mass-vaccination campaign. Four cross-sectional carriage evaluation rounds were conducted in two districts of Burkina Faso, Kaya and Ouahigouya. Oropharyngeal swabs were collected for the detection of Neisseria meningitidis by culture. Confirmed N. meningitidis isolates underwent whole-genome sequencing for molecular characterization. Among 13 758 participants, 1035 (7.5 %) N. meningitidis isolates were recovered. Most isolates (934/1035; 90.2 %) were non-groupable and primarily belonged to clonal complex (CC) 192 (822/934; 88 %). Groupable isolates (101/1035; 9.8 %) primarily belonged to CCs associated with recent outbreaks in the region, such as CC11 (serogroup W) and CC10217 (serogroup C); carried serogroup A isolates were not detected. Phylogenetic analysis revealed several CC11 strains circulating within the country, several of which were closely related to invasive isolates. Three sequence types (STs) were identified among eleven CC10217 carriage isolates, two of which have caused recent outbreaks in the region (ST-10217 and ST-12446). Our results show the importance of carriage studies to track the outbreak-associated strains circulating within the population in order to inform future vaccination strategies and molecular surveillance programmes.

Identification of Streptococcus suis Meningitis by Direct Triplex Real-Time PCR, Burkina Faso.

Meningitis confirmation in Burkina Faso uses PCR for detecting Streptococcus pneumoniae, Neisseria meningitidis, or Hemophilus influenzae. We identified 38 cases of meningitis among 590 that were PCR-positive for 3 nonpneumococcal streptococcal pathogens, including 21 cases of Streptococcus suis. Among the country's 13 regions, 10 had S. suis-positive cases.

Molecular characterization of hepatitis B virus in blood donors from Burkina Faso: Prevalence of quasi-subgenotype A3, genotype E, and mixed infections.

Burkina Faso is a highly endemic area for Hepatitis B virus (HBV) which remains a major challenge for blood safety with >13% of candidate blood donors being chronically infected. However, little is known about the molecular epidemiology of the viral strains currently circulating. In this study, 99 HBV strains from HBsAg positive candidate blood donors in Ougadougou were genetically characterized by sequencing the pre-S/S region of the viral genome. Phylogenetic analyses revealed a 25% prevalence of HBV quasi-subgenotype A3 (A3QS ) co-circulating with the confirmed dominant HBV genotype E (72%). HBV/A3QS sequences formed a sub-cluster closely related to West-African sequences previously characterized, and showed a low intra-group genetic diversity (0.75%) suggesting a relatively recent spreading of HBV/A3QS strains in Burkina Faso. Low genetic diversity of genotype E strains compared to A3QS was confirmed. Mixed infections with the two genotypes were identified in 3% of the donors tested and contributed to artifacts during PCR amplification of the viral genome leading to erroneous apparent intergenotype recombinant sequences. While the co-circulation of two HBV genotypes in a restricted area may favor the emergence of intergenotype recombinant variants, strictly controlled molecular experimental procedures should be used to accurately characterize HBV circulating recombinant forms. J. Med. Virol. 88:2145-2156, 2016. © 2016 Wiley Periodicals, Inc.

Molecular diagnostic of cytomegalovirus, Epstein Barr virus and Herpes virus 6 infections among blood donors by multiplex real-time PCR in Ouagadougou, Burkina Faso.

INTRODUCTION: In most developing countries, Cytomegalovirus (CMV), Epstein Barr virus (EBV) and Herpes virus 6 (HHV-6) are not diagnosed in blood donors. The aim of this study is to determine the prevalence of these viruses in blood donors from the city of Ouagadougou, Burkina Faso. METHODS: The study included 198 blood donors of the Regional Blood Transfusion Centre of Ouagadougou. Multiplex real time PCR was used to diagnose the three viruses. Statistical analysis was performed with the software EpiInfo version 6 and SPSS version 17. P values ≤ 0.05 were considered significant. RESULTS: Of 198 samples tested, 18 (9.1%) were positive to at least one of the three viruses. In fact, 10 (5.1%) were positive for EBV, 10 (5.1%) positive for CMV and 12 (6.1%) positive for HHV-6. Viral infections were higher in women than in men, EBV (8,6% versus 4.3%), CMV (8.6% versus 3.7%) and HHV-6 (11.4% versus 4.9%). EBV / CMV / HHV-6 co-infection was found in 3.5% (7/198) of blood donors. CONCLUSION: The prevalence recorded in this study is low compared to those found in previous studies from the sub-region among blood donors. The molecular diagnostic test used in our study could explain the differences with previous studies.

