Phenotypic and genetic characterisation of bacterial sexually transmitted infections in Bissau, Guinea-Bissau, West Africa: a prospective cohort study

BACKGROUND: Knowledge regarding characteristics and transmission of Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium and antibiotic resistance in N gonorrhoeae in Guinea-Bissau, West Africa, is entirely lacking. OBJECTIVES: To characterise N gonorrhoeae, C trachomatis and M genitalium samples from Guinea-Bissau and to define bacterial populations, possible transmission chains and for N gonorrhoeae spread of antibiotic-resistant isolates. DESIGN: Prospective cohort study. SETTING: Two sexual health and family planning clinics, Bissau, Guinea-Bissau. PARTICIPANTS: Positive samples from 711 women and 27 men. MATERIAL AND METHODS: Positive samples for N gonorrhoeae (n=31), C trachomatis (n=60) and M genitalium (n=30) were examined. The gonococcal isolates were characterised with antibiograms, serovar determination and N gonorrhoeae multiantigen sequence typing (NG-MAST). The C trachomatis ompA gene and the M genitalium mgpB gene were sequenced, and phylogenetic analyses were performed. RESULTS: For N gonorrhoeae, the levels of resistance (intermediate susceptibility) to ciprofloxacin, erythromycin, rifampicin, ampicillin, tetracycline, penicillin G and cefuroxime were 10% (0%), 6% (10%), 13% (10%), 68% (0%), 74% (0%), 68% (16%) and 0% (84%), respectively. All isolates were susceptible to cefixime, ceftriaxone, spectinomycin and azithromycin, and the minimum inhibitory concentrations of kanamycin (range: 8-32 mg/l) and gentamicin (range: 0.75-6 mg/l) were low (no resistance breakpoints exist for these antimicrobials). 19 NG-MAST sequence types (STs) (84% novel STs) were identified. Phylogenetic analysis of the C trachomatis ompA gene revealed genovar G as most prevalent (37%), followed by genovar D (19%). 23 mgpB STs were found among the M genitalium isolates, and 67% of isolates had unique STs. CONCLUSIONS: The diversity among the sexually transmitted infection (STI) pathogens may be associated with suboptimal diagnostics, contact tracing, case reporting and epidemiological surveillance. In Guinea-Bissau, additional STI studies are vital to estimate the STI burden and form the basis for a national sexual health strategy for prevention, diagnosis and surveillance of STIs

Low Postseroconversion CD4+ T-cell Level Is Associated with Faster Disease Progression and Higher Viral Evolutionary Rate in HIV-2 Infection

L

Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naive patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-alpha (pegIFN-alpha), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-alpha, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-alpha. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log(10) IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log(10) IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-alpha and thus shortened treatment duration (P <0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P <0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an antiviral effect differently regulated across IL28B genotypes.Peer reviewe

Frequent CXCR4 tropism of HIV-1 subtype A and CRF02_AG during late-stage disease - indication of an evolving epidemic in West Africa

<p>Abstract</p> <p>Background</p> <p>HIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease.</p> <p>Results</p> <p>We found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%).</p> <p>Conclusions</p> <p>The increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.</p

HIV-2 infection in Guinea-Bissau, West Africa, with special reference to clinical, immunological and epidemiological aspects

We have followed a cohort of police officers in Guinea-Bissau between 1990 and 1997 for the study of clinical, immunological and epidemiological aspects of HIV-2 infection. Initially the prevalence of HIV-2 was high (11.6 %) and HIV-1 infection was rare (0.4 %), but over the study period the prevalence of HIV-1 increased significantly whereas the incidence of HIV-1 was relatively stable. For HIV-2, there was a significant decline of the prevalence as well as the incidence. No protective effect of HIV-2 against subsequent HIV-1 infection was observed. In a sentinel surveillance study of pregnant women in Bissau between 1987 and 1997, a similar pattern of increasing prevalence rates of HIV-1 and declining prevalence rates of HIV-2 was found. HIV-2 infection was associated with generalized lymphadenopathy, weight loss > 10 % and prolonged fever or diarrhoea, and the mortality in HIV-2 infected individuals was 6 times higher than in uninfected individuals. CD4 cell counts were significantly lower among HIV-2 positive subjects compared with HIV negative individuals. In HIV-2 infected individuals, there was a gradual decline of CD4 cells in more advanced clinical stages (according to the WHO clinical staging system), reflecting the increasing level of immunosuppression in each stage. Conversely, proviral DNA load was significantly higher in HIV-2 infected AIDS patients compared with asymptomatic carriers. All HIV-2 positive subjects investigated with phylogenetic analyses carried subtype A, regardless of clinical status. In a hospital-based study we found a significant association between severe bacterial pneumonia, sepsis or pyomyositis and HIV-2 infection. CD4 counts were markedly suppressed in the HIV-2 positive patients with any of these three bacterial infections, and the mortality was significantly higher in sepsis and pyomyositis among HIV-2 positive patients than in HIV negative patients. In contrast, the clinical outcome in patients with pneumonia was good, regardless of HIV status

Persistent elevation of fibrosis biomarker cartilage oligomeric matrix protein following hepatitis C virus eradication

