Showing papers by "Myron S. Cohen published in 1998"

The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers

Abstract: Iron, an essential nutrient for most microorganisms, is sequestered by the host to decrease the concentration of iron available to bacterial pathogens. Neisseria gonorrhoeae, the causative agent of gonorrhoea, can acquire iron by direct interaction with human iron-binding proteins, including the serum glycoprotein, transferrin. Iron internalization from host transferrin requires the expression of a bacterial receptor, which specifically recognizes the human form of transferrin. Two gonococcal transferrin-binding proteins have been implicated in transferrin receptor function, TbpA and TbpB. We constructed a gonococcal transferrin receptor mutant without the introduction of additional antibiotic resistance markers and tested its ability to cause experimental urethritis in human male volunteers. The transferrin receptor mutant was incapable of initiating urethritis, although the same inoculum size of the wild-type parent strain, FA1090, causes urethritis in >90% of inoculated volunteers. To our knowledge, this is the first experimental demonstration that a bacterial iron acquisition system is an essential virulence factor for human infection.

Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission

Abstract: Objectives: To evaluate blood and genital secretions from HIV-infected men for HIV-1 resistant to antiretroviral agents. Design: A longitudinal study of 11 men with HIV infection and persistent detectable HIV RNA levels in blood and semen on antiretroviral therapy. Methods: HIV-1 from the blood and seminal plasma, obtained before the initiation of a new therapeutic regimen and on therapy, were evaluated by population-based sequencing of reverse transcriptase (RT) and protease RNA for the development of resistance to antiretroviral therapy. The genetic relatedness of sequences over time was compared. Results: RT genotypic resistance markers were present in seminal plasma at baseline in three out of six individuals with previous RT inhibitor experience. Eight out of 10 men, from whom the viral sequence was available on new therapy, demonstrated the evolution of new resistance mutations in the blood or seminal plasma, or both. The evolution of resistance mutations in blood and semen were frequently discordant, although over time similar patterns were seen. In two individuals, protease inhibitor resistance mutations evolved in the blood but not in the major variant in seminal plasma. Comparisons of the viral sequences between blood and seminal plasma from six men revealed two patterns. Three men showed a clustering of sequences from blood and semen. Three had sequences that appeared to evolve separately in the two compartments. Conclusions: HIV-1 variants with genotypic resistance markers are present in the male genital tract and evolve over time on incompletely suppressive antiretroviral therapy. The absence of genotypic changes consistent with protease inhibitor resistance in the semen, despite their presence in blood plasma, suggests the possibility of limited penetration of these agents into the male genital tract. Sexual transmission of resistant variants may have a negative impact on treatment outcome in newly infected individuals and on the spread of the diseases within a population. Therapeutic strategies that fully suppress HIV-1 in the genital tract should be a public health priority.

Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi

Abstract: CD4 cell counts and blood plasma and seminal plasma human immunodeficiency virus type 1 (HIV-1) concentrations were compared in HIV-1 RNA-seropositive men with urethritis and with or without genital ulcer disease (GUD). GUD was associated with lower CD4 cell counts (median, 258 vs. 348/microL) and increased blood plasma HIV-1 RNA (median, 240 x 10[3] vs. 79.4 x 10[3] copies/mL). Men with nongonococcal urethritis and GUD shed significantly greater quantities of HIV-1 in semen (median, 195 x 10[3] vs. 4.0 x 10[3] copies/mL) than men with nongonococcal urethritis without GUD. These levels decreased approximately 4-fold following antibiotic therapy. The results indicate an association between GUD and increased blood HIV-1 RNA levels. Increased HIV-1 in semen was demonstrated in some men with GUD; such an increase could lead to increased transmission, thus complicating interpretation of the role of the genital ulcer itself in the infectiousness of HIV. Reasons for increased HIV RNA in semen in men with GUD remain to be determined.

High Levels of Human Immunodeficiency Virus Type 1 in Blood and Semen of Seropositive Men in Sub-Saharan Africa

Abstract: High levels of human immunodeficiency virus type 1 (HIV-1) replication, as reflected in HIV-1 RNA concentrations in blood and semen, probably contribute to both rapid disease progression and enhanced sexual transmission. Semen and blood were collected from 49 Malawian and 61 US and Swiss (US/Swiss) HIV-1-seropositive men with similar CD4 cell counts and no urethritis or exposure to antiretroviral drugs. Median seminal plasma and blood plasma HIV-1 RNA concentrations were >3-fold (P = .034) and 5-fold (P = .0003) higher, respectively, in the Malawian men. Similar differences were observed in subsets of the Malawian and US/Swiss study groups matched individually for CD4 cell count (P = .035 and P < .002, respectively). These observations may help explain the high rates of HIV-1 sexual transmission and accelerated HIV-1 disease progression in sub-Saharan Africa.