Quality of life in persons living with HIV in Burkina Faso: a follow-up over 12 months.

BACKGROUND: In Burkina Faso, very little is known about the quality of life of persons living with HIV through their routine follow- up. This study aimed to assess the quality of life of persons living with HIV, and its change over a 1-year period. METHODS: Four hundred and twenty four (424) persons living with HIV were monitored during twelve (12) months from September 2012 to September 2013 in Ouagadougou, the capital city of Burkina Faso. Three interviews were conducted in order to assess the quality of life of patients and its change over time, using the World Health Organization Quality of Life assessment brief scale in patients with Human Immunodeficiency Virus infection (WHOQOL HIV-BREF). The Friedman test was used to assess significant differences in quantitative variables at each of the three follow-up interviews. Groups at baseline, at 6 months and at 12 months were compared using Wilcoxon signed rank test for quantitative data and McNemar test for qualitative variables. Pearson Chi(2) was used when needed. Multivariable logistic regression models were fit to estimate adjusted odds ratio (OR) and 95% confidence intervals (95% CI). Trends in global quality of life score and subgroups (status related to Highly Active Anti Retroviral Treatment (HAART) using univariate repeated measures analysis of variance were assessed. A p-value less than 0.05 was considered significant. RESULTS: At baseline, quality of life scores were highest in the domain of spirituality, religion and personal beliefs (SRPB) and lowest in the environmental domain. This trend was maintained during the 12-month follow-up. The global score increased significantly from the beginning up to the twelfth month of follow-up. Over the 12 months, the baseline factors that were likely to predict an increase in the global quality of life score were: not having support from relatives for medical care (P = 0.04), being under HAART (P = 0.001), being self-perceived as healthy (P = 0.03), and having a global quality of life score under 77 (P < 0.001). CONCLUSIONS: Our findings suggest the need to promote interventions to empower people living with HIV/AIDS through income generating activities. Such activities will enhance the quality of life of persons living with HIV in Burkina Faso. This could focus mostly on treatment-naïve HIV patients, lacking support from relatives and those who perceive themselves as ill.

Quality of life in people living with HIV: a cross-sectional study in Ouagadougou, Burkina Faso.

HIV/AIDS is a leading cause of death in most of sub-Saharan countries. HIV/AIDS impact on the quality of life of persons living with HIV in Burkina Faso hasn't been well documented. The aim of the study was to assess the quality of life in persons living with HIV and its associated factors. A cross-sectional study was conducted in Ouagadougou. 424 persons living with HIV were included in the study according to their status with regard to Highly Active Anti Retroviral Treatment: 115 were not yet under treatment, 21 started the treatment within the three months preceding the enrolment and 288 were under treatment for at least 12 months. The quality of life was assessed through the WHOQOL HIV-BREF. Statistical comparisons were made using Mann Whitney U test, Kruskal-Wallis H test, Pearson's khi2 or Fisher's exact test. Correlations were appreciated using Spearman's rho. Logistic regression was used to examine associations between the quality of life scores and sociodemographic or clinical variables. The mean global score of quality of life in all patients was 82.4. Better scores were recorded in the spiritual domain and worst scores in the environmental domain. Men had a higher global score than women (p < 0.001). Illiteracy was significantly associated with a lower quality of life (p = 0.001). Patients having support for medical treatment had a significantly better quality of life (p < 0.01). In multivariate analysis, being a man, having a support for medical care, getting older and self-perceived as healthy, were associated with a global score of quality of life higher than 77, that corresponds to the mid-range of the score in our data. These findings suggest the importance of the socio-psychological support and of a good environment in order to improve the quality of life of people living with HIV, especially in women, in younger and in those having no support for medical care. In the environmental domain, actions of HIV services providers should focus on better accessibility to social and health care, promotion of income-generating activities especially for women and youth living with HIV.

Characterisation of hepatitis C virus genotype among blood donors at the regional blood transfusion centre of Ouagadougou, Burkina Faso.