Serum levels of cartilage oligomeric matrix protein (COMP) has been presented as a biomarker of liver fibrosis in several cross-sectional studies. COMP is also an essential mediator in carcinoma development and has also been associated with hepatocellular carcinoma. We present a prospective analysis of this biomarker in 38 patients with chronic hepatitis C who were subject to eradication therapy with direct acting antivirals. We confirm previous studies associating COMP elevation with liver cirrhosis. We also show how viral levels are correlated with COMP at baseline. In our prospective analysis, we report that successful eradication of hepatitis C results in improvement in liver stiffness and laboratory liver function tests at 1 year follow-up. In contrast, median COMP-levels remain unchanged during the study period. We conclude that the biomarker potential of COMP in the prospective evaluation of liver diseases, remains to be elucidated

HIV-1 molecular epidemiology in Guinea-Bissau, West Africa: origin, demography and migrations.

The HIV-1 epidemic in West Africa has been dominated by subtype A and the recombinant form CRF02_AG. Little is known about the origins and the evolutionary history of HIV-1 in this region. We employed Maximum likelihood and Bayesian methods in combination with temporal and spatial information to reconstruct the HIV-1 subtype distribution, demographic history and migration patterns over time in Guinea-Bissau, West Africa. We found that CRF02_AG and subsubtype A3 were the dominant forms of HIV-1 in Guinea-Bissau and that they were introduced into the country on at least six different occasions between 1976 and 1981. These estimates also corresponded well with the first reported HIV-1 cases in Guinea-Bissau. Migration analyses suggested that (1) the HIV-1 epidemic started in the capital Bissau and then dispersed into more rural areas, and (2) the epidemic in Guinea-Bissau was connected to both Cameroon and Mali. This is the first study that describes the HIV-1 molecular epidemiology in a West African country by combining the results of subtype distribution with analyses of epidemic origin and epidemiological linkage between locations. The multiple introductions of HIV-1 into Guinea-Bissau, during a short time-period of five years, coincided with and were likely influenced by the major immigration wave into the country that followed the end of the independence war (1963-1974)

Higher mortality in HIV-2/HTLV-1 co-infected patients with pulmonary tuberculosis in Guinea-Bissau, West Africa, compared to HIV-2-positive HTLV-1-negative patients.

OBJECTIVES: To investigate the effect of human T-lymphotropic virus type 1 (HTLV-1) on CD4 counts and mortality in tuberculosis (TB) patients with or without human immunodeficiency virus (HIV). METHODS: A prospective study on 280 hospitalized patients with pulmonary TB was performed in Guinea-Bissau, 1994-1997, including HIV, CD4 counts and clinical outcome. We compared the CD4 count levels at the time of inclusion between HIV-negative and HIV-positive patients, with or without HTLV-1. Mortality was determined while patients were on treatment for TB. RESULTS: Median CD4% was significantly higher in HIV-positive subjects co-infected with HTLV-1 compared to HTLV-1-negative patients. Two hundred thirty-three individuals were included in the analysis of mortality, and among HIV-negative subjects the mortality was 18.6/100 person-years . In HIV-2-positive HTLV-1-negative subjects the mortality was 39.5/100 person-years and in HIV-2/HTLV-1 co-infected patients it was 113.6/100 person-years (adjusted mortality rate ratio 4.7, 95% CI 1.5-14.4; p < 0.01). When all HIV-positive patients were analyzed together, corresponding mortality rates were 53.5/100 person-years and 104.8/100 person-years , respectively (not significant). CONCLUSIONS: HIV/HTLV-1 co-infected patients hospitalized for pulmonary TB had a high mortality and had significantly higher CD4% compared to only HIV-positive subjects. This may imply that HTLV-1 has an adverse effect on the immune system in HIV-infected subjects, independently of the CD4 count, that makes co-infected subjects more vulnerable to TB

Clinical progression in early and late stages of disease in a cohort of individuals infected with human immunodeficiency virus-2 in Guinea-Bissau

The aim of this study was to assess the rate of clinical progression to early and late stages of human immunodeficiency virus-2 (HIV-2) infection. CD4 cell counts and other potential prognostic markers for disease progression were also evaluated. In January 1990 an open prospective cohort of police officers in Guinea-Bissau was initiated with yearly serological and clinical follow-up. Follow-up ended in June 1998. Symptoms were classified according to the World Health Organization staging system. The analysis included 148 HIV-2-seropositive subjects and 177 HIV-seronegative controls. 25 of the HIV-2-positive individuals were seroconverters (seroincident cases). The progression rate to stage 3 of HIV-2-positive subjects in stage 1 + 2 was 8.6/100 person-years (py) ( rate ratio 6.2 compared with HIV-negative controls, 95% confidence interval 2.7 - 14.2, p< 0.001), and the progression rate to stage 4, i.e. acquired immunodeficiency syndrome ( AIDS), was 2.1/100 py. HIV-2-positive people in stage 3 at inclusion progressed to AIDS at a rate of 16.9/100 py. CD4% &LE; 20 was found to be a significant prognostic marker for progression to stage 4, both from stage 1 + 2 and from stage 3. The clinical progression in this cohort of HIV-2-infected subjects was generally lower than that in HIV-1-positive cohorts