Improving sexually transmitted disease management in the private sector: the Jamaica experience.

Abstract: The Jamaican Ministry of Health has estimated that over 60% of all sexually transmitted diseases (STDs) are managed within the private sector where 800 (66%) of the countrys 1200 registered physicians practice. To improve the quality of STD case management provided by these practitioners the Medical Association of Jamaica organized a series of 6 half-day seminars repeated at 3-4 month intervals in three geographic locations between December 1993 and July 1995. Topics addressed included urethritis genital ulcer disease HIV/AIDS vaginal discharge pelvic inflammatory disease and STDs in children and adolescents. A total of 628 private practitioners attended at least one seminar and almost half the physicians attended two or more. Comparisons of scores on a written pretest completed before the seminar and those from a post-test conducted by telephone after the seminar revealed significant improvements in all four general STD management categories: counseling/education diagnostics/screening treatment and knowledge. The proportion of practitioners who obtained syphilis serologies during pregnancy rose from 38.3% to 83.8% and those providing effective treatment for gonorrhea increased from 57.8% to 81.1%. Overall 96% of practitioners were providing some level of risk-reduction counseling at the time of the post-test and 74% were prescribing correct treatment regimens. Ongoing education and motivation by the national STD control program or the Medical Association are recommended to improve STD case management even further.

Factors associated with changes in HIV shedding in semen.

Abstract: The efficiency and duration of transmissibilty of HIV seems to be highly variable and dependent on a number of factors related to both the donor and the recipient as well as characteristics intrinsic to the virus itself Some of the factors likely to be important in sexual transmission of HIV include stage of disease, antiretroviral therapy, and concomitant systemic or mucosal infections, including sexually transmitted diseases This paper describes recent work from our group in each of these areas

Specificity of dysuria and discharge complaints and presence of urethritis in male patients attending an STD clinic in Malawi.

Abstract: The World Health Organization (WHO) has recommended a syndromic approach to the case management of sexually transmitted diseases (STDs) in areas with inadequate laboratories and trained personnel. This study evaluated the specificity of discharge and dysuria for laboratory confirmed urethritis among 517 consecutive symptomatic men presenting to an urban STD clinic in Malawi in 1992-93. Patients were randomized to receive one of five antibiotic regimens with an efficacy range of 33-95% and instructed to return for a follow-up visit in 8-10 days. The present analysis was limited to the 330 men with follow-up data. Overall 257 men (70%) had gonococcal urethritis and 13 (4%) had chlamydia urethritis. Laboratory evidence of urethritis was identified in over 90% of symptomatic patients with discharge or dysuria. Men with complaints of dysuria alone were significantly more likely to have sought treatment elsewhere before presenting to the clinic than men with both discharge and dysuria (72% vs. 48%) and were less likely to have had gonorrhea (64% vs. 83%). 92% of those who returned for the follow-up visit had no symptoms of either discharge or dysuria but 22 of these men (9.2%) had gonorrhea and 52 (21.8%) had nongonococcal urethritis. Among men with symptoms at the time of the follow-up visit 26 (28%) had gonorrhea and 12 (13%) had nongonococcal urethritis. These findings suggest that the symptom of dysuria should be added to discharge as an entry criterion for evaluation for urethritis in WHOs treatment recommendations. Moreover given the high prevalence of asymptomatic infection at follow-up in men who received suboptimal antimicrobial therapy it is recommended that the most effective treatment available should be provided at the first clinic visit.

Approaches to control sexually transmitted diseases in Haiti, 1992-95.

Abstract: Despite major obstacles, activities to control sexually transmitted diseases (STDs) were initiated in Haiti in 1992 in collaboration with local nongovernmental organizations. The approaches included review of available local data, assessment of STD case management practices and constraints, and development of specific STD control activities at the primary health care level, such as systematic screening of all pregnant women for syphilis and improved comprehensive syndrome-based STD case management. The activities included conduct of local studies, presentation and dissemination of results to key audiences, training of health care providers, improvement of local capacities, and consensus-building on implementation of STD control approaches. STD awareness and case management improved considerably; for example, 69% of the clinicians interviewed reported correct STD treatments in the north-eastern primary health care centres in 1995, compared with < 10% in 1992. At the end of the project, national STD case management guidelines were developed by consensus between the various organizations and the Ministry of Health. Lessons learned included the importance of local data generation and of communication and collaboration with various institutions for consensus-building, the need for continued training, and field supervision to ensure behaviour change among STD care providers. A national STD control programme should be implemented as soon as possible in both the public and private sector. External funding will remain critical to control this important public health problem in Haiti.