BACKGROUND: Hepatitis C virus (HCV) is responsible for about 900 deaths every year in Burkina Faso. In this country, serological screening for hepatitis B and C viruses is only carried out systematically among blood donors. The aim of this study was to determine the prevalence and genotypes of HCV among blood donors using reverse transcription polymerase chain reaction (PCR) and real-time PCR, respectively. MATERIALS AND METHODS: Serum samples were screened for antibodies to HCV using an enzyme-linked immunosorbent assay (ARCHITECT-i1000SR-ABBOTT). All the reactive samples for HCV antibodies were re-tested using a second enzyme-linked immunosorbent assay (Bio-Rad, Marnes la Coquette, France) for confirmation. RNA was detected in all the reactive samples for antibodies to HCV. HCV RNA positive samples were genotyped using the HCV Real-TM Genotype kit (Sacace Biotechnologies, Italy). RESULTS: Among 2,200 blood donors, the prevalences of antibodies to HCV and viral RNA were 4.4% (95% confidence interval=3.5-5.3) and 1.5% (95% confidence interval=1.0-2.0), respectively. Among HCV RNA carriers, genotyping showed that HCV genotypes 2 and 3 were the most prevalent as they were detected in 18 (56.3%) and 5 (15.6%) individuals, respectively. HCV genotypes 1a and 4 were the least frequent among the blood donors. HCV mixed genotypes 2/3 and 2/4 were also detected among the blood donors. CONCLUSION: The prevalence of HCV found in this study is lower than previously reported prevalences. Large-scale studies are needed to obtain a better picture of the molecular epidemiology of HCV in Burkina Faso.

Importance of extending the use of polymerase chain reaction in the diagnosis of venereal syphilis in a blood transfusion center in Burkina Faso, West Africa.

INTRODUCTION: Due to the existence of a variety of types of non-venereal syphilis caused by the related T. pallidum, regular serological testing such as Rapid Plasma Reagin (RPR) and Chemiluminescent Microparticle Immunoassay Technique (CMIA) are often unable to differentiate venereal syphilis from the non- venereal one, hence, the interest in the use of molecular biology testing for a confirmation diagnosis of syphilis caused by Treponema pallidum subspecies pallidum. OBJECTIVE: The study is designed to assess the effectiveness of PCR testing and serological methods in the diagnosis of Treponema pallidum subsp pallidum among blood donors in Burkina Faso. METHODS: The study included 6375 samples of volunteer blood donors from the regional blood transfusion center of Ouagadougou (CRTS/O). Among samples, 183 positive and 59 negative in RPR were analyzed to detect antibodies anti-T. pallidum subsp pallidum with a immunoassay method (CMIA) and were confirmed using the Polymerase Chain Reaction testing. RESULTS: In RPR, we obtained a prevalence rate of 2.9% (183/6375) for treponematosis. From the 183 RPR+ specimen, 108 (59%) were found CMIA+ and 11 (6%) were confirmed PCR+. While the 59 pattern RPR-; 31 (52.5%) were CMIA + including 3 (5.1%) tested PCR+. Seventy-five (75) samples RPR + /CMIA-; 2 (2.7%) were confirmed positive by PCR. All 28 samples RPR-/CMIA- were confirmed negative by PCR. CONCLUSION: PCR testing confirmed a low distribution of T. pallidum subsp pallidum in comparison to serological methods. Cross-reactions, existence of non-venereal treponemal or immunological scars could account for the discrepancy between the results obtained.

Screening of Hepatitis G and Epstein-Barr Viruses Among Voluntary non Remunerated Blood Donors (VNRBD) in Burkina Faso, West Africa.

In most sub-Saharan countries screening of blood-transmitted infections includes mainly HIV, HBV, HCV and syphilis. Many viruses such as Hepatitis G (HGV) and Epstein-Barr virus (EBV) which also carry a risk of transmission by blood transfusion raise the question of the extent of screening for these pathogens. This work aims to evaluate the prevalence of HGV and EBV in first-time blood donors in Ouagadougou. The prevalence of HGV and EBV in 551 blood donors was 7.4% and 5.4% respectively. HGV prevalence was significantly higher in blood donors with hepatitis B antigens and positive for HCV compared to donors negative for HCV and no hepatitis B antigens (respectively p<0.001 and p=0.004). EBV prevalence was higher among blood donors of < 20 years age group. HBV and HCV positive individuals are not eligible for blood donation. This study shows significant results with regard to the prevalence of HGV and EBV prevalence in blood donors in Burkina Faso and emphasizes the need for a general screening.

