Showing papers by "Myron S. Cohen published in 2001"

Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model.

Abstract: Objective: To develop a model to predict transmission of HIV-1 from men to women. Design: HIV-1 in seminal plasma, and endocervical CCR5 receptors were correlated with epidemiological studies of HIV-1 transmission to develop a probabilistic model. Settings: Semen samples were collected from patient subjects in Seattle Washington, Chapel Hill, North Carolina, and St. Gallen, Switzerland. Endocervical biopsy specimens were obtained from women in Chicago, Illinois. Participants: Eighty-six men (not receiving antireroviral therapy) in whom CD4 cell count and semen volume were available, and 24 women in whom the number of endocervical CCR5 receptors were determined. Main outcome measures: Prediction of transmission of HIV-1 from men to women per episode of vaginal intercourse based on the absolute burden of HIV (volume 3 HIV RNA copies/ml seminal plasma). Results: The model suggests efficient heterosexual transmission of HIV-1 when semen viral burden is high. When semen contains 100 000 copies of non-syncytium-inducing (NSI) HIV RNA the probability of HIV-1 transmission is 1 per 100 episodes of intercourse; conversely, with 1000 copies NSI HIV RNA in semen, transmission probability is 3 per 10 000 episodes of intercourse. Conclusions: This model links biological and epidemiological data related to heterosexual HIV-1 transmission. The model can be used to estimate transmission of HIV from men with high semen viral burden from inflammation, or reduced burden after antiretroviral therapy. The results offer a biological explanation for the magnitude of the HIV epidemic in places where earlier studies have shown men have high semen viral burden, such as in sub-Saharan Africa. The model can be used to develop and test HIV-1 prevention strategies.

Antigenic variation of gonococcal pilin expression in vivo: analysis of the strain FA1090 pilin repertoire and identification of the pilS gene copies recombining with pilE during experimental human infection.

Abstract: Antigenic variation of gonococcal pilin involves a family of variable genes that undergo homologous recombination, resulting in transfer of variant sequences from the pilS silent gene copies into the complete pilE expression locus. Little is known about the specific recombination events that are involved in assembling new variant pilin genes in vivo. One approach to understanding pilin variation in vivo is to carry out experimental human infections with a gonococcal strain having a fully characterized repertoire of pilin genes, so that the specific recombination events occurring in vivo can be determined. To this end, the authors cloned, sequenced and mapped the pilin genes of strain FA1090 of Neisseria gonorrhoeae. This strain contains one pilE locus and 19 silent gene copies that are arranged in five pilS loci; the pilE locus and four of the pilS loci are clustered in a 35 kb region of the chromosome. The general features of the pilin loci in FA1090 are similar to those in strain MS11, in which the mechanism of pilin variation has been extensively studied. However, none of the silent copy sequences are identical in the two strains, which emphasizes the extreme variability in this gene family among gonococci. Three male volunteers were inoculated with the same variant of strain FA1090 and developed urethritis within 2–4 d. The pilE gene sequences from a total of 23 colonies cultured from the subjects were analysed, determining which pilS silent copy donated each portion of the expressed pilE genes. There were 12 different pilin variants, one of which was the original inoculum variant, among the in vivo-expressed pilE gene sequences. The pilE of the inoculum variant was derived entirely from a single silent copy (pilS6c1). However, the pilE genes in the majority of the colonies cultured from the infected subjects were chimeras of sequence derived from two or three silent copies. Recombination to generate new pilE sequences involved exchange of single variable minicassettes, multiple minicassettes, entire silent gene copies, or (rarely) recombination within a minicassette.

Sexually transmitted infections and associated socio-demographic and behavioural factors in women seeking primary care suggest Madagascar's vulnerability to rapid HIV spread.