Epidemiology of syphilis in regional blood transfusion centres in Burkina Faso, West Africa.

INTRODUCTION: Syphilis remains a major public health problem in sub-Saharan Africa, including Burkina Faso. However, few published data are available on the prevalence of syphilis in the population. This study had two main objectives: to determine the seroprevalence of syphilis in a cohort of 37,210 first time blood donors and to study socio-demographic factors associated with the risk of infection by Treponema pallidum. METHODS: Antibodies to Treponema pallidum were screened by using Reagin Rapid Test (RPR) and confirmed by treponema pallidum haemagglutination test (TPHA). RESULTS: The overall seroprevalence of syphilis was 1.5% among first time blood donors and was significantly different between centers (p <0.001). The infection was significantly higher in men than women among blood donors in Ouagadougou and Fada N'gourma (P = 0.001 and P = 0.034). The overall seroprevalence of syphilis among blood donors was not associated with either age group or HIV status. In contrast, a significantly high seroprevalence of syphilis was observed in blood donors with HBsAg (P = 0.014) and anti-HCV (P = 0.007) positive. CONCLUSION: Our report shows a low seroprevalence of syphilis in the representative sample of the population of Burkina Faso. The seroprevalence of syphilis remains unequally distributed between urban and rural areas and was not associated with HIV infection.

Seroprevalence of toxoplasmosis and rubella in pregnant women attending antenatal private clinic at Ouagadougou, Burkina Faso.

OBJECTIVE: To evaluate the prevalence of toxoplasmosis and rubella among pregnant women at Ouagadougou in Burkina Faso. METHODS: All patient sera were tested for rubella and toxoplasmosis anti-IgG using commercial ELISA kits (Platelia™ Rubella IgG and Platelia™ Toxo IgG). The presence of anti-rubella and anti-toxoplasmosis IgM in serum samples was tested using commercial ELISA kits Platelia Rubella IgM and Platelia Toxo IgM. RESULTS: Among all the pregnant women tested for toxoplasmosis and rubella, their prevalence were 20.3% and 77.0%, respectively. Pregnant women in the age group of 18-25 years showed the highest frequency of anti-toxoplasmosis (34.5%) and anti-rubella IgG (84.6%). The prevalence of anti-toxoplasma and anti-rubella IgG decreased between 2006 and 2008 from 32.7% to 12.1% and 84.6% to 65.0%, respectively. There was no significant association between age and the mean titer of anti-toxoplasmosis IgG among pregnant women. CONCLUSIONS: The diagnosis of toxoplasmosis and rubella is necessary in pregnant women in Burkina Faso because of the low immunization coverage rate of rubella and the high level of exposure to these two infections which can be harmful to the newborn if contracted by women before the third trimester of pregnancy.

Seroprevalence and incidence of transfusion-transmitted infectious diseases among blood donors from regional blood transfusion centres in Burkina Faso, West Africa.

BACKGROUND AND OBJECTIVE: The high prevalence of numerous transfusion-transmitted infectious diseases such as HIV, HBV, HCV and syphilis in sub-Saharan Africa affects blood safety for transfusion recipients. The aim of this study was to evaluate the prevalence and incidence of transfusion-transmissible infectious diseases among blood donors in Burkina Faso. METHODS: A retrospective study of blood donors' records from January to December 2009 was conducted. Prevalence and incidence of viral infections were calculated among repeat and first-time blood donors. RESULTS: Of the total of 31405 first-time volunteer blood donors in 2009, 24.0% were infected with at least one pathogen and 1.8% had serological evidence of multiple infections. The seroprevalence of HIV, HBV, HCV and syphilis in first-time volunteer donors was 1.8%, 13.4%, 6.3% and 2.1%, respectively. In 3981 repeat donors, the incidence rate was 3270.2, 5874.1 and 6784.6 per 100000 donations for anti-HIV-1, HBsAg and anti-HCV, respectively. These numbers varied significantly according to populations where blood is collected and blood centres in Burkina Faso. CONCLUSION: The relatively high prevalence of viral markers in first-time volunteers and remarkably high incidence of infections in repeat donors raise concerns regarding the safety of these donors and suggest that implementation of NAT might significantly improve the situation.