Abstract: OBJECTIVES To examine sexually transmitted infections (STIs) and associated socio-demographic and behavioural factors in women seeking care for genital discharge syndrome in Antananarivo, Madagascar. METHODS One thousand and sixty-six consecutive symptomatic women were interviewed and examined; bacterial vaginosis (BV), vulvovaginal candidiasis, trichomoniasis (TV), cervical infection (CI) due to chlamydial or gonococcal infections, and syphilis seroreactivity were determined by laboratory diagnosis. Associations between STIs and individual characteristics were evaluated using bivariate and logistic regression analyses. RESULTS The prevalence of BV, TV, CI, and syphilis seroreactivity was, respectively, 85%, 16%, 49%, 16% in 94 prostitutes; 70%, 18%, 30%, 13% in 96 occasional sex traders; and 53%, 24%, 17%, and 4% in 876 general women. CI was independently and positively associated with a symptomatic partner, new sex partner in last 3 months, unfaithful partner, prostitution, joblessness and being 1 sex partner in the previous 3 months. CONCLUSIONS These high STI rates and associated characteristics suggest the local vulnerability to rapid HIV spread and show the need for prevention efforts that involve youth, prostitutes, occasional sex traders, sex clients, and men who have concurrent sexual partnerships.

Antiretroviral therapy effects on genetic and morphologic end points in lymphocytes and sperm of men with human immunodeficiency virus infection

Abstract: Many human immunodeficiency virus (HIV)-infected persons receive prolonged treatment with DNA-reactive antiretroviral drugs. A prospective study was conducted of 26 HIV-infected men who provided samples before treatment and at multiple times after beginning treatment, to investigate effects of antiretrovirals on lymphocyte and sperm chromosomes and semen quality. Several antiretroviral regimens, all including a nucleoside component, were used. Lymphocyte metaphase analysis and sperm fluorescence in situ hybridization were used for cytogenetic studies. Semen analyses included conventional parameters (volume, concentration, viability, motility, and morphology). No significant effects on cytogenetic parameters, semen volume, or sperm concentration were detected. However, there were significant improvements in sperm motility for men with study entry CD4 cell counts >200 cells/mm(3), sperm morphology for men with entry CD4 cell counts < or =200 cells/mm(3), and the percentage of viable sperm in both groups. These findings suggest that nucleoside-containing antiretrovirals administered via recommended protocols do not induce chromosomal changes in lymphocytes or sperm but may produce improvements in semen quality.

Biological correlates of sexual transmission of HIV: Practical consequences and potential targets for public health

Abstract: The probability of sexual transmission of HIV depends on the infectiousness of the index case and the susceptibility of the sexual contact. The risk of HIV transmission is heterogeneous and may be greatest during the initial sexual contacts in a steady partnership. Several factors, including systemic and mucosal acquired protective immune-response might be responsible for the apparent decrease of per-sex-act risk of transmission in a given partnership over time. Biological studies can be used to better understand the complex information obtained by epidemiological surveys. The infectiousness of HIV depends on the inoculum, and virologic factors. The genital tract viral load of the index case is likely the most important determinant of transmission. At the population level, interventions that reduce the genital shedding of HIV by reducing systemic blood viral load and/or local inflammatory processes are likely to have a beneficial impact on HIV incidence. Antiretroviral drugs are likely to reduce sexual transmission of HIV. However, these drugs may not all prove equally. Compartmentalized HIV replication in the male and female genital tract have been observed. Treatment with antiretroviral drugs that poorly penetrate the genital tract harbour the risk of local production and spread of resistant viruses. In addition, increased risk taking behaviour could offset the benefits of reduced probability of transmission at the population level. Biological data about HIV transmission must be used to inform public health policies and optimize HIV prevention strategies.

Adequacy of Fellowship Training: Results of a Survey of Recently Graduated Fellows

Abstract: The adequacy of fellowship training in the field of infectious diseases was assessed by means of a survey of recently graduated fellows. Surveys were mailed to all individuals who had passed the American Board of Internal Medicine's board certification examination in infectious diseases since 1992. A total of 666 completed surveys were returned by the deadline (response rate, 36%). Although most recent graduates thought that training in the standard components of clinical infectious diseases was adequate, only 50% thought that training in infection control was adequate. Fewer than 1 in 3 believed that they had received adequate training in the business aspects of infectious diseases practice. The adequacy and duration of research training were linked to ultimate career choice. These results form the basis for the Infectious Diseases Society of America's new initiatives to assist with more-diversified and relevant fellowship training.

Syndromic treatment of gonococcal and chlamydial infections in women seeking primary care for the genital discharge syndrome: decision-making

Abstract: The syndromic treatment of gonococcal and chlamydial infections in women seeking primary care in clinics where resources are scarce, as recommended by WHO and implemented in many developing countries, necessitates a balance to be struck between overtreatment and undertreatment. The present paper identifies factors that are relevant to the selection of specific strategies for syndromic treatment in the above circumstances. Among them are the general aspects of decision-making and caveats concerning the rational decision-making approach. The positive and negative implications are outlined of providing or withholding treatment following a specific algorithm with a given accuracy to detect infection, i.e. sensitivity, specificity and predictive values. Other decision-making considerations that are identified are related to implementation and include the stability of risk factors with regard to time, space and the implementer, acceptability by stakeholders, and environmental constraints. There is a need to consider empirically developed treatment algorithms as a basis for policy discourse, to be evaluated together with the evidence, alternatives and arguments by the stakeholders.

Domestic Cat Model for Predicting Human Nucleoside Analogue Pharmacokinetics in Blood and Seminal Plasma

Abstract: To establish whether a feline model can predict nucleoside analogue behavior in human semen, zidovudine (ZDV) and lamivudine (3TC) pharmacokinetic parameters (PKs) were determined in the blood and seminal plasma of healthy cats. Our results show considerable similarity in ZDV and 3TC PKs between cats and humans. As in humans, ZDV and 3TC tend to accumulate in feline seminal plasma. Area under the blood plasma concentration-time curve was predictive of seminal plasma excretion. The felid model offers a unique in vivo experimental alternative for investigating the pharmacokinetics of nucleoside analogues in the male genital tract.

Preventing transmission of HIV: a biological and medical perspective.

Abstract: 427 IN MY COMMENTS I will summarize our understanding of the transmission of HIV, and describe how this knowledge has been used to develop prevention strategies—many of which have already been used successfully. The probability of transmission of HIV depends on the route. HIV-contaminated blood used for a transfusion is still a problem in some resource poor countries, and causes infection more than 90% of the time. In contrast, someone stuck with a contaminated needle has only a 1/300 chance of acquiring HIV. The chance of HIV transmission during childbirth is about 30%. The chances of acquiring HIV from sexual exposure is highly variable, but is often very inefficient, so that dozens or even hundreds of episodes of intercourse appear to be required for transmission to occur. This ought to be surprising since HIV is first and foremost an STD! More than 70% of HIV is sexually transmitted. Given the relative inefficiency of the sexual transmission of HIV, how can we explain the magnitude of the HIV epidemic? Other factors must define the epidemic. These include the duration of time a person remains contagious, and the number of people exposed. Indeed, we can multiply these factors together to predict the spread of HIV. Thus, the ferocity of the AIDS epidemic is not because the virus is so easily transmitted. Rather, it is because of the many years that infected people remain sexually active, and because of the large number of different sexual encounters that might occur, particularly where commercial sex work is common. Now let’s look more closely at sexual transmission of HIV by both the infectiousness of the HIV carrier, and the susceptibility of the person exposed. Infectiousness of HIV is determined by the amount of virus in the blood or genital secretions, and special features of the viral swarm which can render the virus either more or less contagious. Higher concentrations of HIV in blood and genital secretions greatly increase the chance for HIV transmission. Many experts believe that the type of virus found in Sub-Saharan Africa, which is different than the virus found in the United States, is more contagious. The HIV virus in China, as you will hear from Dr. Shao Yiming, is unfortunately caused by a virus similar to that found in Sub-Saharan Africa. Not everyone is equally susceptible to HIV. Indeed, here are three kinds of resistance to HIV: hereditary, innate, and acquired. Hereditary resistance is observed in about 1/100 Caucasians who have cells that cannot be readily infected with the virus because of a genetic